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Immune T Cells May Offer Lasting Protection Against COVID-19

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Healthy human T Cell
Caption: Scanning electron micrograph of a human T lymphocyte (T cell) from a healthy donor’s immune system. Credit: National Institute of Allergy and Infectious Diseases/NIH

Much of the study on the immune response to SARS-CoV-2, the novel coronavirus that causes COVID-19, has focused on the production of antibodies. But, in fact, immune cells known as memory T cells also play an important role in the ability of our immune systems to protect us against many viral infections, including—it now appears—COVID-19.

An intriguing new study of these memory T cells suggests they might protect some people newly infected with SARS-CoV-2 by remembering past encounters with other human coronaviruses. This might potentially explain why some people seem to fend off the virus and may be less susceptible to becoming severely ill with COVID-19.

The findings, reported in the journal Nature, come from the lab of Antonio Bertoletti at the Duke-NUS Medical School in Singapore [1]. Bertoletti is an expert in viral infections, particularly hepatitis B. But, like so many researchers around the world, his team has shifted their focus recently to help fight the COVID-19 pandemic.

Bertoletti’s team recognized that many factors could help to explain how a single virus can cause respiratory, circulatory, and other symptoms that vary widely in their nature and severity—as we’ve witnessed in this pandemic. One of those potential factors is prior immunity to other, closely related viruses.

SARS-CoV-2 belongs to a large family of coronaviruses, six of which were previously known to infect humans. Four of them are responsible for the common cold. The other two are more dangerous: SARS-CoV-1, the virus responsible for the outbreak of Severe Acute Respiratory Syndrome (SARS), which ended in 2004; and MERS-CoV, the virus that causes Middle East Respiratory Syndrome (MERS), first identified in Saudi Arabia in 2012.

All six previously known coronaviruses spark production of both antibodies and memory T cells. In addition, studies of immunity to SARS-CoV-1 have shown that T cells stick around for many years longer than acquired antibodies. So, Bertoletti’s team set out to gain a better understanding of T cell immunity against the novel coronavirus.

The researchers gathered blood samples from 36 people who’d recently recovered from mild to severe COVID-19. They focused their attention on T cells (including CD4 helper and CD8 cytotoxic, both of which can function as memory T cells). They identified T cells that respond to the SARS-CoV-2 nucleocapsid, which is a structural protein inside the virus. They also detected T cell responses to two non-structural proteins that SARS-CoV-2 needs to make additional copies of its genome and spread. The team found that all those recently recovered from COVID-19 produced T cells that recognize multiple parts of SARS-CoV-2.

Next, they looked at blood samples from 23 people who’d survived SARS. Their studies showed that those individuals still had lasting memory T cells today, 17 years after the outbreak. Those memory T cells, acquired in response to SARS-CoV-1, also recognized parts of SARS-CoV-2.

Finally, Bertoletti’s team looked for such T cells in blood samples from 37 healthy individuals with no history of either COVID-19 or SARS. To their surprise, more than half had T cells that recognize one or more of the SARS-CoV-2 proteins under study here. It’s still not clear if this acquired immunity stems from previous infection with coronaviruses that cause the common cold or perhaps from exposure to other as-yet unknown coronaviruses.

What’s clear from this study is our past experiences with coronavirus infections may have something important to tell us about COVID-19. Bertoletti’s team and others are pursuing this intriguing lead to see where it will lead—not only in explaining our varied responses to the virus, but also in designing new treatments and optimized vaccines.

Reference:

[1] SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Le Bert N, Tan AT, Kunasegaran K, et al. Nature. 2020 July 15. [published online ahead of print]

Links:

Coronavirus (COVID-19) (NIH)

Overview of the Immune System (National Institute of Allergy and Infectious Diseases/NIAID)

Bertoletti Lab (Duke-NUS Medical School, Singapore)


Finding Antibodies that Neutralize SARS-CoV-2

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Neutralizing Antibodies
Caption: Model of three neutralizing antibodies (blue, purple and orange) bound to the spike protein, which allows SARS-CoV-2 attach to our cells. Credit: Christopher Barnes and Pamela Bjorkman, California Institute of Technology, Pasadena.

It’s now clear that nearly everyone who recovers from coronavirus disease 2019 (COVID-19) produces antibodies that specifically target SARS-CoV-2, the novel coronavirus that causes the infection. Yet many critical questions remain. A major one is: just how well do those particular antibodies neutralize the virus to fight off the infection and help someone recover from COVID-19? Fortunately, most people get better—but should the typical antibody response take the credit?

A new NIH-funded study of nearly 150 people who recovered from COVID-19 offers some essential insight. The study, published in the journal Nature, shows that most people, in fact, do produce antibodies that can effectively neutralize SARS-CoV-2. But there is a catch: 99 percent of the study’s participants didn’t make enough neutralizing antibodies to mount an ideal immune response.

The good news is that when researchers looked at individuals who mounted a strong immune response, they were able to identify three antibodies (depicted above) that were extremely effective at neutralizing SARS-CoV-2. By mass-producing copies of these antibodies as so-called monoclonal antibodies, the researchers can now better evaluate their potential as treatments to help people who don’t make strongly neutralizing antibodies, or not enough of them.

These findings come from a team led by Michel Nussenzweig, Paul Bieniasz, and Charles Rice at The Rockefeller University, New York, and Pamela Bjorkman at the California Institute of Technology, Pasadena. In the Nussenzweig lab, the team has spent years searching for broadly neutralizing antibodies against the human immunodeficiency virus (HIV). In response to the COVID-19 pandemic and its great urgency, Nussenzweig and team shifted their focus recently to look for promising antibodies against SARS-CoV-2.

Antibodies are blood proteins that the immune system makes to neutralize viruses or other foreign invaders. The immune system doesn’t make just one antibody to thwart an invader; it makes a whole family of antibodies. But not all antibodies in that family are created equal. They can vary widely in where they latch onto a virus like SARS-CoV-2, and that determines how effective each will be at blocking it from infecting human cells. That’s one reason why people respond differently to infections such as COVID-19.

In early April, Nussenzweig’s team began analyzing samples from volunteer survivors who visited The Rockefeller Hospital to donate plasma, which contains the antibodies. The volunteers had all recovered from mild-to-severe cases of COVID-19, showing their first signs of illness about 40 days prior to their first plasma collection.

Not surprisingly, all volunteers had produced antibodies in response to the virus. To test the strength of the antibodies, the researchers used a special assay that shows how effective each one is at blocking the virus from infecting human cells in lab dishes.

Overall, most of the plasma samples—118 of 149—showed at best poor to modest neutralizing activity. In about one-third of individuals, their plasma samples had below detectable levels of neutralizing activity. It’s possible those individuals just resolved the infection quickly, before more potent antibodies were produced.

More intriguing to the researchers were the results from two individuals that showed an unusually strong ability to neutralize SARS-CoV-2. Among these two “elite responders” and four other individuals, the researchers identified 40 different antibodies that could neutralize SARS-CoV-2. But again, not all antibodies are created equal. Three neutralized the virus even when present at extremely low levels, and they now will be studied further as possible monoclonal antibodies.

The team determined that those strongly neutralizing antibodies bind three distinct sites on the receptor-binding domain (RBD) of the coronavirus spike protein. This portion of the virus is important because it allows SARS-CoV-2 to bind and infect human cells. Importantly, when the researchers looked more closely at plasma samples with poor neutralizing ability, they found that they also contained those RBD-binding antibodies, just not in very large numbers.

These findings help not only to understand the immune response to COVID-19, they are also critical for vaccine design, revealing what a strong neutralizing antibody for SARS-CoV-2 should look like to help the immune system win. If a candidate vaccine can generate such strongly neutralizing antibodies, researchers will know that they are on the right track.

While this research showed that there’s a lot of variability in immune responses to SARS-CoV-2, it appears that most of us are inherently capable of producing antibodies to neutralize this devastating virus. That brings more reason for hope that the many vaccines now under study to elicit such neutralizing antibodies in sufficient numbers may afford us with much-needed immune protection.

Reference:

[1] Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Robbiani DF, Gaebler C, Muecksch F, et al. Nature. 2020 Jun 18. [Published online ahead of print].

Links:

Coronavirus (COVID-19) (NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)

Nussenzweig Lab (The Rockefeller University, New York)

Bjorkman Lab (California Institute of Technology, Pasadena)

NIH Support: National Institute of Allergy and Infectious Diseases


Discussing the Need for Reliable Antibody Testing for COVID-19

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At Home with Ned Sharpless

There’s been a great deal of discussion about whether people who recover from coronavirus disease 2019 (COVID-19), have neutralizing antibodies in their bloodstream to guard against another infection. Lots of interesting data continue to emerge, including a recent preprint from researchers at Sherman Abrams Laboratory, Brooklyn, NY [1]. They tested 11,092 people for antibodies in May at a local urgent care facility and found nearly half had long-lasting IgG antibodies, a sign of exposure to the novel coronavirus SARS-CoV-2, the cause of COVID-19. The researchers also found a direct correlation between the severity of a person’s symptoms and their levels of IgG antibodies.

This study and others remind us of just how essential antibody tests will be going forward to learn more about this challenging pandemic. These assays must have high sensitivity and specificity, meaning there would be few false negatives and false positives, to tell us more about a person’s exposure to SARS-CoV-2. While there are some good tests out there, not all are equally reliable.

Recently, I had a chance to discuss COVID-19 antibody tests, also called serology tests, with Dr. Norman “Ned” Sharpless, Director of NIH’s National Cancer Institute (NCI). Among his many talents, Dr. Sharpless is an expert on antibody testing for COVID-19. You might wonder how NCI got involved in COVID-19 testing. Well, you’re going to find out. Our conversation took place while videoconferencing, with him connecting from North Carolina and me linking in from my home in Maryland. Here’s a condensed transcript of our chat:

Collins: Ned, thanks for joining me. Maybe we should start with the basics. What are antibodies anyway?

Sharpless: Antibodies are proteins that your body makes as part of the learned immune system. It’s the immunity that responds to a bacterium or a virus. In general, if you draw someone’s blood after an infection and test it for the presence of these antibodies, you can often know whether they’ve been infected. Antibodies can hang around for quite a while. How long exactly is a topic of great interest, especially in terms of the COVID-19 pandemic. But we think most people infected with coronavirus will make antibodies at a reasonably high level, or titer, in their peripheral blood within a couple of weeks of the infection.

Collins: What do antibodies tell us about exposure to a virus?

Sharpless: A lot of people with coronavirus are infected without ever knowing it. You can use these antibody assays to try and tell how many people in an area have been infected, that is, you can do a so-called seroprevalence survey.

You could also potentially use these antibody assays to predict someone’s resistance to future infection. If you cleared the infection and established immunity to it, you might be resistant to future infection. That might be very useful information. Maybe you could make a decision about how to go out in the community. So, that part is of intense interest as well, although less scientifically sound at the moment.

Collins: I have a 3D-printed model of SARS-CoV-2 on my desk. It’s sort of a spherical virus that has spike proteins on its surface. Do the antibodies interact with the virus in some specific ways?

Sharpless: Yes, antibodies are shaped like the letter Y. They have two binding domains at the head of each Y that will recognize something about the virus. We find antibodies in the peripheral blood that recognize either the virus nucleocapsid, which is the structural protein on the inside; or the spikes, which stick out and give coronavirus its name. We know now that about 99 percent of people who get infected with the virus will develop antibodies eventually. Most of those antibodies that you can detect to the spike proteins will be neutralizing, which means they can kill the virus in a laboratory experiment. We know from other viruses that, generally, having neutralizing antibodies is a promising sign if you want to be immune to that virus in the future.

Collins: Are COVID-19 antibodies protective? Are there reports of people who’ve gotten better, but then were re-exposed and got sick again?

Sharpless: It’s controversial. People can shed the virus’s nucleic acid [genetic material], for weeks or even more than a month after they get better. So, if they have another nucleic acid test it could be positive, even though they feel better. Often, those people aren’t making a lot of live virus, so it may be that they never stopped shedding the virus. Or it may be that they got re-infected. It’s hard to understand what that means exactly. If you think about how many people worldwide have had COVID-19, the number of legitimate possible reinfection cases is in the order of a handful. So, it’s a pretty rare event, if it happens at all.

Collins: For somebody who does have the antibodies, who apparently was previously infected, do they need to stop worrying about getting exposed? Can they can do whatever they want and stop worrying about distancing and wearing masks?

Sharpless: No, not yet. To use antibodies to predict who’s likely to be immune, you’ve got to know two things.

First: can the tests actually measure antibodies reliably? I think there are assays available to the public that are sufficiently good for asking this question, with an important caveat. If you’re trying to detect something that’s really rare in a population, then any test is going to have limitations. But if you’re trying to detect something that’s more common, as the virus was during the recent outbreak in Manhattan, I think the tests are up to the task.

Second: does the appearance of an antibody in the peripheral blood mean that you’re actually immune or you’re just less likely to get the virus? We don’t know the answer to that yet.

Collins: Let’s be optimistic, because it sounds like there’s some evidence to support the idea that people who develop these antibodies are protected against infection. It also sounds like the tests, at least some of them, are pretty good. But if there is protection, how long would you expect it to last? Is this one of those things where you’re all set for life? Or is this going to be something where somebody’s had it and might get it again two or three years from now, because the immunity faded away?

Sharpless: Since we have no direct experience with this virus over time, it’s hard to answer. The potential for this cell-based humoral immunity to last for a while is there. For some viruses, you have a long-lasting antibody protection after infection; for other viruses, not so much.

So that’s the unknown thing. Is immunity going to last for a while? Of course, if one were to bring up the topic of vaccines, that’s very important to know, because you would want to know how often one would have to give that vaccine, even under optimal circumstances.

Collins: Yes, our conversation about immunity is really relevant to the vaccines we’re trying to develop right now. Will these vaccines be protective for long periods of time? We sure hope so, but we’ve got to look carefully at the issue. Let’s come back, though, to the actual performance of the tests. The NCI has been right in the middle of trying to do this kind of validation. How did that happen, and how did that experience go?

Sharpless: Yes, I think one might ask: why is the National Cancer Institute testing antibody kits for the FDA? It is unusual, but certainly not unheard of, for NCI to take up problems like this during a time of a national emergency. During the HIV era, NCI scientists, along with others, identified the virus and did one of the first successful compound screens to find the drug AZT, one of the first effective anti-HIV therapies.

NCI’s Frederick National Lab also has a really good serology lab that had been predominantly working on human papillomavirus (HPV). When the need arose for serologic testing a few months ago, we pivoted that lab to a coronavirus serology lab. It took us a little while, but eventually we rounded up everything you needed to create positive and negative reference panels for antibody testing.

At that time, the FDA had about 200 manufacturers making serology tests that hoped for approval to sell. The FDA wanted some performance testing of those assays by a dispassionate third party. The Frederick National Lab seemed like the ideal place, and the manufacturers started sending us kits. I think we’ve probably tested on the order of 20 so far. We give those data back to the FDA for regulatory decision making. They’re putting all the data online.

Collins: How did it look? Are these all good tests or were there some clunkers?

Sharpless: There were some clunkers. But we were pleased to see that some of the tests appear to be really good, both in our hands and those of other groups, and have been used in thousands of patients.

There are a few tests that have sensitivities that are pretty high and specificities well over 99 percent. The Roche assay has a 99.8 percent specificity claimed on thousands of patients, and for the Mt. Sinai assay developed and tested by our academic collaborators in a panel of maybe 4,000 patients, they’re not sure they’ve ever had a false positive. So, there are some assays out there that are good.

Collins: There’s been talk about how there will soon be monoclonal antibodies directed against SARS-CoV-2. How are those derived?

Sharpless: They’re picked, generally, for appearing to have neutralizing activity. When a person makes antibodies, they don’t make one antibody to a pathogen. They make a whole family of them. And those can be individually isolated, so you can know which antibodies made by a convalescent individual really have virus-neutralizing capacity. That portion of the antibody that recognizes the virus can be engineered into a manufacturing platform to make monoclonal antibodies. Monoclonal means one kind of antibody. That approach has worked for other infectious diseases and is an interesting idea here too.

Collins: I can say a bit about that, because we are engaged in a partnership with industry and FDA called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). One of the hottest ideas right now is monoclonal antibodies, and we’re in the process of devising a master protocol, one for outpatients and one for inpatients.

Janet Woodcock of Operation Warp Speed tells me 21 companies are developing monoclonal antibodies. While doing these trials, we’d love to do comparisons, which is why it’s good to have an organization like ACTIV to bring everybody together, making sure you’re using the same endpoints and the same laboratory measures. I think that, maybe even by late summer, we might have some results. For people who are looking at what’s the next most-hopeful therapeutic option for people who are really sick with COVID-19, so far we have remdesivir. It helps, but it’s not a home run. Maybe monoclonal antibodies will be the next thing that really gives a big boost in survival. That would be the hope.

Ned, let me ask you one final question about herd, or group, immunity. One hears a bit about that in terms of how we are all going to get past this COVID-19 pandemic. What’s that all about?

Sharpless: Herd immunity is when a significant portion of the population is immune to a pathogen, then that pathogen will die out in the population. There just aren’t enough susceptible people left to infect. What the threshold is for herd immunity depends on how infectious the virus is. For a highly infectious virus, like measles, maybe up to 90 percent of the population must be immune to get herd immunity. Whereas for other less-infectious viruses, it may only be 50 percent of the population that needs to be immune to get herd immunity. It’s a theoretical thing that makes some assumptions, such as that everybody’s health status is the same and the population mixes perfectly every day. Neither of those are true.

How well that actual predictive number will work for coronavirus is unknown. The other thing that’s interesting is a lot of that work has been based on vaccines, such as what percentage do you have to vaccinate to get herd immunity? But if you get to herd immunity by having people get infected, so-called natural herd immunity, that may be different. You would imagine the most susceptible people get infected soonest, and so the heterogeneity of the population might change the threshold calculation.

The short answer is nobody wants to find out. No one wants to get to herd immunity for COVID-19 through natural herd immunity. The way you’d like to get there is with a vaccine that you then could apply to a large portion of the population, and have them acquire immunity in a more safe and controlled manner. Should we have an efficacious vaccine, this question will loom large: how many people do we need to vaccinate to really try and protect vulnerable populations?

Collins: That’s going to be a really critical question for the coming months, as the first large-scale vaccine trials get underway in July, and we start to see how they work and how successful and safe they are. But I’m also worried seeing some reports that 1 out of 5 Americans say they wouldn’t take a vaccine. It would be truly a tragedy if we have a safe and effective vaccine, but we don’t get enough uptake to achieve herd immunity. So, we’ve got some work to do on all fronts, that’s for sure.

Ned, I want to thank you for sharing all this information about antibodies and serologies and other things, as well as thank you for your hard work with all your amazing NCI colleagues.

Sharpless: Thanks for having me.

Reference:
[1] SARS-CoV-2 IgG Antibody Responses in New York City. Reifer J, Hayum N, Heszkel B, Klagsbald I, Streva VA. medRxiv. Preprint posted May 26, 2020.

Links:

Coronavirus (COVID-19) (NIH)

At NCI, A Robust and Rapid Response to the COVID-19 Pandemic. Norman E. Sharpless. Cancer Currents Blog. April 17, 2020 (National Cancer Institute/NIH)

Serological Testing for SARS-CoV-2 Antibodies (American Medical Association, Chicago)

COVID-19 Antibody Testing Primer (Infectious Diseases Society of America, Arlington, VA)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (NIH)


How Mucus Tames Microbes

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Scanning EM of mucus
Credit: Katharina Ribbeck, Massachusetts Institute of Technology, Cambridge

Most of us think of mucus as little more than slimy and somewhat yucky stuff that’s easily ignored until you come down with a cold like the one I just had. But, when it comes to our health, there’s much more to mucus than you might think.

Mucus covers the moist surfaces of the human body, including the eyes, nostrils, lungs, and gastrointestinal tract. In fact, the average person makes more than a liter of mucus each day! It houses trillions of microbes and serves as a first line of defense against the subset of those microorganisms that cause infections. For these reasons, NIH-funded researchers, led by Katharina Ribbeck, Massachusetts Institute of Technology, Cambridge, are out to gain a greater understanding of the biology of healthy mucus—and then possibly use that knowledge to develop new therapeutics.

Ribbeck’s team used a scanning electron microscope to take the image of mucus you see above. You’ll notice right away that mucus doesn’t look like simple slime at all. In fact, if you could zoom into this complex web, you’d discover it’s made up of mucin proteins and glycans, which are sugar molecules that resemble bottle brushes.

Ribbeck and her colleagues recently discovered that the glycans in healthy mucus play a long-overlooked role in “taming” bacteria that might make us ill [1]. This work builds on their previous findings that mucus interferes with bacterial behavior, preventing these bugs from attaching to surfaces and communicating with each other [2].

In their new study, published in Nature Microbiology, Ribbeck, lead author Kelsey Wheeler, and their colleagues studied mucus and its interactions with Pseudomonas aeruginosa. This bacterium is a common cause of serious lung infections in people with cystic fibrosis or compromised immune systems.

The researchers found that in the presence of glycans, P. aeruginosa was rendered less harmful and infectious. The bacteria also produced fewer toxins. The findings show that it isn’t just that microbes get trapped in a tangled web within mucus, but rather that glycans have a special ability to moderate the bugs’ behavior. The researchers also have evidence of similar interactions between mucus and other microorganisms, such as those responsible for yeast infections.

The new study highlights an intriguing strategy to tame, rather than kill, bacteria to manage infections. In fact, Ribbeck views mucus and its glycans as a therapeutic gold mine. She hopes to apply what she’s learned to develop artificial mucus as an anti-microbial therapeutic for use inside and outside the body. Not bad for a substance that you might have thought was nothing more than slimy stuff.

References:

[1] Mucin glycans attenuate the virulence of Pseudomonas aeruginosa in infection. Wheeler KM, Cárcamo-Oyarce G, Turner BS, Dellos-Nolan S, Co JY, Lehoux S, Cummings RD, Wozniak DJ, Ribbeck K. Nat Microbiol. 2019 Oct 14.

[2] Mucins trigger dispersal of Pseudomonas aeruginosa biofilms. Co JY, Cárcamo-Oyarce, Billings N, Wheeler KM, Grindy SC, Holten-Andersen N, Ribbeck K. NPJ Biofilms Microbiomes. 2018 Oct 10;4:23.

Links:

Cystic Fibrosis (National Heart, Lung, and Blood Institute/NIH)

Video: Chemistry in Action—Katharina Ribbeck (YouTube)

Katharina Ribbeck (Massachusetts Institute of Technology, Cambridge)

NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Environmental Health Sciences; National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases


How Measles Leave the Body Prone to Future Infections

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Boy with measles
Credit: gettyimages/CHBD

As a kid who was home-schooled on a Virginia farm in the 1950s, I wasn’t around other kids very much, and so didn’t get exposed to measles. And there was no vaccine yet. Later on as a medical resident, I didn’t recognize that I wasn’t immune. So when I was hospitalized with a severe febrile illness at age 29, it took a while to figure out the diagnosis. Yes, it was measles. I have never been that sick before or since. I was lucky not to have long-term consequences, and now I’m learning that there may be even more to consider.

With the big push to get kids vaccinated, you’ve probably heard about some of the very serious complications of measles: hearing-threatening ear infections, bronchitis, laryngitis, and even life-threatening forms of pneumonia and encephalitis. But now comes word of yet another way in which the measles can be devastating—one that may also have long-term consequences for a person’s health.

In a new study in the journal Science, a research team, partly funded by NIH, found that the measles virus not only can make children deathly ill, it can cause their immune systems to forget how to ward off other common infections [1]. The virus does this by wiping out up to nearly three-quarters of the protective antibodies that a child’s body has formed in response to past microbial invaders and vaccinations. This immune “amnesia” can leave a child more vulnerable to re-contracting infections, such as influenza or respiratory syncytial virus (RSV), that they may have been protected against before they came down with measles.

The finding comes as yet another reason to feel immensely grateful that, thanks to our highly effective vaccination programs, most people born in the U.S. from the 1960s onward should never have to experience the measles.

There had been hints that the measles virus might somehow suppress a person’s immune system. Epidemiological evidence also had suggested that measles infections might lead to increased susceptibility to infection for years afterwards [2]. Scientists had even suspected this might be explained by a kind of immune amnesia. The trouble was that there wasn’t any direct proof that such a phenomenon actually existed.

In the new work, the researchers, led by Michael Mina, Tomasz Kula, and Stephen Elledge, Howard Hughes Medical Institute and Brigham and Women’s Hospital, Boston, took advantage of a tool developed a few years ago in the Elledge lab called VirScan [3]. VirScan detects antibodies in blood samples acquired as a result of a person’s past encounters with hundreds of viruses, bacteria, or vaccines, providing a comprehensive snapshot of acquired immunity at a particular moment in time.

To look for evidence of immune amnesia following the measles, the research team needed blood samples gathered from people both before and after infection. These types of samples are currently hard to come by in the U.S. thanks to the success of vaccines. By partnering with Rik de Swart, Erasmus University Medical Center, Rotterdam, Netherlands, they found the samples that they needed.

During a recent measles outbreak in the Netherlands, de Swart had gathered blood samples from children living in communities with low vaccination rates. Elledge’s group used VirScan with 77 unvaccinated kids to measure antibodies in samples collected before and about two months after their measles infections.

That included 34 children who had mild infections and 43 who had severe measles. The researchers also examined blood samples from five children who remained uninfected and 110 kids who hadn’t been exposed to the measles virus.

The VirScan data showed that the infected kids, not surprisingly, produced antibodies to the measles virus. But their other antibodies dropped and seemed to be disappearing. In fact, depending on the severity of measles infection, the kids showed on average a loss of around 40 percent of their antibody memory, with greater losses in children with severe cases of the measles. In at least one case, the loss reached a whopping 73 percent.

This all resonates with me. I do recall that after my bout with the measles, I seemed to be coming down with a lot of respiratory infections. I attributed that to the lifestyle of a medical resident—being around lots of sick patients and not getting much sleep. But maybe it was more than that.

The researchers suggest that the loss of immune memory may stem from the measles virus destroying some of the long-lived cells in bone marrow. These cells remember past infections and, based on that immunological memory, churn out needed antibodies to thwart reinvading viruses.

Interestingly, after a measles infection, the children’s immune systems still responded to new infections and could form new immune memories. But it appears the measles caused long term, possibly permanent, losses of a significant portion of previously acquired immunities. This loss of immune memory put the children at a distinct disadvantage should those old bugs circulate again.

It’s important to note that, unlike measles infection, the MMR (measles, mumps, rubella) vaccine does NOT compromise previously acquired immunity. So, these findings come as yet another reminder of the public value of measles vaccination.

Prior to 1963, when the measles vaccine was developed, 3 to 4 million Americans got the measles each year. As more people were vaccinated, the incidence of measles plummeted. By the year 2000, the disease was declared eliminated from the U.S.

Unfortunately, measles has made a come back, fueled by vaccine refusals. In October, the Centers for Disease Control and Prevention (CDC) reported an estimated 1,250 measles cases in the United States so far in 2019, surpassing the total number of cases reported annually in each of the past 25 years [4].

Around the world, measles continues to infect 7 million people each year, leading to an estimated 120,000 deaths. Based on the new findings, Elledge’s team now suspects the actual toll of the measles may be five times greater, due to the effects of immune amnesia.

The good news is those numbers can be reduced if more people get the vaccine, which has been shown repeatedly in many large and rigorous studies to be safe and effective. The CDC recommends that children should receive their first dose by 12 to 15 months of age and a second dose between the ages of 4 and 6. Older people who’ve been vaccinated or have had the measles previously should consider being re-vaccinated, especially if they live in places with low vaccination rates or will be traveling to countries where measles are endemic.

References:

[1] Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Mina MJ, Kula T, Leng Y, Li M, de Vries RD, Knip M, Siljander H, Rewers M, Choy DF, Wilson MS, Larman HB, Nelson AN, Griffin DE, de Swart RL, Elledge SJ. et al. Science. 2019 Nov 1; 366 (6465): 599-606.

[2] Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Mina MJ, Metcalf CJE, De Swart RL, Osterhaus ADME, Grenfell BT. Science. 2015 May 8; 348(6235).

[3] Viral immunology. Comprehensive serological profiling of human populations using a synthetic human virome. Xu GJ, Kula T, Xu Q, Li MZ, Vernon SD, Ndung’u T, Ruxrungtham K, Sanchez J, Brander C, Chung RT, O’Connor KC, Walker B, Larman HB, Elledge SJ. Science. 2015 Jun 5;348(6239):aaa0698.

[4] Measles cases and outbreaks. Centers for Disease Control and Prevention. Oct. 11, 2019.

Links:

Measles (MedlinePlus Medical Encyclopedia/National Library of Medicine/NIH)

Measles History (Centers for Disease Control and Prevention)

Vaccines (National Institute of Allergy and Infectious Diseases/NIAID)

Vaccines Protect Your Community (Vaccines.gov)

Elledge Lab (Harvard Medical School, Boston)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases


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