tag:theconversation.com,2011:/uk/topics/b-cell-91737/articlesB-cell – The Conversation2020-10-08T15:20:15Ztag:theconversation.com,2011:article/1462552020-10-08T15:20:15Z2020-10-08T15:20:15ZAn autoimmune-like antibody response is linked with severe COVID-19<figure><img src="https://images.theconversation.com/files/361230/original/file-20201001-22-6caup7.jpg?ixlib=rb-1.1.0&rect=38%2C58%2C6438%2C4253&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Are patients with severe COVID-19 victims of their own immune response?</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/an-emergency-ventilator-is-tested-on-a-person-at-the-news-photo/1228031636?adppopup=true">JOAQUIN SARMIENTO/Getty Images</a></span></figcaption></figure><p>In the earliest days of the pandemic, many immunologists, including me, assumed that patients who produced high quantities of antibodies early in infection would be free from disease. We were wrong.</p>
<p>Several months into studying COVID-19, like other scientists, I’ve come to realize the picture is far more complicated. <a href="https://doi.org/10.1038/s41590-020-00814-z">A recent research study</a> published by my colleagues and me adds more evidence to the idea that in some patients, preventing dysregulated immune system responses may be as important as treating the virus itself. </p>
<p><a href="http://scholar.google.com/citations?user=-oDHlFYAAAAJ&hl=en">I am an immunologist</a> at Emory University working under the direction of <a href="https://winshipcancer.emory.edu/bios/faculty/sanz-ignacio.html">Dr. Ignacio Sanz</a>, Emory’s chief of rheumatology. Immune dysregulation is our specialty. </p>
<h2>Inflammation in COVID-19</h2>
<p>A harrowing turn in the COVID-19 pandemic occurred with the realization that the immune system’s power in fighting infection was sometimes pyrrhic. In patients with severe COVID-19 infections, evidence emerged that the inflammatory process used to fight the SARS-CoV-2 virus were, in addition to fighting the virus, <a href="http://doi.org/10.1002/art.41285">potentially responsible for harming the patient.</a> Clinical studies described so-called <a href="http://doi.org/10.3389/fimmu.2020.01708">cytokine storms</a> in which the immune system produced an overwhelming quantity of inflammatory molecules, <a href="http://doi.org/10.1056/NEJMc2007575">antibodies triggering dangerous blood clots</a> and <a href="http://doi.org/10.1056/NEJMoa2021680">inflammation of multiple organ systems</a>, including blood vessels, in COVID-recovered children. All these were warning signs that in some patients, immune responses to the SARS-CoV-2 virus, which causes COVID-19, may have tipped from healing to destructive.</p>
<p>Quick thinking and courageous decisions made by physicians on the front lines led to the <a href="http://doi.org/10.1056/NEJMoa2021436">use of steroids</a>, medicines that <a href="https://theconversation.com/steroids-cut-covid-19-death-rates-but-not-for-everyone-heres-who-benefits-and-who-doesnt-145605">dampen the immune response</a>, early on in the course of infection of hospitalized patients. This approach has saved lives. </p>
<p>But it’s not yet clear what parts of the immune system physicians are dampening that is having the effect. Understanding the nature of immune dysregulation in COVID-19 could help identify patients in whom these treatments are most effective. It may even justify more targeted and powerful approaches for modulating the immune system currently reserved for autoimmune diseases.</p>
<h2>The right antibodies take time</h2>
<p>Antibodies are powerful weapons. Produced by white blood cells called B cells, they latch onto infectious agents like viruses and bacteria and prevent them from infecting your healthy cells. These antibody-virus aggregates unleash powerful inflammatory reactions and serve as homing beacons that allow the rest of your immune system to target the pathogens efficiently. In some circumstances, they can even kill. </p>
<p>Antibodies are so powerful that cases of mistaken identity – when a B cell produces antibodies that attack a person’s own cells – can lead to widespread organ damage and establish a perpetual cycle of immune self-targeting. We refer to this state of self-destruction as an <a href="https://www.niaid.nih.gov/diseases-conditions/autoimmune-diseases">autoimmune disease</a>.</p>
<p>To avoid autoimmune disaster, and to ensure effective response against the invading pathogen, B cells undergo a training process. Those that respond to the virus refine their antibodies and mature, ensuring potent antibodies capable of disabling the invader. B cells that target your own tissue are destroyed. </p>
<p>But that maturation process takes time. Two weeks of B cell “training” during a severe infection can mean the difference between life and death. Faster antibody responses are needed. To bridge that gap, the immune system has an alternative form of B cell activation – called extrafollicular activation – that generates fast-acting antibodies that seem to bypass many of the known safety checks that accompany a more precise response. </p>
<p>Extrafollicular responses develop quickly, are short-lived by design and die back when the more targeted responses emerge onto the scene.</p>
<p>Except when they don’t. </p>
<h2>Autoimmune-like responses in COVID-19</h2>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/361231/original/file-20201001-16-18ekd1b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/361231/original/file-20201001-16-18ekd1b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/361231/original/file-20201001-16-18ekd1b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=578&fit=crop&dpr=1 600w, https://images.theconversation.com/files/361231/original/file-20201001-16-18ekd1b.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=578&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/361231/original/file-20201001-16-18ekd1b.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=578&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/361231/original/file-20201001-16-18ekd1b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=726&fit=crop&dpr=1 754w, https://images.theconversation.com/files/361231/original/file-20201001-16-18ekd1b.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=726&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/361231/original/file-20201001-16-18ekd1b.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=726&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">When B cells produce antibodies that attack human tissues rather than an invading pathogen like a virus or bacterium, autoimmune disease can result.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/tissues-of-the-human-body-affected-by-royalty-free-illustration/1029807722?adppopup=true">ttsz/Getty Images</a></span>
</figcaption>
</figure>
<p>Between <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/26006014/">2015</a> and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217820/">2018</a>, our lab found that these
extrafollicular immune system responses were a common characteristic of people who suffered from autoimmune diseases, such as lupus. Patients suffering from this disease show chronically active extrafollicular responses that led to high levels of self-targeted antibodies and destruction of organs such as the lungs, heart and kidneys. </p>
<p>The presence of specific kinds of B cells generated by extrafollicular responses in the blood can be an important indicator of disease severity in lupus, and now also COVID-19.</p>
<p>In a recently <a href="https://doi.org/10.1038/s41590-020-00814-z">published paper</a>, my colleagues and I have identified extrafollicular B cell signatures in cases of severe COVID-19 similar to those we saw in active lupus. We showed that early on in the response to infection, patients with severe disease undergo a rapid activation of this fast-track pathway for antibody production. These patients produce high levels of viral-specific antibodies, some which are capable of neutralizing the virus. However, in addition to those protective antibodies, some that we saw look suspiciously like the ones found in autoimmune disorders such lupus. </p>
<p>In the end, patients with these autoimmune-like B cell responses fare poorly, with high incidences of systemic organ failure and death.</p>
<h2>Tempering immune responses in COVID-19</h2>
<p>Let me be clear here: COVID-19 is not an autoimmune disorder. The autoimmune-like inflammatory responses my team discovered could simply reflect a “normal” response to a viral infection already out of hand. </p>
<p>However, even if this kind of response is “normal,” it doesn’t mean that it’s not dangerous. These prolonged extrafollicular responses have been shown to contribute to autoimmune disease severity both through the production of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152497/">self-targeted antibodies</a> and <a href="https://www.jimmunol.org/content/178/10/6092.long">through inflammation</a> that can damage tissue like the lung and kidney. This suggests that these early immune responses to a viral infection like COVID-19 are in tension with the later-targeted antibody response; in other words, the body’s rapid antibody production to nab the virus runs the risk of targeting not the virus, but the patient’s own organs and tissues.</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>Immunologists like me need to learn more. Why are only some patients turning on such strong extrafollicular B cell responses? Are the antibodies that result from this response particularly prone to attacking and destroying the host’s organs? Would an ongoing autoreactive response help explain instances of “lingering” COVID-19 even after the viral infection has cleared?</p>
<p>Despite these uncertainties, the medical community needs to recognize that, in the appropriate patients, dampening immune responses through steroid treatment (or perhaps even more powerful autoimmune-focused therapies) is a critical weapon in combating COVID-19. Physicians and scientists must continue to build our arsenal of therapeutics around the idea that in some cases of COVID-19, controlling your response to the virus might be as important as controlling the virus itself.</p><img src="https://counter.theconversation.com/content/146255/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Matthew Woodruff's research is supported by the National Institute of Health (NIH). </span></em></p>Patients suffering from severe COVID-19 may be experiencing a rogue antibody response similar to that seen in autoimmune diseases. The findings offer new approaches for COVID-19 therapy.Matthew Woodruff, Instructor, Lowance Center for Human Immunology, Emory UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1433232020-08-26T12:22:26Z2020-08-26T12:22:26ZDeclining antibodies and immunity to COVID-19 – why the worry?<figure><img src="https://images.theconversation.com/files/350678/original/file-20200731-25-14azhjx.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C6540%2C4442&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">An artist's impression of antibodies (red and blue) responding to an infection with the new coronavirus SARS-CoV-2 (purple). </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/antibodies-responding-to-covid-19-royalty-free-illustration/1227513276?adppopup=true">KTSDESIGN/SCIENCE PHOTO LIBRARY / Getty Images</a></span></figcaption></figure><p>Most people are aware that testing for antibodies in a person’s blood can show if someone has had a specific disease, such as COVID-19. Those antibodies provide protection from getting the disease again.</p>
<p>But in a <a href="https://www.nejm.org/doi/full/10.1056/NEJMc2025179">paper published in the New England Journal of Medicine</a>, researchers found that antibody levels decline in individuals who have recovered from COVID-19, dropping by half every 36 days. Does that mean people who have recovered from COVID-19 have lost their immunity? </p>
<p><a href="https://scholar.google.com/citations?user=VMa6rFgAAAAJ&hl=en">I am a geneticist</a> interested in innate immune response – the part of the immune system that we have at birth – and how the innate immune cells “educate” antibody-producing cells about a pathogen and how to identify and destroy it. As I’ll explain, antibodies are important for immunity, but they aren’t the only factor that counts.</p>
<h2>Two arms of the immune system</h2>
<p>The immune system is made up of two parts: innate immunity and adaptive – or acquired – immunity. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/books/NBK279396/">The innate immune system</a>, which includes white blood cells called dendritic cells, monocytes and neutrophils, is present at birth and responds instantly to invaders. This group of white blood cells bombard pathogens with destructive chemicals and swallow and destroy viruses and bacteria. The innate immune system provides an instantaneous reaction to a pathogen. The problem is that it’s a blunt instrument – it responds the same way to all perceived threats. </p>
<p>The adaptive immune system, which is made up of B cells and T cells, must learn about a pathogen and its characteristics from the innate immune cells. This system takes longer to kick in, but the up side is that it is very specific and in many cases lasts a lifetime.</p>
<h2>The immune system’s memory</h2>
<p>The history of pathogen exposure is carried in so-called memory T cells and memory B cells. When an infection is defeated and gone, these cells reside in the peripheral tissues of the body such as lymph nodes or spleen and serve as a memory of the disease-causing virus. This immunological memory is responsible for the host defense and kicks into action in case of the second wave or attack of the pathogen. </p>
<p>It is normal for <a href="https://www.scientificamerican.com/article/concerns-about-waning-covid-19-immunity-are-likely-overblown/">antibody levels to decline</a> after a person has recovered from a disease. But the New England Journal of Medicine paper <a href="https://www.cidrap.umn.edu/news-perspective/2020/07/study-covid-19-antibodies-decay-quickly-after-mild-illness">raised concerns</a> because it suggests that we are losing our immunological memory – which is as bad as losing a real memory.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/351399/original/file-20200805-237-1wd13k0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/351399/original/file-20200805-237-1wd13k0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/351399/original/file-20200805-237-1wd13k0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=472&fit=crop&dpr=1 600w, https://images.theconversation.com/files/351399/original/file-20200805-237-1wd13k0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=472&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/351399/original/file-20200805-237-1wd13k0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=472&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/351399/original/file-20200805-237-1wd13k0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=593&fit=crop&dpr=1 754w, https://images.theconversation.com/files/351399/original/file-20200805-237-1wd13k0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=593&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/351399/original/file-20200805-237-1wd13k0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=593&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Basophils, Neurophils, Eosinophils and Monocytes (left) make up the innate immune system. B cells and T cells are part of the adaptive immune system.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/vector-types-of-blood-cells-erythrocytes-royalty-free-illustration/1216602031?adppopup=true">Vitalii Dumma / Getty Images</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<h2>What role do T cells play in immunity?</h2>
<p>B cells and antibodies are only part of the immune response. T cells help B cells produce antibodies – which are proteins that can bind to a specific pathogen and destroy it.</p>
<p>The way this happens is that first the B cells swallow the virus and start producing antibodies. </p>
<p>T cells cannot swallow the virus. But a type of white blood cell called an antigen-presenting cell can. After it does, it “shows” different parts of the virus to the T cells. The T cells then learn about the virus which they can now seek and destroy. </p>
<p>T cells also stick to the B cells and send them the activation signals that help B cells ramp up antibody production.</p>
<h2>If antibodies decline, what does this mean for COVID-19 immunity?</h2>
<p>It suggests that when there are fewer antibodies in the blood, there is a greater chance that a number of individual virus particles, called virions, will survive and escape destruction. Therefore, the remaining virions will continue to proliferate and cause disease.</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>
<h2>What do declining antibody levels mean for establishing herd immunity?</h2>
<p>Herd immunity refers to a population and occurs when a sufficiently high number of people within a community are immune to the virus and incapable of transmitting it. That provides protection for those who are still vulnerable. For example, if 60% of people are protected against COVID – because they have survived the infection and carry antibodies – it might protect (via less frequent interactions) the remaining 40% from getting sick. </p>
<p>But the results in the New England Journal of Medicine suggest that people with lower levels of antibody may still have the virus and may not have symptoms of the disease. </p>
<p>That means that if these people with low antibody levels hang around healthy, uninfected people, they present a danger to them because they can transmit the virus. </p>
<h2>When antibody levels fall, does immunity disappear?</h2>
<p>In general, the answer is no. If the virus attempts to cause a second infection, the memory B and T cells are able to recognize it, multiply million of times and defend the body against the virus, preventing it from triggering another full-blown infection. </p>
<p>The protection provided by memory T and B cells is the reason that vaccine-based protection works.</p>
<p>However, there are exceptions. A lifelong vaccine against the flu does not work because flu’s genetic code changes rapidly, altering the appearance of the flu, and therefore requires a new vaccine every season. </p>
<p>But with SARS-CoV-2, the problem as I see it, seems to be that those <a href="https://doi.org/10.1038/s41467-020-17292-4">memory T cells </a><a href="https://doi.org/10.1038/s41591-020-1038-6">and B cells</a> seem to be wiped out. </p>
<p>Antibodies are proteins and last for only between three and four weeks in the blood circulation. To keep antibody levels high, B cells need to replenish them with a fresh supply. But in COVID-19, the declining antibody levels suggest that the cells that produce these antibodies are not present in sufficient numbers, which would explain the drop in antibody levels. Studies of how long immunity from COVID-19 last may shed more light, but for now we do not know the reason why.</p><img src="https://counter.theconversation.com/content/143323/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Alexander (Sasha) Poltorak does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>If antibody levels drop dramatically after an infection, what does that mean for immunity? An expert explains how B and T cells contribute to immunity and why antibodies don’t tell the full story.Alexander (Sasha) Poltorak, Professor of Immunology, Tufts UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1449912020-08-25T12:24:42Z2020-08-25T12:24:42ZA man was reinfected with coronavirus after recovery – what does this mean for immunity?<figure><img src="https://images.theconversation.com/files/354454/original/file-20200824-22-kbunl3.jpg?ixlib=rb-1.1.0&rect=14%2C36%2C4808%2C3176&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Is it possible to get COVID-19 twice?</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/man-wearing-a-face-mask-as-a-precautionary-measure-against-news-photo/1228166500?adppopup=true">May James/AFP via Getty Images</a></span></figcaption></figure><p>A 33-year old man was found to have <a href="https://www.statnews.com/2020/08/24/first-covid-19-reinfection-documented-in-hong-kong-researchers-say/">a second SARS-CoV-2 infection</a> some four-and-a-half months after he was diagnosed with his first, from which he recovered. The man, who showed no symptoms, was diagnosed when he returned to Hong Kong after a trip to Spain. </p>
<p><a href="https://scholar.google.com/citations?user=ubfhdQwAAAAJ&hl=en">I am a virologist</a> with expertise in coronaviruses and enteroviruses, and I’ve been curious about reinfections since the beginning of the pandemic. Because people infected with SARS-CoV-2 can often test positive for the virus for weeks to months, likely due to the sensitivity of the test and <a href="https://doi.org/10.1002/jmv.25952">leftover RNA fragments</a>, the only way to really answer the question of reinfection is by sequencing the viral genome at the time of each infection and looking for differences in the genetic code. </p>
<p>There is no published peer-review report on this man – only a press release from the University of Hong Kong – although reports say the work will be published in the journal <a href="https://academic.oup.com/cid">Clinical Infectious Diseases</a>. Here I address some questions raised by the current news reports. </p>
<h2>Why wasn’t the man immune to reinfection?</h2>
<p>Immunity to endemic coronaviruses – those that cause symptoms of the common cold – <a href="http://doi.org/10.1136/adc.58.7.500">is relatively short-lived</a>, <a href="http://doi.org/10.1017/s0950268800048019">with reinfections occurring</a> even within the same season. So it isn’t completely surprising that reinfection with SARS-CoV-2, the virus that causes COVID-19, might be possible.</p>
<p><a href="https://www.ncbi.nlm.nih.gov/books/NBK279396/">Immunity is complex and involves multiple mechanisms</a> in the body. That includes the generation of antibodies – through what’s known as the adaptive immune response – and through the actions of T-cells, which can help to educate the immune system and to specifically eliminate virus-infected cells. However, researchers around the world are still learning about immunity to this virus and so can’t say for sure, based on this one case, whether reinfection will be a cause for broad concern.</p>
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<h2>How different is the second strain that infected the Hong Kong man?</h2>
<p>“Strain” has a particular definition when referring to viruses. Often a different “strain” is a virus that behaves differently in some way. The coronavirus that infected this man in Europe is likely not a new strain. </p>
<p>A <a href="https://www.statnews.com/2020/08/24/first-covid-19-reinfection-documented-in-hong-kong-researchers-say/">STAT News article</a> reports that the <a href="https://nextstrain.org/ncov/global">genetic make up of the sequenced virus</a> from the patient’s second infection had 24 nucleotides – building blocks of the virus’s RNA genome – that differed from the <a href="https://www.ncbi.nlm.nih.gov/nuccore/1798174254">SARS-CoV-2 isolate</a> that infected him the first time. </p>
<p>SARS-CoV-2 has a genome that is made up of about 30,000 nucleotides, so the virus from the man’s second infection was roughly 0.08% different than the original in genome sequence. That shows that the virus that caused the second infection was new; not a recurrence of the first virus. </p>
<h2>The man was asymptomatic – what does that mean?</h2>
<p>The man wasn’t suffering any of the hallmark COVID-19 symptoms which might mean he had some degree of protective immunity to the second infection because he didn’t seem sick. But this is difficult to prove.</p>
<p>I see three possible explanations. The first is that the immunity he gained from the first infection protected him and allowed for a mild second infection. Another possibility is that the infection was mild because he was presymptomatic, and went on to develop symptoms in the coming days. Finally, sometimes infections with SARS-CoV-2 are asymptomatic – at the moment it is difficult to determine whether this was due to the differences in the virus or in the host.</p>
<h2>What can we say about reinfection based on this one case?</h2>
<p>Only that it seems to be possible after enough time has elapsed. We do not know how likely or often it is to occur.</p>
<h2>Should people who have recovered from COVID-19 still wear a mask?</h2>
<p>As we are still learning about how humans develop immunity to SARS-CoV-2 after infection, my recommendation is for continued masking, hand hygiene and distancing practices, even after recovery from COVID-19, to protect against the potential for reinfection.</p><img src="https://counter.theconversation.com/content/144991/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Megan Culler Freeman is funded by the Pediatric Infectious Diseases Society St. Jude Children's Research Hospital Fellowship in Basic and Translational Research. </span></em></p>Reports describe a Hong Kong man who was reinfected with the coronavirus after returning from Europe. Does that mean he wasn’t immune after the first infection?Megan Culler Freeman, Pediatric Infectious Diseases Fellow, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1441052020-08-21T12:37:51Z2020-08-21T12:37:51ZI’m a lung doctor testing the blood plasma from COVID-19 survivors as a treatment for the sick – a century-old idea that could be a fast track to treatment<figure><img src="https://images.theconversation.com/files/353706/original/file-20200819-42831-ejqrr6.jpg?ixlib=rb-1.1.0&rect=18%2C0%2C5988%2C4016&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A nurse holds plasma donated by a man who recovered from COVID-19.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/nurse-lina-acevedo-checks-the-plasma-donated-by-a-man-who-news-photo/1266354320?adppopup=true">Guillermo Legaria /Getty Images South America</a></span></figcaption></figure><p>Imagine going to the doctor for a cough and getting a transfusion of blood from a goat. It probably sounds strange today, but that is exactly how antibody therapy started in the late 1800s. </p>
<p>Researchers found that plasma, the part of blood left when you get rid of the cells, had healing properties. In fact, the first Nobel Prize in physiology or medicine was awarded to Emil von Behring in 1901 for his <a href="https://doi.org/10.1080/19420862.2017.1325051">work using this approach to treat diphtheria</a>. </p>
<p>Scientists understand healing properties of plasma come from antibodies, which are proteins in the blood that recognize and destroy foreign invaders. The goal of a vaccine is to induce the body to make more of these protective antibodies and lessen the severity of the infection or prevent it altogether. As Americans wait for a COVID-19 vaccine, antibody therapy provides a potentially effective treatment option – but one that warrants further study. </p>
<p>As a <a href="https://scholar.google.com/citations?user=1TStnTcAAAAJ&hl=en&oi=ao">physician-scientist</a> in pulmonary and critical care medicine, I take care of patients with lung diseases and those who are critically ill in the intensive care unit. I also study the role of antibodies and the cells that make them, called B cells, in lung disease. So when the worst public health crisis in a hundred years struck in my first year out of training, like many of my colleagues, I saw it as a call to arms and an opportunity to rigorously test the power of plasma. That quest has become even more important since U.S. Food and Drug Administration just issued an <a href="https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment">emergency use authorization</a> for convalescent plasma, which the Trump administration has dubbed a <a href="https://www.statnews.com/2020/08/23/fda-under-pressure-from-trump-expected-to-authorize-blood-plasma-as-covid-19-treatment/">“major therapeutic breakthrough.”</a> </p>
<h2>The most efficient laboratory – your own immune system</h2>
<p>Since von Behring’s pioneering work, antibodies have been used to <a href="https://doi.org/10.1093/clinids/21.1.150">treat a variety of different infections</a>. This approach waned with the advent of antibiotics in the 1930s. </p>
<p>In the case of epidemics of novel infections, antibodies have reemerged as a therapeutic partly due to one factor: time. Developing a drug in the laboratory takes a long time. In the case of antibodies, the human immune system does this for us. Our bodies are equipped with <a href="https://doi.org/10.1038/s41586-019-0879-y">an astounding repertoire of B cells</a> capable of making up to one quadrillion different antibodies. </p>
<p>Each one of these antibodies can recognize different parts of an infection. When a B cell recognizes a virus like SARS-CoV-2, which causes COVID-19, as foreign, that B cell makes antibodies that then float around in the blood, binding to the viruses and protecting us from infection. </p>
<p>Three to four weeks after a person recovers from the infection, doctors can harvest these antibodies in what is known as convalescent plasma. If effective, this provides a fast track to treatment. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/353711/original/file-20200819-25336-ubg3ze.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Man attached to ventilator." src="https://images.theconversation.com/files/353711/original/file-20200819-25336-ubg3ze.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/353711/original/file-20200819-25336-ubg3ze.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/353711/original/file-20200819-25336-ubg3ze.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/353711/original/file-20200819-25336-ubg3ze.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/353711/original/file-20200819-25336-ubg3ze.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/353711/original/file-20200819-25336-ubg3ze.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/353711/original/file-20200819-25336-ubg3ze.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Physicians are hoping that convalescent plasma will prevent patients with mild disease from progressing to severe when they require a ventilator.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/patient-who-is-treated-with-a-helmet-based-ventilator-lies-news-photo/1227820244?adppopup=true">Go Nakamura/Getty Images North America</a></span>
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</figure>
<h2>Opportunity in crisis</h2>
<p><a href="https://doi.org/10.1093/infdis/jiu396">Convalescent plasma has been tried in recent epidemics</a> such as SARS, MERS and Ebola. In each case, there has been at least some evidence that the treatment is safe and may be effective. </p>
<p>Fortunately for humanity, these outbreaks have been relatively limited in scope, preventing the kinds of numbers necessary in clinical trials to demonstrate that a treatment works. The COVID-19 pandemic, as devastating as it has been, provides a unique opportunity to study whether convalescent plasma is effective.</p>
<p>The pandemic was a chance to do important work to understand the biology of the disease and how to treat it. I am now helping to establish and lead a <a href="https://clinicaltrials.gov/ct2/show/NCT04374565?term=NCT04374565&draw=2&rank=1">trial testing the effect of convalescent plasma</a> in COVID-19 patients. </p>
<p>In our trial, my colleagues and I have targeted patients who are hospitalized but not yet critically ill. We hope to test whether convalescent plasma can prevent the progression of this disease to critical illness and death. Entering into the sixth month of this pandemic, we have now completed enrolling patients for the trial and our analysis is underway.</p>
<p>Hopefully, in the coming months this trial will help determine whether convalescent plasma is an effective treatment for some patients with COVID-19. Importantly, we will not only evaluate the clinical outcomes but we will also study the immune system responses to convalescent plasma so we can better understand the underlying mechanisms by which it impacts disease. </p>
<h2>Early studies show promise</h2>
<p>Several studies have already shown promise for convalescent plasma in COVID-19. A retrospective study from investigators in <a href="https://doi.org/10.1101/2020.05.20.20102236">New York</a> as well as a prospective study out of <a href="https://doi.org/10.1016/j.ajpath.2020.08.001">Houston</a> suggest that convalescent plasma may be effective, particularly when given early, before the patient is on a ventilator. Additionally, in a recent report from the Expanded Access Program for convalescent plasma, <a href="https://doi.org/10.1101/2020.08.12.20169359">an analysis of over 35,000 transfused patients</a> showed that earlier transfusion with higher concentrations of antibodies was associated with improved outcomes.</p>
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<p>Convalescent plasma is also the foundation upon which specific antibody therapy is based. In specific antibody therapy, the specific neutralizing antibodies present in convalescent plasma that bind to the virus are isolated and then synthesized in the lab. This has been shown to be <a href="https://doi.org/10.1056/NEJMoa1910993">effective in the case of Ebola</a>. Researchers have now <a href="https://doi.org/10.1056/NEJMoa1910993">isolated these neutralizing antibodies for COVID-19</a>, and clinical trials are underway to test their efficacy as well. </p>
<p>These studies and ours provide important steps in developing therapeutics. But even during the urgency of a pandemic, it is critically important to perform large, randomized phase 3 clinical trials before changing clinical practice. </p>
<p>After initially delaying it over concerns for lack of strong evidence, the Food and Drug Administration <a href="https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment">recently approved an emergency use authorization</a> for convalescent plasma. Politics aside, this is likely to increase the use of convalescent plasma in COVID-19 patients outside of clinical trials. </p>
<p>From a scientific point of view, I and many researchers like me are <a href="https://abcnews.go.com/Health/fda-issue-emergency-authorization-convalescent-plasma-treatment-hospitalized/story?id=72556828">concerned</a> about the effect this may have on the ability to enroll patients in these important randomized trials wherein the subject has a 50-50 chance of getting the plasma treatment versus placebo. Only by following these rigorous standards of evidence can we finally answer the question: Does convalescent plasma work? In this case, no goat’s blood needed.</p>
<p><em>This story has been updated to reflect the FDA’s emergency use authorization of convalescent plasma to treat COVID-19.</em></p><img src="https://counter.theconversation.com/content/144105/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jeffrey M. Sturek does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>In the blood of COVID-19 survivors are antibodies that can defeat SARS-CoV-2. Researchers are testing whether these antibodies can be collected and injected into others to save them from the virus.Jeffrey M. Sturek, Assistant Professor of Medicine, University of VirginiaLicensed as Creative Commons – attribution, no derivatives.