tag:theconversation.com,2011:/ca/topics/t-cells-4511/articlesT cells – The Conversation2024-03-08T13:37:11Ztag:theconversation.com,2011:article/2235232024-03-08T13:37:11Z2024-03-08T13:37:11ZImmune cells can adapt to invading pathogens, deciding whether to fight now or prepare for the next battle<figure><img src="https://images.theconversation.com/files/579022/original/file-20240229-16-4ad8vr.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2000%2C1500&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Understanding the flexibility of T cell memory can lead to improved vaccines and immunotherapies.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/maturing-t-lymphocyte-illustration-royalty-free-illustration/1489195717">Juan Gaertner/Science Photo Library via Getty Images</a></span></figcaption></figure><p>How does your immune system decide between fighting invading pathogens now or preparing to fight them in the future? Turns out, it can <a href="https://doi.org/10.1016/j.immuni.2023.12.006">change its mind</a>.</p>
<p>Every person has <a href="https://doi.org/10.1073/pnas.1409155111">10 million to 100 million unique T cells</a> that have a critical job in the immune system: patrolling the body for invading pathogens or cancerous cells to eliminate. Each of these T cells has a unique receptor that allows it to recognize foreign proteins on the surface of infected or cancerous cells. When the right T cell encounters the right protein, it rapidly forms many copies of itself to destroy the offending pathogen. </p>
<p>Importantly, this process of proliferation gives rise to both short-lived effector T cells that shut down the immediate pathogen attack and long-lived memory T cells that provide protection against future attacks. But how do T cells decide whether to form cells that kill pathogens now or protect against future infections?</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/580789/original/file-20240308-16-w72oqc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram of cytotoxic T cell killing a target cell" src="https://images.theconversation.com/files/580789/original/file-20240308-16-w72oqc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/580789/original/file-20240308-16-w72oqc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=418&fit=crop&dpr=1 600w, https://images.theconversation.com/files/580789/original/file-20240308-16-w72oqc.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=418&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/580789/original/file-20240308-16-w72oqc.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=418&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/580789/original/file-20240308-16-w72oqc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=526&fit=crop&dpr=1 754w, https://images.theconversation.com/files/580789/original/file-20240308-16-w72oqc.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=526&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/580789/original/file-20240308-16-w72oqc.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=526&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Cytotoxic T cells bind to foreign proteins on infected or cancerous cells and subsequently destroy those target cells by releasing molecules like granzyme and perforin.</span>
<span class="attribution"><a class="source" href="https://pressbooks.ccconline.org/bio106/chapter/lymphatic-levels-of-organization/">Anatomy & Physiology/SBCCOE</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span>
</figcaption>
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<p><a href="https://www.researchgate.net/scientific-contributions/Kathleen-Abadie-2232092055">We are</a> <a href="https://www.researchgate.net/scientific-contributions/Elisa-Clark-2148857839">a team</a> <a href="https://scholar.google.com/citations?user=ckyY7T8AAAAJ&hl=en">of bioengineers</a> studying how immune cells mature. In our <a href="https://doi.org/10.1016/j.immuni.2023.12.006">recently published research</a>, we found that having multiple pathways to decide whether to kill pathogens now or prepare for future invaders boosts the immune system’s ability to effectively respond to different types of challenges.</p>
<h2>Fight or remember?</h2>
<p>To understand when and how T cells decide to become effector cells that kill pathogens or memory cells that prepare for future infections, we <a href="https://doi.org/10.1016/j.immuni.2023.12.006">took movies of T cells dividing</a> in response to a stimulus mimicking an encounter with a pathogen. </p>
<p>Specifically, we tracked the activity of a gene called T cell factor 1, or TCF1. This gene is essential for the longevity of memory cells. We found that stochastic, or probabilistic, silencing of the TCF1 gene when cells confront invading pathogens and inflammation <a href="https://doi.org/10.1016/j.immuni.2023.12.006">drives an early decision</a> between whether T cells become effector or memory cells. Exposure to higher levels of pathogens or inflammation increases the probability of forming effector cells.</p>
<p>Surprisingly, though, we found that some effector cells that had turned off TCF1 early on were able to <a href="https://doi.org/10.1016/j.immuni.2023.12.006">turn it back on</a> after clearing the pathogen, later becoming memory cells. </p>
<p>Through mathematical modeling, we determined that this flexibility in decision making among memory T cells is critical to generating the right number of cells that respond immediately and cells that prepare for the future, appropriate to the severity of the infection. </p>
<h2>Understanding immune memory</h2>
<p>The proper formation of persistent, long-lived T cell memory is critical to a person’s ability to fend off diseases ranging from the common cold to COVID-19 to cancer.</p>
<p>From a <a href="https://doi.org/10.1016/0377-2217(93)E0210-O">social and cognitive science perspective</a>, flexibility allows people to adapt and respond optimally to uncertain and dynamic environments. Similarly, for immune cells responding to a pathogen, flexibility in decision making around whether to become memory cells may enable greater responsiveness to an evolving immune challenge.</p>
<p>Memory cells can be <a href="https://doi.org/10.1016/j.immuni.2018.02.010">subclassified into different types</a> with distinct features and roles in protective immunity. It’s possible that the pathway where memory cells diverge from effector cells early on and the pathway where memory cells form from effector cells later on give rise to particular subtypes of memory cells. </p>
<p>Our study focuses on T cell memory in the context of acute infections the immune system can successfully clear in days, such as cold, the flu or food poisoning. In contrast, chronic conditions such as HIV and cancer require persistent immune responses; long-lived, memory-like cells are critical for this persistence. Our team is investigating whether flexible memory decision making also applies to chronic conditions and whether we can leverage that flexibility to improve cancer immunotherapy.</p>
<p>Resolving uncertainty surrounding how and when memory cells form could help improve vaccine design and therapies that boost the immune system’s ability to provide long-term protection against diverse infectious diseases.</p>
<p><em>This article was updated to replace a figure of T cell differentiation with cytotoxic T cell activity.</em></p><img src="https://counter.theconversation.com/content/223523/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kathleen Abadie was funded by a NSF (National Science Foundation) Graduate Research Fellowships. She performed this research in affiliation with the University of Washington Department of Bioengineering. </span></em></p><p class="fine-print"><em><span>Elisa Clark performed her research in affiliation with the University of Washington (UW) Department of Bioengineering and was funded by a National Science Foundation Graduate Research Fellowship (NSF-GRFP) and by a predoctoral fellowship through the UW Institute for Stem Cell and Regenerative Medicine (ISCRM). </span></em></p><p class="fine-print"><em><span>Hao Yuan Kueh receives funding from the National Institutes of Health.</span></em></p>When faced with a threat, T cells have the decision-making flexibility to both clear out the pathogen now and ready themselves for a future encounter.Kathleen Abadie, Ph.D. Candidate in Bioengineering, University of WashingtonElisa Clark, Ph.D. Candidate in Bioengineering, University of WashingtonHao Yuan Kueh, Associate Professor of Bioengineering, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2152172023-11-20T13:18:45Z2023-11-20T13:18:45ZImmune health is all about balance – an immunologist explains why both too strong and too weak an immune response can lead to illness<figure><img src="https://images.theconversation.com/files/559704/original/file-20231115-15-wutiiv.png?ixlib=rb-1.1.0&rect=0%2C0%2C2044%2C1593&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">When immune cells become overactive, your immune system itself can cause disease.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/2oHpNSe">NIAID/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>For immune health, some influencers seem to think the Goldilocks philosophy of “just right” is overrated. Why settle for less immunity when you can have more? Many social media posts push supplements and other life hacks that “boost your immune system” to keep you healthy and fend off illness.</p>
<p>However, these claims are not based on science and what is known about immune function. Healthy immune systems don’t need to be “boosted.” Instead, the immune system works best when it is <a href="https://doi.org/10.1038/ni.2430">perfectly balanced</a>. Scientific experts on the immune system – immunologists – know that too much of an immune reaction could result in allergies, autoimmune disorders or <a href="https://theconversation.com/what-is-inflammation-two-immunologists-explain-how-the-body-responds-to-everything-from-stings-to-vaccination-and-why-it-sometimes-goes-wrong-193503">chronic inflammation</a>. On the flip side, <a href="https://theconversation.com/immunocompromised-people-make-up-nearly-half-of-covid-19-breakthrough-hospitalizations-an-extra-vaccine-dose-may-help-166241">too little of an immune reaction</a> could result in illness or infection.</p>
<p>Your immune system requires a delicate balance to operate properly. When it’s out of balance, your immune system itself can cause disease.</p>
<h2>Cellular balance</h2>
<p>The immune system is the mobile defense system of your body. It is a complex network of cells and organs that work together to protect your body from infection and disease. Your immune cells are continually on patrol, traveling throughout your body looking for infectious invaders and damage. </p>
<p>New immune cells are created in your bone marrow. Certain immune cells – called <a href="https://theconversation.com/coronavirus-b-cells-and-t-cells-explained-141888">B and T cells</a> – are the special forces of the immune system, playing an important role in the elimination of infectious invaders. Because of this role, these cells undergo a rigorous boot camp during their development to ensure they will not discharge friendly fire on healthy cells in the body. </p>
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<figcaption><span class="caption">Your immune system is an extensive network of cells and many other components that constantly surveil your body.</span></figcaption>
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<p>Any <a href="https://doi.org/10.1038/nri.2017.19">B cell</a> or <a href="https://doi.org/10.1146/annurev-immunol-101320-022432">T cell</a> exhibiting activity against the self – or autoreactivity – is killed during training. Millions of newly created B and T cells are killed every day because they fail this training process. If these self-reactive cells escape destruction, they could turn against the body and carry out an inappropriate <a href="https://doi.org/10.1038/ni.3731">autoimmune attack</a>. </p>
<p><a href="https://scholar.google.com/citations?view_op=list_works&hl=en&hl=en&user=PGIEO34AAAAJ">My research</a> investigates how B cells are able to slip past the checkpoints the immune system has in place to guard against autoreactivity. These <a href="https://doi.org/10.1172/jci12462">tolerance checkpoints</a> ensure that autoreactive immune cells are either purged from the body or held in permanent lockdown and unable to engage in inappropriate responses that would target healthy tissue.</p>
<h2>More isn’t necessarily better</h2>
<p>You’ve likely seen advertisements for dietary supplements that promise to “boost immune function.” While this may sound appealing, it is important to keep in mind that the immune system functions best when perfectly balanced.</p>
<p>If the immune system is like a thermostat, turning it up too high results in overactivation and uncontrolled inflammation, while turning it down too low results in a failure to respond to infection and disease. </p>
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<a href="https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram of immune activation scale in the shape of a rainbow wedge, with 'vulnerable to infection' at the smaller end, 'sweet spot' in the middle, and 'autoimmunity' at the larger end" src="https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=260&fit=crop&dpr=1 600w, https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=260&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=260&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=326&fit=crop&dpr=1 754w, https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=326&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=326&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Too much or too little immune activation can lead to illness.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Inflammation_scale.svg">Kevbonham/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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<p>Because sustaining <a href="https://www.nature.com/collections/mxwslsscsf">immune balance</a> is critical, tinkering with the immune system through the use of supplements is not a good idea unless you have a clinical deficiency in certain vital nutrients. For people with healthy levels of nutrients, taking supplements could lead to a false sense of security, particularly since the fine print on the back of supplements usually has <a href="https://www.fda.gov/food/information-consumers-using-dietary-supplements/questions-and-answers-dietary-supplements">this disclaimer</a> about their listed benefits: “This statement has not been evaluated by the FDA. Not intended to diagnose, treat, cure, or prevent any disease.”</p>
<p>Eating a <a href="https://www.hsph.harvard.edu/nutritionsource/nutrition-and-immunity/">well-balanced diet</a>, exercising regularly, reducing stress and getting decent sleep, on the other hand, can help your body maintain a functioning and healthy immune system. Although these lifestyle behaviors are not foolproof, they contribute to overall good health and ultimately to a more healthy immune system.</p>
<p>In reality, <a href="https://doi.org/10.1080/07853890.2017.1407035">vaccines are the only safe and effective tool</a> beyond healthy lifestyle behaviors to support your immune system. Vaccines contain harmless forms of pathogens that help to train your immune cells to recognize and fight them. When you come into contact with the real and harmful version of the pathogen out in the wild – whether it’s at a grocery store, social event or school – at a later date, these fully trained immune memory cells will immediately begin to fight and destroy the pathogen, sometimes so quickly that you don’t even realize you’ve been infected.</p>
<p>In a world where people are continually bombarded by the marketing mantra that more is better, rest assured that when it comes to the immune system, maintaining perfect balance is just right.</p><img src="https://counter.theconversation.com/content/215217/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Aimee Pugh Bernard is affiliated with Immunize Colorado and Colorado Immunization Advocates as an unpaid board member.</span></em></p>Dietary supplements claim to be able to ‘boost your immune system’ to combat disease. But attaining immune balance through a healthy lifestyle and vaccination is a safer bet to keep in good health.Aimee Pugh Bernard, Assistant Professor of Immunology and Microbiology, University of Colorado Anschutz Medical CampusLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2109472023-08-03T15:01:05Z2023-08-03T15:01:05ZImmune cells that fight cancer become exhausted within hours of first encountering tumors – new research<figure><img src="https://images.theconversation.com/files/540881/original/file-20230802-24657-u8hz8s.png?ixlib=rb-1.1.0&rect=0%2C0%2C538%2C359&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">This microscopy image shows a cytotoxic T cell (blue) attacking a cancer cell (green) by releasing toxic chemicals (red).</span> <span class="attribution"><a class="source" href="https://flic.kr/p/wyPJtV">Alex Ritter and Jennifer Lippincott Schwartz and Gillian Griffiths/National Institutes of Health via Flickr</a></span></figcaption></figure><p>A key function of our immune system is to detect and eliminate foreign pathogens such as bacteria and viruses. Immune cells like <a href="https://theconversation.com/coronavirus-b-cells-and-t-cells-explained-141888">T cells</a> do this by distinguishing between different types of proteins within cells, which allows them to detect the presence of infection or disease. </p>
<p>A type of T cell called <a href="https://doi.org/10.1038/s41416-020-01048-4">cytotoxic T cells</a> can recognize the mutated proteins on cancer cells and should therefore be able to kill them. However, in most patients, cancer cells grow unchecked despite the presence of T cells.</p>
<p>The current explanation scientists have as to why T cells fail to eliminate cancer cells is because <a href="https://doi.org/10.1038/s41577-019-0221-9">they become “exhausted.”</a> The idea is that T cells initially function well when they first face off against cancer cells, but gradually lose their ability to kill the cancer cells after repeated encounters. </p>
<p>Cancer immunotherapies such as <a href="https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors">immune checkpoint inhibitors</a> and <a href="https://theconversation.com/anti-cancer-car-t-therapy-reengineers-t-cells-to-kill-tumors-and-researchers-are-expanding-the-limited-types-of-cancer-it-can-target-196471">CAR-T cell therapy</a> have shown remarkable promise by inducing long-lasting remission in some patients with otherwise incurable cancers. However, these therapies <a href="https://doi.org/10.1038/s41571-022-00689-z">often fail to induce long-term responses</a> in most patients, and T cell exhaustion is a major culprit.</p>
<p><a href="https://www.philiplab.org/">We are researchers</a> who study ways to harness the immune system to treat cancer. Scientists like us have been working to determine the mechanisms controlling how well T cells function against tumors. In our newly published research, we found that <a href="https://www.nature.com/articles/s41590-023-01578-y">T cells become exhausted within hours</a> after encountering cancer cells.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/vponeaNiewE?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">T cells recognize tumor cells by the specific proteins called antigens they display on their surfaces.</span></figcaption>
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<h2>Timing T cell exhaustion</h2>
<p>By the time most patients are diagnosed with cancer, their immune system has been interacting with developing cancer cells <a href="https://doi.org/10.1038/nrc3397">for months to years</a>. We wanted to go back earlier in time to figure out what happens when T cells first encounter tumor cells. </p>
<p>To do this, we used mice genetically engineered to develop liver cancers as they age, similarly to how liver cancers develop in people. We introduced trackable cytotoxic T cells that specifically recognize liver cancer cells to analyze the T cells’ function and monitor which of the genes are activated or turned off over time.</p>
<p>We also used these same trackable T cells to study their response in mice infected with the bacteria <em>Listeria</em>. In these mice, we found that the T cells were highly functional and eliminated infected cells. By comparing the differences between dysfunctional T cells from tumors and highly functional T cells from infected mice, we can home in on the genes that code for critical proteins that T cells use to regulate their function.</p>
<p><a href="https://doi.org/10.1038/nature22367">In our previous work</a>, we found that T cells become dysfunctional with dramatically altered genetic structure within five days of encountering cancer cells in mice. We had originally decided to focus on the very earliest time points after T cells encounter cancer cells in mice with liver cancer or metastatic melanoma because we thought there would be fewer genetic changes. That would have allowed us to identify the earliest and most critical regulators of T cell dysfunction. </p>
<p>Instead, we found multiple surprising hallmarks of T cell dysfunction within <a href="https://www.nature.com/articles/s41590-023-01578-y">six to 12 hours</a> after they encountered cancer cells, including thousands of changes in genetic structure and gene expression.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of a human T cell colored blue" src="https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">T cells play an important role in fighting against disease.</span>
<span class="attribution"><a class="source" href="https://www.nist.gov/image/healthyhumantcelljpg">National Institute of Allergy and Infectious Diseases</a></span>
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<p>We analyzed the different regulatory genes and pathways in T cells encountering cancer cells compared to those of T cells encountering infected cells. We found that genes associated with inflammation were highly activated in T cells interacting with infected cells but not in T cells interacting with cancer cells.</p>
<p>Next, we looked at how the initial early changes to the genetic structure of T cells evolved over time. We found that very early DNA changes were stabilized and reinforced with continued exposure to cancer cells, effectively “imprinting” dysfunctional gene expression patterns in the T cells. This meant that when the T cells were removed from the tumors after five days and transferred to tumor-free mice, they still remained dysfunctional.</p>
<h2>Boosting T cell killing</h2>
<p>Altogether, our research suggests that T cells in tumors are not necessarily working hard and getting exhausted. Rather, they are blocked right from the start. This is because the negative signals cancer cells send out to their surrounding environment induce T cell dysfunction, and a lack of positive signals like inflammation results in a failure to kick T cells into high gear.</p>
<p>Our team is now exploring strategies to stimulate inflammatory pathways in T cells encountering cancer cells to make them function as though they are encountering an infection. Our hope is that this will help T cells kill their cancer targets more effectively.</p><img src="https://counter.theconversation.com/content/210947/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>T cells recognize and kill cancer cells but quickly lose their effectiveness. This fast dysfunction may help explain why immunotherapy doesn’t lead to long-term remission for many patients.Mary Philip, Assistant Professor of Medicine and Pathology, Vanderbilt UniversityMichael Rudloff, MD-Ph.D. Candidate in Molecular Pathology and Immunology, Vanderbilt UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2097742023-07-19T15:02:22Z2023-07-19T15:02:22ZAsymptomatic COVID-19 is linked to a gene variant that boosts immune memory after exposure to prior seasonal cold viruses<figure><img src="https://images.theconversation.com/files/538083/original/file-20230718-33186-1uz5zq.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2429%2C1220&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Genetics may play a role in COVID-19 disease severity.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/virus-wide-royalty-free-image/1312985523">BlackJack3D/E+ via Getty Images</a></span></figcaption></figure><p><em>The <a href="https://theconversation.com/us/topics/research-brief-83231">Research Brief</a> is a short take about interesting academic work.</em></p>
<h2>The big idea</h2>
<p>A <a href="https://www.nature.com/articles/s41586-023-06331-x">common genetic variant</a> explains why some people are asymptomatic after being infected with the virus that causes COVID-19, according to our recently published study in the journal Nature.</p>
<p>Early in the pandemic, we were intrigued that many people did not develop COVID-19 symptoms while still testing positive for it. Because asymptomatic people are unlikely to seek medical help, we knew that collecting DNA samples to study the role of genetics in asymptomatic infections would be difficult. So instead, we took advantage of existing genetic data stored in the <a href="https://bethematch.org/about-us/how-we-help-patients/be-the-match-registry/">Be The Match</a> U.S. bone marrow donor registry. </p>
<p>We invited volunteers registered as donors to track their experience with COVID-19 via a smartphone app developed by the <a href="https://covid19.eurekaplatform.org">COVID-19 Citizen Science Study</a>. This allowed us to analyze the genetics of nearly 30,000 people without collecting biological samples and to identify COVID-19 positive individuals who never became sick.</p>
<p>We were particularly interested in analyzing the variation of <a href="https://www.uptodate.com/contents/human-leukocyte-antigens-hla-a-roadmap">human leukocyte antigen, or HLA, genes</a>. These key components of the immune system encode for proteins that display the viral particles that <a href="https://theconversation.com/coronavirus-b-cells-and-t-cells-explained-141888">T cells</a> – a group of immune system cells critical for fighting infections – recognize. Because HLA molecules are important in the immune response to pathogens and are highly variable among people, we thought they might play a role in COVID-19.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/538087/original/file-20230718-18870-crqach.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Computer illustration of HLA-B*1501." src="https://images.theconversation.com/files/538087/original/file-20230718-18870-crqach.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/538087/original/file-20230718-18870-crqach.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=815&fit=crop&dpr=1 600w, https://images.theconversation.com/files/538087/original/file-20230718-18870-crqach.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=815&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/538087/original/file-20230718-18870-crqach.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=815&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/538087/original/file-20230718-18870-crqach.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1024&fit=crop&dpr=1 754w, https://images.theconversation.com/files/538087/original/file-20230718-18870-crqach.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1024&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/538087/original/file-20230718-18870-crqach.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1024&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This is a 3D model of the protein that the gene variant HLA-B*15:01 codes for.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:HLA_B%5E1501.png">Pdeitiker/Wikimedia Commons</a></span>
</figcaption>
</figure>
<p>We found that 1,428 unvaccinated individuals reported a positive COVID-19 test, of whom 136 reported no COVID-19 symptoms. Our analysis identified a common variant of an HLA gene <a href="https://www.nature.com/articles/s41586-023-06331-x">called <em>HLA-B*15:01</em></a> that is associated with asymptomatic infection. This variant is present in <a href="https://doi.org/10.1016/j.humimm.2013.06.025">about 10% of the population with European ancestry</a>. </p>
<p>We found that people carrying the variant were more than twice as likely to remain asymptomatic after being infected with COVID-19, and those carrying two copies of this variant were more than eight times more likely to not have any symptoms. </p>
<p>Next, we used cells from people with the HLA variant who donated blood several years before the pandemic to see whether they had preexisting immunity to the virus that causes COVID-19. We found that people who had never been exposed to COVID-19 had memory T cells that worked against a specific particle of the virus, enabling them to elicit a very effective immune response against COVID-19. We also found that, when bound to HLA, this viral particle looks very similar to fragments of seasonal coronaviruses recognized by T cells. </p>
<p>Our findings suggest that <a href="https://www.nature.com/articles/s41586-023-06331-x">preexposure to seasonal cold viruses</a> allowed people with <em>HLA-B*15:01</em> to develop a very effective immune memory that helped them to quickly kill the virus before they developed symptoms. </p>
<h2>Why it matters</h2>
<p>Identifying the genetic factors associated with how the disease progresses after infection provides the basis for understanding why people respond differently to the virus that causes COVID-19 as well as other viral illnesses. Focusing on asymptomatic infections also sheds light on the early stages of infection and how the immune system fights against COVID-19. </p>
<p>Most existing vaccines protect against severe COVID-19 symptoms. Therefore, identifying the viral fragments that mediate asymptomatic infection, such as the one we discovered, can help develop more specific vaccines or therapies for COVID-19.</p>
<h2>What still isn’t known</h2>
<p>Although the genetic association we identified is strong, the immune system is very complex. It remains unclear what other mechanisms regulate asymptomatic infections, or why not everyone carrying this specific variant remains without symptoms.</p>
<h2>What’s next</h2>
<p>We want to know if the genetic variant we identified is shared by individuals from different ancestries. This will help us understand which genetic variants are important among those in these groups with asymptomatic COVID-19. We also hope to learn what makes the cross-reactive T cells in people with <em>HLA-B*15:01</em> so remarkably effective at keeping the symptoms associated with this virus at bay.</p><img src="https://counter.theconversation.com/content/209774/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jill Hollenbach receives funding from National Institutes of Health</span></em></p><p class="fine-print"><em><span>Danillo Augusto receives funding from the National Institutes of Health</span></em></p>Researchers found that people with a specific gene variant were two to eight times more likely to not have symptoms after infection.Jill Hollenbach, Professor of Neurology, University of California, San FranciscoDanillo Augusto, Assistant Professor of Biological Sciences, University of North Carolina – CharlotteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2019022023-03-24T15:49:30Z2023-03-24T15:49:30ZCould the common cold give children immunity against COVID? Our research offers clues<figure><img src="https://images.theconversation.com/files/516450/original/file-20230320-2149-tvxyat.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C5399%2C3892&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/kids-playing-cheerful-park-outdoors-concept-419185651">Rawpixel.com/Shuttersock</a></span></figcaption></figure><p>Why children are less likely to become severely ill with COVID compared with adults is not clear. Some have suggested that it might be because children are less likely to <a href="https://www.sciencedirect.com/science/article/pii/S2666379122000659">have diseases</a>, such as type 2 diabetes and high blood pressure, that are known to be linked to more severe COVID. Others have suggested that it could be because of a difference in <a href="https://www.sciencedirect.com/science/article/pii/S1521661620307488?via%3Dihub">ACE2 receptors</a> in children – ACE2 receptors being the route through which the virus enters our cells.</p>
<p>Some scientists have also suggested that children may have a higher level of existing immunity to COVID compared with adults. In particular, this immunity is thought to come from <a href="https://www.nature.com/articles/s41577-022-00809-x">memory T cells</a> (immune cells that help your body remember invading germs and destroy them) generated by common colds – some of which are caused by coronaviruses.</p>
<p>We put this theory to the test in a <a href="https://www.pnas.org/doi/10.1073/pnas.2220320120">recent study</a>. We found that T cells previously activated by a coronavirus that causes the common cold recognise SARS-CoV-2 (the virus that causes COVID) in children. And these responses declined with age.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/does-covid-really-damage-your-immune-system-and-make-you-more-vulnerable-to-infections-the-evidence-is-lacking-197253">Does COVID really damage your immune system and make you more vulnerable to infections? The evidence is lacking</a>
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<p>Early in the pandemic, scientists observed the presence of memory T cells able to recognise SARS-CoV-2 in people who had never been exposed to the virus. Such cells are often called cross-reactive T cells, as they stem from past infections due to pathogens other than SARS-CoV-2. Research has suggested these cells may provide some <a href="https://www.nature.com/articles/s41577-022-00809-x">protection against COVID</a>, and even enhance responses to COVID vaccines.</p>
<h2>What we did</h2>
<p>We used blood samples from children, sampled at age two and then again at age six, before the pandemic. We also included adults, none of whom had previously been infected with SARS-CoV-2.</p>
<p>In these blood samples, we looked for T cells specific to one of the coronaviruses that causes the common cold (called OC43) and for T cells that reacted against SARS-CoV-2.</p>
<p>We used an advanced technique called <a href="https://www.frontiersin.org/articles/10.3389/fimmu.2019.01515/full">high-dimensional flow cytometry</a>, which enabled us to identify T cells and characterise their state in significant detail. In particular, we looked at T cells’ reactivity against OC43 and SARS-CoV-2.</p>
<p>We found SARS-CoV-2 cross-reactive T cells were closely linked to the frequency of OC43-specific memory T cells, which was higher in children than in adults. The cross-reactive T cell response was evident in two-year-olds, strongest at age six, and then subsequently became weaker with advancing age. </p>
<p>We don’t know for sure if the presence of these T cells translates to <a href="https://www.nature.com/articles/s41577-022-00809-x">protection against COVID</a>, or how much. But this existing immunity, which appears to be especially potent in early life, could go some way to explaining why children tend to fare better than adults with a COVID infection.</p>
<figure class="align-center ">
<img alt="A little boy sleeps with a teddy bear." src="https://images.theconversation.com/files/516453/original/file-20230320-1833-16if7k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/516453/original/file-20230320-1833-16if7k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/516453/original/file-20230320-1833-16if7k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/516453/original/file-20230320-1833-16if7k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/516453/original/file-20230320-1833-16if7k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/516453/original/file-20230320-1833-16if7k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/516453/original/file-20230320-1833-16if7k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Children are less likely to get very sick from COVID than adults.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/photo-baby-boy-sleeping-together-teddy-1507922393">Dragana Gordic/Shutterstock</a></span>
</figcaption>
</figure>
<h2>Some limitations</h2>
<p>Our study is based on samples from adults (26-83 years old) and children at age two and six. We didn’t analyse samples from children of other ages, which will be important to further understand age differences, especially considering that the mortality rate from COVID in children is lowest from ages five to nine, and <a href="https://www.nature.com/articles/s41586-020-2918-0">higher in younger children</a>. We also didn’t have samples from teenagers or adults younger than 26. </p>
<p>In addition, our study investigated T cells circulating in the blood. But immune cells are also found in other parts of the body. It remains to be determined whether the age differences we observed in our study would be similar in samples from the <a href="https://www.nature.com/articles/s41590-022-01292-1">lower respiratory tract</a> or <a href="https://www.science.org/doi/10.1126/sciimmunol.abk0894">tonsil tissue</a>, for example, in which T cells reactive against SARS-CoV-2 have also been detected in adults who haven’t been exposed to the virus.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/colds-flu-and-covid-how-diet-and-lifestyle-can-boost-your-immune-system-197151">Colds, flu and COVID: how diet and lifestyle can boost your immune system</a>
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</em>
</p>
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<p>Nonetheless, this study provides new insights into T cells in the context of COVID in children and adults. Advancing our understanding of memory T cell development and maturation could help guide future vaccines and therapies.</p><img src="https://counter.theconversation.com/content/201902/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Marion Humbert received funding from KI Foundation for Virus Research (Karolinsk Institutet, Sweden) and Läkare mot AIDS (Sweden).</span></em></p><p class="fine-print"><em><span>Annika Karlsson receives funding from the Swedish Research Council (Dnr 2020-02033), CIMED project grant, senior (Dnr: 20190495), and Karolinska Institutet (Dnr: 2019-00931 and 2020-01599). </span></em></p>Certain immune cells acquired from a coronavirus that causes the common cold appear to react to COVID – but more so in children that adults.Marion Humbert, Postdoctoral Researcher in Immunology, Karolinska InstitutetAnnika Karlsson, Researcher, Department of Laboratory Medicine, Karolinska InstitutetLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1970032023-01-17T13:33:25Z2023-01-17T13:33:25ZModerna’s experimental cancer vaccine treats but doesn’t prevent melanoma – a biochemist explains how it works<figure><img src="https://images.theconversation.com/files/503900/original/file-20230110-22-kni45q.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2120%2C1414&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Moderna is testing an mRNA vaccine in combination with pembrolizumab to treat melanoma.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/mrna-vaccine-vial-for-cancer-immunotherapy-on-blue-royalty-free-image/1311515350">Javier Zayas Photography/Moment via Getty Images</a></span></figcaption></figure><p><a href="https://www.washingtonpost.com/health/2022/12/13/experimental-cancer-vaccine-messenger-rna-melanoma/">Media</a> <a href="https://www.reuters.com/business/healthcare-pharmaceuticals/moderna-merck-vaccine-combo-cut-melanoma-recurrence-by-44-study-2022-12-13/">outlets</a> have reported the encouraging findings of clinical trials for a new experimental vaccine developed by the biotech company <a href="https://investors.modernatx.com/news/news-details/2022/Moderna-and-Merck-Announce-mRNA-4157V940-an-Investigational-Personalized-mRNA-Cancer-Vaccine-in-Combination-with-KEYTRUDAR-pembrolizumab-Met-Primary-Efficacy-Endpoint-in-Phase-2b-KEYNOTE-942-Trial/default.aspx">Moderna</a> to treat an aggressive type of skin cancer called <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/melanoma">melanoma</a>. </p>
<p>Although this is potentially very good news, it occurred to me that the headlines may be unintentionally misleading. The vaccines most people are familiar with prevent disease, whereas this experimental new skin cancer vaccine treats only patients who are already sick. Why is it called a vaccine if it does not prevent cancer?</p>
<p>I am a <a href="https://scholar.google.com/citations?user=iAbB1kMAAAAJ&hl=en">biochemist</a> and <a href="https://medicine.buffalo.edu/faculty/profile.html?ubit=mrobrian">molecular biologist</a> studying the roles that microbes play in health and disease. I also teach cancer genetics to medical students and am interested in how the public understands science. While preventive and therapeutic vaccines are administered for different health care goals, they both train the immune system to recognize and fight off a specific disease agent that causes illness.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/503907/original/file-20230110-26-2w4dwp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Close-up of melanoma" src="https://images.theconversation.com/files/503907/original/file-20230110-26-2w4dwp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/503907/original/file-20230110-26-2w4dwp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/503907/original/file-20230110-26-2w4dwp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/503907/original/file-20230110-26-2w4dwp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/503907/original/file-20230110-26-2w4dwp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/503907/original/file-20230110-26-2w4dwp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/503907/original/file-20230110-26-2w4dwp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Melanoma is an aggressive form of skin cancer.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/melanoma-skin-cancer-royalty-free-image/1134489746">Callista Images/Image Source via Getty Images</a></span>
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</figure>
<h2>How do preventive vaccines work?</h2>
<p>Most vaccines are administered to healthy people before they get sick to prevent illnesses caused by viruses or bacteria. These include vaccines that prevent polio, measles, COVID-19 and many other diseases. Researchers have also developed vaccines to <a href="https://www.cancer.org/healthy/cancer-causes/infectious-agents/infections-that-can-lead-to-cancer/viruses.html">prevent some types of cancers</a> that are caused by such viruses as the human papillomaviruses and Epstein-Barr virus.</p>
<p>Your <a href="https://www.niaid.nih.gov/research/immune-system-overview">immune system</a> recognizes objects such as certain microbes and allergens that do not belong in your body and initiates a series of cellular events to attack and destroy them. Thus, a virus or bacterium that enters the body is recognized as something foreign and triggers an immune response to fight off the microbial invader. This results in a <a href="https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Book%3A_Anatomy_and_Physiology_(Boundless)/20%3A_Immune_System/20.6%3A_Humoral_Immune_Response/20.6D%3A_Immunological_Memory">cellular memory</a> that will elicit an even faster immune response the next time the same microbe intrudes.</p>
<p>The problem is that sometimes the initial infection causes serious illness before the immune system can mount a response against it. While you may be better protected against a second infection, you have suffered the potentially damaging consequences of the first one.</p>
<p>This is where preventive vaccines come in. By introducing a harmless version or a portion of the microbe to the immune system, the body can learn to mount an effective response against it without causing the disease.</p>
<p>For example, the <a href="https://www.cdc.gov/vaccines/vpd/hpv/public/index.html">Gardasil-9 vaccine</a> protects against the human papillomavirus, or HPV, which causes cervical cancer. It contains protein components found in the virus that cannot cause disease but do elicit an immune response that protects against future HPV infection, thereby preventing cervical cancer. </p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/KOz-bNhEHhQ?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">The HPV vaccine can prevent cervical cancer.</span></figcaption>
</figure>
<h2>How does the Moderna cancer vaccine work?</h2>
<p>Unlike cervical cancer, skin melanoma isn’t caused by a viral infection, according the <a href="https://doi.org/10.1002/jmv.27924">latest evidence</a>. Nor does Moderna’s experimental vaccine prevent cancer as Gardasil-9 does.</p>
<p>The Moderna vaccine trains the immune system to fight off an invader in the same way preventive vaccines most people are familiar with do. However, in this case the invader is a tumor, a rogue version of normal cells that harbors abnormal proteins that the immune system can recognize as foreign and attack.</p>
<p>What are these abnormal proteins and where do they come from?</p>
<p>All cells are made up of proteins and other biological molecules such as carbohydrates, lipids and nucleic acids. Cancer is caused by mutations in regions of genetic material, or DNA, that encode instructions on what proteins to make. Mutated genes result in abnormal proteins called <a href="https://www.ucir.org/therapies/neoantigen-based-therapy">neoantigens</a> that the body recognizes as foreign. That can trigger an immune response to fight off a nascent tumor. However, sometimes the immune response fails to subdue the cancer cells, either because the immune system is unable to mount a strong enough response or the cancer cells have found a way to circumvent the immune system’s defenses.</p>
<p>Moderna’s experimental melanoma vaccine contains genetic information that encodes for portions of the neoantigens in the tumor. This genetic information is in the form of <a href="https://theconversation.com/what-is-mrna-the-messenger-molecule-thats-been-in-every-living-cell-for-billions-of-years-is-the-key-ingredient-in-some-covid-19-vaccines-158511">mRNA</a>, which is the same form used in the Moderna and <a href="https://www.pfizer.com/products/product-detail/pfizer-biontech-covid-19-vaccine">Pfizer-BioNtech</a> COVID-19 vaccines. Importantly, the vaccine cannot cause cancer, because it encodes for only small, nonfunctional parts of the protein. When the genetic information is translated into those protein pieces in the body, they trigger the immune system to mount an attack against the tumor. Ideally, this immune response will cause the tumor to shrink and disappear. </p>
<p>Notably, the Moderna melanoma vaccine is tailor-made for each patient. Each tumor is unique, and so the vaccine needs to be unique as well. To customize vaccines, researchers first biopsy the patient’s tumor to determine what neoantigens are present. The vaccine manufacturer then designs specific mRNA molecules that encode those neoantigens. When this custom mRNA vaccine is administered, the body translates the genetic material into proteins specific to the patient’s tumor, resulting in an immune response against the tumor.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/vponeaNiewE?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Identifying the neoantigens of a tumor can help researchers personalize cancer vaccines.</span></figcaption>
</figure>
<h2>Combining vaccination with immunotherapy</h2>
<p>Vaccines are a form of <a href="https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy.html">immunotherapy</a>, because they treat diseases by harnessing the immune system. However, other immunotherapy cancer drugs are not vaccines because, while they also stimulate the immune system, they do not target specific neoantigens.</p>
<p>In fact, the Moderna vaccine is co-administered with the immunotherapy drug <a href="https://www.cancer.gov/about-cancer/treatment/drugs/pembrolizumab">pembrolizumab</a>, which is marketed as Keytruda. Why are two drugs needed?</p>
<p>Certain immune cells called <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/t-cell">T-cells</a> have <a href="https://doi.org/10.21037/aob-21-3">molecular accelerator and brake components</a> that serve as checkpoints to ensure they are revved up only in the presence of a foreign invader such as a tumor. However, sometimes tumor cells find a way to keep the T-cell brakes on and suppress the immune response. In these cases, the Moderna vaccine correctly identifies the tumor, but T-cells cannot respond to it. </p>
<p>Pembrolizumab, however, can bind directly to a brake component on the T-cell, inactivating the brake system and allowing the immune cells to attack the tumor.</p>
<p>Although pembrolizumab is <a href="https://www.cancer.gov/news-events/cancer-currents-blog/2021/adjuvant-pembrolizumab-early-stage-melanoma">currently used by itself</a> to treat melanoma, recent clinical trials show additional benefits when combined with the Moderna vaccine. In those studies, the company reported that administering the mRNA vaccine with pembrolizumab <a href="https://investors.modernatx.com/news/news-details/2023/Moderna-and-Merck-Announce-mRNA-4157-V940-an-Investigational-Individualized-Neoantigen-Therapy-in-Combination-with-KEYTRUDAR-Pembrolizumab-Demonstrated-Superior-Recurrence-Free-Survival-in-Patients-with-High-Risk-Stage-IIIIV-Melanoma-Following-Comple/default.aspx">reduced the risk of recurrence or death by 44%</a> compared to pembrolizumab alone in melanoma patients who were at high risk of recurrence. </p>
<h2>Not a preventive cancer vaccine</h2>
<p>So why can’t the Moderna vaccine be administered to healthy people to prevent melanoma before it arises? </p>
<p>Cancers are highly variable from person to person. Each melanoma harbors a different neoantigen profile that cannot be predicted in advance. Therefore, a vaccine cannot be developed in advance of the illness.</p>
<p>The experimental mRNA melanoma vaccine, currently still in early-phase clinical trials, is an example of the new frontier of personalized medicine. By understanding the molecular basis of diseases, researchers can explore how their underlying causes vary among people, and offer personalized therapeutic options against those diseases.</p>
<p><em>This article was updated to note new clinical trial findings presented on April 16, 2023.</em></p><img src="https://counter.theconversation.com/content/197003/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mark R. O'Brian receives funding from the National Institutes of Health.</span></em></p>Preventive and therapeutic vaccines both train the immune system to fight disease, but they are used in different ways.Mark R. O'Brian, Professor and Chair of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at BuffaloLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1964712022-12-15T19:00:18Z2022-12-15T19:00:18ZAnti-cancer CAR-T therapy reengineers T cells to kill tumors – and researchers are expanding the limited types of cancer it can target<figure><img src="https://images.theconversation.com/files/501134/original/file-20221214-14385-pkk4by.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2048%2C1364&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Killer T cells (green and red), or cytotoxic T cells, surround a cancer cell (blue, center).</span> <span class="attribution"><a class="source" href="https://flic.kr/p/LDRpJN">NICHD/J. Lippincott-Schwartz</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span></figcaption></figure><p>Teaching the body’s immune cells to recognize and fight cancer is one of the holy grails in medicine. Over the past two decades, researchers <a href="https://doi.org/10.1084%2Fjem.20182395">have developed new immunotherapy drugs</a> that stimulate a patient’s immune cells to significantly shrink or even eliminate tumors. These treatments often focus on increasing the cancer-killing ability of <a href="https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_Biology_(Kimball)/15%3A_The_Anatomy_and_Physiology_of_Animals/15.04%3A_Immune_System/15.4I%3A_Cytotoxic_T_lymphocytes_(CTL)">cytotoxic T cells</a>. However, these treatments appear to only work for the <a href="https://doi.org/10.1056/nejmoa1501824">small group of patients</a> who already have T cells within their tumors. One 2019 study estimated that <a href="https://doi.org/10.1001%2Fjamanetworkopen.2019.2535">under 13%</a> of cancer patients responded to immunotherapy.</p>
<p>To bring the benefits of immunotherapy to more patients, scientists have turned to <a href="https://www.genome.gov/about-genomics/policy-issues/Synthetic-Biology">synthetic biology</a>, a new field of study that seeks to redesign nature with new and more useful functions. Researchers have been developing a novel type of therapy that directly gives patients a new set of T cells engineered to attack tumors: chimeric antigen receptor T cells, or CAR-T cells for short.</p>
<p>As an <a href="https://scholar.google.com/citations?user=qkIs7VUAAAAJ&hl=en">oncology physician and researcher</a>, I believe that CAR-T cell therapy has the potential to transform cancer treatment. It’s already being used to treat <a href="https://doi.org/10.1056/NEJMoa1708566">lymphoma</a> and <a href="https://doi.org/10.1056/NEJMoa1817226">multiple myeloma</a>, and has shown remarkable response rates where other treatments have failed.</p>
<p>However, similar success against certain types of tumors such as lung or pancreatic cancer has been slower to develop because of the unique obstacles they put up against T cells. In our <a href="https://www.science.org/doi/10.1126/science.aba1624">newly published research</a>, my colleagues and I have found that adding a synthetic circuit to CAR-T cells could potentially help them bypass the barriers that tumors put up and enhance their ability to eliminate more types of cancer. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/uC16iDy2XoI?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">CAR-T cell therapy is currently only used for certain types of blood cancers.</span></figcaption>
</figure>
<h2>How does CAR-T cell therapy work?</h2>
<p>CAR-T cell therapy starts with doctors isolating a patient’s T cells from a sample of their blood. These T cells are then taken back to the lab, where they are genetically engineered to produce a <a href="https://doi.org/10.1056/NEJMra1706169">chimeric antigen receptor, or CAR</a>. </p>
<p>CARs are synthetic receptors specifically designed to redirect T cells from their usual targets have them recognize and hone in on tumor cells. On the outside of a CAR is a binder that allows the T cell to stick to tumor cells. Binding to a tumor cell activates the engineered T cell to kill and produce <a href="https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/cytokines.html">inflammatory cytokines</a> proteins that support T cell growth and function and boost their cancer-killing abilities.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Digram of CAR-T therapy process" src="https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=605&fit=crop&dpr=1 600w, https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=605&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=605&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=760&fit=crop&dpr=1 754w, https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=760&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/501154/original/file-20221214-14389-lnfqzu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=760&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">CAR-T therapy involves engineering a patient’s own T cells to attack their cancer.</span>
<span class="attribution"><a class="source" href="https://visualsonline.cancer.gov/details.cfm?imageid=12069">National Cancer Institute (NCI)</a></span>
</figcaption>
</figure>
<p>These CAR-T cells are then stimulated to divide into large numbers over seven to 10 days, then given back to the patient via infusion. The infusion process usually takes place at a hospital where clinicians can monitor for signs of an <a href="https://doi.org/10.1186%2Fs40425-018-0343-9">overactive immune response</a> against tumors, which can be deadly for the patient.</p>
<h2>Driving T cells into solid tumors</h2>
<p>While CAR-T cell therapy has seen success in blood cancers, it has faced hurdles when fighting what are called solid tumor cancers like pancreatic cancer and melanoma. Unlike cancers that begin in the blood, these types of cancers grow into a solid mass that produces a <a href="https://doi.org/10.1016/j.omto.2022.03.009">microenvironment</a> of molecules, cells and structures that prevent T cells from entering into the tumor and triggering an immune response. Here, even CAR-T cells engineered to specifically target a patient’s unique tumor are unable to access it, suppressing their ability to kill tumor cells.</p>
<p>For the synthetic biology community, the failures of the first generation of CAR-T cell therapy was a call to action to develop a new family of synthetic receptors to tackle the unique challenges solid tumors posed. In 2016, my colleagues in the <a href="https://limlab.ucsf.edu">Lim Lab</a> at the University of California, San Francisco developed a new synthetic receptor that could complement the first CAR design. This receptor, called <a href="https://doi.org/10.1016/j.cell.2016.01.012">synthetic Notch receptor, or synNotch</a>, is based on the natural form of Notch in the body, which plays an important role in organ development across many species. </p>
<p>Similar to CARs, the outside of synNotch has a binder that allows T cells to stick to tumor cells. Unlike CARs, the inside of synNotch has a protein that is released when a T cell binds to the tumor. This protein, or transcription factor, allows researchers to better control the T cell by inducing it to produce a specific protein. </p>
<p>For example, one of the most useful applications of synNotch thus far has been to use it to ensure that engineered T cells are only activated when bound to a tumor cell and not healthy cells. Because a CAR may bind to both tumor and healthy cells and induce T cells to kill both, my colleagues engineered T cells that are only activated when <a href="https://doi.org/10.1016/j.cell.2016.01.011">both synNotch and CAR</a> are bound to the tumor cell. Because T cells now require both CAR and synNotch receptors to recognize tumors, this increases the precision of T cell killing.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/f4pwNIhylDo?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Researchers are engineering CAR-T cells to be more precise, and subsequently reduce side effects.</span></figcaption>
</figure>
<p>We wondered if we could use synNotch to improve CAR-T cell activity against solid tumors by inducing them to produce more of the inflammatory cytokines, such as IL-2, that enable them to kill tumor cells. Researchers have made many attempts to provide extra IL-2 to help CAR-T cells clear tumors. But because these cytokines are <a href="https://doi.org/10.4049/jimmunol.1490019">highly toxic</a>, there is a limit to how much IL-2 a patient can safely tolerate, limiting their use as a drug.</p>
<p>So we designed CAR-T cells to <a href="https://www.science.org/doi/10.1126/science.aba1624">produce IL-2 using synNotch</a>. Now, when a CAR-T cell encounters a tumor, it produces IL-2 within the tumor instead of outside it, avoiding causing harm to surrounding healthy cells. Because synNotch is able to bypass the barriers tumors put up, it is able to help T cells amp up and maintain the amount of IL-2 they can make, allowing the T cells to keep functioning even in a hostile microenvironment.</p>
<p>We tested our CAR-T cells modified with synNotch on mice with pancreatic cancer and melanoma. We found that CAR-T cells with synNotch-induced IL-2 were able to produce enough extra IL-2 to overcome the tumors’ defensive barriers and fully activate, completely eliminating the tumors. While all of the mice receiving synNotch modified CAR-T cells survived, none of the CAR-T-only mice did.</p>
<p>Furthermore, our synNotch modified CAR-T cells were able to trigger IL-2 production without causing toxicity to healthy cells in the rest of the body. This suggests that our method of engineering T cells to produce this toxic cytokine only where it is needed can help improve the effectiveness of CAR-T cells against cancer while reducing side effects.</p>
<h2>Next steps</h2>
<p>Fundamental questions remain on how this work in mice will translate to people. Our group is currently conducting more studies on using CAR-T cells with synNotch to produce IL-2, with the goal of entering early stage clinical trials to examine its safety and efficacy in patients with pancreatic cancer. </p>
<p>Our findings are one example of how advances in synthetic biology make it possible to engineer solutions to the most fundamental challenges in medicine.</p><img src="https://counter.theconversation.com/content/196471/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gregory Allen receives funding from NIH/NCI and Jane Coffin Childs Memorial Fund for Medical Research. </span></em></p>Immunotherapy has the potential to eliminate tumors, but works best for select patients. Engineering T cells to bypass cancer’s defenses could help expand treatment eligibility to more patients.Gregory Allen, Assistant Professor of Medicine, University of California, San FranciscoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1935032022-11-07T13:35:27Z2022-11-07T13:35:27ZWhat is inflammation? Two immunologists explain how the body responds to everything from stings to vaccination and why it sometimes goes wrong<figure><img src="https://images.theconversation.com/files/493585/original/file-20221104-18-efs0p0.jpg?ixlib=rb-1.1.0&rect=107%2C242%2C5883%2C3745&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Insect bites or stings, like the one on this person's hand, are a manifestation of inflammation.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/cropped-hand-with-mosquito-bite-against-white-royalty-free-image/1187314357?phrase=insect%20bite&adppopup=true">Suthep Wongkhad/EyeEm via Getty Images</a></span></figcaption></figure><p>When your body fights off an infection, you develop a fever. If you have arthritis, your joints will hurt. If a bee stings your hand, your hand will swell up and become stiff. These are all manifestations of <a href="https://doi.org/10.1007/s11515-011-1123-9">inflammation</a> occurring in the body.</p>
<p>We are two <a href="https://scholar.google.com/citations?user=jJVj3sUAAAAJ&hl=en&oi=ao">immunologists</a> <a href="https://scholar.google.com/citations?user=af7TahQAAAAJ&hl=en&oi=ao">who study</a> how the immune system reacts <a href="https://pubmed.ncbi.nlm.nih.gov/?term=nagarkatti+p&sort=date">during infections, vaccination and autoimmune diseases</a> where the body starts attacking itself.</p>
<p>While inflammation is commonly associated with the pain of an injury or the many diseases it can cause, it is an important part of the normal immune response. The problems arise when this normally helpful function overreacts or overstays its welcome.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="An image showing many small white cells swarming a larger sphere." src="https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=565&fit=crop&dpr=1 754w, https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=565&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=565&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Inflammation is a process in which antibody-producing cells – like the large beige cell on the left of this image – rush to the site of an infection to attack an invader, such as the flu virus in yellow.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/immune-response-to-a-virus-illustration-royalty-free-illustration/724237117?phrase=antibodies%20infection&adppopup=true">Juan Gaertner/Science Photo Library via Getty Images</a></span>
</figcaption>
</figure>
<h2>What is inflammation?</h2>
<p>Generally speaking, the term inflammation refers to all activities of the immune system that occur where the body is trying to fight off potential or real infections, clear toxic molecules or recover from physical injury. There are <a href="https://doi.org/10.1186%2F1476-9255-1-1">five classic physical signs</a> of acute inflammation: heat, pain, redness, swelling and loss of function. Low-grade inflammation might not even produce noticeable symptoms, but the underlying cellular process is the same.</p>
<p>Take a bee sting, for example. The immune system is like a military unit with a wide range of tools in its arsenal. After sensing the toxins, bacteria and physical damage from the sting, the immune system <a href="https://theconversation.com/coronavirus-b-cells-and-t-cells-explained-141888">deploys various types of immune cells</a> to the site of the sting. These include <a href="https://www.niaid.nih.gov/research/immune-cells">T cells, B cells, macrophages and neutrophils</a>, among other cells.</p>
<p>The <a href="https://www.ncbi.nlm.nih.gov/books/NBK26884/">B cells produce antibodies</a>. Those antibodies can kill any bacteria in the wound and neutralize toxins from the sting. <a href="https://doi.org/10.3389/fimmu.2012.00174">Macrophages and neutrophils engulf bacteria</a> and destroy them. <a href="https://doi.org/10.1038/d41586-021-00367-7">T cells don’t produce antibodies, but kill any virus-infected cell</a> to prevent viral spread. </p>
<p>Additionally, these immune cells produce <a href="https://doi.org/10.1177/1091581815584918">hundreds of types of molecules</a> called cytokines – otherwise known as mediators – that help fight threats and repair harm to the body. But just like in a military attack, inflammation comes with collateral damage.</p>
<p>The mediators that help kill bacteria also kill some healthy cells. Other similar mediating molecules cause blood vessels to leak, leading to accumulation of fluid and influx of more immune cells. </p>
<p>This collateral damage is the reason you develop swelling, redness and pain around a bee sting or after getting a flu shot. Once the immune system clears an infection or foreign invader – whether the toxin in a bee sting or a chemical from the environment – different parts of the inflammatory response take over and help repair the damaged tissue.</p>
<p>After a few days, your body will neutralize the poison from the sting, eliminate any bacteria that got inside and heal any tissue that was harmed. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A diagram of a man showing two airways, one open and the other more constricted." src="https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Asthma is caused by inflammation that leads to swelling and a narrowing of airways in the lungs, as seen in the right cutaway in this image.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Asthma_(Lungs).png#/media/File:Asthma_(Lungs).png">BruceBlaus/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<h2>Inflammation as a cause of disease</h2>
<p>Inflammation is a double-edged sword. It is critical for fighting infections and repairing damaged tissue, but when inflammation occurs for the wrong reasons or <a href="https://theconversation.com/long-covid-how-researchers-are-zeroing-in-on-the-self-targeted-immune-attacks-that-may-lurk-behind-it-169911">becomes chronic</a>, the damage it causes <a href="https://theconversation.com/despite-its-disastrous-effects-covid-19-offers-some-gifts-to-medicine-an-immunology-expert-explains-what-it-can-teach-us-about-autoimmune-disease-174952">can be harmful</a>. </p>
<p><a href="https://doi.org/10.1111/j.1600-065x.2011.01020.x">Allergies</a>, for example, develop when the immune system mistakenly recognizes innocuous substances – like peanuts or pollen – as dangerous. The harm can be minor, like itchy skin, or dangerous if someone’s throat closes up.</p>
<p>Chronic inflammation damages tissues over time and can lead to <a href="https://doi.org/10.1038/s41591-019-0675-0">many noninfectious clinical disorders</a>, including cardiovascular diseases, neurodegenerative disorders, obesity, diabetes and some types of cancers. </p>
<p>The immune system can sometimes mistake one’s own organs and tissues for invaders, leading to inflammation throughout the body or in specific areas. This self-targeted inflammation is what causes the symptoms of <a href="https://doi.org/10.1289/ehp.99107s5661">autoimmune diseases</a> such as lupus and arthritis. </p>
<p>Another cause of chronic inflammation that researchers like us are currently studying is defects in the <a href="https://doi.org/10.3389/fimmu.2016.00160">mechanisms that curtail inflammation</a> after the body clears an infection.</p>
<p>While inflammation mostly plays out at a cellular level in the body, it is far from a simple mechanism that happens in isolation. Stress, diet and nutrition, as well as genetic and environmental factors, have all been shown <a href="https://doi.org/10.3389%2Ffimmu.2020.570083">to regulate inflammation</a> in some way. </p>
<p>There is still a lot to be learned about what leads to harmful forms of inflammation, but a <a href="https://doi.org/10.3390%2Fnu11081933">healthy diet</a> and <a href="https://doi.org/10.1016%2Fj.copsyc.2015.03.007">avoiding stress</a> can go a long way toward helping maintain the delicate balance between a strong immune response and harmful chronic inflammation.</p><img src="https://counter.theconversation.com/content/193503/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Prakash Nagarkatti receives funding from the National Science Foundation and the National Institutes of Health. </span></em></p><p class="fine-print"><em><span>Mitzi Nagarkatti receives funding from the National Institutes of Health.</span></em></p>Inflammation is a complicated and important part of how the immune system responds to threats to the body. But when the inflammatory response goes awry, it can lead to serious problems.Prakash Nagarkatti, Professor of Pathology, Microbiology and Immunology, University of South CarolinaMitzi Nagarkatti, Professor of Pathology, Microbiology and Immunology, University of South CarolinaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1908352022-09-19T06:08:13Z2022-09-19T06:08:13ZTreatment offers new hope for lupus – and maybe for other autoimmune diseases too<figure><img src="https://images.theconversation.com/files/485052/original/file-20220916-19-mljo8r.jpg?ixlib=rb-1.1.0&rect=7%2C3%2C2488%2C1657&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Actor and singer Selena Gomez had a kidney transplant due to damage from lupus. </span> <span class="attribution"><a class="source" href="https://photos-cdn.aap.com.au/Image/20200404001461718746?path=/aap_dev4/device/imagearc/2020/04-04/ac/80/c4/aapimage-79zq7gumfjsb0ror1qlz_layout.jpg">Richard Shotwell/Invision/AP</a></span></figcaption></figure><p>When real patients have unprecedented positive outcomes to a new treatment, it’s tempting to talk about it as “breakthrough” for medical science. This describes the excitement around a <a href="https://www.nature.com/articles/s41591-022-02017-5">new report</a> from researchers in Germany of a radical new treatment for lupus. </p>
<p>The patients in the study – five people with severe lupus – went into remission following pioneering CAR T-cell treatment, which uses genetically altered cells. </p>
<p>So what is lupus, why is this such big news, and what could it mean for other patients and diseases?</p>
<h2>Lupus and the immune system</h2>
<p>Around <a href="https://www.lupus.org/resources/lupus-facts-and-statistics">5 million people</a> are affected by some form of lupus worldwide. The most common form of <a href="https://theconversation.com/explainer-what-is-lupus-and-how-is-stress-implicated-92699">lupus</a> is technically known as systemic lupus erythematosus. Though not widespread, it is more common than <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720355/">multiple sclerosis</a> (MS). Both are “autoimmune” diseases where the immune system attacks its owner instead of the germs it is supposed to fight. </p>
<p>MS is an autoimmune disease where the immune system attacks nerve tissue. In contrast, lupus can affect any organ in the body. Treatments for lupus have been so poor for so long that even wealthy and famous people with the disease – like pop star and actor <a href="https://www.healthline.com/health/lupus/selena-gomez-kidney-transplant-lupus">Selena Gomez</a> – have had organ failure resulting in the need for a kidney transplant. A lot of complicating factors have made it hard to improve outcomes for people with the disease. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/485053/original/file-20220916-25-beee7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="man with rash on face" src="https://images.theconversation.com/files/485053/original/file-20220916-25-beee7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/485053/original/file-20220916-25-beee7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=355&fit=crop&dpr=1 600w, https://images.theconversation.com/files/485053/original/file-20220916-25-beee7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=355&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/485053/original/file-20220916-25-beee7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=355&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/485053/original/file-20220916-25-beee7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=446&fit=crop&dpr=1 754w, https://images.theconversation.com/files/485053/original/file-20220916-25-beee7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=446&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/485053/original/file-20220916-25-beee7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=446&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Lupus can cause a characteristic ‘butterfly’ rash across the face.</span>
<span class="attribution"><a class="source" href="https://image.shutterstock.com/image-photo/age-spots-redness-on-face-600w-1817519783.jpg">Shutterstock</a></span>
</figcaption>
</figure>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-lupus-and-how-is-stress-implicated-92699">Explainer: what is lupus and how is stress implicated?</a>
</strong>
</em>
</p>
<hr>
<p>Firstly, the variety of tissues lupus can affect means no two patients are exactly alike. Diagnosis is hard and often delayed. This also means we researchers have to deal with a lot of complexity as we try to work out what is causing the disease. </p>
<p>This clinical variability makes measuring improvement in response to treatment difficult, and many <a href="https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(21)00119-3/fulltext">clinical trials</a> have likely failed due to measurement issues.</p>
<p>Second, there is <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667782/">variation between patients</a> in which part of the immune system goes wrong. This means different patients will need different treatments – and we still do not know with certainty how to get this right. </p>
<p>But progress is happening fast. </p>
<h2>Innate and adaptive immunity</h2>
<p>The immune system is in <a href="https://www.ncbi.nlm.nih.gov/books/NBK279396/">two parts</a>. </p>
<p>The “innate” immune system responds fast but non-specifically to viruses and other germs that hit the body with a slug of germ-killing inflammatory proteins. The “adaptive” immune system is slower but more precise. It swings into action after the innate immune system and provides long lasting defense against the invading germ. </p>
<p>When you are vaccinated against a disease (such as COVID), the fever and aches you might get in the first day or two is your innate immune system at work. But the long-lasting protection from antibodies is provided by a part of your adaptive immune system, a key part of which is delivered by cells called “<a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/b-cell">B cells</a>”. </p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1570628523840229378"}"></div></p>
<p>In lupus, both parts of the immune system are involved, and both have been successfully used to develop medicines. Earlier this year, the Therapeutic Goods Administration approved <a href="https://www.tga.gov.au/resources/auspmd/saphnelo">anifrolumab</a>, a drug which blocks “interferon”, a crucial protein made by the innate immune system. </p>
<p>Another drug which works on B cells of the adaptive immune system, called <a href="https://www.tga.gov.au/resources/auspar/auspar-belimumab">belimumab</a>, was approved a few years ago. Unfortunately, neither drug is on the Pharmaceutical Benefits Scheme yet so access is extremely limited. </p>
<p>However, we now know that interferon and B cells are both important, and so very strong treatments that almost completely eradicate either could be useful. That is where this potential new treatment comes in. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/how-mrna-and-dna-vaccines-could-soon-treat-cancers-hiv-autoimmune-disorders-and-genetic-diseases-170772">How mRNA and DNA vaccines could soon treat cancers, HIV, autoimmune disorders and genetic diseases</a>
</strong>
</em>
</p>
<hr>
<h2>Already used to treat cancer</h2>
<p>Treatments to destroy B cells are <a href="https://www.cancer.org/cancer/non-hodgkin-lymphoma/treating/b-cell-lymphoma.html#:%7E:text=Diffuse%20large%20B%2Dcell%20lymphoma,-Diffuse%20large%20B&text=Most%20often%2C%20the%20treatment%20is,in%20cycles%203%20weeks%20apart.">used in cancers</a> like lymphoma. The most powerful of these uses <a href="https://www.petermac.org/car-t">CAR-T cells</a>, which train a type of natural cell to be an assassin of the B cell. </p>
<p>CAR-T medicines are highly complex to make, and extremely expensive – but they work. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/UlBVMtcRZWQ?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">T cells are collected from the blood, then re-engineered in a special laboratory.</span></figcaption>
</figure>
<p>Now, this <a href="https://www.nature.com/articles/s41591-022-02017-5">new report</a> shows targeting B cells using this approach could be effective in lupus too. Building on a first-ever patient treated in this way by the same group a year ago, doctors in Germany created a “homemade” CAR-T treatment and used it in five patients with severe lupus. </p>
<p>Remarkably, all five patients had near complete eradication of disease, allowing them to stop conventional medicines, like <a href="https://www.hopkinslupus.org/lupus-treatment/lupus-medications/steroids/">steroids</a>, with potentially harmful side effects. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/long-covid-how-researchers-are-zeroing-in-on-the-self-targeted-immune-attacks-that-may-lurk-behind-it-169911">Long COVID: How researchers are zeroing in on the self-targeted immune attacks that may lurk behind it</a>
</strong>
</em>
</p>
<hr>
<h2>What this means for other patients</h2>
<p>So what does it mean for patients in Australia? Well, most centres aren’t able to make their own CAR-T treatments, so delivering this potential treatment will require a commercial approach.</p>
<p>However, it might be quicker to market than other treatments in development as it takes a proven approach into a new disease, rather than being new from the ground up. </p>
<p>One day we might even be able to extend such treatments to other autoimmune diseases, like MS, where B cell-directed treatments have been helpful, as well as in lupus. </p>
<p>This would need to be balanced against risk. Importantly, short term <a href="https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/car-t-cell1.html">side effects</a> of CAR-T treatment (which include brain and bone marrow problems) can be severe. For this reason, such a treatment would only be used for the most severe cases in which standard treatments have failed, like the patients in the German trial. </p>
<p>Long-term side effects are also unknown at this time, and of course suppressing the immune system so profoundly in the setting of a pandemic is not without major risks. </p>
<p>Formal trials of a commercial CAR-T medicine for lupus are in the advanced planning stages already, and Australia is likely to be front and centre of these due to our lupus expertise and trial-friendly regulatory environment. With all these advances, we can at last tell our patients, and our friends and family with lupus, that there is light at the end of what has been a very long tunnel.</p><img src="https://counter.theconversation.com/content/190835/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Eric Morand consults to companies involved in lupus drug development including Novartis and AstraZeneca. He receives funding from the NH&MRC, Lupus Research Alliance US, and multiple companies. He is affiliated with Monash University and Monash Health, and is a Director of Rare Voices Australia. </span></em></p>German doctors have reported success in treating patients with severe lupus, using cell treatments like those used for some forms of blood cancer.Eric Morand, Head, School of Clincial Sciences at Monash Health, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1888992022-09-18T20:15:03Z2022-09-18T20:15:03ZI’ve had COVID and am constantly getting colds. Did COVID harm my immune system? Am I now at risk of other infectious diseases?<figure><img src="https://images.theconversation.com/files/483171/original/file-20220907-24-ekxrkx.jpg?ixlib=rb-1.1.0&rect=2%2C2%2C1914%2C1276&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.pexels.com/photo/photo-of-a-cold-woman-6753163/">Pavel Danilyuk/Pexels</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>So you’ve had COVID and have now recovered. You don’t have ongoing symptoms and luckily, you don’t seem to have developed <a href="https://theconversation.com/long-covid-how-researchers-are-zeroing-in-on-the-self-targeted-immune-attacks-that-may-lurk-behind-it-169911">long COVID</a>. </p>
<p>But what impacts has COVID had on your overall immune system?</p>
<p>It’s early days yet. But growing evidence suggests there are changes to your immune system that may put you at risk of other infectious diseases.</p>
<p>Here’s what we know so far.</p>
<h2>A round of viral infections</h2>
<p>Over this past winter, many of us have had what seemed like a <a href="https://theconversation.com/why-do-i-and-my-kids-get-so-many-colds-and-with-all-this-covid-around-should-we-be-isolating-too-179302">continual round</a> of viral illness. This may have included COVID, <a href="https://www.who.int/health-topics/influenza-seasonal#tab=tab_1">influenza</a> or infection with <a href="https://www.mayoclinic.org/diseases-conditions/respiratory-syncytial-virus/symptoms-causes/syc-20353098">respiratory syncytial virus</a>. We may have recovered from one infection, only to get another.</p>
<p>Then there is the re-emergence of infectious diseases globally such as <a href="https://theconversation.com/we-need-to-talk-about-monkeypox-without-shame-and-blame-188295">monkeypox</a> or <a href="https://theconversation.com/the-latest-polio-cases-have-put-the-world-on-alert-heres-what-this-means-for-australia-and-people-travelling-overseas-188989">polio</a>.</p>
<p>Could these all be connected? Does COVID somehow weaken the immune system to make us more prone to other infectious diseases?</p>
<p>There are <a href="https://www.sciencedirect.com/science/article/pii/B9780128009475000168?via%3Dihub">many reasons</a> for infectious diseases to emerge in new locations, after many decades, or in new populations. So we cannot jump to the conclusion COVID infections have given rise to these and other viral infections.</p>
<p>But evidence is building of the negative impact of COVID on a healthy <em>individual’s</em> immune system, several weeks after symptoms have subsided.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/the-latest-polio-cases-have-put-the-world-on-alert-heres-what-this-means-for-australia-and-people-travelling-overseas-188989">The latest polio cases have put the world on alert. Here's what this means for Australia and people travelling overseas</a>
</strong>
</em>
</p>
<hr>
<h2>What happens when you catch a virus?</h2>
<p>There are three possible outcomes after a viral infection:</p>
<p>1) your immune system clears the infection and you recover (for instance, with <a href="https://www.healthychildren.org/English/health-issues/conditions/ear-nose-throat/Pages/Rhinovirus-Infections.aspx">rhinovirus</a> which causes the common cold)</p>
<p>2) your immune system fights the virus into “latency” and you recover with a virus dormant in our bodies (for instance, <a href="https://www.healthdirect.gov.au/chickenpox">varicella zoster virus</a>, which causes chickenpox) </p>
<p>3) your immune system fights, and despite best efforts the virus remains “chronic”, replicating at very low levels (this can occur for <a href="https://www.who.int/news-room/fact-sheets/detail/hepatitis-c">hepatitis C virus</a>).</p>
<p>Ideally we all want option 1, to clear the virus. In fact, most of us <a href="https://biosignaling.biomedcentral.com/articles/10.1186/s12964-022-00856-w">clear SARS-CoV-2</a>, the virus that causes COVID. That’s through a complex process, using many different parts of our immune system.</p>
<p>But international evidence suggests changes to our immune cells after SARS-CoV-2 infection may have other impacts. It may affect our ability to fight other viruses, as well as other pathogens, such as bacteria or fungi. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/no-the-extra-hygiene-precautions-were-taking-for-covid-19-wont-weaken-our-immune-systems-143690">No, the extra hygiene precautions we're taking for COVID-19 won't weaken our immune systems</a>
</strong>
</em>
</p>
<hr>
<h2>How much do we know?</h2>
<p>An <a href="https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-02228-6">Australian study</a> has found SARS-CoV-2 alters the balance of immune cells up to 24 weeks after clearing the infection. </p>
<p>There were changes to the relative numbers and types of immune cells between people who had recovered from COVID compared with healthy people who had not been infected.</p>
<p>This included changes to cells of the <a href="https://www.khanacademy.org/test-prep/mcat/organ-systems/the-immune-system/a/innate-immunity">innate immune system</a> (which provides a non-specific immune response) and the <a href="https://www.ncbi.nlm.nih.gov/books/NBK21070/">adaptive immune system</a> (a specific immune response, targeting a recognised foreign invader).</p>
<p><a href="https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009742">Another study</a> focused specifically on <a href="https://www.immunology.org/public-information/bitesized-immunology/cells/dendritic-cells">dendritic cells</a> – the immune cells that are often considered the body’s “first line of defence”.</p>
<p>Researchers found fewer of these cells circulating after people recovered from COVID. The ones that remained were less able to activate white blood cells known as <a href="https://www.britannica.com/science/T-cell">T-cells</a>, a critical step in activating anti-viral immunity.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Dendritic cells (red) attacking viruses (green)" src="https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Fewer dendritic cells (red) were circulating after COVID.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/antiviral-immunity-dendritic-cells-binding-viruses-1781314607">Shutterstock</a></span>
</figcaption>
</figure>
<p>Other studies have found different impacts on T-cells, and other types of white blood cells known as <a href="https://askabiologist.asu.edu/b-cell">B-cells</a> (cells involved in producing antibodies).</p>
<p>After SARS-CoV-2 infection, one study <a href="https://doi.org/10.1172/JCI140491">found evidence</a> many of these cells had been activated and “exhausted”. This suggests the cells are dysfunctional, and might not be able to adequately fight a subsequent infection. In other words, sustained activation of these immune cells after a SARS-CoV-2 infection may have an impact on other inflammatory diseases.</p>
<p><a href="https://www.nature.com/articles/s41392-021-00749-3#citeas">One study</a> found people who had recovered from COVID have changes in different types of B-cells. This included changes in the cells’ metabolism, which may impact how these cells function. Given B-cells are critical for producing antibodies, we’re not quite sure of the precise implications.</p>
<p>Could this influence how our bodies produce antibodies against SARS-CoV-2 should we encounter it again? Or could this impact our ability to produce antibodies against pathogens more broadly – against other viruses, bacteria or fungi? The study did not say.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-the-immune-system-19240">Explainer: what is the immune system?</a>
</strong>
</em>
</p>
<hr>
<h2>What impact will these changes have?</h2>
<p>One of the main concerns is whether such changes may impact how the immune system responds to other infections, or whether these changes
might worsen or cause other chronic conditions. </p>
<p>So more work needs to be done to understand the long-term impact of SARS-CoV-2 infection on a person’s immune system.</p>
<p>For instance, we still don’t know how long these changes to the immune system last, and if the immune system recovers. We also don’t know if SARS-CoV-2 triggers other chronic illnesses, such as <a href="https://www.healthdirect.gov.au/chronic-fatigue-syndrome-cfs-me">chronic fatigue syndrome</a> (myalgic encephalomyelitis). Research into this is ongoing.</p>
<p>What we do know is that having a healthy immune system and being vaccinated (when a vaccine has been developed) is critically important to have the best chance of fighting any infection.</p><img src="https://counter.theconversation.com/content/188899/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Lara Herrero receives funding from NHMRC.</span></em></p>Evidence is growing there are changes to your immune system that may put you at risk of other infectious diseases.Lara Herrero, Research Leader in Virology and Infectious Disease, Griffith UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1844272022-07-13T12:29:46Z2022-07-13T12:29:46ZGut bacteria nurture the immune system – for cancer patients, a diverse microbiome can protect against dangerous treatment complications<figure><img src="https://images.theconversation.com/files/473639/original/file-20220712-26-brwdj.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1999%2C1499&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Stem cell transplants involve completely eliminating and then replacing the immune system of a patient, often by transplanting the bone marrow.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/red-bone-marrow-100x-light-micrograph-royalty-free-image/1168856200">xia yuan/Moment via Getty Images</a></span></figcaption></figure><p>One promising treatment for patients with blood cancers is <a href="https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/stem-cell-transplant/why-stem-cell-transplants-are-used.html">stem cell transplantation</a>. Doctors completely eliminate the patient’s immune system by aiming chemotherapy, radiation or both at their bone marrow before replacing it with a donor’s immune system. Because the bone marrow produces blood and immune cells, completely substituting cancerous bone marrow with healthy cells could help the body reestablish a functioning immune system and replace cancerous blood cells.</p>
<p>This procedure is not without risks. A key complication <a href="https://scholar.google.com.au/citations?user=jjjJeeEAAAAJ&hl=en">hematologists like me</a> worry about is <a href="https://my.clevelandclinic.org/health/diseases/10255-graft-vs-host-disease-an-overview-in-bone-marrow-transplant">graft-versus-host disease</a>, where the donor’s immune system recognizes the patient’s body as “foreign” and launches an attack. <a href="https://www.ncbi.nlm.nih.gov/books/NBK538235/">Up to 50% of patients</a> who receive a stem cell transplant develop graft-versus-host disease.</p>
<p>One unexpected part of the body that may play a key role in protecting transplant patients from complications, however, is their gut bacteria.</p>
<p>Alongside my colleagues <a href="https://www.mskcc.org/research/ski/labs/members/hana-andrlova">Hana Andrlova</a> and <a href="https://www.mskcc.org/research/ski/labs/marcel-van-den-brink">Marcel van den Brink</a>, <a href="https://research.fredhutch.org/markey/en.html">I</a> study how the composition of your microbiome, or the microorganisms living in your body, can affect how well cancer treatments work. While <a href="https://doi.org/10.1056/NEJMoa1900623">previous studies</a> have shown that disruptions to the diversity of organisms in the gut microbiome is linked to a higher risk of death after transplantation, the precise reasons for this are not clear.</p>
<p>In our <a href="https://doi.org/10.1126/scitranslmed.abj2829">recently published study</a>, we found that gut bacteria help the immune system recover from stem cell transplants by nurturing two special types of immune cells that protect against complications.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/oLMWPgo6jUY?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Allogeneic stem cell transplants involve taking the bone marrow of a donor and giving it to a patient through an IV.</span></figcaption>
</figure>
<h2>Gut bacteria and T cells</h2>
<p>To explore the relationship between gut bacteria and the immune system, we first needed to identify the types of bacteria present in a given microbiome. So we sequenced all the bacterial genes in the stool samples of 174 stem cell transplant patients. We then took blood samples from the same patients to identify which types of immune cells were circulating and how they were functioning.</p>
<p>We learned that a diverse intestinal microbiome after transplantation is associated with expansion of a particular type of cell called <a href="https://doi.org/10.1038/s41577-019-0191-y">MAIT, or mucosal-associated invariant T cells</a>. MAIT cells are linked to improved transplant outcomes like a lower risk of graft-versus-host disease and longer survival in both <a href="https://doi.org/10.1172/JCI91646">mice</a> and <a href="https://doi.org/10.1016%2Fj.bbmt.2017.10.003">people</a>. We found that the more MAIT cells patients had in their blood after transplant, the longer they survived and the fewer their complications. Patients with the highest levels of MAIT cells had the lowest incidence of graft-versus-host disease.</p>
<p>The precise mechanism behind the protective effects of MAIT cells is unclear. But researchers do know that these cells require molecules that come from the process of producing <a href="https://doi.org/10.1111/imcb.12057">riboflavin, or vitamin B2</a>, in the body to develop and multiply. Turns out, these riboflavin derivatives are produced by the microbes in the gut. </p>
<p>We also found that high MAIT cell numbers were linked to the presence of another special population of T cells, <a href="https://doi.org/10.1038/ni.3298">V-delta-2</a>, that are also stimulated by bacterial byproducts. Above-average levels of these cells were also associated with better survival and less graft-versus-host disease in transplant patients.</p>
<p>These findings suggest that one of the reasons why a healthy, diverse microbiome is <a href="https://doi.org/10.1056/NEJMoa1900623">linked to good results for stem cell transplant recipients</a> could be that gut bacteria support the development of immune cells that protect against transplant complications like graft-versus-host disease.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/473680/original/file-20220712-20-4xv5oq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Person lying in bed attached to tubes donating bone marrow" src="https://images.theconversation.com/files/473680/original/file-20220712-20-4xv5oq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/473680/original/file-20220712-20-4xv5oq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=327&fit=crop&dpr=1 600w, https://images.theconversation.com/files/473680/original/file-20220712-20-4xv5oq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=327&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/473680/original/file-20220712-20-4xv5oq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=327&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/473680/original/file-20220712-20-4xv5oq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=412&fit=crop&dpr=1 754w, https://images.theconversation.com/files/473680/original/file-20220712-20-4xv5oq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=412&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/473680/original/file-20220712-20-4xv5oq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=412&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Stem cells can also be donated through the blood circulating in the body instead of directly from the bone marrow.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/high-angle-view-of-person-during-bone-marrow-royalty-free-image/678898899">Dani Blanchette/EyeEm via Getty Images</a></span>
</figcaption>
</figure>
<h2>Protecting against transplant complications</h2>
<p>Our next step was to figure out how these special T cells protect against transplant complications. We took blood samples from five patients who had high numbers of MAIT and V-delta-2 cells. We then used a technique called <a href="https://doi.org/10.1186/s13073-017-0467-4">single-cell RNA sequencing</a> to analyze thousands of individual cells and explore all the potential functions any particular cell type may have in the body.</p>
<p>When we compared the MAIT and V-delta-2 cells of transplant patients and healthy people, our findings were very surprising. We had originally hypothesized that genes linked with tissue repair would be active in these T cells – that would explain why patients with high numbers of these cells do better after such intense treatment that’s so tough on the body. Instead, we found that these cells had highly expressed genes involved in inflammatory processes with the capacity to induce cell damage – sometimes necessary to fight off infections when the patient’s immune system is still recovering. This suggests that MAIT and V-delta-2 cells may be protecting patients from transplant complications in ways that we haven’t previously been aware of or understood.</p>
<p>It’s possible that T cells that are activated by the microbiome like MAIT and V-delta-2 help reduce transplant complications by killing infected cells or cells involved in graft-versus-host disease. While we aren’t able to confirm this hypothesis with our study, future work may help scientists better understand the important links between the microbiome, the immune system and successful stem cell transplants for cancer patients.</p><img src="https://counter.theconversation.com/content/184427/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kate Ann Markey holds equity in and is on the advisory board of PostBiotics Plus. She receives funding from the DKMS and the American Society of Hematology. </span></em></p>Patients with blood cancer undergoing stem cell transplantation have a high risk of complications. The bacteria in their gut, however, can help their immune system recover and fight infections.Kate Ann Markey, Assistant Professor of Medical Oncology, School of Medicine, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1849052022-06-15T12:27:46Z2022-06-15T12:27:46ZSocial stress can speed up immune system aging – new research<figure><img src="https://images.theconversation.com/files/468840/original/file-20220614-26-b250v0.jpg?ixlib=rb-1.1.0&rect=6%2C202%2C2133%2C1451&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Immunosenescence, or immune aging, can lead to less effective responses to vaccines and greater vulnerability to invading pathogens.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/man-with-weak-immune-system-not-protected-royalty-free-illustration/1302827254">Kudryavtsev Pavel/iStock via Getty Images Plus</a></span></figcaption></figure><p>As people age, their immune systems naturally begin to decline. This aging of the immune system, called <a href="https://doi.org/10.1016/j.exger.2017.10.024">immunosenescence</a>, may be an important part of such <a href="https://doi.org/10.1038/s41586-021-03547-7">age-related</a> health problems as <a href="https://doi.org/10.3390/ijms20112810">cancer</a> and <a href="https://doi.org/10.3389/fimmu.2017.00195">cardiovascular disease</a>, as well as older people’s <a href="https://doi.org/10.1016/j.exger.2020.110887">less effective response to vaccines</a>.</p>
<p>But not all immune systems age at the same rate. In our <a href="https://doi.org/10.1073/pnas.2202780119">recently published study</a>, my colleagues <a href="https://scholar.google.com/citations?user=iLr8LkEAAAAJ&hl=en">and I</a> found that social stress is associated with signs of accelerated immune system aging.</p>
<h2>Stress and immunosenescence</h2>
<p>To better understand why people with the same chronological age can have different immunological ages, my colleagues and I looked at data from the <a href="https://hrs.isr.umich.edu/">Health and Retirement Study</a>, a large, nationally representative survey of U.S. adults over age 50. HRS researchers ask participants about different kinds of stressors they have experienced, including stressful life events, such as job loss; discrimination, such as being treated unfairly or being denied care; major lifetime trauma, such as a family member’s having a life-threatening illness; and chronic stress, such as financial strain.</p>
<p>Recently, HRS researchers have also started collecting blood from a sample of participants, counting the number of different types of immune cells present, including <a href="https://my.clevelandclinic.org/health/body/21871-white-blood-cells">white blood cells</a>. These cells play a central role in immune responses to viruses, bacteria and other invaders. This is the first time such detailed information about immune cells has been collected in a large national survey.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/468828/original/file-20220614-15-k597vz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Scanning electron microscope image of a human T cell" src="https://images.theconversation.com/files/468828/original/file-20220614-15-k597vz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/468828/original/file-20220614-15-k597vz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/468828/original/file-20220614-15-k597vz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/468828/original/file-20220614-15-k597vz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/468828/original/file-20220614-15-k597vz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/468828/original/file-20220614-15-k597vz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/468828/original/file-20220614-15-k597vz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">As people age, the T cells in the immune systems become less effective at fighting pathogens.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/ni2rkv">National Institute of Allergy and Infectious Diseases/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
</figcaption>
</figure>
<p>By analyzing the data from 5,744 HRS participants who both provided blood and answered survey questions about stress, my research team and I found that people who experienced more stress had a lower proportion of <a href="https://doi.org/10.1016/j.exger.2020.110887">“naive” T cells</a> – fresh cells needed to take on new invaders the immune system hasn’t encountered before. They also have a larger proportion of <a href="https://doi.org/10.1111/acel.13272">“late differentiated” T cells</a> – older cells that have exhausted their ability to fight invaders and instead produce proteins that can increase harmful inflammation. People with low proportions of newer T cells and high proportions of older T cells have a <a href="https://doi.org/10.3389/fimmu.2019.02247">more aged immune system</a>.</p>
<p>After we controlled for poor diet and low exercise, however, the connection between stress and accelerated immune aging wasn’t as strong. This suggests that improving these health behaviors might help offset the hazards associated with stress. </p>
<p>Similarly, after we accounted for potential exposure to <a href="https://www.cdc.gov/cmv/overview.html">cytomegalovirus</a> – a common, usually asymptomatic virus known to <a href="https://doi.org/10.1186/1742-4933-9-23">accelerate immune aging</a> – the link between stress and immune cell aging was reduced. While CMV normally stays dormant in the body, researchers have found that <a href="https://doi.org/10.1016/j.bbi.2014.01.012">stress can cause CMV to flare up</a> and force the immune system to commit more resources to control the reactivated virus. Sustained infection control can use up naive T cell supplies and result in more exhausted T cells that circulate throughout the body and cause <a href="https://doi.org/10.1093/gerona/glu057">chronic inflammation</a>, an important contributor to age-related disease.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/468826/original/file-20220614-13-4y37mx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Electron microscope image of cytomegalovirus visions" src="https://images.theconversation.com/files/468826/original/file-20220614-13-4y37mx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/468826/original/file-20220614-13-4y37mx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=395&fit=crop&dpr=1 600w, https://images.theconversation.com/files/468826/original/file-20220614-13-4y37mx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=395&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/468826/original/file-20220614-13-4y37mx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=395&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/468826/original/file-20220614-13-4y37mx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=497&fit=crop&dpr=1 754w, https://images.theconversation.com/files/468826/original/file-20220614-13-4y37mx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=497&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/468826/original/file-20220614-13-4y37mx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=497&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">After an initial infection, cytomegalovirus stays in the body for life.</span>
<span class="attribution"><a class="source" href="https://phil.cdc.gov/Details.aspx?pid=14429">Centers for Disease Control and Prevention</a></span>
</figcaption>
</figure>
<h2>Understanding immune aging</h2>
<p>Our study helps clarify the association between social stress and faster immune aging. It also highlights potential ways to slow down immune aging, such as changing how people cope with stress and improving lifestyle behaviors like diet, smoking and exercise. Developing effective <a href="https://doi.org/10.1016%2Fj.vaccine.2018.02.089">cytomegalovirus vaccines</a> may also help alleviate immune system aging.</p>
<p>It is important to note, however, that epidemiological studies cannot completely establish cause and effect. More research is needed to confirm whether stress reduction or lifestyle changes will lead to improvements in immune aging, and to better understand how stress and latent pathogens like cytomegalovirus interact to cause illness and death. We are currently using additional data from the Health and Retirement Study to examine how these and other factors like childhood adversity affect immune aging over time.</p>
<p>Less aged immune systems are <a href="https://doi.org/10.1038/ni.2588">better able to fight infections and generate protective immunity from vaccines</a>. Immunosenescence may help explain why people are likely to have more severe cases of COVID-19 and a weaker response to vaccines as they age. Understanding what influences immune aging may help researchers better address age-related disparities in health and illness.</p><img src="https://counter.theconversation.com/content/184905/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Eric Klopack receives funding from the USC/UCLA Center on Biodemography and Population Health through a grant from NIA (P30AG017265).
The HRS (Health and Retirement Study) is sponsored by the National Institute on Aging (grant number NIA U01AG009740) and is conducted by the University of Michigan.</span></em></p>While the immune system naturally gets weaker with age, social stressors like trauma and discrimination can hasten immunosenescence.Eric Klopack, Postdoctoral Researcher in Gerontology, University of Southern CaliforniaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1835882022-06-01T12:14:37Z2022-06-01T12:14:37Z‘Masked’ cancer drug stealthily trains immune system to kill tumors while sparing healthy tissues, reducing treatment side effects<figure><img src="https://images.theconversation.com/files/466370/original/file-20220531-14-t0h7ly.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2048%2C2048&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Dendritic cells (green) produce cytokines like IL-12, which can train T cells (pink) to attack tumors.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/JRzxEb">Victor Segura Ibarra and Rita Serda/National Cancer Institute via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p>Many cancer treatments are notoriously savage on the body. Drugs often attack both healthy cells and tumor cells, causing a plethora of side effects. <a href="https://www.cancer.gov/about-cancer/treatment/types/immunotherapy">Immunotherapies</a> that help the immune system recognize and attack cancer cells are no different. Though they have <a href="https://doi.org/10.1001/jamanetworkopen.2019.2535">prolonged the lives of countless patients</a>, they work in only a subset of patients. One study found that <a href="https://doi.org/10.3389/fonc.2020.600573">fewer than 30% of breast cancer patients</a> respond to one of the most common forms of immunotherapy. </p>
<p>But what if drugs could be engineered to attack only tumor cells and spare the rest of the body? To that end, <a href="https://pme.uchicago.edu/group/hubbell-lab">my colleagues</a> <a href="https://scholar.google.com/citations?user=7KTLoToAAAAJ&hl=en&oi=ao">and I</a> at the University of Chicago’s <a href="https://pme.uchicago.edu/">Pritzker School of Molecular Engineering</a> have <a href="https://doi.org/10.1038/s41551-022-00888-0">designed a method</a> to keep one promising cancer drug from wreaking havoc by “masking” it until it reaches a tumor.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/K09xzIQ8zsg?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Immunotherapies help the immune system recognize and target cancer cells.</span></figcaption>
</figure>
<h2>The promise of IL-12</h2>
<p><a href="https://doi.org/10.1038/s41416-018-0328-y">Cytokines</a> are proteins that can modulate how the immune system responds to threats. One way they do this is by activating <a href="https://doi.org/10.1038/nri819">killer T cells</a>, a type of white blood cells that can attack cancer cells. Because cytokines can train the immune system to kill tumors, this makes them very promising as cancer treatments.</p>
<p>One such cytokine is interleukin-12, or IL-12. Though it was <a href="https://doi.org/10.1084%2Fjem.2045fta">discovered more than 30 years ago</a>, IL-12 still isn’t an FDA-approved therapy for cancer patients because of its <a href="https://doi.org/10.1126/science.270.5238.908.a">severe side effects</a>, such as liver damage. This is in part because IL-12 instructs immune cells to produce a large amount of inflammatory molecules that can damage the body.</p>
<p>Scientists have since been working to reengineer IL-12 to be more tolerable while retaining its powerful cancer-killing effects.</p>
<h2>Masking the killer</h2>
<p>To create a safer version of IL-12, my colleagues and I took advantage of one of the main differences between healthy and cancerous tissue: an excess of growth-promoting enzymes in cancers. Because cancer cells proliferate very rapidly, they overproduce <a href="https://doi.org/10.1186/s12885-019-5768-0">certain enzymes</a> that help them invade the nearby healthy tissue and <a href="https://doi.org/10.1007/s002800051097">metastasize to other parts of the body</a>. Healthy cells grow at a much slower pace and produce fewer of these enzymes.</p>
<p>With this in mind, we “masked” IL-12 with a cap that covers the part of the molecule that normally binds to immune cells to activate them. The cap is removed only when it comes into contact with enzymes found in the vicinity of tumors. When these enzymes chop off the cap, IL-12 is reactivated and spurs nearby killer T cells to attack the tumor.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&rect=0%2C0%2C540%2C360&q=45&auto=format&w=1000&fit=clip"><img alt="Killer T cells surrounding a cancer cell" src="https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&rect=0%2C0%2C540%2C360&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/465808/original/file-20220527-13-galqhz.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Killer T cells (green and red) can attach to cancer cells (blue, center) and kill them by releasing toxic chemicals (red), a move scientists have dubbed ‘the kiss of death.’</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/xuSZkh">NIH/Flickr</a></span>
</figcaption>
</figure>
<p>When we applied these masked IL-12 molecules to both healthy and tumor tissue donated by melanoma and breast cancer patients, our results confirmed that only the tumor samples were able to remove the cap. This indicated that masked IL-12 could potentially drive a strong immune response against tumors without causing damage to healthy organs.</p>
<p>We then examined how safe masked IL-12 is by measuring <a href="https://www.mayoclinic.org/tests-procedures/liver-function-tests/about/pac-20394595">liver damage biomarkers</a> in mice. We found that immune-related side effects typically <a href="https://doi.org/10.1177%2F019262339902700112">associated with IL-12</a> were notably absent in mice treated with masked IL-12 over a period of several weeks, indicating improved safety.</p>
<p>In breast cancer models, our masked IL-12 resulted in a 90% cure rate, while treatment with a commonly used immunotherapy called a <a href="https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/immunotherapy/types/checkpoint-inhibitors">checkpoint inhibitor</a> resulted in only a 10% cure rate. In a model of colon cancer, masked IL-12 showed a 100% cure rate.</p>
<p>Our next step is to test the modified IL-12 in cancer patients. While it <a href="https://theconversation.com/from-the-research-lab-to-your-doctors-office-heres-what-happens-in-phase-1-2-3-drug-trials-138197">will take time</a> to bring this encouraging development directly to patients, we believe a promising new treatment is on the horizon.</p><img src="https://counter.theconversation.com/content/183588/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Aslan Mansurov consults to and owns shares in Arrow Immune Inc, which is developing the technology presented in the article. </span></em></p>One promising cancer treatment has been in the works for decades, but severe side effects have kept it out of the clinic. A reengineered version may offer a way to safely harness its potent effects.Aslan Mansurov, Postdoctoral Researcher in Molecular Engineering, University of Chicago Pritzker School of Molecular EngineeringLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1756532022-01-30T19:08:50Z2022-01-30T19:08:50ZWhat we know now about COVID immunity after infection – including Omicron and Delta variants<figure><img src="https://images.theconversation.com/files/443100/original/file-20220128-15-1419tzc.jpg?ixlib=rb-1.1.0&rect=8%2C16%2C5599%2C3715&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://photos-cdn.aap.com.au/Image/20211215001606766150?path=/aap_dev12/device/imagearc/2021/12-15/d4/18/2b/aapimage-7iueq5j875g1mxnmv9ks_layout.jpg">AAP Image/Bianca De Marchi</a></span></figcaption></figure><p>COVID is rampant in Australia and many parts of the world right now. Some people battling or recovering from infection may wonder if catching COVID will give them longer term immunity for when the next wave comes.</p>
<p>Since the early days of the pandemic we’ve known COVID induces a wide range of <a href="https://www.nature.com/articles/s41591-020-0995-0">immune responses</a> and one infection provides <a href="https://www.nature.com/articles/s41577-021-00550-x">partial protection from future infections</a>. </p>
<p>Unfortunately, immunity wanes over time – <a href="https://www.sciencedirect.com/science/article/pii/S2666524721002676">people lose half their immunity every 3 months</a>. Further, new variants continue to emerge that are partially resistant to key immune responses – antibodies that neutralise earlier strains – <a href="https://www.nature.com/articles/s41586-022-04399-5">this is especially true of Omicron</a>.</p>
<p>We’re starting to get a more detailed understanding of COVID immunity across variants. Here’s what we know so far …</p>
<h2>Breakthrough infection happens but vaccines are still a must</h2>
<p>Since around <a href="https://www.health.gov.au/initiatives-and-programs/covid-19-vaccines/numbers-statistics">95% of Australians over 16</a> have had at least two COVID vaccines, most people catching COVID now have previously been vaccinated – this is called “breakthrough infection”. </p>
<p>The vaccines are effective at substantially reducing severe COVID illness. They are less effective, particularly over time, <a href="https://www.sciencedirect.com/science/article/pii/S2666524721002676">at preventing infections, including with new variants</a>. A third vaccine dose <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02249-2/fulltext">helps maintain immunity</a>, and everyone eligible should get a booster as soon as possible. </p>
<p>Because the Astra-Zeneca vaccine is <a href="https://www.nature.com/articles/s41591-021-01377-8">less effective</a> than the Pfizer or Moderna vaccines, it’s critically important for vulnerable older Australians immunised with two Astra-Zeneca vaccinations to be boosted with a third vaccine dose as quickly as possible. </p>
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<figcaption><span class="caption">Professor Peter Doherty explains vaccination and immunity in everyday terms.</span></figcaption>
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Read more:
<a href="https://theconversation.com/should-i-get-my-covid-vaccine-booster-yes-it-increases-protection-against-covid-including-omicron-172965">Should I get my COVID vaccine booster? Yes, it increases protection against COVID, including Omicron</a>
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<p>The good news is people first vaccinated with Astra-Zeneca and subsequently boosted with Pfizer or Moderna <a href="https://www.thelancet.com/action/showPdf?pii=S0140-6736%2821%2902717-3">develop</a> high levels of protective immune responses. </p>
<p>Recent work shows <a href="https://www.medrxiv.org/content/10.1101/2021.12.23.21268285v1">a nice boost in antibody immunity</a> after breakthrough infection. This boost in antibody immunity <a href="https://www.medrxiv.org/content/10.1101/2021.12.23.21268285v1">may not be as fast or strong as getting a vaccine</a>, but it has a big advantage in that the immunity is <a href="https://www.medrxiv.org/content/10.1101/2021.12.01.21266982v2">more specific to the infecting strain</a> such as Delta. </p>
<p>The current vaccines are still based on the original strain isolated in Wuhan, China in early 2020. Several vaccine manufacturer’s are racing to update their vaccines for the Omicron variant (much as we do with the yearly flu vaccines), but these <a href="https://www.nytimes.com/live/2022/01/25/world/omicron-covid-vaccine-tests?campaign_id=7&emc=edit_mbae_20220127&instance_id=51387&nl=morning-briefing%3A-asia-pacific-edition&regi_id=80788140&segment_id=80840&te=1&user_id=dc49badc67c435380a30db1d060cc51b#pfizer-and-biontech-begin-a-study-of-an-omicron-vaccine-with-initial-results-expected-in-the-first-half-of-the-year">variant-specific vaccines</a> are still some months away.</p>
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Read more:
<a href="https://theconversation.com/will-an-omicron-specific-vaccine-help-control-covid-theres-one-key-problem-175137">Will an Omicron-specific vaccine help control COVID? There's one key problem</a>
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<h2>Infection immunity builds where COVID strikes first</h2>
<p>Another potential advantage for immunity derived by infection (acquired in the respiratory tract) compared to vaccination (given into the muscle) is that immunity is better focused to the surfaces of the nose, throat and eyes. This is where COVID is first encountered. </p>
<p>Surface antibodies (termed <a href="https://www.immunology.org/public-information/bitesized-immunology/receptors-and-molecules/immunoglobulin-iga">immunoglobulin A</a>) and specialised tissue “resident” immune cells (B and T-cells) are induced by infection but <a href="https://onlinelibrary.wiley.com/doi/10.1002/cti2.1354">not intramuscular vaccination</a>. </p>
<p>The level of protection offered by these “local” or “mucosal” responses is not yet clear in people, but <a href="https://www.jimmunol.org/content/early/2021/01/12/jimmunol.2001400">some studies in animal models</a> suggest they are helpful.</p>
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<a href="https://images.theconversation.com/files/443098/original/file-20220128-13-lfhj4o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="lab technician at CDC" src="https://images.theconversation.com/files/443098/original/file-20220128-13-lfhj4o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/443098/original/file-20220128-13-lfhj4o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=397&fit=crop&dpr=1 600w, https://images.theconversation.com/files/443098/original/file-20220128-13-lfhj4o.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=397&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/443098/original/file-20220128-13-lfhj4o.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=397&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/443098/original/file-20220128-13-lfhj4o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=499&fit=crop&dpr=1 754w, https://images.theconversation.com/files/443098/original/file-20220128-13-lfhj4o.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=499&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/443098/original/file-20220128-13-lfhj4o.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=499&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Research and understanding of immune responses to COVID is developing.</span>
<span class="attribution"><a class="source" href="https://image.shutterstock.com/image-photo/scientist-working-laboratory-600w-1203801196.jpg">Shutterstock</a></span>
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<h2>Delta infection offers a little protection against Omicron</h2>
<p>The Omicron variant is slowly replacing the Delta variant around the world. It is more transmissible and avoids antibodies more effectively. </p>
<p>Do people who have been infected with the Delta variant have an advantage in terms of protection from the Omicron variant? The two strains share some sequence changes, but Omicron has many more mutations than Delta. </p>
<p>Only a minority of neutralising antibodies that fight <a href="https://doi.org/10.1101/2021.12.13.21267748">Delta can also neutralise the Omicron variant.</a> That said, neutralising antibodies against Delta are better at fighting Omicron than previous strains. This is particularly true for people who have <a href="https://www.medrxiv.org/content/10.1101/2021.12.01.21266982v2">caught Delta and been previously vaccinated</a>. </p>
<p>The reverse is also true – people who have caught Omicron have <a href="https://www.nature.com/articles/s41586-022-04399-5">some improved antibody protection against Delta</a>. This may not be much use as Delta is disappearing from prevalence, but the knowledge could be useful for future variants.</p>
<h2>T-cells might be key to cross-variant protection</h2>
<p>There is considerable interest in a type of immunity called <a href="https://www.news-medical.net/health/What-are-T-Cells.aspx">T-cells</a> and their potential ability to fight COVID infection.</p>
<p>Theoretically, T-cells could assist in protecting against severe infection with new strains because <a href="https://www.nature.com/articles/s41591-022-01700-x">T-cells usually cross react to all variants of SARS-CoV-2</a>, the virus that causes COVID.</p>
<p>However, the evidence to date points to the <a href="https://www.nature.com/articles/s41591-021-01377-8">central role of neutralising antibodies</a> obtained from infection or vaccination in protection from both getting an infection and preventing severe disease. A recent unpublished study suggests neutralising antibodies are <a href="https://www.medrxiv.org/content/10.1101/2021.12.23.21268285v1">boosted by breakthrough infections but not T-cells</a>. We know T-cells are very important in protecting from other infectious diseases and many cancers, but perhaps have a lesser role in COVID.</p>
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Read more:
<a href="https://theconversation.com/welcome-to-our-world-families-of-children-with-cancer-say-the-pandemic-has-helped-them-feel-seen-while-putting-them-in-peril-175143">'Welcome to our world': families of children with cancer say the pandemic has helped them feel seen, while putting them in peril</a>
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<h2>Gaining immunity isn’t the end of the story</h2>
<p>Overall, infections with Delta and Omicron provide a boost in immunity against these strains. Infection will probably help protect individuals from reinfection with the same variant. Infection may offer a small amount of protection from different variants and potentially from future variants. </p>
<p>However, immunity will not be enduring and it is still possible to get severe infections and ongoing symptoms (termed “Long COVID”) from breakthrough infections. They are best avoided! Current booster vaccines along with social measures are our best way to stay healthy while we wait for Omicron-specific vaccines.</p><img src="https://counter.theconversation.com/content/175653/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Stephen Kent receives funding from the Australian and Victorian governments for COVID-19 research. </span></em></p>Infection seems to add a boost to immunity – but vaccination is still vital and breakthrough infections should be avoided as much as possible.Stephen Kent, Professor and Laboratory Head, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1754962022-01-27T13:28:42Z2022-01-27T13:28:42ZIs the omicron variant Mother Nature’s way of vaccinating the masses and curbing the pandemic?<figure><img src="https://images.theconversation.com/files/442657/original/file-20220126-17-75f6ee.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C7592%2C3940&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Preliminary research suggests that the omicron variant may potentially induce a robust immune response.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/coronavirus-royalty-free-image/1357650209?adppopup=true">Olga Siletskaya/Moment via Getty Images</a></span></figcaption></figure><p>In the short time since the omicron variant was <a href="https://www.cnn.com/2021/12/02/world/south-africa-omicron-origins-covid-cmd-intl/index.html">identified in South Africa</a> in November 2021, <a href="https://doi.org/10.12998/wjcc.v10.i1.1">researchers have quickly learned</a> that it has three unique characteristics: It spreads efficiently and quickly, it generally causes milder disease than previous variants and it may confer strong protection against other variants such as delta. </p>
<p>This has many people wondering whether omicron could act as a vaccine of sorts, inoculating enough people to effectively bring about <a href="https://theconversation.com/what-is-herd-immunity-a-public-health-expert-and-a-medical-laboratory-scientist-explain-170520">herd immunity</a> – the threshold at which enough of the population is immune to the virus to stop its spread – and end the COVID-19 pandemic.</p>
<p>As <a href="https://sc.edu/study/colleges_schools/medicine/about_the_school/faculty-staff/nagarkatti_mitzi.php">immunology researchers</a> at the University of South Carolina who are <a href="https://pubmed.ncbi.nlm.nih.gov/?term=nagarkatti+p&sort=date&size=200&show_snippets=off">working on inflammatory and infectious diseases</a>, including COVID-19, we find the characteristics of omicron in the pandemic setting particularly intriguing. And it is these characteristics that can help answer that question. </p>
<p>Some 4.73 billion people across the globe – about 61.6% of the world’s population – have received at least <a href="https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html">one dose of a COVID-19 vaccine</a>. In the United States, 63.4% of the population <a href="https://covid.cdc.gov/covid-data-tracker/#vaccinations_vacc-total-admin-rate-total">is fully vaccinated with two doses</a> as of late January 2022, while only 39.9% of Americans have received the booster dose. Such low levels of vaccination resulting from <a href="https://data.cdc.gov/stories/s/Vaccine-Hesitancy-for-COVID-19/cnd2-a6zw/">vaccine hesitancy</a> and the complexities of the <a href="https://dx.doi.org/10.1016%2Fj.ijpe.2021.108193">global vaccine supply chain</a> cast doubt on reaching <a href="https://theconversation.com/what-is-herd-immunity-a-public-health-expert-and-a-medical-laboratory-scientist-explain-170520">herd immunity</a> through vaccination anytime soon. </p>
<h2>How does omicron mimic a vaccine?</h2>
<p><a href="https://www.hhs.gov/immunization/basics/types/index.html">All vaccines</a> work on the principle of training the immune system to fight against an infectious agent. Each vaccine, regardless of how it is made, exposes the human or animal host to the critical molecules used by the infectious agent – in this case, the SARS-CoV-2 virus – to gain entry into the host’s cells.</p>
<p>Some vaccines expose the host only to select portions of the virus. For example, the Pfizer-BioNTech and Moderna vaccines use a <a href="https://theconversation.com/how-mrna-vaccines-from-pfizer-and-moderna-work-why-theyre-a-breakthrough-and-why-they-need-to-be-kept-so-cold-150238">molecule called messenger RNA</a>, or mRNA, to encode and produce a fragment of the “spike protein” – the knobby protrusion that is expressed on the outside of SARS-CoV-2 viruses – inside a person’s body. These spike proteins are the key way that <a href="https://theconversation.com/what-happens-when-the-covid-19-vaccines-enter-the-body-a-road-map-for-kids-and-grown-ups-164624">the coronavirus invades cells</a>, so the mRNA vaccines are designed to mimic that protein and trigger an immune response against it. </p>
<p>In contrast, some vaccines against other infections, <a href="https://theconversation.com/the-chickenpox-virus-has-a-fascinating-evolutionary-history-that-continues-to-affect-peoples-health-today-168636">such as chickenpox</a> and <a href="https://www.cdc.gov/vaccines/hcp/vis/vis-statements/mmr.html">measles, mumps and rubella (MMR)</a>, expose the host to a “live attenuated” form of the virus. These vaccines use small amounts of a weakened form of the live virus. They mimic a natural infection, trigger a strong immune response and afford lasting resistance to infection. </p>
<p>In some respects, omicron mimics these live attenuated vaccines because it causes milder infection and trains the body to trigger a strong immune response against the delta variant, as shown in a recent <a href="https://doi.org/10.1101/2021.12.27.21268439">study that is not yet peer-reviewed</a> from South Africa. </p>
<h2>Deliberate infection with omicron is not the answer</h2>
<p>While omicron may share certain characteristics with a vaccine, it should not be considered a viable alternative to the existing vaccines. For one, COVID-19 infection can result in <a href="https://www.nytimes.com/live/2022/01/10/world/omicron-covid-testing-vaccines">severe illness, hospitalization or death</a>, especially in <a href="https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html">vulnerable individuals with underlying conditions</a>. It can also cause long-term health effects in some people, called <a href="https://theconversation.com/deciphering-the-symptoms-of-long-covid-19-is-slow-and-painstaking-for-both-sufferers-and-their-physicians-164754">long COVID</a>. In contrast, vaccines currently available against COVID-19 have been tested for safety and efficacy. </p>
<p>The high transmission of omicron combined with ongoing vaccination efforts could help attain herd immunity soon and end the most acute phase of the pandemic. However, there is little chance of it eradicating COVID-19, since all signs point to the likelihood that the virus <a href="https://theconversation.com/is-covid-19-here-to-stay-a-team-of-biologists-explains-what-it-means-for-a-virus-to-become-endemic-168462">will become endemic</a> – meaning SARS-CoV-2 will be in circulation but will likely not be as disruptive to society.</p>
<p>Thus far, smallpox is the only infectious disease that <a href="https://www.cdc.gov/smallpox/index.html#">has been eradicated globally</a>, which shows how difficult it is to fully eliminate a disease. However, it is easier to control an infection effectively. One example is <a href="https://www.cdc.gov/polio/what-is-polio/polio-us.html">polio</a>, which has been reduced or eliminated in most countries through vaccination. </p>
<h2>What happens when the body meets a virus or vaccine</h2>
<p>Both viral infections or the mimicking of a virus through vaccination activate a critical component of the immune system, called B cells, in the body. These cells produce antibodies that bind to the virus, preventing it from infecting cells. These antibodies act much like anti-ballistic missiles that shoot down an incoming virus missile. However, once a virus manages to get inside the body’s cells, antibodies are less effective. </p>
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<a href="https://images.theconversation.com/files/442658/original/file-20220126-13-ngm9rq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A 3-D illustration of antibody proteins attacking a coronavirus pathogen cell." src="https://images.theconversation.com/files/442658/original/file-20220126-13-ngm9rq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/442658/original/file-20220126-13-ngm9rq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=300&fit=crop&dpr=1 600w, https://images.theconversation.com/files/442658/original/file-20220126-13-ngm9rq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=300&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/442658/original/file-20220126-13-ngm9rq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=300&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/442658/original/file-20220126-13-ngm9rq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=377&fit=crop&dpr=1 754w, https://images.theconversation.com/files/442658/original/file-20220126-13-ngm9rq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=377&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/442658/original/file-20220126-13-ngm9rq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=377&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Antibodies behave similarly to anti-ballistic missiles, shooting down their target – in this case, the SARS-CoV-2 virus.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/immunoglobulin-or-antibody-proteins-attack-a-corona-royalty-free-image/1299604801?adppopup=true">Christoph Burgstedt/iStock via Getty Images Plus</a></span>
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<p>That’s where another key player in the immune system, called killer T cells, come in. These cells can recognize and destroy a cell as soon as it is infected, thereby preventing the virus from multiplying and spreading further. Think of this as an anti-ballistic missile that detects and destroys the factory where missiles are manufactured. </p>
<p>Immunologists believe that antibodies against COVID-19 prevent an individual from catching the infection, while the <a href="https://www.nature.com/articles/d41586-021-00367-7">killer T cells are crucial</a> in preventing severe disease. Despite its numerous mutations, omicron can trigger a <a href="https://www.nature.com/articles/d41586-022-00063-0#">strong killer T cell response</a>. This may explain why the COVID-19 vaccines – by triggering the T cells – have provided strong enough immunity against omicron to, in most cases, <a href="https://doi.org/10.1001/jamanetworkopen.2021.42725">prevent hospitalization and death</a>.</p>
<p>But, critically, the first wave of antibodies and killer T cells produced during infection or vaccination last for only a few months. This is why recurrent infections of COVID-19 have occurred even in the vaccinated population, and it’s also <a href="https://www.cdc.gov/coronavirus/2019-ncov/vaccines/booster-shot.html">why booster shots are needed</a>. In contrast, some vaccines – like the one against smallpox – have been shown to trigger immunity that lasts for several years. </p>
<h2>Memory immune response</h2>
<p>So what exactly triggers strong and lasting immunity? The lifelong immunity seen in certain infections such as smallpox can be explained by a phenomenon called “<a href="https://www.ncbi.nlm.nih.gov/books/NBK27158/">immunological memory</a>.”</p>
<p>After the B cells and killer T cells first encounter the virus, some of them get converted into what are called memory cells, which are known to <a href="https://doi.org/10.1038/nm917">live for several decades</a>. As their name suggests, when memory cells “see” a virus again after initial exposure, they recognize it, divide rapidly and mount a robust antibody and killer T cell response, thereby preventing reinfection.</p>
<p>[<em>Over 140,000 readers rely on The Conversation’s newsletters to understand the world.</em> <a href="https://memberservices.theconversation.com/newsletters/?source=inline-140ksignup">Sign up today</a>.]</p>
<p>For this reason, memory cells are critical for establishing strong, long-lasting immunity. This is evidenced from studies with smallpox in which people that were infected or vaccinated were found to have the antibody response <a href="https://dx.doi.org/10.1016%2Fj.amjmed.2008.08.019">even after 88 years</a>! Why some infections or vaccines trigger long-lasting memory and others do not is under active investigation. Because COVID-19 is only two years old, we researchers don’t know yet how long the memory B and T cells last. Based on recurrent infections, it looks like longer-term immunity does not last very long, but that could also in part be due to the evolution of new variants. </p>
<p>All of these considerations leave room for hope that when new variants of SARS-CoV-2 inevitably arise, omicron will have left the population better equipped to fight them. So the COVID-19 vaccines combined with the omicron variant could feasibly move the world to a new stage in the pandemic – one where the virus doesn’t dominate our lives and where hospitalization and death are far less common.</p><img src="https://counter.theconversation.com/content/175496/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Prakash Nagarkatti receives funding from the National Institutes of Health and the National Science Foundation.</span></em></p><p class="fine-print"><em><span>Mitzi Nagarkatti receives funding from the National Institutes of Health.</span></em></p>Some of the omicron variant’s unique properties – such as its ability to spread rapidly while causing milder COVID-19 infections – could usher in a new phase of the pandemic.Prakash Nagarkatti, Professor of Pathology, Microbiology and Immunology, University of South CarolinaMitzi Nagarkatti, Professor of Pathology, Microbiology and Immunology, University of South CarolinaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1707722022-01-24T13:31:35Z2022-01-24T13:31:35ZHow mRNA and DNA vaccines could soon treat cancers, HIV, autoimmune disorders and genetic diseases<figure><img src="https://images.theconversation.com/files/441838/original/file-20220120-9603-u5kjhi.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C3840%2C2160&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Nucleic acid vaccines use mRNA to give cells instructions on how to produce a desired protein.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/messenger-rna-or-mrna-strand-3d-rendering-royalty-free-image/1295693748?adppopup=true">Libre de Droit/iStock via Getty Images</a></span></figcaption></figure><p><em>The two most successful coronavirus vaccines developed in the U.S. – the Pfizer and Moderna vaccines – are both mRNA vaccines. The idea of using genetic material to produce an immune response has opened up a world of research and potential medical uses far out of reach of traditional vaccines. <a href="https://scholar.google.com/citations?user=eNprtJEAAAAJ&hl=en&oi=ao">Deborah Fuller is a microbiologist</a> at the University of Washington who has been studying genetic vaccines for more than 20 years. We spoke to her about the <a href="https://theconversation.com/mrna-vaccines-asteroid-missions-and-collaborative-robots-what-to-watch-in-science-in-2022-podcast-174413">future of mRNA vaccines for The Conversation Weekly podcast</a>.</em> </p>
<p><em>Below are excerpts from that conversation which have been edited for length and clarity.</em> </p>
<h2>How long have gene-based vaccines been in development?</h2>
<p>This type of vaccine has been in the works for <a href="https://doi.org/10.1038/356152a0">about 30 years</a>. Nucleic acid vaccines are based on the idea that DNA makes RNA and then RNA makes proteins. For any given protein, once we know the genetic sequence or code, we can design an mRNA or DNA molecule that prompts a person’s cells to start making it. </p>
<p>When we first thought about this idea of putting a genetic code into somebody’s cells, we were studying both DNA and RNA. The mRNA vaccines did not work very well at first. They <a href="https://www.nature.com/articles/nrd.2017.243">were unstable</a> and they caused pretty strong immune responses that were <a href="https://doi.org/10.1038/nrd.2017.243">not necessarily desirable</a>. For a very long time DNA vaccines took the front seat, and the very <a href="https://dx.doi.org/10.1038%2Fnrg2432">first clinical trials were with a DNA vaccine</a>.</p>
<p>But about seven or eight years ago, mRNA vaccines started to take the lead. Researchers solved a lot of the problems – notably the <a href="https://doi.org/10.1038/mt.2008.200">instability</a> – and discovered <a href="https://doi.org/10.1073/pnas.1209367109">new technologies to deliver mRNA</a> into cells and ways of modifying the coding sequence to <a href="https://doi.org/10.1038/nrd.2017.243">make the vaccines a lot more safe to use in humans</a>.</p>
<p>Once those problems were solved, the technology was really poised to become a revolutionary tool for medicine. This was just when COVID-19 hit. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A scanning electron microscope image of blue lumpy sphere of a T cell." src="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">DNA and mRNA vaccines are much better at producing T cells than are normal vaccines.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/niaid/5950870236/in/photolist-2mEvEdt-a4RLoY-2mEn5zV-bo51Vz-MSuhWU-bo5rrZ-2kLN4tU-2kLN4uF-SjQFf7-2ewYf1r-rx2LVN-su1wdR-2j4icVg-2iKmbjG-2mfURRa-a7RGBX-xvJ8TV-2hVm2XZ-2hVhUoD-2iKjyJj-51svu9-51ojDi-51sByA-ni2rkv-2iKgNob-Fwbp7g-EpF3rg-HKERqY-51sBff-51ojop-2mfSkUp-2mfMhmB-2mfLV8V-2mfQZZp-2mfLTAG-2mfVWsD-2mfRRSs-2mfQJMF-2mfUQ1m-2mfSjPU">NIAID/NIH via Flickr</a></span>
</figcaption>
</figure>
<h2>What makes nucleic acid vaccines different from traditional vaccines?</h2>
<p>Most vaccines induce antibody responses. Antibodies are the primary immune mechanism that blocks infections. As we began to study nucleic acid vaccines, we discovered that because these vaccines are expressed within our cells, they were also <a href="https://www.gavi.org/vaccineswork/what-are-nucleic-acid-vaccines-and-how-could-they-be-used-against-covid-19#:%7E:text=Nucleic%20acid%20vaccines%20use%20genetic,immune%20response%20against%20it">very effective at inducing a T cell response</a>. This discovery really prompted additional thinking about how researchers could use nucleic acid vaccines not just for infectious diseases, but also for immunotherapy to treat cancers and chronic infectious diseases – like HIV, hepatitis B and herpes – as well as autoimmune disorders and even for gene therapy.</p>
<h2>How can a vaccine treat cancers or chronic infectious diseases?</h2>
<p>T cell responses are very important for identifying cells infected with chronic diseases and aberrant cancer cells. They also play a big role in eliminating these cells from the body.</p>
<p>When a cell becomes cancerous, it <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/neoantigen">starts producing neoantigens</a>. In normal cases, the immune system detects these neoantigens, recognizes that something’s wrong with the cell and eliminates it. The reason some people get tumors is that their immune system isn’t quite capable of eliminating the tumor cells, so the cells propagate.</p>
<p>With an mRNA or DNA vaccine, the goal is to make your body better able to recognize the very specific neoantigens the cancer cell has produced. If your immune system can recognize and see those better, it will <a href="https://doi.org/10.1038/d41586-019-03072-8">attack the cancer cells and eliminate them from the body</a>. </p>
<p>This same strategy can be applied to the <a href="https://www.genengnews.com/insights/immunotherapy-targets-emerging-infectious-diseases/">elimination of chronic infections</a> like HIV, hepatitis B and herpes. These viruses infect the human body and stay in the body forever unless the immune system eliminates them. Similar to the way nucleic acid vaccines can train the immune system to eliminate cancer cells, they can be used to train our immune cells to recognize and eliminate chronically infected cells. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A syringe inserted into a vaccine vial." src="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">There are dozens of ongoing trials testing the efficacy of mRNA or DNA vaccines to treat cancers or chronic diseases.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/syringe-and-coronavirus-vaccine-royalty-free-image/1287271384?adppopup=true">Stefan Cristian Cioata/Moment via Getty Images</a></span>
</figcaption>
</figure>
<h2>What is the status of these vaccines?</h2>
<p>Some of the very first clinical trials of nucleic acid vaccines happened in the 1990s and <a href="https://doi.org/10.1073/pnas.90.23.11307">were for cancer</a>, particularly for <a href="https://doi.org/10.1038/nrg2432">melanoma</a>.</p>
<p>Today, there are a <a href="https://www.cancernetwork.com/view/messenger-rna-vaccines-beckoning-of-a-new-era-in-cancer-immunotherapy">number of ongoing mRNA clinical trials</a> for the treatment of melanoma, prostate cancer, ovarian cancer, breast cancer, leukemia, glioblastoma and others, and there have been some promising outcomes. Moderna recently announced promising results with its phase 1 trial using mRNA to <a href="https://www.businesswire.com/news/home/20211112005897/en/Moderna-Announces-Presentation-of-Interim-Data-from-Phase-1-Study-of-mRNA-Triplet-Program-at-2021-SITC-Annual-Meeting">treat solid tumors and lymphoma</a></p>
<p>There are also a lot of ongoing trials looking at cancer DNA vaccines, because DNA vaccines are <a href="https://doi.org/10.1186/s13046-019-1154-7">particularly effective in inducing T cell responses</a>. A company called Inovio recently demonstrated a significant impact on cervical cancer caused by human papilloma virus in women <a href="https://ir.inovio.com/news-releases/news-releases-details/2021/INOVIO-Highlights-Key-Updates-on-Phase-3-Program-for-VGX-3100-its-DNA-based-Immunotherapy-for-the-Treatment-of-Cervical-HSIL-Caused-by-HPV-16-andor-HPV-18/default.aspx">using a DNA vaccine</a>.</p>
<h2>Can nucleic acid vaccines treat autoimmune disorders?</h2>
<p>Autoimmune disorders occur when a person’s immune cells are actually attacking a part of the person’s own body. An example of this is multiple sclerosis. If you have multiple sclerosis, your <a href="https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269">own immune cells are attacking myelin</a>, a protein that coats the nerve cells in your muscles.</p>
<p>The way to eliminate an autoimmune disorder is to modulate your immune cells to prevent them from attacking your own proteins. In contrast to vaccines, whose goal is to stimulate the immune system to better recognize something, treatment for autoimmune diseases seeks to dampen the immune system so that it stops attacking something it shouldn’t. Recently, researchers created an mRNA vaccine encoding a myelin protein with slightly tweaked genetic instructions to prevent it from stimulating immune responses. Instead of activating normal T cells that increase immune responses, the vaccine caused the body to <a href="https://doi.org/10.1126/science.aay3638">produce T regulatory cells</a> that specifically suppressed only the T cells that were attacking myelin.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A diagram showing DNA turning into mRNA which turns into proteins." src="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=618&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=618&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=618&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=776&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=776&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=776&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Many diseases result when people have mutations or are missing certain genes, and nucleic acid vaccines could act as temporary replacements for the missing genes.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/mrna-and-protein-synthesis-difference-royalty-free-illustration/1323350905?adppopup=true">ttsz/iStock via Getty Images</a></span>
</figcaption>
</figure>
<h2>Any other applications of the new vaccine technology?</h2>
<p>The last application is actually one of the very first things that researchers thought about using DNA and mRNA vaccines for: gene therapy. Some people are born missing certain genes. The goal with gene therapy is to supply cells with the missing instructions they need to produce an important protein. </p>
<p>[<em>Over 140,000 readers rely on The Conversation’s newsletters to understand the world.</em> <a href="https://memberservices.theconversation.com/newsletters/?source=inline-140ksignup">Sign up today</a>.]</p>
<p>A great example of this is cystic fibrosis, a genetic disease caused by mutations in a single gene. Using DNA or an mRNA vaccine, researchers are investigating the feasibility of essentially replacing the missing gene and allowing someone’s body to <a href="https://www.cff.org/gene-therapy-cystic-fibrosis#rna-therapy">transiently produce the missing protein</a>. Once the protein is present, the symptoms could disappear, at least temporarily. The mRNA would not persist very long in the human body, nor would it integrate into people’s genomes or change the genome in any way. So additional doses would be needed as the effect wore off.</p>
<p>Research has shown that this concept is feasible, but it still needs some work.</p><img src="https://counter.theconversation.com/content/170772/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Deborah Fuller is co-founder of Orlance, Inc, a biotechnology company developing a needle free technology to deliver RNA and DNA vaccines. She also serves as a scientific advisor for HDT Bio, a biotechnology company developing RNA vaccines for COVID19 and other infectious diseases; scientific advisor for Abacus, Inc., a biotechnology company developing cancer vaccines and scientific advisor for SQZ Biotech, a biotechnology company developing cell-based therapies for cancer and infectious diseases. She is also serving as a vaccine expert for Wilmerhale on legal matters. She receives funding supporting basic and translational research in RNA and DNA vaccines from the National Institutes of Health.</span></em></p>DNA and mRNA vaccines produce a different kind of immune response than traditional vaccines, allowing researchers to tackle some previously unsolvable problems in medicine.Deborah Fuller, Professor of Microbiology, School of Medicine, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1744942022-01-12T17:43:40Z2022-01-12T17:43:40ZCOVID: why T cell vaccines could be the key to long-term immunity<figure><img src="https://images.theconversation.com/files/440462/original/file-20220112-13-1hu5kj8.jpg?ixlib=rb-1.1.0&rect=44%2C17%2C953%2C543&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/lymphocyte-3d-illustration-closeup-view-tcell-1438273259">Kateryna Kon/Shutterstock</a></span></figcaption></figure><p>With omicron having rapidly driven up COVID infections, attention is once again focusing on antibodies, and reasonably so. They play a critical role in fighting off viruses and are important for preventing the coronavirus infecting our cells. This is why some countries have mounted booster campaigns in response to recent COVID surges – to top antibody levels up.</p>
<p>But there’s a problem. COVID antibodies don’t <a href="https://www.nature.com/articles/d41586-021-02532-4">persist that well</a> – hence the desire for boosters. Indeed, while these extra jabs maintain <a href="https://www.gov.uk/government/news/boosters-continue-to-provide-high-levels-of-protection-against-severe-disease-from-omicron-in-older-adults">good protection</a> against severe COVID, it’s estimated that people receiving a third dose of the Pfizer vaccine will see their protection against developing COVID symptoms (of any degree) <a href="https://www.nytimes.com/2021/12/23/health/booster-protection-omicron.html">drop from</a> 75% to 45% over the ten weeks following their booster. Scientists have <a href="https://edition.cnn.com/2022/01/04/health/andrew-pollard-booster-vaccines-feasibility-intl/index.html">questioned</a> whether topping up antibodies, only to see them soon fade away, is sustainable. </p>
<p>If we want to develop lasting immunity to COVID, it’s perhaps time to look again at our wider immune response. Antibodies are just one part of our intricate and intertwined immune system. Specifically, it’s maybe time we focused on T cells.</p>
<h2>How different immune cells work</h2>
<p>When the body is infected, say with a virus, it responds by producing white blood cells called lymphocytes. The <a href="https://theconversation.com/coronavirus-b-cells-and-t-cells-explained-141888">main types</a> are B cells, which make antibodies, and T cells, which either support B cell antibody production or act as killer cells to destroy the virus. Some T cells and B cells also become long-lasting memory cells that know what to do if they meet the same infection again.</p>
<p>B cells and T cells “see” the virus in different ways. Generally speaking, B cells recognise shapes on the outside of the virus, creating antibodies that will lock on to those (a bit like two jigsaw pieces that match). T cells instead recognise bits of the amino acids that build the virus, including bits that might normally be found inside it.</p>
<figure class="align-center ">
<img alt="Illustration of the SARS-CoV-2, showing the spike proteins on its surface" src="https://images.theconversation.com/files/348153/original/file-20200717-25-1v585an.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/348153/original/file-20200717-25-1v585an.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=602&fit=crop&dpr=1 600w, https://images.theconversation.com/files/348153/original/file-20200717-25-1v585an.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=602&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/348153/original/file-20200717-25-1v585an.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=602&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/348153/original/file-20200717-25-1v585an.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=757&fit=crop&dpr=1 754w, https://images.theconversation.com/files/348153/original/file-20200717-25-1v585an.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=757&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/348153/original/file-20200717-25-1v585an.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=757&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Antibodies tend to target outer parts of the virus, whereas T cells can be made to focus on a broader range of targets.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/File:SARS-CoV-2_without_background.png">US CDC/Wikimedia Commons</a></span>
</figcaption>
</figure>
<p>Every virus has lots of unique features, both inside and out. A person’s immune response can end up making a variety of T cells and B cells that between them target a whole range of these features. This is sometimes called “breadth of response”. A good breadth of response has lots of different lymphocytes that see different parts of the virus, making it very tricky for the virus to completely hide from them. </p>
<p>Omicron <a href="https://www.nature.com/articles/d41586-021-03614-z">worried many researchers</a> because a key part of its external structure that’s targeted by antibodies – the <a href="https://theconversation.com/new-coronavirus-variant-what-is-the-spike-protein-and-why-are-mutations-on-it-important-152463">spike protein</a> (in red in the picture above) – is heavily mutated, lessening the ability of antibodies to bind to the virus and neutralise it. However, because T cells focus on other parts of the virus, such mutations might not stop them from identifying it. </p>
<p>Indeed, <a href="https://www.mdpi.com/1999-4915/14/1/79/htm">early data</a>, which is still awaiting review, suggests this is the case. This is reassuring, because the virus’s spike protein has changed a lot during the pandemic, suggesting that it could always be mutating away from the reach of antibodies. T cells, though, should be less susceptible to viral mutation. T cells designed to fight COVID also appear to be <a href="https://onlinelibrary.wiley.com/doi/10.1002/cti2.1319">much longer lasting</a> in the human body than antibodies.</p>
<h2>But do T cells have a strong effect?</h2>
<p>We already know a lot about the <a href="https://theconversation.com/coronavirus-how-t-cells-are-involved-and-what-it-might-mean-for-vaccine-development-140374">critical role</a> of T cells in other viral infections. This knowledge suggests that, against COVID, a good T cell response is not only needed to help B cells produce antibodies but should also create killer T cells that can broadly recognise the coronavirus, protecting against multiple variants.</p>
<p>Evidence directly on COVID and T cells is still being gathered. However, it’s gradually becoming clearer that T cells do seem to play a big role in COVID.</p>
<p>Research has shown that generating <a href="https://www.nature.com/articles/s41590-020-0782-6">broadly reactive T cells</a> that recognise a range of viral features <a href="https://doi.org/10.1016/j.immuni.2020.04.023">is associated</a> with a strong response against the disease. Generating good amounts of broadly reactive killer T cells in particular seems to make COVID <a href="https://www.nature.com/articles/s41590-020-0782-6">less severe</a>. </p>
<p>Conversely, a poor T cell response <a href="https://www.science.org/doi/10.1126/sciimmunol.abd6197">is associated</a> with worse outcomes for patients. Indeed, some people who have had severe COVID have been found to have <a href="https://linkinghub.elsevier.com/retrieve/pii/S266663402100115X">persistent defects</a> in their T cell response. </p>
<p>A common feature of many of the studies demonstrating the effectiveness of T cells in COVID is the need for a wide breadth of response – having T cells (and B cells) that recognise multiple features of the virus. It’s thought that this could be the key to experiencing milder disease. </p>
<p>This breadth might even extend beyond this coronavirus specifically. The COVID virus is a betacoronavirus, and there are several betacoronaviruses that already infect us, including ones that cause the common cold. Shared features between these cold-causing viruses and COVID may mean that T cells we already had against the cold <a href="https://theconversation.com/one-vaccine-to-beat-covid-sars-mers-and-common-cold-possible-141586">are protecting us</a> against COVID now. <a href="https://www.nature.com/articles/s41467-021-27674%20-x">Evidence for this</a> in both <a href="https://www.nature.com/articles/s41577-020-0389-z">adults</a> and <a href="https://www.nature.com/articles/s41590-021-01089-8#Ack1">children</a> is being uncovered. </p>
<h2>What does this mean for vaccines?</h2>
<p>Many of the vaccines designed to date – including Moderna’s, Pfizer’s and AstraZeneca’s – have focused on just one major target on the coronavirus: its spike protein. These vaccines have been tremendously effective at generating antibodies. They also stimulate a T cell response to the spike. </p>
<p>But now that we understand more about the role of T cells, the importance of having a broad T cell response, and the issue of antibodies waning, perhaps we should consider refocusing our vaccine strategies on generating T cells and on targeting more than just one protein.</p>
<p>Work is moving in this direction. <a href="https://www.nature.com/articles/s41586-021-04232-5">Early trials</a> of <a href="https://www.nature.com/articles/s41586-021-04232-5">vaccines</a> that can trigger much more broadly reactive helper and killer T cell responses have been completed, and several other <a href="https://www.staffnet.manchester.ac.uk/news/display/?id=27498">T cell vaccines</a> are also <a href="https://www.nature.com/articles/d41587-021-00025-3">entering trials</a>. </p>
<p>These T cell vaccines may be the key to boosting existing immunity and generating long-lived protection against severe disease from a whole range of COVID variants. If so, they would be a huge part of the world living more safely with COVID.</p><img src="https://counter.theconversation.com/content/174494/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sheena Cruickshank does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Having a range of immune cells that target different parts of the virus appears to make disease milder and could protect against future variants.Sheena Cruickshank, Professor in Biomedical Sciences, University of ManchesterLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1729492021-12-02T05:07:45Z2021-12-02T05:07:45ZOmg, Omicron! Why it’s too soon to panic about COVID vaccines and the new variant<figure><img src="https://images.theconversation.com/files/435192/original/file-20211202-19-wb5o0k.jpg?ixlib=rb-1.1.0&rect=0%2C1%2C998%2C559&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/coronavirus-disease-covid19-outbreak-microscopic-view-1667357200">Shutterstock</a></span></figcaption></figure><p>Researchers around the world are trying to <a href="https://www.nytimes.com/2021/11/28/health/covid-omicron-vaccines-immunity.html">work out</a> whether existing COVID vaccines protect us from the latest variant, Omicron. </p>
<p>The worst-case scenario is the virus has mutated so much in the crucial parts of its genome that it can escape COVID vaccines designed to protect us from earlier versions of the virus – with devastating consequences globally.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1465383670097850374"}"></div></p>
<p>But it’s too soon to panic. And vaccines may end up protecting us against Omicron after all, as they have done with earlier variants.</p>
<p>The World Health Organization (WHO) says it will take us another two to four weeks to figure out what’s going on. Here’s what scientists around the world are racing to find out.</p>
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<a href="https://theconversation.com/not-again-how-to-protect-your-mental-health-in-the-face-of-uncertainty-and-another-covid-variant-172847">Not again ... how to protect your mental health in the face of uncertainty and another COVID variant</a>
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<h2>Why the concern?</h2>
<p>The reason Omicron has caused global alarm is due to the number of <a href="https://outbreak.info/compare-lineages">new mutations</a> throughout the genome of SARS-CoV-2, the virus that causes COVID. </p>
<p>This data, coupled with <a href="https://outbreak.info/situation-reports/omicron?loc=ZAF&loc=GBR&loc=USA&selected=ZAF">real world data</a> on the rapid rise in Omicron cases in South Africa, prompted the WHO to designate Omicron a “<a href="https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern">variant of concern</a>” on November 26. </p>
<p>Omicron has now been detected in <a href="https://outbreak.info/situation-reports/omicron?loc=ZAF&loc=GBR&loc=USA&selected=ZAF">several other countries</a> around the world. </p>
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<p>We’ve already seen some Omicron mutations in other variants.</p>
<p>Individually, some of these mutations have been associated with <a href="https://www.nature.com/articles/s41591-021-01270-4">resistance to neutralising antibodies</a>. In other words, these mutations help the virus evade recognition by an immune system primed with a COVID-19 vaccine.</p>
<p>Some of these individual mutations have also been linked with <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791602/">increased transmissibility</a> of the virus from one person to another. </p>
<p>However, Omicron has many unique mutations. For instance, on the spike protein, the protein used in many current vaccines, Omicron has <a href="https://outbreak.info/compare-lineages">about 30 mutations</a> compared with the virus that came out of Wuhan. Delta has only ten mutations in its spike protein. So you get an idea of the scale of change.</p>
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Read more:
<a href="https://theconversation.com/omicron-why-the-who-designated-it-a-variant-of-concern-172727">Omicron: why the WHO designated it a variant of concern</a>
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<p>Investigating the way these multiple mutations interact with one another, rather than individually, will be key to understanding how Omicron behaves compared with other variants.</p>
<p>Looking at these interactions will tell us more about Omicron’s ability to infect cells, cause disease and escape vaccines. And experiments are under way to investigate these mutations and their impacts.</p>
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Read more:
<a href="https://theconversation.com/will-omicron-the-new-coronavirus-variant-of-concern-be-more-contagious-than-delta-a-virus-evolution-expert-explains-what-researchers-know-and-what-they-dont-169020">Will omicron – the new coronavirus variant of concern – be more contagious than delta? A virus evolution expert explains what researchers know and what they don't</a>
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<p>While we wait for the results, we heard this week from <a href="https://www.theguardian.com/business/2021/nov/30/moderna-boss-predicts-current-vaccines-may-be-less-effective-against-omicron">some of the vaccine manufacturers</a>. Moderna said its vaccine would be less effective against Omicron than against Delta. Meanwhile, Pfizer/BioNTech said its vaccine would still protect against severe disease. Both companies said they could produce tweaked <a href="https://www.theguardian.com/society/2021/nov/26/biontech-says-it-could-tweak-covid-vaccine-in-100-days-if-needed">booster vaccines</a>, if needed.</p>
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<h2>Why will it take weeks to get answers?</h2>
<p>Here’s what researchers around the world are working on and why we won’t have answers for a few weeks.</p>
<p><strong>Growing the virus</strong></p>
<p>Researchers are taking samples of Omicron from infected people and <a href="https://www.science.org/content/article/patience-crucial-why-we-won-t-know-weeks-how-dangerous-omicron">growing the virus in laboratories</a>. This gives them working stocks of the virus to conduct experiments. This can take time as you’re often starting with tiny amounts of virus from a swab.</p>
<p>This process also relies on access to the right types of cells to grow the virus in.</p>
<p>Finally, this needs to be done in laboratories that offer a high level of biosafety, to contain the virus. Not all researchers have access to these facilities.</p>
<p><strong>Make your own ‘virus’</strong></p>
<p>Researchers can also use genetic tools to produce the virus in the laboratory, requiring only the <a href="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001091">genome sequence</a> of SARS-CoV-2 to begin production. This removes the reliance on patient samples. </p>
<p>They can also produce <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936541/">genetically engineered viruses</a>, called pseudotyped viruses, in the laboratory. These carry only the spike protein of SARS-CoV-2.</p>
<p>Researchers can also express small portions of the spike protein on the surface of other organisms, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869748/">such as yeast</a>.</p>
<p>All of these options take time to set up, optimise and be used in the types of studies outlined below.</p>
<h2>Both methods are useful</h2>
<p>Initial studies will look at how Omicron’s mutations impact the fitness of the variant – its transmissibility and ability to evade vaccine-induced immunity.</p>
<p>For instance, initial experiments will look at Omicron’s <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332439/">ability to infect cells</a>. These studies will tell us how well Omicron’s spike protein interacts with the <a href="https://theconversation.com/what-is-the-ace2-receptor-how-is-it-connected-to-coronavirus-and-why-might-it-be-key-to-treating-covid-19-the-experts-explain-136928">ACE2 receptor</a>, the gateway to infecting our cells. Further studies will investigate how well Omicron can replicate in cells after gaining entry.</p>
<p>Neutralisation studies will investigate how well antibodies – induced by current SARS-CoV-2 vaccines – can neutralise Omicron, or prevent it from infecting cells. Such studies rely on access to serum from vaccinated people and are likely to compare the neutralising capacity of Omicron against other SARS-CoV-2 variants.</p>
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<p>Studies are also likely to investigate the effect of vaccine booster regimes and earlier SARS-CoV-2 infection on how well antibodies neutralise Omicron.</p>
<p>So what can we expect? Until we get the results of these experiments, it’s difficult to say for certain.</p>
<p>Studies of how effective COVID-19 vaccines are against other variants show they <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442750/">are generally less able</a> to induce the type of antibody response we’d like to see (neutralising antibodies). However, when previous variants have emerged, vaccines have continued to protect against severe disease. </p>
<p>Vaccine protection is not all or nothing. We are unlikely to get a perfect neutralising antibody response against Omicron, or no response, rather something in between.</p>
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Read more:
<a href="https://theconversation.com/how-well-do-covid-vaccines-work-in-the-real-world-162926">How well do COVID vaccines work in the real world?</a>
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<h2>We’ll also know more as we see more cases</h2>
<p>Continued monitoring of real-world data will also be essential to determine how Omicron impacts the broader pandemic. </p>
<p>Whether Omicron is able to spread from seeding events around the world or compete with Delta are questions to be answered in the coming weeks. </p>
<p>Whether infection with Omicron <a href="https://www.bbc.com/news/av/uk-59450988">causes less or more serious disease</a> also remains unclear. Monitoring hospitalisation rates will be key here.</p>
<h2>We still need to tackle Delta</h2>
<p>Currently <a href="https://outbreak.info/situation-reports">fewer than 200 genetic sequences</a> of Omicron have been compiled compared with more than 2.8 million Delta sequences. Delta remains the most dominant variant. So we should continue to use vaccines and therapies we know work against Delta.</p>
<p>It’s also essential we continue with public health measures, such as wearing masks and social distancing, alongside continued vaccination, to combat the spread of SARS-CoV-2 and the emergence of further variants.</p>
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Read more:
<a href="https://theconversation.com/wealthy-nations-starved-the-developing-world-of-vaccines-omicron-shows-the-cost-of-this-greed-172763">Wealthy nations starved the developing world of vaccines. Omicron shows the cost of this greed</a>
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<img src="https://counter.theconversation.com/content/172949/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Adam Taylor receives funding from the Australian National Health and Medical Research Council. </span></em></p>We won’t know whether Omicron evades COVID vaccines for another few weeks. Here’s why.Adam Taylor, Early Career Research Leader, Emerging Viruses, Inflammation and Therapeutics Group, Menzies Health Institute Queensland, Griffith UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1726092021-11-29T04:25:59Z2021-11-29T04:25:59ZDoes AstraZeneca’s COVID vaccine give longer-lasting protection than mRNA shots?<p>Last week, AstraZeneca’s chief executive officer <a href="https://www.bloomberg.com/opinion/articles/2021-11-24/did-astrazeneca-covid-vaccine-really-keep-britain-safer-than-europe-not-so-fast">said</a> the company’s COVID vaccine may provide longer-lasting protection than mRNA vaccines like Pfizer’s, especially in older people.</p>
<p>CEO Pascal Soriot said this might explain the United Kingdom’s <a href="https://www.ft.com/content/92e77bf1-2266-4534-a043-daa6c8bb413f">more stable hospitalisation rate</a> compared to the escalating COVID situation in continental Europe.</p>
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<p>The UK used the AstraZeneca vaccine a lot more widely than other European countries, many of which <a href="https://www.theguardian.com/world/2021/nov/23/astrazeneca-chief-links-europes-covid-surge-to-rejection-of-firms-vaccine">restricted its use</a> to older age groups or <a href="https://www.bbc.com/news/world-europe-56744474">abandoned using it altogether</a> after reports of very rare blood clots.</p>
<p>The theory behind this is the AstraZeneca vaccine may provide more durable “T cell protection”. T cells are a crucial part of our immune system, and differ from antibodies.</p>
<p>There’s not enough evidence yet to support the CEO’s claim. But we do know a lot more about adenovirus vector vaccines, such as AstraZeneca’s, as they’ve been around for decades, while mRNA vaccines are relatively newer.</p>
<p>Theoretically, it is possible adenovirus vector vaccines do give more durable protection against COVID via T cells.</p>
<p>Let me explain.</p>
<h2>What is AstraZeneca’s vaccine again?</h2>
<p>AstraZeneca’s COVID vaccine is an adenovirus vector vaccine.</p>
<p>This means it uses an adenovirus – a common type of virus that affects humans and many other animals. The adenovirus is genetically modified so it doesn’t replicate.</p>
<p>It’s used as a way to deliver the vaccine’s information into our cells.</p>
<p>In this case, the information packaged in the adenovirus tells our body how to make the coronavirus <a href="https://theconversation.com/revealed-the-protein-spike-that-lets-the-2019-ncov-coronavirus-pierce-and-invade-human-cells-132183">spike protein</a>. This teaches our immune system how to deal with the coronavirus if we’re exposed.</p>
<p>Adenovirus vectors have been used in medicine for a few decades in other vaccines and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507798/">also cancer therapy</a>. They’re very good at stimulating both antibody production and T cell responses.</p>
<h2>What are T cells?</h2>
<p><a href="http://www.biology.arizona.edu/immunology/tutorials/antibody/structure.html">Antibodies</a> bind tightly to a specific target, locking onto invading viruses and preventing them from entering our cells.</p>
<p>But the immune system is more than just antibodies.</p>
<p>T cells are also really important for our immune response, and have different roles. One type, known as “killer T cells”, attack and destroy virus-infected cells.</p>
<p>Another type, known as “helper T cells”, interpret the nature of the infection and help the immune system respond appropriately. This includes activating killer T cells to destroy virus-infected cells, and also helping B cells make antibodies. </p>
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<p>Antibodies wane over time, which can lead to more breakthrough infections <a href="https://theconversation.com/why-are-we-seeing-more-covid-cases-in-fully-vaccinated-people-an-expert-explains-166741">in fully vaccinated people</a>.</p>
<p>When viruses are not stopped by antibodies, we rely on killer T cells to eradicate the virus. And T cells almost certainly help prevent severe outcomes if you get COVID.</p>
<p>It’s a lot harder for a virus to escape a T cell-based immune response. So a vaccine that generates strong T cell immunity should help retain effectiveness over time against variants including Delta and Omicron.</p>
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Read more:
<a href="https://theconversation.com/why-are-we-seeing-more-covid-cases-in-fully-vaccinated-people-an-expert-explains-166741">Why are we seeing more COVID cases in fully vaccinated people? An expert explains</a>
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<p>All COVID vaccines stimulate our bodies to produce both antibodies and T cells.</p>
<p>So the key questions are: does AstraZeneca’s vaccine produce a longer-lasting T cell response than the mRNA vaccines? And might this be one reason why the UK, which relied heavily on the AstraZeneca vaccine, has a more stable hospitalisation rate than other parts of Europe?</p>
<p>Unfortunately, there are not enough data yet to answer these conclusively.</p>
<p>There are many reasons why hospitalisation rates can vary between countries, so it’s difficult to know how much of a factor the use of AstraZeneca’s vaccine would be.</p>
<p>But we can lean on what we know about adenovirus vector vaccines to break down this theory.</p>
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Read more:
<a href="https://theconversation.com/from-adenoviruses-to-rna-the-pros-and-cons-of-different-covid-vaccine-technologies-145454">From adenoviruses to RNA: the pros and cons of different COVID vaccine technologies</a>
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<h2>It’s plausible</h2>
<p>Adenovirus vector vaccines are very good at stimulating immune responses, <a href="https://ashpublications.org/blood/article/110/6/1916/24190/Adenoviral-vectors-persist-in-vivo-and-maintain">particularly T cell responses</a>.</p>
<p>Current wisdom tells us the mRNA vaccines <a href="https://www.bloomberg.com/news/articles/2021-11-15/pfizer-shot-generated-the-most-antibodies-in-a-comparative-study">provide a stronger antibody response</a> than the viral vector vaccines like AstraZeneca’s.</p>
<p>But this antibody protection seems to <a href="https://theconversation.com/why-its-normal-for-covid-19-vaccine-immunity-to-wane-and-how-booster-shots-can-help-171786">wane relatively quickly</a> over 4-6 months.</p>
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<p>It’s possible immune memory with the mRNA vaccines isn’t as strong, and the AstraZeneca vaccine may produce a longer-lasting T cell response that supports more durable immune memory.</p>
<p>This could slow the loss of antibodies and generate a better killer T cell response.</p>
<h2>Why might AstraZeneca produce a longer-lasting response?</h2>
<p>One reason might be because the RNA in Pfizer’s and Moderna’s vaccines doesn’t last very long in the body, <a href="https://theconversation.com/no-covid-vaccines-dont-stay-in-your-body-for-years-169247">only a week or so</a>, because RNA is very fragile.</p>
<p>But the DNA delivered by adenovirus vector vaccines will likely hang around in the body for a bit longer.</p>
<p>DNA is more stable than RNA, and might allow for a more prolonged, low-level activation of our immune system that provides longer-lasting protection.</p>
<p>This might explain longer-lasting T cell responses with the AstraZeneca vaccine.</p>
<p>But this is only speculative for now as such direct tests haven’t been done yet.</p>
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Read more:
<a href="https://theconversation.com/no-covid-vaccines-dont-stay-in-your-body-for-years-169247">No, COVID vaccines don't stay in your body for years</a>
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<h2>If true, we can learn from this</h2>
<p>This isn’t about which vaccine is “<a href="https://theconversation.com/which-covid-vaccine-is-best-heres-why-thats-really-hard-to-answer-161185">better</a>”, or picking and choosing which vaccine to get. </p>
<p>Both are excellent vaccines that have saved many, many lives already. We shouldn’t <a href="https://theconversation.com/covid-vaccination-has-turned-into-a-battle-of-the-brands-but-not-everyones-buying-it-162181">play a tribal game</a> where we say we’re only going to get one type of vaccine.</p>
<p>It’s important to learn from both types of vaccine, while we continue to learn about immunity to COVID, so we can incorporate the best characteristics of both into next-generation vaccines that help us better fight COVID and future pandemics.</p>
<p>I’m sure mRNA vaccine producers will learn from this and develop new formulas to give a longer-lasting response. </p>
<p>It’s worth remembering Pfizer and Moderna’s vaccines are the first mRNA vaccines ever approved for use in humans.</p>
<p>There was an immediate need to get antibodies against COVID in our bodies as soon as possible, and they’ve done a fantastic job doing that.</p><img src="https://counter.theconversation.com/content/172609/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Nathan Bartlett does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>There’s not enough evidence yet to support the AstraZeneca CEO’s statement. But it is theoretically plausible.Nathan Bartlett, Associate Professor, School of Biomedical Sciences and Pharmacy, University of NewcastleLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1692472021-10-07T19:05:54Z2021-10-07T19:05:54ZNo, COVID vaccines don’t stay in your body for years<p>As Australia strives to reach its national COVID vaccination targets, there’s unprecedented focus on the biological effects of vaccines. </p>
<p>While there’s an enormous amount of information available online, it’s increasingly difficult to discern truth from falsehood or even conspiracy.</p>
<p>A common myth of vaccines that has appeared in recent months is the accusation they remain active in the body for extended periods of time – a claim which has increased vaccine hesitancy in some people.</p>
<p>However, vaccines are cleared from your body in mere days or weeks. It’s the immune response against the SARS-CoV-2 virus that appears to last for a long time.</p>
<p>This isn’t due to the vaccines themselves remaining in the body. Instead, the vaccines stimulate our immune system and teach it how to respond if we’re ever exposed to the coronavirus. </p>
<p>Let’s explain.</p>
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<h2>How do vaccines work?</h2>
<p>All vaccines, no matter the technology, have the same fundamental goal – to introduce the immune system to an infectious agent, <a href="https://www.who.int/news-room/feature-stories/detail/how-do-vaccines-work">without the risk that comes from disease</a>.</p>
<p>The vaccine needs to follow a similar pathway a virus would have taken to produce an adequate immune response. Viruses enter our cells and use them to replicate themselves. So, the vaccines also need to be delivered in cells where proteins are produced, which mimics a component of the virus itself.</p>
<p>The COVID vaccines all do this by delivering information into our muscle cells, usually in our upper arm. They do this in different ways, such as using mRNA, like Pfizer’s and Moderna’s, or viral vectors, like AstraZeneca’s. </p>
<p>Regardless of the technology, the effect is similar. Our cells use the genetic template in the vaccine to produce the coronavirus’ <a href="https://theconversation.com/revealed-the-protein-spike-that-lets-the-2019-ncov-coronavirus-pierce-and-invade-human-cells-132183">spike protein</a>, which is a part of the virus that helps it enter our cells. The spike protein is transported to the surface of the cell where it’s detected by the immune cells nearby.</p>
<p>There are also other specialised immune cells nearby, which take up the spike proteins and use them to inform more immune cells – targeting them specifically against COVID.</p>
<p>These immune cells include B cells, which produce antibodies, and T cells, which kill virus-infected cells. They then become long-lasting memory cells, which wait and monitor for the next time it sees a spike protein.</p>
<p>If you’re exposed to the virus, these memory B and T cells allow a faster and larger immune response, <a href="https://www.nature.com/articles/s41541-021-00369-6">destroying the virus before it can cause disease</a>.</p>
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Read more:
<a href="https://theconversation.com/revealed-the-protein-spike-that-lets-the-2019-ncov-coronavirus-pierce-and-invade-human-cells-132183">Revealed: the protein 'spike' that lets the 2019-nCoV coronavirus pierce and invade human cells</a>
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<h2>So what happens to the vaccine?</h2>
<p>Once they’ve initiated the immune response, the vaccines themselves are rapidly broken down and cleared from the body.</p>
<p>The mRNA vaccines consist of a fatty shell, which encapsulates a group of mRNA particles – the genetic recipe for the spike protein. Once this enters a cell, the shell is degraded to harmless fats, and the mRNA is <a href="https://www.idsociety.org/globalassets/idsa/public-health/covid-19/real-time-learning-network-vaccines-faq.pdf">used by the cells to produce spike proteins</a>.</p>
<p>Once the mRNA has been used to produce proteins, it’s broken down and cleared from the cell along with the rest of the mRNAs produced by the normal function of the cell.</p>
<p>In fact, mRNA is very fragile, with the most long lasting <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2241649/">only able to survive for a few days</a>. This is why the Pfizer and Moderna vaccines have to be so carefully preserved at ultra-low temperatures.</p>
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<p>The vector vaccines (AstraZeneca and Johnson and Johnson) use an adenovirus, which is harmless in humans, as a vector to <a href="https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/viralvector.html">deliver a genetic template for the spike protein to the cells</a>.</p>
<p>The vector virus has all of its infectious components removed, so it’s unable to multiply or cause disease. Then a genetic template for the spike protein is inserted into the vector.</p>
<p>Once the vaccine is injected, the vector virus binds to your cells and inserts its genetic components, before the shell breaks down and is removed.</p>
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Read more:
<a href="https://theconversation.com/how-long-does-immunity-last-after-covid-vaccination-do-we-need-booster-shots-2-immunology-experts-explain-164073">How long does immunity last after COVID vaccination? Do we need booster shots? 2 immunology experts explain</a>
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<p>The viral machinery gets the genetic template into the control room of the cell, the nucleus, where it takes advantage of our normal protein building activity. The vaccine <a href="https://www.medpagetoday.com/special-reports/exclusives/91604#:%7E:text=Adenoviruses%20deliver%20DNA%20that%20can,the%20capacity%20to%20alter%20DNA.">doesn’t cause any alteration to our DNA</a>.</p>
<p>Normally, this would cause the cell to start producing more copies of the virus, but since this was all removed, all that’s produced is the spike protein.</p>
<p>Again, after making a large amount of the spike, the genetic templates are <a href="https://www.health.qld.gov.au/news-events/news/long-term-effects-of-vaccines">broken down</a> <a href="https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-moderna-authorisation-eu">in a matter of days or weeks</a>.</p>
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<h2>What about the spike protein?</h2>
<p>While the vaccines themselves are rapidly removed, what then happens to all the spike proteins that are produced as a result?</p>
<p>They’re identified as foreign by the immune system and destroyed – teaching the cells to recognise the coronavirus in the process.</p>
<p>The spike proteins are <a href="https://www.idsociety.org/globalassets/idsa/public-health/covid-19/real-time-learning-network-vaccines-faq.pdf">fully cleared from the body after a few weeks</a>. In this time, they <a href="https://www.science.org/content/blog-post/spike-protein-behavior">don’t appear to leave the vaccination site</a> (most often your upper arm).</p>
<p>But antibodies specifically targeting the spike protein produced by your immune system <a href="https://theconversation.com/how-long-does-immunity-last-after-covid-vaccination-do-we-need-booster-shots-2-immunology-experts-explain-164073">remain in the body for many months after vaccination</a>.</p>
<p>The vaccines also stimulate your immune system to produce memory immune cells. This means even once antibody levels diminish, your immune system is ready to produce more antibodies and other immune cells to tackle the virus if you’re ever exposed to it. </p>
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Read more:
<a href="https://theconversation.com/how-long-does-immunity-last-after-covid-vaccination-do-we-need-booster-shots-2-immunology-experts-explain-164073">How long does immunity last after COVID vaccination? Do we need booster shots? 2 immunology experts explain</a>
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<img src="https://counter.theconversation.com/content/169247/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Vasso Apostolopoulos COVID-19 research has received internal funding from Victoria University place-based Planetary Health research grant and from philanthropic donations. </span></em></p><p class="fine-print"><em><span>Jack Feehan and Maja Husaric do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>But the immune cells that vaccination spurs do last a long time.Vasso Apostolopoulos, Professor of Immunology and Associate Provost, Research Partnerships, Victoria UniversityJack Feehan, Research Officer - Immunology and Translational Research, Victoria UniversityMaja Husaric, Senior Lecturer; MD, Victoria UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1677472021-09-29T15:07:12Z2021-09-29T15:07:12ZCombining an HIV vaccine with immunotherapy may reduce the need for daily medication<figure><img src="https://images.theconversation.com/files/422472/original/file-20210921-13-csnsx2.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1406&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The estimated lifetime costs of antiretroviral therapy for someone who acquires HIV at age 35 is $358,380.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/therapy-pills-on-pink-background-royalty-free-image/1214095662">YakubovAlim/iStock via Getty Images Plus</a></span></figcaption></figure><p><em>The <a href="https://theconversation.com/us/topics/research-brief-83231">Research Brief</a> is a short take about interesting academic work.</em></p>
<h2>The big idea</h2>
<p><a href="https://doi.org/10.1126/sciimmunol.abh3034">A new combination treatment for HIV</a> can strengthen a patient’s immune response against the virus even after they stop taking traditional medications, according to a study published in the journal Science Immunology we co-led at the <a href="http://www.yerkes.emory.edu/research/divisions/microbiology_immunology/amara_rama.html">Amara Lab at Emory Univeristy</a>.</p>
<p>People with HIV take a <a href="https://hivinfo.nih.gov/understanding-hiv/fact-sheets/hiv-treatment-basics">combination of HIV medications</a> to reduce the amount of virus they have in their body. When taken as prescribed, these medications, collectively called <a href="https://www.cdc.gov/hiv/risk/art/index.html">antiretroviral therapy</a>, can reduce the amount of virus in the body to undetectable levels. Antiretroviral therapy must be <a href="https://www.hiv.gov/hiv-basics/staying-in-hiv-care/hiv-treatment/taking-your-hiv-medications-every-day">taken daily</a> so the virus is less likely to mutate and <a href="https://hivinfo.nih.gov/understanding-hiv/fact-sheets/drug-resistance">become resistant to the drugs</a>.</p>
<p>While reducing the amount of virus in the body to undetectable levels means it can <a href="https://www.niaid.nih.gov/diseases-conditions/treatment-prevention">no longer be transmitted</a>, however, the most effective antiretroviral therapy drugs are unable to completely eliminate the virus. This is because HIV hides in <a href="https://dx.doi.org/10.1084%2Fjem.190.9.1197">immune-privileged</a> areas of the body, such as certain parts of the lymphoid tissue, that are less accessible to the immune system to protect them from damage. <a href="https://doi.org/10.1038/nri819">Killer T cells</a>, which search for and eliminate infected cells, are unable to patrol these <a href="https://dx.doi.org/10.1097%2FCOH.0000000000000293">viral reservoirs</a> that harbor HIV.</p>
<p><a href="https://dx.doi.org/10.1097%2FQAD.0b013e32835ecb8b">Constant exposure</a> to the virus can push killer T cells into a <a href="https://doi.org/10.1097/qad.0000000000000314">state of exhaustion</a> in which they don’t work as well. Exhausted killer T cells display more of a protein called <a href="https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html">PD-1</a>, which functions as an “off switch” to its killing activity.</p>
<p>One way to reverse killer T cell exhaustion is to <a href="https://doi.org/10.1038/cddis.2015.162">block the PD-1 off switch</a>, but this does not boost the immune system’s response to the virus. Conversely, an HIV vaccine can significantly boost immunity against the virus. </p>
<p>So we tested whether <a href="https://doi.org/10.1126/sciimmunol.abh3034">combining these two tactics</a> could enhance HIV infection control. We administered a vaccine for <a href="https://www.livescience.com/51972-hiv-related-virus-evolutionary-history.html">SIV</a>, a close cousin to HIV, with a drug that blocks PD-1 in SIV-infected rhesus monkeys treated with antiretroviral therapy. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/422492/original/file-20210921-17-1nmhbxx.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram illustrating immune boosting outcomes of study." src="https://images.theconversation.com/files/422492/original/file-20210921-17-1nmhbxx.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/422492/original/file-20210921-17-1nmhbxx.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=415&fit=crop&dpr=1 600w, https://images.theconversation.com/files/422492/original/file-20210921-17-1nmhbxx.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=415&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/422492/original/file-20210921-17-1nmhbxx.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=415&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/422492/original/file-20210921-17-1nmhbxx.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=522&fit=crop&dpr=1 754w, https://images.theconversation.com/files/422492/original/file-20210921-17-1nmhbxx.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=522&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/422492/original/file-20210921-17-1nmhbxx.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=522&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Combining a vaccine with a PD-1 blockade led to three improvements in immune response.</span>
<span class="attribution"><span class="source">Bhrugu Yagnik/Created with BioRender.com</span>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
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<p>We found that our approach generated robust anti-viral response in multiple parts of the body, including immune-privileged sites in the lymph nodes, and allowed killer T cells to infiltrate and purge viral reservoirs. Most importantly, the monkeys maintained strong immunity against the virus even after they stopped antiretroviral therapy and significantly improved their survival. None of the seven monkeys in the combination treatment group developed AIDS through our six-month follow-up period, compared with half of the monkeys who received only the vaccine or antiretroviral therapy alone.</p>
<h2>Why it matters</h2>
<p>Around <a href="https://www.unaids.org/en/resources/fact-sheet">38 million people worldwide</a> were living with HIV in 2020. If left untreated, HIV can cripple the immune system and leave the body vulnerable to <a href="https://www.hiv.gov/hiv-basics/staying-in-hiv-care/other-related-health-issues/opportunistic-infections">normally harmless infections</a>.</p>
<p>There are accessibility issues with the treatment that must be diligently taken every day for life. A 2015 study estimated that the lifetime antiretroviral therapy cost for someone who acquires HIV at age 35 is <a href="https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/cost-considerations-and-antiretroviral-therapy">US$358,380</a>. And many people don’t have access to daily antiretroviral therapy. Around <a href="https://www.unaids.org/en/resources/documents/2013/20131219_AccessARTAfricaStatusReportProgresstowards2015Targets">three-quarters of adults with HIV in sub-Saharan Africa</a> do not reach persistent <a href="https://clinicalinfo.hiv.gov/en/glossary/viral-suppression">viral suppression</a> due to lack of treatment availability. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/422493/original/file-20210921-23-z98bip.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram illustrating the challenges posed by HIV." src="https://images.theconversation.com/files/422493/original/file-20210921-23-z98bip.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/422493/original/file-20210921-23-z98bip.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=416&fit=crop&dpr=1 600w, https://images.theconversation.com/files/422493/original/file-20210921-23-z98bip.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=416&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/422493/original/file-20210921-23-z98bip.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=416&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/422493/original/file-20210921-23-z98bip.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=522&fit=crop&dpr=1 754w, https://images.theconversation.com/files/422493/original/file-20210921-23-z98bip.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=522&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/422493/original/file-20210921-23-z98bip.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=522&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">HIV poses a number of challenges to both patients and researchers.</span>
<span class="attribution"><span class="source">Bhrugu Yagnik/Created with BioRender.com</span>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
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<p>Finally, even though antiretroviral therapy can thoroughly suppress HIV infection, it does not cure it. There is always a risk that the virus may mutate to <a href="https://www.who.int/news-room/fact-sheets/detail/hiv-drug-resistance">become resistant to existing drugs</a>.</p>
<h2>What still isn’t known</h2>
<p>Completely wiping out HIV from the body is one way to eliminate the need for daily antiretroviral therapy. But a more achievable strategy is to put the infected cells in check. </p>
<p>Currently, only <a href="https://www.massgeneral.org/news/press-release/Hiv-new-study-of-elite-controllers-offers-powerful-evidence-that-a-cure-is-possible">0.5% of HIV positive individuals</a> are considered “<a href="https://clinicalinfo.hiv.gov/en/glossary/long-term-nonprogressors-ltnp">elite controllers</a>” who are able to suppress infection without medication. </p>
<p>While our study showed a potential pathway to control HIV, it is still in development and not ready for human patients. More research is necessary to understand how viral reservoirs form and why certain cells respond differently to different immunotherapies.</p>
<h2>What’s next</h2>
<p>A single form of therapy may not result in complete HIV remission. Our team is currently testing other drug combinations to unleash the full potential of the immune system and overcome barriers to a cure.</p><img src="https://counter.theconversation.com/content/167747/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Rama Rao Amara receives funding from NIAID/NIH. </span></em></p><p class="fine-print"><em><span>Bhrugu Yagnik and Sheikh Abdul Rahman do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>People with HIV need to take daily medication to keep the virus at bay. A study has found that a new treatment combination could boost immunity and control virus levels even after stopping medication.Sheikh Abdul Rahman, Postdoctoral Fellow in Microbiology and Immunology, Emory UniversityBhrugu Yagnik, Postdoctoral Fellow in Microbiology and Immunology, Emory UniversityRama Rao Amara, Professor of Microbology and Immunology, Emory UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1668192021-09-23T02:14:31Z2021-09-23T02:14:31ZCOVID-19 increases the chance of getting an autoimmune condition. Here’s what the science says so far<figure><img src="https://images.theconversation.com/files/422301/original/file-20210921-13-d1dkt8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/woman-unable-get-out-car-this-2020674380">Shutterstock</a></span></figcaption></figure><p>SARS-CoV-2, the virus that causes COVID-19, can sometimes cause the immune system to mistakenly attack the person’s own body. This process, known as “autoimmunity”, can damage a number of different organs. </p>
<p>After COVID-19, a small number of patients <a href="https://www.mdpi.com/1422-0067/22/16/8965/htm">have developed</a> a range of different autoimmune diseases. This includes <a href="https://www.nejm.org/doi/full/10.1056/NEJMc2009191">Guillain-Barré syndrome</a>, a disorder in which the immune system attacks nerves, often resulting in tingling and weakness in arms and legs. </p>
<p>There are also reports of autoimmune responses that don’t clearly correspond to any known autoimmune disease. This suggests COVID-19 disease may trigger new autoimmune illnesses. </p>
<p>The science on how and how often this occurs is still emerging. But here’s what we know so far. </p>
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<p>
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Read more:
<a href="https://theconversation.com/explainer-what-are-autoimmune-diseases-22577">Explainer: what are autoimmune diseases?</a>
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<h2>First, a quick recap on the immune system</h2>
<p>The immune system is tightly regulated. Within it, immune cells known as B and T lymphocytes – the soldiers of the immune system – are normally able to distinguish between itself versus external targets. </p>
<p>When the system becomes confused, B and T cells may start to target our own bodies, which we call autoimmunity. </p>
<p>Viral infection can sometimes trigger this confusion, <a href="https://pubmed.ncbi.nlm.nih.gov/31430946/">resulting in autoimmune diseases</a>.</p>
<h2>How do viruses trigger autoimmunity?</h2>
<p>Two of the key mechanisms are “molecular mimicry” and “bystander activation”. </p>
<p>Molecular mimicry occurs when the part of the virus the B or T cells recognise looks similar to a normal protein in our body. </p>
<p>The B or T cell then sees both the viral and the self-protein as something to attack and eliminate. </p>
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<p>
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<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-the-immune-system-19240">Explainer: what is the immune system?</a>
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<p>Viral infections can also cause organ damage and cell death directly. When our cells die and burst, they release self-proteins. These would normally stay hidden and wouldn’t trigger an immune reaction. </p>
<p>Bystander activation occurs when B and T cells accidentally get in contact with self-proteins, confusing the immune system, which otherwise is trained to ignore self-proteins. </p>
<h2>What autoimmune conditions can COVID-19 trigger?</h2>
<p>There are <a href="https://www.mdpi.com/1422-0067/22/16/8965">multiple reports</a> of antibodies which recognise self-proteins, also known as autoantibodies, emerging in people with severe COVID-19.</p>
<p>Some of these autoantibodies that emerge in people with severe COVID recognise autoantibodies associated with <a href="https://www.mdpi.com/1422-0067/22/16/8965">well-known autoimmune diseases</a>, including:</p>
<ul>
<li><p><a href="https://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-020-02582-8">systemic lupus erythematosus</a> (SLE), which affects joints, skin, blood cells as well as organs such as the brain, lungs and kidneys </p></li>
<li><p><a href="https://ard.bmj.com/content/early/2021/04/26/annrheumdis-2021-220479">rheumatoid arthritis</a>, affecting the joints</p></li>
<li><p><a href="https://onlinelibrary.wiley.com/doi/10.1111/jns.12419">Guillain-Barré syndrome</a>, mentioned above</p></li>
<li><p><a href="https://pubmed.ncbi.nlm.nih.gov/32420612/">immune thrombocytopenia</a>, which attacks blood platelets, resulting in excessive bruising and bleeding</p></li>
<li><p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267601/">autoimmune haemolytic anaemia</a>, which attacks red blood cells which can result in breathlessness, tiredness, headaches and chest pain.</p></li>
</ul>
<figure class="align-center ">
<img alt="Close up of a person's had pushing their wheelchair." src="https://images.theconversation.com/files/422518/original/file-20210922-21-1to343i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/422518/original/file-20210922-21-1to343i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/422518/original/file-20210922-21-1to343i.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/422518/original/file-20210922-21-1to343i.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/422518/original/file-20210922-21-1to343i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/422518/original/file-20210922-21-1to343i.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/422518/original/file-20210922-21-1to343i.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Autoimmune conditions after COVID can affect the joints.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/young-woman-sitting-wheelchair-556849906">Shutterstock</a></span>
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<p>In the reports that describe the onset of these diseases after COVID-19, the autoimmune symptoms start during or after the respiratory symptoms.</p>
<p>It’s unclear whether the patients were already predisposed to these diseases, or the infection unmasked an autoimmune process that had already begun. Or perhaps the infection triggered completely new autoimmunity. The triggers may even vary for different people. </p>
<p>COVID-19 may also trigger new autoimmune responses and, potentially, new autoimmune diseases. This has already occurred with a condition called multi-system inflammatory syndrome in children (MIS-C). </p>
<p>Originally described as a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204765/">Kawasaki-like disease</a> associated with COVID-19, MISC-C causes <a href="https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19">additional symptoms</a> in children and adolescents with the condition. This includes rashes, shock, excessive bleeding, heart problems, and severe gastrointestinal symptoms. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/mis-c-is-a-rare-but-dangerous-illness-striking-children-weeks-after-they-get-covid-19-heres-what-we-know-about-it-145673">MIS-C is a rare but dangerous illness striking children weeks after they get COVID-19 – here's what we know about it</a>
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<p>Autoantibodies measured in children diagnosed with MIS-C <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489877/">have a large variety of targets</a>. Many have no association to known autoimmune diseases, and instead are associated with the heart and surrounding tissue, as well as the gastrointestinal tract. </p>
<p>This indicates a potential mechanism for new autoimmune conditions that affect these organs.</p>
<h2>What’s causing the damage?</h2>
<p>Using computer-based prediction programs we <a href="https://www.frontiersin.org/articles/10.3389/fbinf.2021.709533/full">recently identified</a> regions of SARS-CoV-2 proteins that antibodies are likely to recognise and bind to. </p>
<p>We then compared them to all human proteins in the body, to identify potential similarities.</p>
<p>In doing so we were able to map the potential for SARS-CoV-2 infection to trigger autoantibody formation and existing or new autoimmune diseases, affecting different parts of the body. </p>
<p>Many of the human proteins we identified were associated with other diseases, including multiple sclerosis, SLE and rheumatoid arthritis.</p>
<p>Other human proteins we identified were associated with diseases of the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102662/">heart and vascular system</a>, <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext">airways</a>, as well as <a href="https://pubmed.ncbi.nlm.nih.gov/33315693/">epilepsy</a>, all of which have been reported in COVID-19 patients. </p>
<figure class="align-center ">
<img alt="Woman in a mask holds her chest above her heart." src="https://images.theconversation.com/files/422519/original/file-20210922-17-1muao9e.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/422519/original/file-20210922-17-1muao9e.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/422519/original/file-20210922-17-1muao9e.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/422519/original/file-20210922-17-1muao9e.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/422519/original/file-20210922-17-1muao9e.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/422519/original/file-20210922-17-1muao9e.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/422519/original/file-20210922-17-1muao9e.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Emerging evidence suggests autoimmune conditions after COVID may also affect the heart.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/female-patient-wearing-mask-have-heart-2018442626">Shutterstock</a></span>
</figcaption>
</figure>
<p>Currently much of our work is driven by computer-based predictive work; future laboratory research is needed to confirm the results.</p>
<p>Ultimately, understanding the mechanisms, the immune system targets, and those who are at risk, may offer targeted treatments for autoimmune illnesses after COVID-19.</p>
<h2>Could vaccination help?</h2>
<p>It’s unclear if getting vaccinated reduces your likelihood of getting these autoimmune conditions. </p>
<p>Autoantibodies have mainly been found after severe disease – and vaccination decreases disease severity. </p>
<p>So vaccination could reduce the risk of autoimmune symptoms after COVID-19, but at this stage it’s just speculative. </p>
<h2>What’s next for research in this area?</h2>
<p>Most reports of autoimmune disease after COVID-19 studied small patient numbers or are <a href="https://www.mdpi.com/1422-0067/22/16/8965">case reports</a>. Large studies reviewing the evidence are needed, especially covering multiple autoimmune diseases. </p>
<p>In one study, for example, five cases of Guillain-Barré Syndrome <a href="https://www.nejm.org/doi/full/10.1056/NEJMc2009191">were reported</a> out of 1,000-1,200 cases of COVID-19 admitted to the hospital. Although this indicates a small incidence in the autoimmune disease after COVID, it doesn’t tell us what is occurring worldwide. </p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/an-autoimmune-like-antibody-response-is-linked-with-severe-covid-19-146255">An autoimmune-like antibody response is linked with severe COVID-19</a>
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<p><a href="https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.12805">Reports</a> of the <a href="https://pubmed.ncbi.nlm.nih.gov/32581086/">percentage of people</a> positive for <a href="https://stm.sciencemag.org/content/12/570/eabd3876">autoantibodies to specific targets</a> range from 5% to a massive 50% in COVID-19 positive cases. </p>
<p>But although autoantibodies are <a href="https://www.science.org/doi/10.1126/science.abd4585">frequently found</a> in severe COVID cases, the precise role they play in illness after COVID remains unknown, with further studies required.</p><img src="https://counter.theconversation.com/content/166819/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>It’s unclear whether the patients were already predisposed to these diseases, or the infection unmasked a process that had already begun. Or perhaps the infection triggered a completely new illness.Magdalena Plebanski, Professor of Immunology, RMIT UniversityRhiane Moody, PhD candidate in immunology, RMIT UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1662412021-08-20T12:21:48Z2021-08-20T12:21:48ZImmunocompromised people make up nearly half of COVID-19 breakthrough hospitalizations – an extra vaccine dose may help<figure><img src="https://images.theconversation.com/files/417046/original/file-20210819-27-1m7wgcg.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Cancer and organ transplant patients, people with untreated HIV and people with other immunodeficiencies are at high risk of severe COVID-19 infection.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/woman-wearing-mask-to-avoid-infectious-diseases-royalty-free-image/1216044531">burakkarademir/E+ via Getty Images</a></span></figcaption></figure><figure class="align-center ">
<img alt="Green background with white text noting that 44% is the share of hospitalized breakthrough case patients in the US who are immunocompromised" src="https://images.theconversation.com/files/417070/original/file-20210819-21-14sn3wq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/417070/original/file-20210819-21-14sn3wq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=255&fit=crop&dpr=1 600w, https://images.theconversation.com/files/417070/original/file-20210819-21-14sn3wq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=255&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/417070/original/file-20210819-21-14sn3wq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=255&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/417070/original/file-20210819-21-14sn3wq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=321&fit=crop&dpr=1 754w, https://images.theconversation.com/files/417070/original/file-20210819-21-14sn3wq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=321&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/417070/original/file-20210819-21-14sn3wq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=321&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="attribution"><a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
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<p>The <a href="https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-vaccine-dose-certain-immunocompromised">U.S. Food and Drug Administration</a> and <a href="https://www.cdc.gov/vaccines/acip/meetings/slides-2021-08-13.html">Centers for Disease Control and Prevention</a> officially recommended on Aug. 12 and Aug. 13, 2021, respectively, that people who are moderately to severely immunocompromised <a href="https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html">receive a third dose of the COVID-19 vaccine</a>. </p>
<p>One reason for this recommendation is high hospitalization rates among immunocompromised people who are vaccinated. As of July 2021, <a href="https://www.cdc.gov/media/releases/2021/s0813-additional-mRNA-mrna-dose.html">nearly half of the vaccinated people hospitalized</a> with breakthrough COVID-19 infections were immunocompromised – despite making up only 2.7% of the U.S. adult population. In comparison, the <a href="https://www.kff.org/policy-watch/covid-19-vaccine-breakthrough-cases-data-from-the-states/">rate of breakthrough cases among vaccinated people who are not immunocompromised was less than 1%</a>.</p>
<p>I am a <a href="https://medicine.umich.edu/dept/immunology/jonathan-golob-md-phd">physician scientist specializing in infections in immunocompromised patients</a>. As someone who researches autoimmune disease and has worked on the COVID-19 vaccine trials, I agree that a third dose of COVID-19 vaccine can help protect those with weakened immune systems.</p>
<h2>What does it mean to be immunocompromised?</h2>
<p>People who are immunocompromised have <a href="https://www.hopkinsmedicine.org/health/conditions-and-diseases/disorders-of-the-immune-system">weakened immune systems</a>. This can result from certain diseases and their medical treatments, such as cancer, autoimmune diseases, untreated HIV, organ transplant medications and some forms of kidney disease. The common thread is that the body’s defenses against infection are impaired. </p>
<p>Two parts of the immune system seem to be particularly important in protecting people from getting sick with COVID-19: <a href="https://theconversation.com/coronavirus-b-cells-and-t-cells-explained-141888">T cells and B cells</a>. <a href="https://www.verywellhealth.com/b-cells-2252132">B cells make antibodies</a> that can bind to and inactivate viruses. <a href="https://www.verywellhealth.com/t-cells-2252171">T cells kill off virus-infected cells</a>, prevent infection from further spreading and organize the body’s overall defense response. Different types of immunocompromising conditions and treatments can either <a href="https://medlineplus.gov/ency/article/000818.htm">kill or decrease the effectiveness</a> of these key immune cells.</p>
<p>That can result in a <a href="https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/fully-vaccinated-people.html">hampered response</a> to vaccines. As a result, people who are immunocompromised often need to <a href="https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html">follow different vaccination guidelines</a> from people who are not immunocompromised to best protect themselves from infection. After a bone marrow or solid organ transplant, for instance, patients are <a href="https://doi.org/10.1016/j.clinthera.2017.07.005">routinely revaccinated against such infections</a> as hepatitis B. </p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1426287326045609984"}"></div></p>
<h2>COVID-19 is particularly dangerous for the immunocompromised</h2>
<p>Early on in the pandemic, researchers learned that immunocompromised people infected with COVID-19 tend to have <a href="https://dx.doi.org/10.1093%2Fcid%2Fciaa863">particularly severe and long-lasting infections</a>. This leads to <a href="https://theconversation.com/whats-the-difference-between-viral-shedding-and-reinfection-with-covid-19-150547">prolonged viral shedding</a>, meaning that the period during which these infected people release the virus as they breathe, talk and eat is much longer. Thus, they have a higher chance of transmitting the virus to others.</p>
<p>Long infections with poor immune responses are also <a href="https://www.vox.com/science-and-health/22586816/next-coronavirus-variant-delta-covid-19">ideal environments for the virus to evolve and adapt</a> in ways that allow it to better infect people.</p>
<p>While immunocompromised people <a href="https://doi.org/10.1172/jci.insight.149187">were not included in the initial COVID-19 vaccine trials</a> to avoid putting them at risk, <a href="https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/fully-vaccinated-people.html">subsequent studies</a> revealed that the authorized two-dose mRNA vaccine regimens do not stimulate as strong a defense against COVID-19 for immunocompromised people. In particular, <a href="https://doi.org/10.1001/jama.2021.7489">organ transplant recipients</a> seem to develop fewer COVID-19 antibodies after vaccination. That’s not surprising, given that the medicines used in transplantation <a href="https://pubmed.ncbi.nlm.nih.gov/25734416/">intentionally hamper antibody development</a> to prevent the immune system from rejecting the donated organs. But since then, <a href="https://doi.org/10.1056/NEJMc2111462">pilot trials in organ transplant recipients</a> have shown that an additional dose of vaccine can help boost immune response.</p>
<p>The best protection for everyone against COVID-19 is to have <a href="https://www.nytimes.com/2020/10/04/opinion/coronavirus-vaccines-masks.html">as many people vaccinated</a> as soon as possible. In the interim, a third vaccine dose can <a href="https://doi.org/10.1056/NEJMc2108861">safely and effectively</a> decrease the likelihood of severe COVID-19 in immunocompromised people. And <a href="https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/about-face-coverings.html">consistently wearing masks</a>, regardless of vaccination status and whether or not you’re immunocompromised, can also significantly reduce the spread of COVID-19.</p>
<p>[<em>Get our best science, health and technology stories.</em> <a href="https://theconversation.com/us/newsletters/science-editors-picks-71/?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=science-best">Sign up for The Conversation’s science newsletter</a>.]</p><img src="https://counter.theconversation.com/content/166241/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jonathan Golob does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>People with weakened immune systems are at a high risk of severe and prolonged COVID-19 infections. An extra vaccine dose can bolster protection.Jonathan Golob, Assistant Professor of Infectious Disease, University of MichiganLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1557122021-03-25T12:26:42Z2021-03-25T12:26:42ZWhy you should get a COVID-19 vaccine – even if you’ve already had the coronavirus<figure><img src="https://images.theconversation.com/files/391257/original/file-20210323-2308-kn86fb.jpg?ixlib=rb-1.1.0&rect=314%2C233%2C4778%2C3862&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Vaccination produces a much stronger and more consistent immune response than infection.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/covid-19-vaccine-circular-pattern-royalty-free-image/1287876073?adppopup=true"> Andriy Onufriyenko/Moment via Getty Images</a></span></figcaption></figure><p>A few weeks ago, a message popped up in the corner of my screen. “What do you think about people who have recently had COVID–19 getting the vaccine?” A friend of mine was eligible for a COVID–19 vaccine, but she had recently gotten over an infection with SARS–CoV–2. More people are becoming eligible for vaccines each week – including millions of people who have already <a href="https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html">recovered from a coronavirus infection</a>. Many are wondering whether they need the vaccine, especially people who have already been infected.</p>
<p><a href="https://scholar.google.com/citations?user=MEMHuGoAAAAJ&hl=en&oi=ao">I study immune responses to respiratory infections</a>, so I get a lot of these types of questions. A person can develop immunity – the ability to resist infection – from being infected with a virus or from getting a vaccine. However, immune protection isn’t always equal. The strength of the immune response, the length of time that the protection lasts and the variation of the immune response across people is very different between vaccine immunity and natural immunity for SARS–CoV–2. COVID–19 vaccines offer safer and more reliable immunity than natural infection. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/391258/original/file-20210323-13-vbg1w4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Electron microscope image of four SARS–CoV–2 particles" src="https://images.theconversation.com/files/391258/original/file-20210323-13-vbg1w4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/391258/original/file-20210323-13-vbg1w4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=469&fit=crop&dpr=1 600w, https://images.theconversation.com/files/391258/original/file-20210323-13-vbg1w4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=469&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/391258/original/file-20210323-13-vbg1w4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=469&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/391258/original/file-20210323-13-vbg1w4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=589&fit=crop&dpr=1 754w, https://images.theconversation.com/files/391258/original/file-20210323-13-vbg1w4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=589&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/391258/original/file-20210323-13-vbg1w4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=589&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The immune system will usually generate an immune response to a SARS-CoV-2 infection, but not always.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Novel_Coronavirus_SARS-CoV-2.jpg#/media/File:Novel_Coronavirus_SARS-CoV-2.jpg">National Institutes of Allergy and Infectious Diseases</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<h2>Immunity after infection is unpredictable</h2>
<p>Immunity comes from the immune system’s ability to remember an infection. Using this immune memory, the body will know to fight if it encounters the disease again. Antibodies are proteins that can bind to a virus and prevent infection. T cells are cells that direct the removal of infected cells and viruses already bound by antibodies. These two are some of the main players that contribute to immunity.</p>
<p>After a SARS-CoV-2 infection, a person’s antibody and T cell responses may be strong enough to provide <a href="https://doi.org/10.1126/science.abf4063">protection against reinfection</a>. Research shows that 91% of people who develop antibodies against the coronavirus are unlikely to be infected again <a href="https://doi.org/10.1056/NEJMoa2034545">for six months</a>, even after <a href="https://doi.org/10.1016/j.cell.2020.11.029">a mild infection</a>. People who had no symptoms during the infection are also likely to develop immunity, though they tend to make <a href="https://doi.org/10.1038/s41564-020-00813-8">fewer antibodies</a> than those who felt ill. So for some people, natural immunity may be strong and long-lasting. </p>
<p>The problem is that not everyone will develop immunity after a SARS-CoV-2 infection. As many as 9% of infected people do not have <a href="https://doi.org/10.1056/NEJMoa2026116">detectable antibodies</a>, and up to 7% of people <a href="https://doi.org/10.1126/science.abf4063">don’t have T cells that recognize the virus</a> 30 days after infection. </p>
<p>For people who do develop immunity, the <a href="https://doi.org/10.1038/s41586-020-2456-9">strength and duration</a> of the protection can vary a lot. Up to 5% of people may <a href="https://doi.org/10.1126/science.abf4063">lose their immune protection</a> within a few months. Without a strong immune defense, these people are susceptible to reinfection by the coronavirus. Some have had second bouts of COVID–19 as soon as <a href="https://doi.org/10.1002/jmv.26637">one month after their first infection</a>; and, though rare, some people have been <a href="https://doi.org/10.1016/j.jinf.2021.01.020">hospitalized or even died</a>. </p>
<p>A person who is reinfected may also be able to transmit the coronavirus even <a href="https://doi.org/10.1001/jamanetworkopen.2020.35057">without feeling sick</a>. This could put the person’s loved ones at risk. </p>
<p>And what about the variants? So far, there isn’t any hard data about the new coronavirus variants and natural immunity or reinfection, but it is certainly possible that immunity from one infection won’t be as strong against infection with a different variant.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/391251/original/file-20210323-21-w4qpa2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A healthy human T cell, a large blue rumpled sphere" src="https://images.theconversation.com/files/391251/original/file-20210323-21-w4qpa2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/391251/original/file-20210323-21-w4qpa2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/391251/original/file-20210323-21-w4qpa2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/391251/original/file-20210323-21-w4qpa2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/391251/original/file-20210323-21-w4qpa2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/391251/original/file-20210323-21-w4qpa2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/391251/original/file-20210323-21-w4qpa2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">COVID–19 vaccines produce a strong immune response in terms of both antibodies and T cells, like the T cell in this photo.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Healthy_Human_T_Cell.jpg#/media/File:Healthy_Human_T_Cell.jpg">National Institutes of Allergy and Infectious Diseases/National Institutes of Health</a></span>
</figcaption>
</figure>
<h2>Vaccination leads to reliable protection</h2>
<p>COVID–19 vaccines generate both <a href="https://doi.org/10.1056/NEJMoa2022483">antibody and T cell responses</a> – but this is much stronger and more consistent than immunity from natural infection. One study found that four months after receiving their first dose of the Moderna vaccine, <a href="https://doi.org/10.1056/NEJMc2032195">100% of people tested had antibodies against SARS-CoV-2</a>. This is the longest period that has been studied so far. In a study looking at the Pfizer and Moderna vaccines, antibody levels were also much higher in vaccinated people than in those who had <a href="https://doi.org/10.1056/NEJMoa2028436">recovered from infection</a>.</p>
<p>Even better, a <a href="https://doi.org/10.1056/NEJMoa2101765">study in Israel</a> showed that the Pfizer vaccine blocked 90% of infections after both doses – even with a variant present in the population. And a <a href="https://doi.org/10.1093/cid/ciab229">decrease in infections</a> means people are less likely to transmit the virus to the people around them.</p>
<p>The COVID–19 vaccines aren’t perfect, but they produce strong antibody and T cell responses that offer a safer and more reliable means of protection than natural immunity.</p>
<h2>Infection and vaccination together</h2>
<p>To my friend’s message, I instantly replied that she should absolutely get the vaccine. After getting vaccinated, my friend could be comfortable knowing that she has long-lasting, effective immunity and less of a chance of spreading the coronavirus to her friends and family. </p>
<p>But more good news has emerged since I sent that message. A new study showed that vaccination after infection produces <a href="https://doi.org/10.1056/NEJMc2101667">six times more antibodies</a> than a vaccine by itself. This isn’t to say that anyone should try to get infected before they get vaccinated – vaccine immunity alone is more than strong enough to provide protection and the dangers of a fight with COVID-19 far outweigh the benefits. But when my friend and the many others who were already infected get their vaccines, they’ll be well protected.</p>
<p>Natural immunity from infection is simply far too unreliable in the face of such a devastating virus. Current COVID-19 vaccines offer incredibly strong, consistent protection to the great majority of people. So, for anyone eligible, even those who have already had a SARS-CoV-2 infection, COVID-19 vaccines offer immense benefits.</p>
<p>[<em>Get facts about coronavirus and the latest research.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=coronavirus-facts">Sign up for The Conversation’s newsletter.</a>]</p><img src="https://counter.theconversation.com/content/155712/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jennifer T. Grier does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>If you’ve already had the coronavirus and recovered, you might be tempted to give the vaccine a pass. A scientist explains why the shot offers the best protection against future infection.Jennifer T. Grier, Clinical Assistant Professor of Immunology, University of South CarolinaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1560602021-03-02T13:06:47Z2021-03-02T13:06:47ZParkinson’s disease: blood changes may occur years before diagnosis<figure><img src="https://images.theconversation.com/files/387223/original/file-20210302-13-1ywqh08.jpg?ixlib=rb-1.1.0&rect=54%2C0%2C6048%2C4001&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Patients had fewer lymphocytes in their blood.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/nurse-taking-blood-sample-patient-doctors-153078383">Alexander Raths/ Shutterstock</a></span></figcaption></figure><p>Although Parkinson’s disease affects around <a href="https://jnnp.bmj.com/content/62/1/10.long">1%-2% of people over the age of 65</a>, there is currently no cure. And by the time it is diagnosed – typically by identifying problems with movement, such as slower movements and tremors – the changes in the brain it causes are irreversible. So being able to identify Parkinson’s earlier will be important in finding ways to prevent and cure the disease. </p>
<p>In our latest study, my colleagues and I have identified changes in blood that occur years before a Parkinson’s diagnosis. This could lead to earlier diagnosis of the disease.</p>
<p>The causes of Parkinson’s aren’t completely understood, but clear links have been established with genetic and environmental risk factors – such as exposure to certain <a href="https://www.ncbi.nlm.nih.gov/books/NBK536721/pdf/Bookshelf_NBK536721.pdf">pesticides and solvents</a>. However, we do know that Parkinson’s disease causes the death of certain nerve cells in the brain, <a href="https://www.ncbi.nlm.nih.gov/books/NBK536721/pdf/Bookshelf_NBK536721.pdf">due to a combination</a> of abnormal protein accumulation in cells, problems with mitochrondia (the “power stations” of each cell), inflammation and changes in the immune system.</p>
<p>In <a href="https://onlinelibrary.wiley.com/doi/full/10.1002/ana.26034">our study</a>, we set out to examine markers of inflammation that circulate in the blood of patients with Parkinson’s disease. We found people who later developed Parkinson’s disease had fewer lymphocytes – a type of white blood cell. We also found that this change may occur at least eight years before diagnosis and may contribute to the risk of being diagnosed with Parkinson’s.</p>
<p>Lymphocytes are one of five types of white blood cell that aid the body’s immune response. There are two distinct sub-types of lymphocytes: B cells and T cells. B cells produce antibodies that identify and neutralise harmful microbes, while T cells control how other immune cells respond to these microbes.</p>
<p>To conduct our study, we used data from the UK Biobank cohort. This project recruited approximately 500,000 participants between 2006 and 2010 to study how genetics and the environment impact a wide range of diseases. Blood was collected from participants at enrolment and they had ongoing follow-up appointments throughout. Any new health conditions they were diagnosed with appeared on their health care record, which could then be linked to their UK Biobank data.</p>
<p>From this cohort, we identified people who had been diagnosed with Parkinson’s during follow-up and compared them to people who had not been diagnosed with the disease. We looked at various markers of inflammation that circulate in the blood, such as the presence of certain proteins and immune cells. </p>
<h2>Lymphocytes</h2>
<p>In our first analysis of the data, we found several inflammatory markers were associated with a later diagnosis of Parkinson’s disease. But as we worked through further sub-analyses, we narrowed in on lower lymphocyte count as the main difference between those who did and didn’t develop the disease. </p>
<figure class="align-center ">
<img alt="A 3D depiction of a lymphocyte – a spherical particle covered in irregular bumps." src="https://images.theconversation.com/files/387224/original/file-20210302-15-ujtu99.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/387224/original/file-20210302-15-ujtu99.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/387224/original/file-20210302-15-ujtu99.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/387224/original/file-20210302-15-ujtu99.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/387224/original/file-20210302-15-ujtu99.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/387224/original/file-20210302-15-ujtu99.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/387224/original/file-20210302-15-ujtu99.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Lymphocytes play an important role in the immune system.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/lymphocyte-3d-illustration-closeup-view-tcell-1437298838">Kateryna Kon/ Shutterstock</a></span>
</figcaption>
</figure>
<p>We then went on to examine whether changes in lymphocyte count might cause Parkinson’s, or were merely a result of the disease. To do this we used a method called <a href="https://www.bmj.com/content/362/bmj.k601">Mendelian randomisation</a>. This allows us to look at a person’s genetics, and infer whether changes are cause or effect. We found genetic evidence to support that lower lymphocyte count increases Parkinson’s disease risk, as opposed to simply being a sign of undiagnosed Parkinson’s disease.</p>
<p><a href="https://pubmed.ncbi.nlm.nih.gov/22910543/">Previous studies</a> have shown that lymphocytes are on average lower in patients with Parkinson’s disease and that this could be driven by potential reductions in both B and T cells. However, once a diagnosis of Parkinson’s has been made and medication started, other factors – such as the effect of medication – may explain lower lymphocyte counts. Our research shows these changes occur before the disease develops. </p>
<p>Prior to our research, only <a href="https://onlinelibrary.wiley.com/doi/10.1002/ana.25614">one study</a> had shown that lymphocyte count may be lower prior to being diagnosed with Parkinson’s disease and may be a driver of the disease. Our study builds on this work and confirms that changes in lymphocyte count may be picked up on routine blood tests years before diagnosis, and may be linked to increased risk of Parkinson’s disease. However, we don’t yet know why lymphocyte count decreases.</p>
<p>There’s still a lot more work that needs to be done before the importance of this finding is fully known. For example, future research will need to investigate which lymphocyte types (B cells or T cells) are lower. Another important question is why lymphocytes are low. Is lymphocyte production slowed, their lifespan shortened, or are they moving out of the blood into a different part of the body (such as the brain)? Once further work has been done we might better know how to build on this knowledge to develop better treatments for Parkinson’s disease – and perhaps even methods to prevent it.</p><img src="https://counter.theconversation.com/content/156060/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Alastair Noyce receives funding from the Barts Charity, Parkinson's UK and the Aligning Science Across Parkinson's initiative. </span></em></p>Our study found lower levels of one type of immune cell – which may even be seen years before a person develops the disease.Alastair Noyce, Reader in Neurology and Neuroepidemiology, Queen Mary University of LondonLicensed as Creative Commons – attribution, no derivatives.