tag:theconversation.com,2011:/id/topics/t-cells-31681/articlesT-cells – The Conversation2022-01-30T19:08:50Ztag: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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<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>
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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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<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/1744482022-01-10T13:03:54Z2022-01-10T13:03:54ZT-cells: the superheroes in the battle against omicron<figure><img src="https://images.theconversation.com/files/439911/original/file-20220109-19-i87utd.jpg?ixlib=rb-1.1.0&rect=9%2C0%2C6583%2C4388&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source"> David Guzmán/Shutterstock</span></span></figcaption></figure><p>Omicron is spreading rapidly throughout the world, with experts claiming that 40% of the global population will be infected within the <a href="https://www.statnews.com/2021/12/27/forecasting-the-omicron-winter-experts-envision-various-scenarios-from-bad-to-worse/">next two months</a>. This sounds quite startling, but we still don’t really know whether omicron causes more severe disease than other variants of concern. The signs so far are good, though.</p>
<p>With the previous widespread variant, delta, there was a clear link from infection to hospitalisation and then, in some patients, ICU admission and death. This doesn’t seem to be as apparent <a href="https://www.voanews.com/a/omicron-is-milder-than-delta-but-nothing-to-sneeze-at/6384945.html">with omicron</a>. However, the director general of the World Health Organization, Tedros Ghebreyesus, <a href="https://www.bbc.co.uk/news/world-59901547">said on January 6</a>: “While omicron does appear to be less severe compared to delta, especially in those vaccinated, it does not mean it should be categorised as mild.” </p>
<p>The question is why might it be less severe than delta? Are there changes in omicron that make it less troublesome? There are two aspects to this. First, omicron appears to be <a href="http://www.biorxiv.org/content/10.1101/2021.12.17.473248v2">less able to</a> infect lung cells. It prefers the upper airways, just like other coronaviruses that stay in the nose and throat, such as OC43, one of the coronaviruses that causes the common cold. </p>
<p>This is consistent with the milder symptoms that omicron causes, which are mainly to do with the nose and throat – sniffles and a dry cough. It’s only when SARS-CoV-2 infects the lungs that severe disease happens, which involves symptoms such as breathing difficulties, and omicron seems to be less able to do that. </p>
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<img alt="Woman coughing into her elbow." src="https://images.theconversation.com/files/439914/original/file-20220109-12389-1hdj4v6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/439914/original/file-20220109-12389-1hdj4v6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/439914/original/file-20220109-12389-1hdj4v6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/439914/original/file-20220109-12389-1hdj4v6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/439914/original/file-20220109-12389-1hdj4v6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/439914/original/file-20220109-12389-1hdj4v6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/439914/original/file-20220109-12389-1hdj4v6.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">Omicron symptoms are mainly a runny nose and dry cough.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/sick-woman-buying-supermarket-coughing-into-1685691637">Drazen Zigic/Shutterstock</a></span>
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<p>There is, however, a second aspect as to why omicron doesn’t appear to be causing severe disease. And that is because a key part of the immune system, the T-cells, are well able to handle omicron. </p>
<p>An early concern was that omicron might somehow dodge the immune system, and this indeed is the case when it <a href="https://www.nature.com/articles/d41586-021-03796-6">comes to antibodies</a>. The spike protein on the surface of the SARS-CoV-2 virus is a key target for antibodies. They latch on to the spike and effectively bung it up, stopping it from interacting with the cells the virus is trying to infect and thereby providing protection. However, with omicron, the parts of the spike that antibodies recognise have changed and so antibodies are less able to neutralise the virus. </p>
<p>With antibodies, though, quantity can trump quality. So even if they can’t bind to omicron as effectively as they did with earlier variants, your immune system, especially when boosted, can make enough antibodies to still swamp the spike protein. This is one reason why booster shots are so important. </p>
<p>But the really good news is that our T-cells can still recognise and eliminate omicron. </p>
<p>The “T” in their name comes from the thymus, an organ in the chest where they mature. They work in a different way to antibodies. When a cell is infected with a virus, it takes a piece of the spike protein from the virus and displays it on its surface. This is a bit like the infected cell waving a red flag to say it’s infected. The T cells have sensors for that flag on their own surface. They latch onto the infected cell and kill it. </p>
<h2>Like a controlled explosion</h2>
<p>This might sound dramatic, but it’s very effective. Killing the cell means the virus is eliminated, too. It’s like a controlled explosion. This process can therefore control the virus and prevent severe disease. </p>
<p>Antibodies are like plan A: they stop the virus from getting into cells. T-cells are plan B: if the virus does infect a cell, they come along and kill that cell, stopping the virus in its tracks. They still work against it because the parts of the spike that are put up onto the surface of the infected cell – the red flags – haven’t changed much in omicron. </p>
<p>The T-cells in your body that have been made to fight a previous version of the spike (which is in the vaccines) are well able to do their job. <a href="https://www.medrxiv.org/content/10.1101/2021.12.26.21268380v1">Several</a> studies have <a href="http://www.medrxiv.org/content/10.1101/2021.12.27.21268416v1">shown that</a> T-cells <a href="https://www.biorxiv.org/content/biorxiv/early/2021/12/14/2021.12.12.472315.full.pdf">generated by</a> vaccines have <a href="https://www.medrxiv.org/content/10.1101/2022.01.02.22268634v1">kept their ability</a> to fight omicron in this way.</p>
<p>Your immune system has been sculpted by millions of years of evolution. It has all kinds of tricks up its sleeve and luckily, so far at least, the T-cell trick is holding up against omicron. And like other parts of the immune system, T-cells can remember the fight and do even better next time you’re infected. They may well hold up against future variants, too. The T-cells are one reason for optimism that the pandemic may soon be behind us.</p><img src="https://counter.theconversation.com/content/174448/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Luke O'Neill 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>Omicron may be able to dodge antibodies, but it is no match for our killer T-cells.Luke O'Neill, Professor, Biochemistry, Trinity College DublinLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1667572021-09-01T14:42:39Z2021-09-01T14:42:39ZCOVID-19 vaccines produce T-cell immunity that lasts and works against virus variants<figure><img src="https://images.theconversation.com/files/417998/original/file-20210826-18-khdks9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">By better communicating how vaccines boost the immune system's long term "memory", manufacturers could address vaccine hesitancy.</span> <span class="attribution"><span class="source">i_am_zews/Shutterstock</span></span></figcaption></figure><p>Over the past year or so, ordinary people have learnt a lot about viruses, vaccines and the immune system. We have all had to digest a lot of complex specialist knowledge about how safe and effective COVID-19 vaccines are. </p>
<p>But one important – and positive – aspect of the vaccines hasn’t been well communicated. The statistics about COVID-19 vaccine efficacy have only focused on one aspect of immunity: antibodies. But there’s another aspect too: T-cells, a key part of our immune systems. And the good news is that the current vaccines stimulate your T-cells to fight against both the SARS-CoV-2 virus and its emerging variants in the long term. </p>
<p>Let’s recap how the immune system works. </p>
<p>The <a href="https://www.hopkinsmedicine.org/health/conditions-and-diseases/the-immune-system">immune system</a> protects us from various infectious diseases, caused by bacteria, viruses, fungi or parasites. To do this, it first determines what type of infectious agent, or pathogen, is causing the infection. Then it mounts an appropriate response. Crucially, at the same time it produces memory cells that can recognise the same pathogen in future. That sets the immune system up to fight potential reinfections.</p>
<p>If the immune system determines that an antiviral response is needed, it launches a combination of two kinds of immunity. One is mediated by antibodies and the other is mediated by T-cells, or cell-mediated. The antibodies bind to viruses and neutralise them, preventing them from infecting cells. Meanwhile, T-cells kill cells that have already been infected by the virus. </p>
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<p>While both kinds of immunity are important in fighting viruses, cell-mediated immunity is far more effective at eradicating viruses and <a href="https://www.nature.com/articles/d41586-021-00367-7">more durable</a>. This is important in the continuing fight against COVID-19. </p>
<h2>A powerful weapon</h2>
<p>Research has already established that cell-mediated immunity is a powerful weapon against human coronaviruses, <a href="https://theconversation.com/a-brief-history-of-the-coronavirus-family-including-one-pandemic-we-might-have-missed-134556">the family</a> including SARS-CoV-2. A <a href="https://doi-org.ezproxy.uwc.ac.za/10.1016/j.vaccine.2016.02.063">2016 study</a> showed that T-cell immunity against the SARS-coronavirus persisted for up to 11 years. It provided complete, effective, and lasting protection against SARS. </p>
<p>Our own recent <a href="https://www.mdpi.com/1999-4915/13/8/1457">research</a> argues that a greater focus should be placed on the development of vaccines that are capable of producing antibodies, but would predominantly elicit a cell-mediated immune response against SARS-CoV-2 and its variants. </p>
<p>And, though most people don’t know it, the existing COVID-19 vaccines offer a resilient cell-mediated immune response. </p>
<h2>It’s not just about antibodies</h2>
<p>The immune system is generally quite effective at eradicating most pathogens. But not everyone’s immune system is equally effective at dealing with the same pathogen; sometimes it needs a little help. Vaccines train the immune system to recognise and respond to a particular pathogen, without first having to be infected by it. </p>
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Read more:
<a href="https://theconversation.com/a-brief-history-of-the-coronavirus-family-including-one-pandemic-we-might-have-missed-134556">A brief history of the coronavirus family -- including one pandemic we might have missed</a>
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<p>Traditionally, most <a href="https://www.yalemedicine.org/news/covid-19-vaccine-comparison">vaccines</a> contain only a small part of the pathogen. This prepares the immune system by mimicking the natural infection. </p>
<p>The current COVID-19 vaccines used in South Africa contain small portions of <a href="https://www.biospace.com/article/racing-to-beat-the-wild-card-of-covid-19-variants/">the wild-type SARS-CoV-2 spike protein</a> - this coronavirus was responsible for the initial COVID-19 outbreak and spread during the early stages of the pandemic. </p>
<p>But, as the pandemic progressed, the virus mutated. Mutations in the spike protein confer <a href="https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html">certain selective advantages</a> to the virus. Some of these mutations have made the virus easier to transmit, or helped it to escape the immune system. The emergence of variants has raised concerns over the effectiveness of the existing COVID-19 vaccines.</p>
<p>During the course of the pandemic, <a href="https://www.nature.com/articles/d41586-021-02261-8#ref-CR1">news reports</a> and <a href="https://investors.modernatx.com/news-releases/news-release-details/moderna-provides-clinical-update-neutralizing-activity-its-covid">press releases</a> have informed on the efficacy and effectiveness of various COVID-19 vaccines against emerging variants. But reports have focused almost exclusively on the ability of the vaccine-induced antibodies, and how effective they are at neutralising the variants.</p>
<h2>A resilient cell-mediated immune response</h2>
<p>This focus on antibodies means that any <a href="https://www.aljazeera.com/news/2021/6/16/how-covid-vaccines-work-against-delta-variant">news</a> of decreasing antibody efficacy against emerging variants is seized upon as evidence that vaccines may not work well in the long term. This can foster a lack of trust from the public in the science behind the design of COVID-19 vaccines. And this lack of trust could contribute to vaccine hesitancy. After all, some might argue, why take a vaccine that appears less effective against each emerging variant?</p>
<p>In fact, <a href="https://doi.org/10.1126/sciimmunol.abj1750">several</a> <a href="https://doi.org/10.1016/j.xcrm.2021.100355">recent</a> <a href="https://doi.org/10.1093/ofid/ofab143">papers</a> have demonstrated that while SARS-CoV-2 variants could escape neutralising antibodies, the cell-mediated immune response induced by most currently used COVID-19 vaccines is very resilient and remained effective. </p>
<p>While antibodies induced by the vaccine were able to bind to the variants, they were less capable of neutralising them. The T-cells, on the other hand, were largely as responsive to the variants as they were to the wild-type virus. They were still able to recognise and respond effectively to the variants, conferring resilient protection against the disease.</p>
<p>To date, only Johnson & Johnson has released a <a href="https://www.jnj.com/johnson-johnson-single-shot-covid-19-vaccine-demonstrated-a-durable-immune-response-and-elicited-dual-mechanisms-of-protection-against-delta-and-other-sars-cov-2-variants-of-concern-in-data-published-in-new-england-journal-of-medicine">media statement</a> that includes statistics about both kinds of immune responses induced by its vaccine.</p>
<p>Research shows that antibody levels produced from different vaccines <a href="https://doi.org/10.1136/bmj.n1605">decrease over time</a> and, although immunity varies from person to person, immunity from the <a href="https://theconversation.com/how-long-does-immunity-last-after-covid-vaccination-do-we-need-booster-shots-2-immunology-experts-explain-164073">Pfizer</a> and the <a href="https://www.news-medical.net/news/20210709/Durable-antibody-response-at-least-8-months-following-vaccination-with-JJ-COVID-vaccine.aspx">Johnson & Johnson</a> vaccines typically last for at least six months. </p>
<h2>Build public trust</h2>
<p>Vaccine hesitancy is a major hurdle in fighting the pandemic. A recent <a href="https://www.bloomberg.com/news/articles/2021-08-17/white-adults-most-vaccine-hesitant-south-africans-survey-shows">survey</a> showed that only 72% of South Africans were willing to be vaccinated against COVID-19.</p>
<p>The idea that “the vaccine will be ineffective” was one of the most common reasons people gave for vaccine hesitancy. Hesitancy isn’t surprising if people hear only about how part of the immune response becomes less effective against emerging variants. </p>
<p>Public trust in the vaccine relies on people understanding the complete efficacy of the vaccine-induced immune response and communicating the statistics about both kinds of responses to the variants. The existing COVID-19 vaccines offer a resilient cell-mediated immune response. Knowing this can help people make an informed decision about vaccination.</p><img src="https://counter.theconversation.com/content/166757/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Dewald Schoeman receives funding from the National Research Foundation (NRF) (South Africa) and the Poliomyelitis Research Foundation (PRF).
Any opinion, findings and conclusions or recommendations expressed in this material are those of the authors and, therefore, the NRF and PRF does not accept any liability in regard thereto.</span></em></p><p class="fine-print"><em><span>Burtram C. Fielding receives funding from the National Research Foundation (NRF) (South Africa) and the University of the Western Cape Senate Research Fund. Any opinion, findings and conclusions or recommendations expressed in this material are those of the authors and, therefore, the NRF does not accept any liability in regard thereto.</span></em></p>Cell-mediated immunity is particularly effective at eradicating viruses, and more durable. This is important in the fight against COVID-19.Dewald Schoeman, PhD Candidate, Molecular Biology and Virology, University of the Western CapeBurtram C. Fielding, Professor and Director: Research Development, University of the Western CapeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1526722021-01-11T13:15:58Z2021-01-11T13:15:58ZDelaying second COVID-19 vaccine doses will make supplies last longer but comes with risks<figure><img src="https://images.theconversation.com/files/377814/original/file-20210108-17-i9rw6u.jpg?ixlib=rb-1.1.0&rect=7%2C0%2C5080%2C3323&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Health care workers wait in line for vaccinations at a site in Los Angeles. </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/jan-6-2021-health-care-workers-wait-in-line-for-news-photo/1230475202?adppopup=true">Xinhua News Agency via Getty Images</a></span></figcaption></figure><p>Drugmakers are facing <a href="https://pink.pharmaintelligence.informa.com/PS143400/Pfizers-Expected-2020-COVID19-Vaccine-Production-Fell-By-50-After-Scaleup-Delays">challenges</a> in manufacturing vaccines and building supply chains to meet the demand for COVID-19 vaccines. <a href="https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-supply-us-100-million-additional-doses">Pfizer has even lowered</a> production targets. Scarcity of vaccines has prompted calls for a Band-Aid-like strategy to <a href="https://www.nytimes.com/2020/12/18/opinion/coronavirus-vaccine-doses.html">stretch the precarious supply</a>. </p>
<p>To protect as many people as possible from COVID-19, the U.K.’s medical officers <a href="https://www.health-ni.gov.uk/news/statement-uk-chief-medical-officers-prioritisation-first-doses-covid-19-vaccines">have chosen</a> to prioritize distribution of a first vaccine dose to as many people as possible – by delaying the second doses of the Pfizer/BioNTech COVID vaccine up to 12 weeks from the recommended 3-4. <a href="https://www.nytimes.com/2021/01/08/world/biden-vaccine.html">President-elect Biden wants to release all vaccine doses</a> to speed up the vaccination program – but the risk is that vaccine makers won’t be able to replenish the supply to make sure that the second dose is delivered on time.</p>
<p>These decisions have <a href="https://www.cnn.com/2021/01/01/health/uk-vaccine-doses-chief-medical-officers-intl/index.html">opened up a rift</a> between <a href="https://www.bmj.com/content/372/bmj.n18">experts</a> because <a href="https://www.nytimes.com/2020/12/18/opinion/coronavirus-vaccine-doses.html">some support giving a single vaccine dose</a> to as many people as possible, while <a href="https://www.cnn.com/videos/health/2021/01/01/fauci-coronavirus-vaccine-second-dose-sot-vpx-nr.cnn">others want to vaccinate according to the protocol</a> used during the clinical trials. In the U.S. only around <a href="https://www.washingtonpost.com/business/2020/12/05/operation-warp-speed-coronavirus-vaccine-shortfall/">a 10th</a> of the 300 million doses promised <a href="https://www.hhs.gov/about/news/2020/05/21/trump-administration-accelerates-astrazeneca-covid-19-vaccine-to-be-available-beginning-in-october.html#:%7E:text=Responding%20to%20President%20Trump's%20call,called%20AZD1222%2C%20with%20the%20first">by January</a> under Operation Warp Speed are actually available. Nevertheless, the Food and Drug Administration has <a href="https://www.fda.gov/news-events/press-announcements/fda-statement-following-authorized-dosing-schedules-covid-19-vaccines">reminded the medical community</a> of the importance of receiving both doses of COVID-19 vaccines in line with the way they were tested in clinical trials. The FDA says there is no data that demonstrates vaccine efficacy if the second dose is delayed.</p>
<p>I’m interested in this debate because I coordinate an international <a href="https://clinicaltrials.gov/ct2/show/NCT04354701">registry of patients with cancer</a> who have been diagnosed with COVID-19. Patients with current or prior cancers are <a href="https://doi.org/10.1158/2159-8290.cd-20-1817">twice as likely</a> to die from COVID-19 than those without cancer. The Centers for Disease Control and Prevention has not included current or surviving cancer patients for inclusion in the <a href="https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations.html">first group of COVID-19 vaccine recipents</a>. Altering vaccine doses seems an easy fix to stretch limited supplies and provide vaccines for more vulnerable populations. But is it the right thing to do?</p>
<h2>What is a vaccine?</h2>
<p>A <a href="https://www.cdc.gov/vaccines/hcp/conversations/downloads/vacsafe-understand-color-office.pdf">vaccine</a> gives the human body a glimpse of the disease-causing virus. This preview trains the immune system for exposure to the real virus. Early vaccines, like the <a href="https://www.cdc.gov/vaccines/vpd/polio/public/index.html">oral poliovirus vaccines</a>, contained <a href="https://vaccine-safety-training.org/live-attenuated-vaccines.html">live but weakened</a> viruses. These provide robust immunity but carry a small risk of illness because even a weakened virus can become active and cause disease in rare cases. </p>
<p>Modern vaccines are safer because they increasingly rely on only parts of the virus, called antigens. In the case of COVID-19, the antigen is the <a href="https://pdb101.rcsb.org/motm/246">spike protein</a> that enables the SARS-CoV-2 virus to enter cells. <a href="https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/how-they-work.html">Various COVID-19 vaccines</a> under development are based on a synthetic spike protein or its genetic code. </p>
<p>The FDA has so far given <a href="https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs">emergency use authorization</a> to two <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">mRNA-based COVID-19 vaccines;</a> from <a href="https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/moderna-covid-19-vaccine">Moderna</a> and <a href="https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/pfizer-biontech-covid-19-vaccine">Pfizer-BioNTech</a>. In the U.K., a DNA vaccine created by <a href="https://theconversation.com/oxford-astrazeneca-vaccine-is-cheaper-than-pfizers-and-modernas-and-doesnt-require-supercold-temperature-150697">AstraZeneca</a> is <a href="https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-astrazeneca/information-for-healthcare-professionals-on-covid-19-vaccine-astrazeneca">also authorized</a>. These three vaccines supply the genetic material that encodes the viral spike protein. After injection in the upper arm, the muscle cells read the genetic instructions and use them to make the viral spike protein directly in the body. </p>
<p>The downside to these safer, newer vaccines is that a single dose triggers a less effective immune response than a weakened virus vaccine and often requires <a href="https://www.cdc.gov/vaccines/hcp/conversations/downloads/vacsafe-understand-color-office.pdf">repeated vaccinations to get more complete immunity</a>. Many current human vaccines, such as against <a href="https://www.cdc.gov/vaccines/hcp/vis/vis-statements/td.html">tetanus</a>, <a href="https://www.cdc.gov/hepatitis/hbv/vaccadults.htm">hepatitis B</a>, <a href="https://www.cdc.gov/measles/vaccination.html">measles</a>, <a href="https://www.cdc.gov/vaccines/vpd/polio/index.html">polio</a> and <a href="https://www.cdc.gov/vaccines/vpd/hpv/public/index.html">HPV</a>, require two doses: the first to prime the immune system and the second to boost the immune response.</p>
<p>Efficacy of all three authorized COVID-19 vaccines was studied in the two-dose regimens. For the Pfizer-BioNTech COVID-19 vaccine, the studied and approved interval is <a href="https://www.fda.gov/media/144245/download">21 days</a> between the first and second dose. For the Moderna COVID-19 vaccine, the interval is <a href="https://www.fda.gov/media/144434/download">28 days</a>. For the AstraZeneca vaccine, the trial is for two doses <a href="https://doi.org/10.1016/S0140-6736(20)32661-1">28 days</a> apart. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/377816/original/file-20210108-19-yhxtte.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/377816/original/file-20210108-19-yhxtte.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/377816/original/file-20210108-19-yhxtte.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=395&fit=crop&dpr=1 600w, https://images.theconversation.com/files/377816/original/file-20210108-19-yhxtte.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=395&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/377816/original/file-20210108-19-yhxtte.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=395&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/377816/original/file-20210108-19-yhxtte.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=496&fit=crop&dpr=1 754w, https://images.theconversation.com/files/377816/original/file-20210108-19-yhxtte.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=496&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/377816/original/file-20210108-19-yhxtte.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=496&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">In clinical trials, the two doses of the Pfizer/BioNTech vaccine were taken three weeks apart. This led to 95% efficacy against the COVID-19 virus.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/concepts-of-mrna-vaccine-for-coronavirus-royalty-free-illustration/1285089812?adppopup=true">iStock/Getty Images Plus</a></span>
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</figure>
<h2>What happens after vaccination?</h2>
<p>An effective vaccine should produce immunological memory similar to or better than what is acquired by exposure to the natural disease – but without causing the disease. To do so, <a href="https://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf">after the first exposure</a>, from a vaccine or a natural infection, a <a href="https://theconversation.com/declining-antibodies-and-immunity-to-covid-19-why-the-worry-143323">class of white blood cells</a> called the naïve B cells produce antibodies as the first line of defense against infection. </p>
<p>These early antibodies reach peak levels usually four weeks after the first immunization but decline significantly thereafter. Fewer antibodies means it’s more likely that invading virus particles can escape destruction. So the protective immunity from the first or prime vaccination dose is generally not very effective or durable. </p>
<p>After the first exposure, some B cells and another type of <a href="https://theconversation.com/declining-antibodies-and-immunity-to-covid-19-why-the-worry-143323">white blood cell</a> called T cells become “memory” cells that remember the antigen – in this case the spike protein. On second and subsequent booster exposures, these memory cells quickly reactivate to produce more potent antibodies that are able to recognize and bind to the target virus tightly. The antibodies produced by memory cells after the booster dose rise rapidly at tens to hundreds-fold higher protective levels and persist longer. </p>
<h2>Why is the timing of the second dose important?</h2>
<p>Both mRNA vaccines, even after the first dose, offer protection well above the <a href="https://www.fda.gov/media/142749/download">50% minimum threshold</a> set for emergency use authorization criteria for COVID-19 vaccines based on the clinical trials. But the efficacy of these vaccines was tested in a two-dose regimen. </p>
<figure class="align-right ">
<img alt="Gloved hand holding two syringes." src="https://images.theconversation.com/files/377819/original/file-20210108-15-8xg7or.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/377819/original/file-20210108-15-8xg7or.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/377819/original/file-20210108-15-8xg7or.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/377819/original/file-20210108-15-8xg7or.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/377819/original/file-20210108-15-8xg7or.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/377819/original/file-20210108-15-8xg7or.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/377819/original/file-20210108-15-8xg7or.jpg?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">
<figcaption>
<span class="caption">In clinical trials the volunteers received two doses of the vaccine 3-4 weeks apart. Will immunity be complete if the second dose is delayed?</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/doctors-hand-with-a-syringe-of-covid-19-coronavirus-royalty-free-image/1216432557?adppopup=true">Jose A. Bernat Bacete/Moment/Getty Images</a></span>
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</figure>
<p>During Pfizer-BioNTech’s vaccine trial, one vaccinated participant and nine who received a placebo developed a severe case of COVID-19 after the first dose. This suggests that <a href="https://www.fda.gov/media/144245/download">participants developed partial protection</a> as early as 12 days after the first dose. However, all vaccine recipients eventually received their second dose just nine days later, so the data does not exist for how long the protection from the single dose would have lasted. </p>
<p>Similarly, for <a href="https://www.fda.gov/media/144434/download">Moderna’s vaccine trial</a>, there appeared to be some protection against COVID-19 following one dose; but the limited data does not provide sufficient information about longer-term protection beyond 28 days after the single dose. </p>
<p>In the absence of supporting evidence, nothing definitive can be concluded about the depth or duration of protection after just a single dose of currently authorized vaccines, or choosing between the studied and longer gaps between doses.</p>
<p>While the efficacy of the mRNA COVID-19 vaccines against symptomatic COVID-19 has exceeded expectations, researchers still do not know how long that protection lasts. In the <a href="https://doi.org/10.1056/NEJMc2032195">follow-up of the phase 1 trial of Moderna’s vaccine</a> during the 119 days after the first dose, the antibodies declined in all participants and the neutralizing antibodies – which not only bind the virus but also block infection – fell 50% to 75% in the people older than 56. </p>
<h2>What can happen if vaccination is incomplete?</h2>
<p>Viruses naturally mutate because of copying errors in their genetic code as they multiply in the host’s body, or due to swapping of genetic codes between different viruses co-infecting the same host. </p>
<p>But they also evolve to evade the immunity of the host, specially if competing against weak but sustained immune response. SARS-CoV-2 can already lie low in infected individuals, and approximately <a href="https://doi.org/10.7326/M20-3012">40% to 45% of those infected display no symptoms at all</a>. In an immunocompromised patient – using therapies to fight autoimmune disease or cancer – the virus has been found to be present for <a href="https://doi.org/10.1056/nejmc2031364">up to 154 days</a>. In such situations there are increased odds that a virus variant can emerge that can escape the immune response and spread fast. Indeed, it is suspected that the new highly infectious <a href="https://doi.org/:10.1001/jama.2020.27124">U.K. variant</a>, which is <a href="https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant-cases.html">also spreading in the U.S.</a>, could have <a href="https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563">originated</a> in a chronically infected individual. </p>
<p>Although evolution of vaccine resistance is considered <a href="https://doi.org/10.1016/j.mib.2012.08.002">very rare</a> because of effective and rigorously developed vaccines, <a href="https://doi.org/10.1098/rspb.2003.2664">mathematical modeling</a> suggests that a resistant virus can readily arise if immune response is too weak to destroy all the viruses in the host. </p>
<p>Rushed and ineffective vaccines can produce antibodies that fail to recognize and bind viruses poorly, which <a href="https://www.nature.com/articles/nm0109-21">can do more harm than good</a>. </p>
<p>Changing the dosing to overcome supply shortages is a contentious and ongoing debate. However, making wrong decisions without adequate scientific evidence could be counterproductive.</p><img src="https://counter.theconversation.com/content/152672/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sanjay Mishra receives funding from the National Cancer Institute (NCI) and has previously received support from the National Institutes of Health (NIH). </span></em></p>With vaccine shortages looming, experts are debating whether it is important to receive two doses or whether it’s better to give one dose to more people and give a second when the supply is better.Sanjay Mishra, Project Coordinator & Staff Scientist, Vanderbilt University Medical Center, Vanderbilt UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1473912020-10-02T14:02:45Z2020-10-02T14:02:45ZOlder people like President Trump are at more risk from COVID-19 because of how the immune system ages<figure><img src="https://images.theconversation.com/files/361389/original/file-20201002-22-1i0nzfk.jpg?ixlib=rb-1.1.0&rect=391%2C270%2C4173%2C2891&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Masking up is one way to cut down on risk of COVID-19 infection.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/president-donald-trump-wears-a-face-mask-while-he-pays-his-news-photo/1228685397">Alex Brandon/Getty Images News via Getty Images</a></span></figcaption></figure><p>President Donald Trump’s announcement that <a href="https://twitter.com/realDonaldTrump/status/1311892190680014849">he’s tested positive for COVID-19</a> is especially concerning because of his age. At 74 years old, Trump is solidly within an age group that’s been hit hard during the coronavirus pandemic.</p>
<p>People of all ages can get sick from SARS-CoV-2, the virus that causes COVID-19. But the severity of the illness tends to worsen the older the patient is. Through the end of September, <a href="https://www.cdc.gov/nchs/nvss/vsrr/covid_weekly/index.htm#AgeAndSex">79% of COVID-19 deaths</a> in the United States had been in patients over 65. These statistics are <a href="https://doi.org/10.3855/jidc.12600">broadly similar</a> <a href="https://ourworldindata.org/coronavirus">in countries around the world</a>.</p>
<p>What is it that puts older people at increased risk from viruses like SARS-CoV-2? Scientists think it’s primarily due to changes in the human immune system as we age.</p>
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<h2>Your body’s tools to fight off virus infections</h2>
<p>As you go about your life, your body is constantly bombarded by pathogens – the bacteria, fungi and viruses that can make you sick. A human body is a great place for these organisms to grow and thrive, providing a nice warm environment with plenty of nutrients.</p>
<p>That’s where your immune system comes in. It’s your body’s defense system against these kinds of invaders. Before you’re even born, your body starts producing specialized B-cells and T-cells – types of white blood cells that can recognize pathogens and help block their growth.</p>
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<a href="https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.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">An artist’s rendering of the white blood cells that help recognize and fight off invaders.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/lymphocytes-illustration-royalty-free-illustration/685027719">Kateryna Kon/Science Photo Library via Getty Images</a></span>
</figcaption>
</figure>
<p>During an infection, your B-cells can proliferate and produce antibodies that grab onto pathogens and block their ability to spread within your body. T-cells work by recognizing infected cells and killing them. Together they make up what scientists call your “adaptive” immune system.</p>
<p>Maybe your physician has checked your white blood cell levels. That’s a measurement of whether you have more B-cells and T-cells in your blood than usual, presumably because they’re fighting infection.</p>
<p>When you’re very young, you don’t have a lot of these B- or T-cells. It can be a challenge for your body to control infection because it’s simply not used to the job. As you mature, your adaptive immune system learns to recognize pathogens and handle these constant invasions, allowing you to fight off infection quickly and effectively.</p>
<p>While white blood cells are powerful people-protectors, they’re not enough on their own. Luckily, your immune system has another layer, what’s called your <a href="https://doi.org/10.1159/000453397">“innate” immune response</a>. Every cell has its own little immune system that allows it to directly respond to pathogens quicker than it takes to mobilize the adaptive response.</p>
<p>The innate immune response is tuned to pounce on types of molecules that are commonly found on bacteria and viruses but not in human cells. When a cell detects these invader molecules, it triggers production of an antiviral interferon protein. Interferon triggers the infected cell to die, limiting infection. </p>
<p>Another type of innate immune cell, called a monocyte, acts as a sort of cellular bouncer, getting rid of any infected cells it finds and signaling the adaptive immune response to shift into gear.</p>
<p>The innate and adaptive immune systems can act together as a fine-tuned machine to detect and clear out pathogens.</p>
<p><iframe id="tjyf5" class="tc-infographic-datawrapper" src="https://datawrapper.dwcdn.net/tjyf5/1/" height="400px" width="100%" style="border: none" frameborder="0"></iframe></p>
<h2>Older immune systems are weaker</h2>
<p>When a pathogen invades, the difference between illness and health is a race between how fast the pathogen can spread within you and how fast your immune response can react without causing too much collateral damage.</p>
<p>As people age, their innate and adaptive immune responses change, shifting this balance.</p>
<p><a href="https://doi.org/10.1016/j.humimm.2009.07.005">Monocytes from older individuals</a> <a href="https://doi.org/10.1093/infdis/jir048">produce less interferon</a> in response to viral infections. They have a harder time killing infected cells and signaling the adaptive immune response to get going.</p>
<p>Low-grade chronic inflammation in individuals that commonly occurs during aging can also <a href="https://doi.org/10.1111/j.1749-6632.2000.tb06651.x">dull the ability of the innate and adaptive immune responses</a> to react to pathogens. It’s similar to becoming used to an annoying sound over time.</p>
<p>As you age, the reduced “attention span” of your innate and adaptive immune responses make it harder for the body to respond to viral infection, giving the virus the upper hand. Viruses can take advantage of your immune system’s slow start and quickly overwhelm you, resulting in serious disease and death.</p>
<h2>Social distancing is vital</h2>
<p>Everyone, no matter their age, needs to protect themselves from infection, not just to keep themselves healthy but also to help protect the most vulnerable. Given the difficulty older individuals have in controlling viral infection, the best option is for these individuals to avoid becoming infected by viruses in the first place.</p>
<p>This is where washing hands, avoiding touching your face, self-isolation and <a href="https://theconversation.com/social-distancing-what-it-is-and-why-its-the-best-tool-we-have-to-fight-the-coronavirus-133581">social distancing</a> all become important, <a href="https://www.cdc.gov/coronavirus/2019-ncov/prepare/prevention.html">especially for COVID-19</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=378&fit=crop&dpr=1 600w, https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=378&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=378&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=475&fit=crop&dpr=1 754w, https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=475&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=475&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 mist ejected by a sneeze can launch viruses airborne, so other people can inhale them.</span>
<span class="attribution"><a class="source" href="https://phil.cdc.gov/Details.aspx?pid=11161">James Gathany</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>COVID-19 is caused by a respiratory virus, which can spread via tiny virus-containing droplets. Larger droplets fall to the ground quickly; very small droplets dry up. Mid-range droplets are of most concern because they can <a href="https://www.medscape.com/viewarticle/741245_3">float in the air for a few feet</a> before drying. These droplets can be inhaled into the lungs.</p>
<p>Keeping at least 6 feet away from other people helps significantly reduce your chance of being <a href="https://doi.org/10.1186/s12879-019-3707-y">infected by these aerosol droplets</a>. But there’s still the <a href="https://theconversation.com/viruses-live-on-doorknobs-and-phones-and-can-get-you-sick-smart-cleaning-and-good-habits-can-help-protect-you-133054">possibility for virus to contaminate surfaces</a> that infected people have touched or coughed on. Therefore, the best way to protect vulnerable older and immunocompromised people is to stay away from them until there is no longer a risk. By stopping the spread of SARS-CoV-2 throughout the whole population, we help protect those who have a harder time fighting infection.</p>
<p><em>This article draws on material from <a href="https://theconversation.com/older-people-are-at-more-risk-from-covid-19-because-of-how-the-immune-system-ages-133899">an article originally published</a> on March 19, 2020.</em></p><img src="https://counter.theconversation.com/content/147391/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Brian Geiss receives funding from the National Institutes of Health.</span></em></p>Older coronavirus patients face grimmer outlooks. A virologist explains the aging-related changes in how immune systems work that are to blame.Brian Geiss, Associate Professor of Microbiology, Immunology & Pathology, Colorado State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1441762020-08-21T18:09:51Z2020-08-21T18:09:51ZIBD: How a class of killer T cells goes rogue in inflammatory bowel disease<figure><img src="https://images.theconversation.com/files/353234/original/file-20200817-18-1fz4mrb.jpg?ixlib=rb-1.1.0&rect=18%2C28%2C6211%2C4119&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">There are currently no permanent treatments for most patients with inflammatory bowel disease.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/woman-having-painful-stomach-ache-royalty-free-image/1188226212?adppopup=true">PokPak05/iStock/Getty Images Plus</a></span></figcaption></figure><p>Between <a href="https://doi.org/10.1016/S2468-1253(19)30333-4">6 and 8 million people worldwide</a> suffer from inflammatory bowel disease, a group of chronic intestinal disorders that can cause belly pain, urgent and frequent bowel movements, bloody stools and weight loss. New research suggests that a malfunctioning member of the patient’s own immune system called a killer T cell may be one of the culprits. This discovery may provide a new target for IBD medicines.</p>
<p>The two main types of IBD are <a href="http://doi.org/10.1016/S0140-6736(16)32126-2">ulcerative colitis,</a> which mainly affects the colon, and <a href="https://doi.org/10.1016/S0140-6736(16)31711-1">Crohn’s disease,</a> which can affect the entire digestive tract. Researchers currently believe that IBD is triggered when an <a href="https://www.nejm.org/doi/full/10.1056/nejmra0804647">overactive immune system attacks harmless bacteria in the intestines</a>. Although there are many treatments for IBD, <a href="https://doi.org/10.1097/mog.0000000000000536">for as many as 75% of individuals with IBD</a> there are no effective long-term treatments. This leaves many patients without good options. </p>
<p>I am a <a href="https://changlab.ucsd.edu">physician-scientist</a> conducting research in immunology and IBD and in a <a href="http://immunology.sciencemag.org/lookup/doi/10.1126/sciimmunol.abb4432">new study</a>, <a href="https://medschool.ucsd.edu/som/medicine/research/labs/chang-lab/people/Pages/default.aspx">my team</a> and our colleagues specializing in <a href="https://goldrathlab.com/">immunology</a>, <a href="https://health.ucsd.edu/specialties/gastro/areas-expertise/ibd-center/Pages/default.aspx">gastroenterology</a> and <a href="https://yeolab.github.io/">genomics</a> examined immune cells from the blood and intestines of healthy individuals and compared them with those collected from patients with ulcerative colitis to gain a better understanding of how the immune system malfunctions in IBD. There are many reasons why current treatments aren’t permanent, but one reason is that scientists don’t fully understand how the immune system is involved in IBD. It is our hope that closing the current knowledge gap about how the immune system is involved in this disorder will eventually lead to new durable treatments for IBD that target the right immune cells.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/353284/original/file-20200817-16-1titleg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/353284/original/file-20200817-16-1titleg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/353284/original/file-20200817-16-1titleg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/353284/original/file-20200817-16-1titleg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/353284/original/file-20200817-16-1titleg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/353284/original/file-20200817-16-1titleg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/353284/original/file-20200817-16-1titleg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/353284/original/file-20200817-16-1titleg.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">Ulcerative colitis is a type of inflammatory bowel disease that results in chronic inflammation and damage to the large intestine.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/ulcerative-colitis-royalty-free-illustration/1143632545?adppopup=true">Graphic_BKK1979/iStock via Getty Images</a></span>
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<h2>Immunology 101</h2>
<p>The immune system can be divided into <a href="https://www.youtube.com/watch?v=jeN8v5I5VNA">innate and adaptive branches</a>. The innate branch is our first line of defense and acts quickly – within minutes to hours. But this system senses changes caused by microbes generally. It does not mount a targeted response against a specific pathogen, which means that some invaders can be overlooked. </p>
<p>The adaptive branch is designed to detect specific threats, but is slower and takes a couple of days to get going. T cells are a part of the adaptive immune system and can be further subdivided into <a href="https://theconversation.com/coronavirus-b-cells-and-t-cells-explained-141888">CD4⁺ and CD8⁺ T cells</a>. </p>
<p>CD4⁺ T cells are helpers that aid other immune cells by releasing soluble molecules called cytokines that can induce inflammation.</p>
<p>CD8⁺ T cells can also release cytokines, but their main function is to kill cells infected by microbial invaders. This is why CD8⁺ T cells are often referred to as serial killers. </p>
<p>After the infection is cleared and the pathogen has been destroyed, cells called memory T cells remain. These memory T cells “remember” the pathogen they’ve just encountered and if they see it again, they mount a stronger and faster response than the first time. They and their descendants can also live for a long time, even decades in the case of certain infections like <a href="https://doi.org/10.1099/0022-1317-81-5-1313">measles</a>. </p>
<p>The goal of a <a href="https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html">vaccine</a> is to provide a preview of the microbe so that the immune system can build an army of memory cells against an infectious agent, such as SARS-CoV-2, the virus that causes COVID-19. That way, <a href="https://www.theatlantic.com/health/archive/2020/08/covid-19-immunity-is-the-pandemics-central-mystery/614956/">if the virus attacks</a>, the memory T cells will spring into action and activate an immune response including the <a href="https://www.nature.com/articles/s41467-017-00843-7">production of antibodies from B cells</a>.</p>
<h2>Memory T cells that reside in organs</h2>
<p>Immunologists further subdivide <a href="https://doi.org/10.1038/ni.3031">memory T cells</a> into different classes depending on if and where they travel in the body. Circulating memory T cells are scouts that look for signs of infection by patrolling the blood, lymph nodes and spleen. </p>
<p><a href="https://doi.org/10.1016/j.coi.2018.03.017">Tissue-resident memory cells</a>, abbreviated TRM, are sentries stationed at key ports of entry into the human body – including the skin, lungs, and intestines – and act rapidly to counter an infectious threat. Intestinal TRM also function as peacekeepers and do not tend to overreact against the many harmless microbes living in the intestines.</p>
<p>In the <a href="http://immunology.sciencemag.org/lookup/doi/10.1126/sciimmunol.abb4432">new study</a>, our team analyzed blood and intestinal samples to discover that intestinal CD8⁺ TRM come in at least four different varieties, each with unique features and functions. </p>
<p>We noticed that individuals with ulcerative colitis had higher numbers and proportions of cells belonging to one of these four varieties. This particular variety, which we’ll call inflammatory TRM here, carried instructions to make very large amounts of cytokines and other protein factors that allow them to kill other cells. High levels of certain cytokines can cause inflammation and tissue damage in the body.</p>
<p>[<em>Deep knowledge, daily.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=deepknowledge">Sign up for The Conversation’s newsletter</a>.]</p>
<p>It seems that in individuals with ulcerative colitis, the balance of memory cells is shifted in favor of this rogue population of inflammatory TRM that may become part of the problem by causing persistent inflammation and tissue damage.</p>
<p>We also found evidence consistent with the possibility that these inflammatory TRM might be exiting the intestinal tissue and entering the blood. Other studies in <a href="https://doi.org/10.1038/s41590-020-0607-7">mice</a> and <a href="https://doi.org/10.1126/sciimmunol.aav8995">people</a> have shown that TRM, despite being called “tissue-resident,” can leave tissues in certain circumstances. </p>
<p>By leaving the tissue and entering the blood, inflammatory TRM may be able to travel to other parts of the body and cause damage. This possibility may explain why autoimmune diseases that start in one organ, like <a href="https://doi.org/10.1007/s11894-019-0698-1">IBD</a> in the digestive tract or <a href="https://www.emjreviews.com/dermatology/article/psoriasis-beyond-the-skin/">psoriasis</a> in the skin, often affect other parts of the body.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/353248/original/file-20200817-22-1e2ytlu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/353248/original/file-20200817-22-1e2ytlu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/353248/original/file-20200817-22-1e2ytlu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/353248/original/file-20200817-22-1e2ytlu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/353248/original/file-20200817-22-1e2ytlu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/353248/original/file-20200817-22-1e2ytlu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/353248/original/file-20200817-22-1e2ytlu.jpg?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">
<figcaption>
<span class="caption">The balance of memory T cell subtypes changes in individuals with ulcerative colitis. Illustrations created with BioRender.com.</span>
<span class="attribution"><span class="source">John Chang</span></span>
</figcaption>
</figure>
<h2>IBD and other autoimmune diseases as a memory problem</h2>
<p>The very features that make memory T cells so desirable for vaccines – their capacity to live for such a long time and mount a stronger response when they encounter a microbial invader for the second time – may explain why autoimmune diseases are chronic and lifelong.</p>
<p>It is important to point out that none of the current drug treatments for IBD specifically target long-lived memory cells, which might be a reason why these therapies don’t work long-term in many individuals. One therapeutic approach might be to target inflammatory TRM for destruction, but this could result in side effects like suppression of the immune system and increased infections.</p>
<p>Our findings build on previous studies showing that <a href="https://doi.org/10.1053/j.gastro.2017.07.047">different TRM varieties</a>, like the <a href="https://doi.org/10.1038/s41590-018-0298-5">CD4⁺ subtype</a>, may also be involved in IBD, while other studies show that TRM play a role in autoimmune diseases affecting other organs like the <a href="https://doi.org/10.1126/scitranslmed.3010641">skin</a> and <a href="https://doi.org/10.1126/sciimmunol.aba4163">kidneys</a>.</p>
<p>The possibility that T cell memory is co-opted in IBD is exciting, but there is much that we still don’t understand about TRM. Can we selectively target inflammatory TRM for destruction? Would this be an effective treatment for IBD? Can we do so without causing major side effects? Further research will be needed to answer these important questions and to strengthen the link between TRM and IBD.</p><img src="https://counter.theconversation.com/content/144176/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>John Chang receives research grant funding from the National Institutes of Health, the Kenneth Rainin Foundation, Takeda, and Eli Lilly.</span></em></p>Researchers discover clues to the origin of inflammatory bowel disease and a possible strategy for treatment.John Chang, Professor of Medicine, University of California, San DiegoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1371452020-05-05T12:20:41Z2020-05-05T12:20:41ZYour genes could determine whether the coronavirus puts you in the hospital – and we’re starting to unravel which ones matter<figure><img src="https://images.theconversation.com/files/332506/original/file-20200504-83725-1ijhd03.jpg?ixlib=rb-1.1.0&rect=286%2C0%2C8411%2C4900&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The relationship between the coronavirus and human genetics is murky. </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/virus-cells-attacking-a-dna-strand-royalty-free-image/1183281148?adppopup=true">fatido/E+ via Getty Images</a></span></figcaption></figure><p><em>The Research Brief is a short take about interesting academic work.</em></p>
<h2>The big idea</h2>
<p>When some people become infected with the coronavirus, they only develop <a href="https://theconversation.com/infected-with-the-coronavirus-but-not-showing-symptoms-a-physician-answers-5-questions-about-asymptomatic-covid-19-137029">mild or undetectable cases of COVID-19</a>. Others suffer severe symptoms, fighting to breathe on a ventilator for weeks, if they survive at all. </p>
<p>Despite a concerted global scientific effort, doctors <a href="https://fivethirtyeight.com/features/why-are-some-young-healthy-people-getting-severe-covid-19/">still lack a clear picture</a> of why this is. </p>
<p>Could genetic differences explain the differences we see in symptoms and severity of COVID-19?</p>
<p>To test this, we used computer models to analyze known genetic variation within the human immune system. The <a href="https://dx.doi.org/10.1128/JVI.00510-20">results of our modeling</a> suggest that there are in fact differences in people’s DNA that could influence their ability to respond to a SARS-CoV-2 infection.</p>
<h2>What we did</h2>
<p>When a virus infects human cells, the body reacts by turning on what are essentially anti-virus alarm systems. These alarms identify viral invaders and tell the immune system to send cytotoxic T cells – a type of white blood cell – to destroy the infected cells and hopefully slow the infection.</p>
<p>But not all alarm systems are created equal. People have different versions of the same genes – called alleles – and some of these alleles are more <a href="https://dx.doi.org/10.1128%2FCMR.00048-08">sensitive to certain viruses or pathogens than others</a>. </p>
<p>To test whether different alleles of this alarm system could explain some of the range in immune responses to SARS-CoV-2, we first retrieved a list of all the proteins that make up the coronavirus from an <a href="https://www.ncbi.nlm.nih.gov/refseq/">online database</a>.</p>
<p>We then took that list and used existing computer algorithms to predict how well different versions of the anti-viral alarm system detected these coronavirus proteins. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=802&fit=crop&dpr=1 600w, https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=802&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=802&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1008&fit=crop&dpr=1 754w, https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1008&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1008&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A model of an HLA protein (green and yellow) bound to a piece of a virus (orange and blue) – in this case, influenza.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/HLA-B27#/media/File:HLA-B*2705-peptide_in_complex_with_influenza_nucleoprotein_NP383-391.png">Prot reimage via Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<h2>Why it matters</h2>
<p>The part of the alarm system that we tested is called the human leukocyte antigen system, or HLA. Each person has multiple alleles of the genes that make up their HLA type. Each allele codes for a different HLA protein. These proteins are the sensors of the alarm system and find intruders by binding to various peptides – chains of amino acids that make up parts of the coronavirus – that are foreign to the body.</p>
<p>Once an HLA protein binds to a virus or piece of a virus, it transports the intruder to the cell surface. This “marks” the cell as infected and from there the immune system will kill the cell.</p>
<p>In general, the more peptides of a virus that a person’s HLAs can detect, the <a href="https://dx.doi.org/10.4049%2Fjimmunol.1302101">stronger the immune response</a>. Think of it like a more sensitive sensor of the alarm system. </p>
<p>The results of our modeling predict that some HLA types bind to a large number of the SARS-CoV-2 peptides while others bind to very few. That is to say, some sensors may be better tailored to SARS-CoV-2 than others. If true, the specific HLA alleles a person has would likely be a factor in how effective their immune response is to COVID-19. </p>
<p>Because our study only used a computer model to make these predictions, we decided to test the results using clinical information from the 2002-2004 SARS outbreak.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=1216&fit=crop&dpr=1 600w, https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=1216&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=1216&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1528&fit=crop&dpr=1 754w, https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1528&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1528&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 section of DNA that codes for HLAs is on the sixth chromosome.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:HLA_MHC_Complex_illustration.jpg">Pdeitiker at English Wikipedia / Wikipedia</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>We found similarities in how effective alleles were at identifying SARS and SARS-CoV-2. If an HLA allele appeared to be bad at recognizing SARS-CoV-2, it was also bad at recognizing SARS. Our analysis predicted that one allele, called B46:01, is particularly bad with regards to both SARS-CoV-2 and SARS-CoV. Sure enough, previous studies showed that people with this allele tended to have more <a href="https://doi.org/10.1186/1471-2350-4-9">severe SARS infections</a> and higher viral loads than people with other versions of the HLA gene. </p>
<h2>What’s next?</h2>
<p>Based on our study, we think variation in HLA genes is part of the explanation for the huge differences in infection severity in many COVID-19 patients. These differences in the HLA genes are probably not the only genetic factor that affects severity of COVID-19, but they may be a significant piece of the puzzle. It is important to further study how HLA types can clinically affect COVID-19 severity and to test these predictions using real cases. Understanding how variation in HLA types may affect the clinical course of COVID-19 could help identify individuals at higher risk from the disease.</p>
<p>To the best of our knowledge, this is the first study to evaluate the relationship between viral proteins across a wide range of HLA alleles. Currently, we know very little about the relationship between many other viruses and HLA type. In theory, we could repeat this analysis to better understand the genetic risks of many viruses that currently or could potentially infect humans.</p>
<p>[<em>Deep knowledge, daily.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=deepknowledge">Sign up for The Conversation’s newsletter</a>.]</p><img src="https://counter.theconversation.com/content/137145/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Reid Thompson receives funding from the Department of Veterans Affairs, and the Sunlin and Priscilla Chou Foundation. </span></em></p><p class="fine-print"><em><span>Abhinav Nellore and Austin Nguyen 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>Researchers from Oregon Health and Science University found that variations in genes that code for parts of the cellular alarm system might play a role in how well people fight off COVID-19.Austin Nguyen, PhD Candidate in Computational Biology and Biomedical Engineering, Oregon Health & Science UniversityAbhinav Nellore, Assistant Professor of Biomedical Engineering & Surgery, Oregon Health & Science UniversityReid Thompson, Assistant Professor of Radiation Medicine, Oregon Health & Science UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1338992020-03-19T12:06:52Z2020-03-19T12:06:52ZOlder people are at more risk from COVID-19 because of how the immune system ages<figure><img src="https://images.theconversation.com/files/321466/original/file-20200319-126270-1h2b5un.jpg?ixlib=rb-1.1.0&rect=207%2C39%2C3367%2C2441&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A nursing home resident who tested positive for the virus visits through the window with her daughter.</span> <span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Virus-Outbreak-US/ad2fd7eca51e46b5a390af76f9d8aa7e/2/0">AP Photo/Ted S. Warren</a></span></figcaption></figure><p><em>An updated version of this article was published on Oct. 2, 2020. <a href="https://theconversation.com/older-people-like-president-trump-are-at-more-risk-from-covid-19-because-of-how-the-immune-system-ages-147391">Read it here</a>.</em></p>
<p>The rapidly spreading coronavirus pandemic is taking a particularly harsh toll on older people.</p>
<p><a href="https://doi.org/10.3855/jidc.12600">Data from the initial outbreak in China and then Italy</a> show that infected people under the age of 60 are at low – but not no – risk of dying from COVID-19. More recent data from the U.S. suggest that a <a href="https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm?s_cid=mm6912e2_w">higher rate of people in their 30s and 40s</a> have experienced severe illness and even death than previously thought. Curiously, <a href="https://www.washingtonpost.com/health/2020/03/17/coronavirus-looks-different-kids-than-adults/">young children</a> do not appear to be at increased risk of serious COVID-19 complications, in contrast to what happens with other viruses, <a href="https://www.cdc.gov/flu/highrisk/children.htm">like the seasonal flu</a>. </p>
<p>However, the statistics get <a href="https://doi.org/10.3855/jidc.12600">grimmer as the patients get older</a>. Whereas people in their 60s have a 0.4% chance of dying, people in their 70s have a 1.3% chance of dying, and people over 80 have a 3.6% chance of dying. While this may not sound like a high chance of death, during the current outbreak in Italy, <a href="https://doi.org/10.1016/S0140-6736(20)30627-9">83% of those who succumbed to COVID-19</a> infection were over the age of 60.</p>
<p>The new coronavirus SARS-CoV-2, which causes COVID-19, is therefore a <a href="https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm">very serious pathogen for people over 60</a>. As it continues to spread, this older age group will continue to be at risk for serious disease and death.</p>
<p>What is it that puts older people at increased risk from viruses like this? It’s primarily thought to be due to changes in the human immune system as we age.</p>
<h2>Your body’s tools to fight off virus infections</h2>
<p>As you go about your life, your body is constantly bombarded by pathogens – the bacteria, fungi and viruses that can make you sick. A human body is a great place for these organisms to grow and thrive, providing a nice warm environment with plenty of nutrients.</p>
<p>That’s where your immune system comes in. It’s your body’s defense system against these kinds of invaders. Before you’re even born, your body starts producing specialized B-cells and T-cells – types of white blood cells that can recognize pathogens and help block their growth.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/321468/original/file-20200319-126300-18zc0vh.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">An artist’s rendering of the white blood cells that help recognize and fight off invaders.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/lymphocytes-illustration-royalty-free-illustration/685027719">KATERYNA KON/Science Photo Library via Getty Images</a></span>
</figcaption>
</figure>
<p>During an infection, your B-cells can proliferate and produce antibodies that grab onto pathogens and block their ability to spread within your body. T-cells work by recognizing infected cells and killing them. Together they make up what scientists call your “adaptive” immune system.</p>
<p>Maybe your physician has checked your white blood cell levels. That’s a measurement of whether you have more B-cells and T-cells in your blood than usual, presumably because they’re fighting infection.</p>
<p>When you’re very young, you don’t have a lot of these B- or T-cells. It can be a challenge for your body to control infection because it’s simply not used to the job. As you mature, your adaptive immune system learns to recognize pathogens and handle these constant invasions, allowing you to fight off infection quickly and effectively.</p>
<p>While white blood cells are powerful people protectors, they’re not enough on their own. Luckily, your immune system has another layer, what’s called your <a href="https://doi.org/10.1159/000453397">“innate” immune response</a>. Every cell has its own little immune system that allows it to directly respond to pathogens quicker than it takes to mobilize the adaptive response.</p>
<p>The innate immune response is tuned to pounce on types of molecules that are commonly found on bacteria and viruses but not in human cells. When a cell detects these invader molecules, it triggers production of an antiviral interferon protein. Interferon triggers the infected cell to die, limiting infection. </p>
<p>Another type of innate immune cell, called a monocyte, acts as a sort of cellular bouncer, getting rid of any infected cells it finds and signaling the adaptive immune response to shift into gear.</p>
<p>The innate and adaptive immune systems can act together as a fine-tuned machine to detect and clear out pathogens.</p>
<h2>Older immune systems are weaker</h2>
<p>When a pathogen invades, the difference between illness and health is a race between how fast the pathogen can spread within you and how fast your immune response can react without causing too much collateral damage.</p>
<p>As people age, their innate and adaptive immune responses change, shifting this balance.</p>
<p><a href="https://doi.org/10.1016/j.humimm.2009.07.005">Monocytes from older individuals</a> <a href="https://doi.org/10.1093/infdis/jir048">produce less interferon</a> in response to viral infection. They have a harder time killing infected cells and signaling the adaptive immune response to get going.</p>
<p>Low-grade chronic inflammation in individuals that commonly occurs during aging can also <a href="https://doi.org/10.1111/j.1749-6632.2000.tb06651.x">dull the ability of the innate and adaptive immune responses</a> to react to pathogens. It’s similar to becoming used to an annoying sound over time.</p>
<p>As you age, the reduced “attention span” of your innate and adaptive immune responses make it harder for the body to respond to viral infection, giving the virus the upper hand. Viruses can take advantage of your immune system’s slow start and quickly overwhelm you, resulting in serious disease and death.</p>
<h2>Social distancing is vital</h2>
<p>Everyone, no matter their age, needs to protect themselves from infection, not just to keep themselves healthy but also to help protect the most vulnerable. Given the difficulty older individuals have in controlling viral infection, the best option is for these individuals to avoid becoming infected by viruses in the first place.</p>
<p>This is where washing hands, avoiding touching your face, self-isolation and <a href="https://theconversation.com/social-distancing-what-it-is-and-why-its-the-best-tool-we-have-to-fight-the-coronavirus-133581">social distancing</a> all become important, <a href="https://www.cdc.gov/coronavirus/2019-ncov/prepare/prevention.html">especially for COVID-19</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=378&fit=crop&dpr=1 600w, https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=378&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=378&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=475&fit=crop&dpr=1 754w, https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=475&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/321445/original/file-20200318-1905-pndn5q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=475&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 mist ejected by a sneeze can launch viruses airborne, so other people can inhale them.</span>
<span class="attribution"><a class="source" href="https://phil.cdc.gov/Details.aspx?pid=11161">James Gathany</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>COVID-19 is caused by a respiratory virus, which can spread via tiny virus-containing droplets. Larger droplets fall to the ground quickly; very small droplets dry up. Mid-range droplets are of most concern because they can <a href="https://www.medscape.com/viewarticle/741245_3">float in the air for a few feet</a> before drying. These droplets can be inhaled into the lungs.</p>
<p>Keeping at least 6 feet away from other people helps significantly reduce your chance of being <a href="https://doi.org/10.1186/s12879-019-3707-y">infected by these aerosol droplets</a>. But there’s still the <a href="https://theconversation.com/viruses-live-on-doorknobs-and-phones-and-can-get-you-sick-smart-cleaning-and-good-habits-can-help-protect-you-133054">possibility for virus to contaminate surfaces</a> that infected people have touched or coughed on. Therefore, the best way to protect vulnerable older and immunocompromised people is to stay away from them until there is no longer a risk. By stopping the spread of SARS-CoV-2 throughout the whole population, we help protect those who have a harder time fighting infection.</p>
<p><em>This article has been updated to clarify that people of all ages are at risk of coming down with COVID-19.</em></p><img src="https://counter.theconversation.com/content/133899/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Brian Geiss receives funding from the National Institutes of Health. </span></em></p>Different demographics are more or less vulnerable to serious complications from the coronavirus. A virologist explains the aging-related changes in how immune systems work that are to blame.Brian Geiss, Associate Professor of Microbiology, Immunology & Pathology, Colorado State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1291722020-01-01T18:07:22Z2020-01-01T18:07:22ZA new way to give an old TB vaccine proves highly effective in monkeys<figure><img src="https://images.theconversation.com/files/308133/original/file-20191220-11939-1xcmstg.jpg?ixlib=rb-1.1.0&rect=18%2C0%2C5979%2C4007&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Chest x-ray of a person with TB infection in both the right and left lungs. </span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/pulmonary-tuberculosis-tb-chest-xray-show-504766408">Schira/Shutterstock.com</a></span></figcaption></figure><p>What if you could make the tuberculosis vaccine much more powerful, not by altering the ingredients, but just by changing the way it is given to people? It would help prevent the infection that kills more people every year than any other microbe. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/308130/original/file-20191220-11896-5pf1kg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/308130/original/file-20191220-11896-5pf1kg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/308130/original/file-20191220-11896-5pf1kg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=922&fit=crop&dpr=1 600w, https://images.theconversation.com/files/308130/original/file-20191220-11896-5pf1kg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=922&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/308130/original/file-20191220-11896-5pf1kg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=922&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/308130/original/file-20191220-11896-5pf1kg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1159&fit=crop&dpr=1 754w, https://images.theconversation.com/files/308130/original/file-20191220-11896-5pf1kg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1159&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/308130/original/file-20191220-11896-5pf1kg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1159&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A poster from the 1920s showing how to avoid spreading disease.</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/8/8e/TB_poster.jpg">U.S. National Library of Medicine / Wikipedia</a></span>
</figcaption>
</figure>
<p>Tuberculosis is caused by a bacterium, called <em>Mycobacterium tuberculosis</em>, which causes a lung infection that progresses slowly but can destroy the lungs if not treated. Although we might not think of it too often here in the United States, it remains a major killer worldwide. In 2018 alone, there were <a href="https://www.who.int/tb/publications/global_report/en/">10 million new cases of active TB and almost 1.5 million</a> deaths from TB infections. What makes the disease particularly insidious is that because symptoms are slow to manifest and can resemble other diseases, it takes a long time before people with TB are diagnosed and given treatment. But until a person with TB gets treated with drugs, they can pass it on to other people - and this bacterium spreads fast through coughing, sneezing, and even singing. </p>
<p>You might be surprised to learn that most of the people who die from TB were actually vaccinated as a baby, using a <a href="https://www.cdc.gov/tb/publications/factsheets/prevention/bcg.htm">vaccine called bacille Calmette-Guerin</a> (BCG). BCG has been used for almost 100 years and is a live but crippled version of a similar bacterium to the one that causes TB. This vaccine is pretty good at preventing certain types of TB in children, but not adolescents or adults. My team here in Pittsburgh together with collaborators at the National Institutes of Health have figured out a <a href="http://doi.org/10.1038/s41586-019-1817-8">better way to administer this vaccine</a> to prevent this devastating disease – which often affects the poorest people in the world.</p>
<h2>TB in mice and monkeys</h2>
<p>I was originally trained as a microbiologist, studying bacteria that cause disease, and later developed an interest in how the body’s immune system fights off infections. Combining my passions for microbiology and immunology, I began investigating tuberculosis almost 30 years ago. I started my own lab at the University of Pittsburgh School of Medicine with the goal of understanding TB disease and how we might prevent it. </p>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/308135/original/file-20191220-11914-j6f33w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/308135/original/file-20191220-11914-j6f33w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/308135/original/file-20191220-11914-j6f33w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=589&fit=crop&dpr=1 600w, https://images.theconversation.com/files/308135/original/file-20191220-11914-j6f33w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=589&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/308135/original/file-20191220-11914-j6f33w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=589&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/308135/original/file-20191220-11914-j6f33w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=741&fit=crop&dpr=1 754w, https://images.theconversation.com/files/308135/original/file-20191220-11914-j6f33w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=741&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/308135/original/file-20191220-11914-j6f33w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=741&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">The signs of an active TB infection.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/symptoms-tuberculosis-world-day-march-24-1012615285">Timonina/Shutterstock.com</a></span>
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<p>I started by using mice to study TB. But then, 20 years ago, I began using monkeys and discovered that <a href="http://doi.org/10.1128/iai.71.10.5831-5844.2003">monkeys develop the same type of TB disease that humans do</a>. Studying TB in monkeys was a breakthrough that enabled me to begin the search for new vaccines against this deadly disease.</p>
<p>TB is such a fascinating disease and has been causing illness in humans for thousands of years. Anthropologists have discovered, for example, <a href="http://doi.org/10.1098/rspb.2009.1484">tuberculosis in Egyptian mummies</a>. It infects nearly all mammals. Yet, even though the cause of TB has been known since the late 1800s, it is still not clear why some humans can suppress the infection and not become sick while others are more vulnerable and develop disease. I wanted to use my understanding of this complicated bacterium to find more effective ways to prevent the disease.</p>
<h2>A new vaccine strategy</h2>
<p>My colleague <a href="https://www.niaid.nih.gov/research/robert-seder-md">Robert Seder</a>, a vaccine expert at the National Institutes of Health, had discovered that <a href="http://doi.org/10.1126/science.1241800">delivering a malaria vaccine directly into the bloodstream</a>, through a vein, was much more effective than any other route of delivery such as the skin or muscle, and was a much better way to prevent the disease.</p>
<p>Together, we decided to try a similar approach with TB using the current BCG vaccine. We vaccinated monkeys with BCG by injecting the vaccine under the skin (the usual route for babies), by aerosolizing the vaccine and spraying it directly into the lungs, or injecting it directly into the the blood using an IV. </p>
<p>After two months we found that when the vaccine was delivered via IV, the numbers of specialized immune cells, called T cells, which can recognize and kill the bacteria, increased by 100-fold in the lungs. Then, months later, we exposed the monkeys to <em>M. tuberculosis</em>. </p>
<p>Unvaccinated monkeys developed severe TB disease within a few months. BCG administered through the skin or into the lungs gave a little bit of protection, but the monkeys still had signs of TB.</p>
<p>The IV vaccine provided incredible protection. In most of the animals, there were <a href="https://www.nature.com/articles/s41586-019-1817-8">no <em>M. tuberculosis</em> bacteria in the entire monkey</a>. We also used specialized imaging, called PET-CT, and showed that the lungs of most of these monkeys were free of any disease. This means that BCG vaccine prevented TB infection and disease when given intravenously.</p>
<p>This is an exciting breakthrough in the field of TB, since most vaccines tested in any models provide relatively limited protection. If we can figure out how BCG IV prevents <em>M. tuberculosis</em> infection, we may be on the path to developing a new vaccine for humans. Although we have a long way to go before it is ready for humans, the lessons we learn from the BCG IV studies will be critical in developing new TB vaccines and, we hope, saving millions of lives. </p>
<p>[ <em>Deep knowledge, daily.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=deepknowledge">Sign up for The Conversation’s newsletter</a>. ]</p><img src="https://counter.theconversation.com/content/129172/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>JoAnne L. Flynn receives funding from National Institutes of Health, Aeras, and the Bill and Melinda Gates Foundation.
JoAnne L Flynn is a member of the American Association of Immunologists (AAI) Council, and immediate Past President.</span></em></p>There are more effective ways to give the tuberculosis vaccine.JoAnne L. Flynn, Professor of Microbiology and Molecular Genetics, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/649792016-10-02T19:16:08Z2016-10-02T19:16:08Z20 years on, what impact has the Nobel Prize for medicine had on our immune systems?<figure><img src="https://images.theconversation.com/files/139530/original/image-20160928-721-bxiain.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The science is now used to tackle a range of diseases.</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-379602502/stock-photo-close-up-image-of-thermometer-showing-high-temperature.html?src=G4eiVm8wzr1ZH5q3QbC0bw-4-45">tuthelens/Shutterstock</a></span></figcaption></figure><p>This time of year, Australians obsess over an annual spectacle that celebrates the achievements of our most gifted citizens – though usually, they’re fixating on their respective football codes.</p>
<p>But an even bigger prize is up for grabs tonight – the Nobel Prize in Physiology or Medicine. It’s the first of a big week celebrating the international heroes who receive Nobel Prizes for a range of disciplines, from physics, to economics, to literature.</p>
<p>Twenty years ago, the Nobel Prize in Physiology or Medicine was awarded jointly to Peter Doherty and Rolf Zinkernagel “for their discoveries concerning the specificity of the cell mediated immune defence”. </p>
<h2>What did they find?</h2>
<p>Doherty and Zinkernagel made their Nobel-winning discovery while working at Canberra’s Australian National University (ANU) in the early 1970s. Doherty, a veterinarian from Queensland, had only just returned to Canberra to set up a laboratory as an independent scientist. Zinkernagel had come to the ANU from Switzerland in 1973 to do his PhD. </p>
<p>The pair happened to share a lab and started talking. A year later, they co-authored two landmark papers in Nature, the Rolls-Royce journal for scientists in all disciplines globally.</p>
<p>Doherty and Zinkernagel had discovered how one critical part of the immune system, the T-cell, recognised and killed virus-infected cells. These killer T-cells patrol our bodies looking for foreign enemies – such as infections or cancer cells – and then move in to attack. </p>
<p>What Doherty and Zinkernagel discovered was the exquisite elegance with which the killer T-cells recognise the enemy. </p>
<p>They proved a radical new idea of how T-cells worked by recognising an “altered self”: the enemy (for example, a virus) could only be recognised when it was presented in combination with the body’s own machinery. </p>
<p>The body’s protein alone or the virus alone didn’t generate the molecular target for the killer T-cell to recognise. </p>
<p>Sounds simple, but the concept was revolutionary.</p>
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<img alt="" src="https://images.theconversation.com/files/139534/original/image-20160928-725-1pygwmo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/139534/original/image-20160928-725-1pygwmo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=428&fit=crop&dpr=1 600w, https://images.theconversation.com/files/139534/original/image-20160928-725-1pygwmo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=428&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/139534/original/image-20160928-725-1pygwmo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=428&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/139534/original/image-20160928-725-1pygwmo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=538&fit=crop&dpr=1 754w, https://images.theconversation.com/files/139534/original/image-20160928-725-1pygwmo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=538&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/139534/original/image-20160928-725-1pygwmo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=538&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">Doherty and Zinkernagel discovered how killer T-cells recognise the enemy.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-297770426/stock-photo-a-microcopic-view-of-virus-with-depth-of-field.html?src=ZQfKytBY2Vw9l1_o9fghmw-1-15">Tischenko Irina/Shutterstock</a></span>
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<p>At the time, Doherty and Zinkernagel were studying mice infected with a virus called <a href="https://www.cdc.gov/vhf/lcm/">lymphocytic choriomeningitis virus</a> (LCMV). But they and others went on to demonstrate that exactly the same process is used to tackle diseases as diverse as influenza, HIV and cancer. The implications of their findings have been spectacular and far-reaching.</p>
<p>In Doherty’s Nobel speech, given in 1996 in Stockholm, he credited for his success the local intellectual environment in Canberra, the excellence in immunology across Australia and that there was “time to discuss and think things through” in the pre-fax, pre-email days. I suspect there was a bit more to it!</p>
<h2>What does it mean for patients?</h2>
<p>Doherty and Zinkernagel’s insights into how killer T-cells recognise the enemy proved crucial for understanding how viral infections are controlled. More practically, this understanding now shapes modern treatment strategies for cancer and the design of vaccines.</p>
<p>To recover from the common flu, for example, we need T-cells and antibodies, another arm of the immune system. And recent findings by Katherine Kedzierska, a former trainee with Doherty, have shown how T-cell “memory” protects us against the flu. </p>
<p>Following HIV infection, as in flu, people also generate loads of antibodies and killer T-cells. Neither get rid of HIV completely in anyone. But in some people with the right genetic make-up and the right virus, they manage to keep the virus under control.</p>
<p>The explanation? These so-called “elite controllers” make stunningly potent killer T-cells that are able to recognise part of the HIV virus together with part of the body’s immune system. </p>
<p>This finding in HIV-infected elite controllers has revamped our approach to searching for a successful HIV vaccine. We don’t have one yet, but most think that generating effective killer T-cells will be critical.</p>
<p>Great strides have been made in the last few years about how to harness killer T-cells for cancer therapy. These drugs have literally just hit the clinic – only 12 months ago in Australia – with some spectacular results. </p>
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<img alt="" src="https://images.theconversation.com/files/139535/original/image-20160928-716-1q1u6l2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/139535/original/image-20160928-716-1q1u6l2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/139535/original/image-20160928-716-1q1u6l2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/139535/original/image-20160928-716-1q1u6l2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/139535/original/image-20160928-716-1q1u6l2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/139535/original/image-20160928-716-1q1u6l2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/139535/original/image-20160928-716-1q1u6l2.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">Cancer immunotherapy has just become available.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-425741998/stock-photo-forceps-holding-vial.html?src=SY8_0juucQrzLp_fIahHdQ-1-25">CI Photos/Shutterstock</a></span>
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<p>In cancer (and in chronic infections such as HIV and indeed LCMV), killer T-cells can become exhausted. They are massively outnumbered by the enemy and they surrender. </p>
<p>New drugs can now revitalise these exhausted T-cells, returning them to their fighting-fit selves. These drugs have transformed the outlook for some cancers, such as melanoma and lung cancer, but only in some people. There are still many puzzles to be solved in this new era of immunotherapy.</p>
<h2>What’s next?</h2>
<p>After 14 years in the United States working at St Jude Children’s Research Hospital in Memphis, Doherty returned to Australia and the University of Melbourne in 2002. He continued to train and mentor generations of scientists, many of whom still work on killer T-cells and how they tackle viruses like influenza.</p>
<p>The tools of modern immunology have changed. But the principles of good science – intense curiosity to solve a problem, asking the right question and planning the right experiments – are the same now as in 1973.</p>
<p>In 2014, the Doherty Institute was opened. As patron and namesake, Peter still loves to talk science and to interact with young researchers. A joint venture between the University of Melbourne and Royal Melbourne Hospital, the institute has more than 700 staff, all working on infection and immunity. </p>
<p>From basic discovery research, through to clinical and translational research and public health, the institute has the vision to improve health globally through discovery research and the prevention, treatment and cure of infectious diseases. To achieve this ambitious goal, we will use the same principles of great science, “time to talk and think things through” and the humanitarian values of its namesake to continue Peter’s legacy.</p>
<p>Tonight when we hear the next inspiring stories from the winner of the 2016 Nobel Prize in Medicine or Physiology, we should be immensely proud of what Peter Doherty and our own scientists have achieved – and what’s yet to come.</p>
<p><em>Thanks to Professor Andrew Brooks and Associate Professor Katherine Kedzierska for helpful discussions and input.</em></p><img src="https://counter.theconversation.com/content/64979/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sharon Lewin receives funding from the National Health and Medical Research Council, the National Institutes for Health, The Wellcome Trust and the American Foundation for AIDS Research and investigator initiated research funding from Viiv, Merck and Gilead Sciences.</span></em></p>Peter Doherty’s Nobel Prize-winning insights proved crucial for understanding how viral infections are controlled.Sharon Lewin, Director, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital and Consultant Physician, Department of Infectious Diseases, Alfred Hospital and Monash University, The Peter Doherty Institute for Infection and ImmunityLicensed as Creative Commons – attribution, no derivatives.