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How COVID-19 Immunity Holds Up Over Time

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Antibody protection. Graph showing gradient of many antibodies early and less as time goes on

More than 215 million people in the United States are now fully vaccinated against the SARS-CoV-2 virus responsible for COVID-19 [1]. More than 40 percent—more than 94 million people—also have rolled up their sleeves for an additional, booster dose. Now, an NIH-funded study exploring how mRNA vaccines are performing over time comes as a reminder of just how important it will be to keep those COVID-19 vaccines up to date as coronavirus variants continue to circulate.

The results, published in the journal Science Translational Medicine, show that people who received two doses of either the Pfizer or Moderna COVID-19 mRNA vaccines did generate needed virus-neutralizing antibodies [2]. But levels of those antibodies dropped considerably after six months, suggesting declining immunity over time.

The data also reveal that study participants had much reduced protection against newer SARS-CoV-2 variants, including Delta and Omicron. While antibody protection remained stronger in people who’d also had a breakthrough infection, even that didn’t appear to offer much protection against infection by the Omicron variant.

The new study comes from a team led by Shan-Lu Liu at The Ohio State University, Columbus. They wanted to explore how well vaccine-acquired immune protection holds up over time, especially in light of newly arising SARS-CoV-2 variants.

This is an important issue going forward because mRNA vaccines train the immune system to produce antibodies against the spike proteins that crown the surface of the SARS-CoV-2 coronavirus. These new variants often have mutated, or slightly changed, spike proteins compared to the original one the immune system has been trained to detect, potentially dampening the immune response.

In the study, the team collected serum samples from 48 fully vaccinated health care workers at four key time points: 1) before vaccination, 2) three weeks after the first dose, 3) one month after the second dose, and 4) six months after the second dose.

They then tested the ability of antibodies in those samples to neutralize spike proteins as a correlate for how well a vaccine works to prevent infection. The spike proteins represented five major SARS-CoV-2 variants. The variants included D614G, which arose very soon after the coronavirus first was identified in Wuhan and quickly took over, as well as Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529).

The researchers explored in the lab how neutralizing antibodies within those serum samples reacted to SARS-CoV-2 pseudoviruses representing each of the five variants. SARS-CoV-2 pseudoviruses are harmless viruses engineered, in this case, to bear coronavirus spike proteins on their surfaces. Because they don’t replicate, they are safe to study without specially designed biosafety facilities.

At any of the four time points, antibodies showed a minimal ability to neutralize the Omicron spike protein, which harbors about 30 mutations. These findings are consistent with an earlier study showing a significant decline in neutralizing antibodies against Omicron in people who’ve received the initial series of two shots, with improved neutralizing ability following an additional booster dose.

The neutralizing ability of antibodies against all other spike variants showed a dramatic decline from 1 to 6 months after the second dose. While there was a marked decline over time after both vaccines, samples from health care workers who’d received the Moderna vaccine showed about twice the neutralizing ability of those who’d received the Pfizer vaccine. The data also suggests greater immune protection in fully vaccinated healthcare workers who’d had a breakthrough infection with SARS-CoV-2.

In addition to recommending full vaccination for all eligible individuals, the Centers for Disease Control and Prevention (CDC) now recommends everyone 12 years and up should get a booster dose of either the Pfizer or Moderna vaccines at least five months after completing the primary series of two shots [3]. Those who’ve received the Johnson & Johnson vaccine should get a booster at least two months after receiving the initial dose.

While plenty of questions about the durability of COVID-19 immunity over time remain, it’s clear that the rapid deployment of multiple vaccines over the course of this pandemic already has saved many lives and kept many more people out of the hospital. As the Omicron threat subsides and we start to look forward to better days ahead, it will remain critical for researchers and policymakers to continually evaluate and revise vaccination strategies and recommendations, to keep our defenses up as this virus continues to evolve.

References:

[1] COVID-19 vaccinations in the United States. Centers for Disease Control and Prevention. February 27, 2022.

[2] Neutralizing antibody responses elicited by SARS-CoV-2 mRNA vaccination wane over time and are boosted by breakthrough infection. Evans JP, Zeng C, Carlin C, Lozanski G, Saif LJ, Oltz EM, Gumina RJ, Liu SL. Sci Transl Med. 2022 Feb 15:eabn8057.

[3] COVID-19 vaccine booster shots. Centers for Disease Control and Prevention. Feb 2, 2022.

Links:

COVID-19 Research (NIH)

Shan-Lu Liu (The Ohio State University, Columbus)

NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development


COVID-19 Vaccines Protect the Family, Too

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Multigenerational family walks at the beach
Credit: Shutterstock

Any of the available COVID-19 vaccines offer remarkable personal protection against the coronavirus SARS-CoV-2. So, it also stands to reason that folks who are vaccinated will reduce the risk of spreading the virus to family members within their households. That protection is particularly important when not all family members can be immunized—as when there are children under age 12 or adults with immunosuppression in the home. But just how much can vaccines help to protect families from COVID-19 when only some, not all, in the household have immunity?

A Swedish study, published recently in the journal JAMA Internal Medicine, offers some of the first hard figures on this topic, and the findings are quite encouraging [1]. The data show that people without any immunity against COVID-19 were at considerably lower risk of infection and hospitalization when other members of their family had immunity, either from a natural infection or vaccination. In fact, the protective effect on family members went up as the number of immune family members increased.

The findings come from a team led by Peter Nordström, Umeå University, Sweden. Like in the United States, vaccinations in Sweden initially were prioritized for high-risk groups and people with certain preexisting conditions. As a result, Swedish families have functioned, often in close contact, as a mix of immune and susceptible individuals over the course of the pandemic.

To explore these family dynamics in greater detail, the researchers relied on nationwide registries to identify all Swedes who had immunity to SARS-COV-2 from either a confirmed infection or vaccination by May 26, 2021. The researchers identified more than 5 million individuals who’d been either diagnosed with COVID-19 or vaccinated and then matched them to a control group without immunity. They also limited the analysis to individuals in families with two to five members of mixed immune status.

This left them with about 1.8 million people from more than 800,000 families. The situation in Sweden is also a little unique from most Western nations. Somewhat controversially, the Swedish government didn’t order a mandatory citizen quarantine to slow the spread of the virus.

The researchers found in the data a rising protective effect for those in the household without immunity as the number of immune family members increased. Families with one immune family member had a 45 to 61 percent lower risk of a COVID-19 infection in the home than those who had none. Those with two immune family members enjoyed more protection, with a 75 to 86 percent reduction in risk of COVID-19. For those with three or four immune family members, the protection went up to more than 90 percent, topping out at 97 percent protection. The results were similar when the researchers limited the analysis to COVID-19 illnesses serious enough to warrant a hospital stay.

The findings confirm that vaccination is incredibly important not only for individual protection, but also for reducing transmission, especially within families and those with whom we’re in close physical contact. It’s also important to note that the findings apply to the original SARS-CoV-2 variant, which was dominant when the study was conducted. But we know that the vaccines offer good protection against Delta and other variants of concern.

These results show quite clearly that vaccines offer protection for individuals who lack immunity, with important implications for finally ending this pandemic. This doesn’t change the fact that all those who can and still need to get fully vaccinated should do so as soon as possible. If you are eligible for a booster shot, that’s something to consider, too. But, if for whatever reason you haven’t gotten vaccinated just yet, perhaps these new findings will encourage you to do it now for the sake of those other people you care about. This is a chance to love your family—and love your neighbor.

Reference:

[1] Association between risk of COVID-19 infection in nonimmune individuals and COVID-19 immunity in their family members. Nordström P, Ballin M, Nordström A. JAMA Intern Med. 2021 Oct 11.

Links:

COVID-19 Research (NIH)

Peter Nordström (Umeå University, Sweden)


Most Vaccine-Hesitant People Remain Willing to Change Their Minds

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A young black woman looks thoughful. A graph show changes in willingness to recieve the vaccine
Credit: fizkes/Shutterstock; adapted from Siegler, JAMA Netw Open. 2021

As long and difficult as this pandemic has been, I remain overwhelmingly grateful for the remarkable progress being made, including the hard work of so many people to develop rapidly and then deploy multiple life-saving vaccines. And yet, grave concerns remain that vaccine hesitancy—the reluctance of certain individuals and groups to get themselves and their children vaccinated—could cause this pandemic to go on much longer than it should.

We’re seeing the results of such hesitancy in the news every day, highlighting the rampant spread of COVID-19 that’s stretching our healthcare systems and resources dangerously thin in many places. The vast majority of those currently hospitalized with COVID-19 are unvaccinated, and most of those tragic 2,000 deaths each day could have been prevented. The stories of children and adults who realized too late the importance of getting vaccinated are heartbreaking.

With these troubling realities in mind, I was encouraged to see a new study in the journal JAMA Network Open that tracked vaccine hesitancy over time in a random sample of more than 4,600 Americans. This national study shows that vaccine hesitancy isn’t set in stone. Over the course of this pandemic, hesitancy has decreased, and many who initially said no are now getting their shots. Many others who remain unvaccinated lean toward making an appointment.

The findings come from Aaron Siegler and colleagues, Emory University, Atlanta. They were interested in studying how entrenched vaccine hesitancy would be over time. The researchers also wanted to see how often those who were initially hesitant went on to get their shots.

To find out, they recruited a diverse, random, national sampling of individuals from August to December 2020, just before the first vaccines were granted Emergency Use Approval and became widely available. They wanted to get a baseline, or starting characterization, on vaccine hesitancy. Participants were asked two straightforward questions, “Have you received the COVID-19 vaccine?” and “How likely are you to get it in the future?” From March to April 2021, the researchers followed up by asking participants the same questions again when vaccines were more readily available to many (although still not all) adults.

The survey’s initial results showed that nearly 70 percent of respondents were willing to get vaccinated at the outset, with the other 30 percent expressing some hesitancy. The good news is among the nearly 3,500 individuals who answered the survey at follow-up, about a third who were initially vaccine hesitant already had received at least one shot. Another third also said that they’d now be willing to get the vaccine, even though they hadn’t just yet.

Among those who initially expressed a willingness to get vaccinated, about half had done so at follow up by spring 2021 (again, some still may not have been eligible). Forty percent said they were likely to get vaccinated. However, 7 percent of those who were initially willing said they were now less likely to get vaccinated than before.

There were some notable demographic differences. Folks over age 65, people who identified as non-Hispanic Asians, and those with graduate degrees were most likely to have changed their minds and rolled up their sleeves. Only about 15 percent in any one of these groups said they weren’t willing to be vaccinated. Most reluctant older people ultimately got their shots.

The picture was more static for people aged 45 to 54 and for those with a high school education or less. The majority of those remained unvaccinated, and about 40 percent still said they were unlikely to change their minds.

At the outset, people of Hispanic heritage were as willing as non-Hispanic whites to get vaccinated. At follow-up, however, fewer Hispanics than non-Hispanic whites said they’d gotten their shots. This finding suggests that, in addition to some hesitancy, there may be significant barriers still to overcome to make vaccination easier and more accessible to certain groups, including Hispanic communities from Central and South America.

Willingness among non-Hispanic Blacks was consistently lowest, but nearly half had gotten at least one dose of vaccine by the time they completed the second survey. That’s comparable to the vaccination rate in white study participants. For more recent data on vaccination rates by race/ethnicity, see this report from the Kaiser Family Foundation.

Overall, while a small number of respondents grew more reluctant over time, most people grew more comfortable with the vaccines and were more likely to say they’d get vaccinated, if they hadn’t already. In fact, by the end of the study, the hesitant group had shrunk from 31 to 15 percent. It’s worth noting that the researchers checked the validity of self-reported vaccination using antibody tests and the results matched up rather well.

This is all mostly good news, but there’s clearly more work to do. An estimated 70 million eligible Americans have yet to get their first shot, and remain highly vulnerable to infection and serious illness from the Delta variant. They are capable of spreading the virus to other vulnerable people around them (including children), and incubating the next variants that might provide more resistance to the vaccines and therapies. They are also at risk for Long COVID, even after a relatively mild acute illness.

The work ahead involves answering questions and addressing concerns from people who remain hesitant. It’s also incredibly important to reach out to those willing, but unvaccinated, individuals, to see what can be done to help them get their shots. If you happen to be one of those, it’s easy to find the places near you that have free vaccines ready to administer. Go to vaccines.gov, or punch 438829 on your cell phone and enter your zip code—in less than a minute you will get the location of vaccine sites nearby.

Nearly 400 million COVID-19 vaccine doses have been administered in communities all across the United States. More than 600,000 more are being administered on average each day. And yet, more than 80,000 new infections are still reported daily, and COVID-19 still steals the lives of about 2,000 mostly unvaccinated people each day.

These vaccines are key for protecting yourself and ultimately beating this pandemic. As these findings show, the vast majority of Americans understand this and either have been vaccinated or are willing to do so. Let’s keep up the good work, and see to it that even more minds will be changed—and more individuals protected before they may find it’s too late.

Reference:

[1] Trajectory of COVID-19 vaccine hesitancy over time and association of initial vaccine hesitancy with subsequent vaccination. Siegler AJ, Luisi N, Hall EW, Bradley H, Sanchez T, Lopman BA, Sullivan PS. JAMA Netw Open. 2021 Sep 1;4(9):e2126882.

Links:

COVID-19 Research (NIH)

COVID-19 Vaccinations in the United States (Centers for Disease Control and Prevention, Atlanta)

Aaron Siegler (Emory University, Atlanta)

NIH Support: National Institute for Allergy and Infectious Diseases


mRNA Vaccines May Pack More Persistent Punch Against COVID-19 Than Thought

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Many people, including me, have experienced a sense of gratitude and relief after receiving the new COVID-19 mRNA vaccines. But all of us are also wondering how long the vaccines will remain protective against SARS-CoV-2, the coronavirus responsible for COVID-19.

Earlier this year, clinical trials of the Moderna and Pfizer-BioNTech vaccines indicated that both immunizations appeared to protect for at least six months. Now, a study in the journal Nature provides some hopeful news that these mRNA vaccines may be protective even longer [1].

In the new study, researchers monitored key immune cells in the lymph nodes of a group of people who received both doses of the Pfizer-BioNTech mRNA vaccine. The work consistently found hallmarks of a strong, persistent immune response against SARS-CoV-2 that could be protective for years to come.

Though more research is needed, the findings add evidence that people who received mRNA COVID-19 vaccines may not need an additional “booster” shot for quite some time, unless SARS-CoV-2 evolves into new forms, or variants, that can evade this vaccine-induced immunity. That’s why it remains so critical that more Americans get vaccinated not only to protect themselves and their loved ones, but to help stop the virus’s spread in their communities and thereby reduce its ability to mutate.

The new study was conducted by an NIH-supported research team led by Jackson Turner, Jane O’Halloran, Rachel Presti, and Ali Ellebedy at Washington University School of Medicine, St. Louis. That work builds upon the group’s previous findings that people who survived COVID-19 had immune cells residing in their bone marrow for at least eight months after the infection that could recognize SARS-CoV-2 [2]. The researchers wanted to see if similar, persistent immunity existed in people who hadn’t come down with COVID-19 but who were immunized with an mRNA vaccine.

To find out, Ellebedy and team recruited 14 healthy adults who were scheduled to receive both doses of the Pfizer-BioNTech vaccine. Three weeks after their first dose of vaccine, the volunteers underwent a lymph node biopsy, primarily from nodes in the armpit. Similar biopsies were repeated at four, five, seven, and 15 weeks after the first vaccine dose.

The lymph nodes are where the human immune system establishes so-called germinal centers, which function as “training camps” that teach immature immune cells to recognize new disease threats and attack them with acquired efficiency. In this case, the “threat” is the spike protein of SARS-COV-2 encoded by the vaccine.

By the 15-week mark, all of the participants sampled continued to have active germinal centers in their lymph nodes. These centers produced an army of cells trained to remember the spike protein, along with other types of cells, including antibody-producing plasmablasts, that were locked and loaded to neutralize this key protein. In fact, Ellebedy noted that even after the study ended at 15 weeks, he and his team continued to find no signs of germinal center activity slowing down in the lymph nodes of the vaccinated volunteers.

Ellebedy said the immune response observed in his team’s study appears so robust and persistent that he thinks that it could last for years. The researcher based his assessment on the fact that germinal center reactions that persist for several months or longer usually indicate an extremely vigorous immune response that culminates in the production of large numbers of long-lasting immune cells, called memory B cells. Some memory B cells can survive for years or even decades, which gives them the capacity to respond multiple times to the same infectious agent.

This study raises some really important issues for which we still don’t have complete answers: What is the most reliable correlate of immunity from COVID-19 vaccines? Are circulating spike protein antibodies (the easiest to measure) the best indicator? Do we need to know what’s happening in the lymph nodes? What about the T cells that are responsible for cell-mediated immunity?

If you follow the news, you may have seen a bit of a dust-up in the last week on this topic. Pfizer announced the need for a booster shot has become more apparent, based on serum antibodies. Meanwhile, the Food and Drug Administration and Centers for Disease Control and Prevention said such a conclusion would be premature, since vaccine protection looks really good right now, including for the delta variant that has all of us concerned.

We’ve still got a lot more to learn about the immunity generated by the mRNA vaccines. But this study—one of the first in humans to provide direct evidence of germinal center activity after mRNA vaccination—is a good place to continue the discussion.

References:

[1] SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. Turner JS, O’Halloran JA, Kalaidina E, Kim W, Schmitz AJ, Zhou JQ, Lei T, Thapa M, Chen RE, Case JB, Amanat F, Rauseo AM, Haile A, Xie X, Klebert MK, Suessen T, Middleton WD, Shi PY, Krammer F, Teefey SA, Diamond MS, Presti RM, Ellebedy AH. Nature. 2021 Jun 28. [Online ahead of print]

[2] SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. Turner JS, Kim W, Kalaidina E, Goss CW, Rauseo AM, Schmitz AJ, Hansen L, Haile A, Klebert MK, Pusic I, O’Halloran JA, Presti RM, Ellebedy AH. Nature. 2021 May 24. [Online ahead of print]

Links:

COVID-19 Research (NIH)

Ellebedy Lab (Washington University, St. Louis)

NIH Support: National Institute of Allergy and Infectious Diseases; National Center for Advancing Translational Sciences


How Immunity Generated from COVID-19 Vaccines Differs from an Infection

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Orginal viral spike is shown binding to antibody from vaccine and from infection. Variant spikes only bind to antibody from vaccine.

A key issue as we move closer to ending the pandemic is determining more precisely how long people exposed to SARS-CoV-2, the COVID-19 virus, will make neutralizing antibodies against this dangerous coronavirus. Finding the answer is also potentially complicated with new SARS-CoV-2 “variants of concern” appearing around the world that could find ways to evade acquired immunity, increasing the chances of new outbreaks.

Now, a new NIH-supported study shows that the answer to this question will vary based on how an individual’s antibodies against SARS-CoV-2 were generated: over the course of a naturally acquired infection or from a COVID-19 vaccine. The new evidence shows that protective antibodies generated in response to an mRNA vaccine will target a broader range of SARS-CoV-2 variants carrying “single letter” changes in a key portion of their spike protein compared to antibodies acquired from an infection.

These results add to evidence that people with acquired immunity may have differing levels of protection to emerging SARS-CoV-2 variants. More importantly, the data provide further documentation that those who’ve had and recovered from a COVID-19 infection still stand to benefit from getting vaccinated.

These latest findings come from Jesse Bloom, Allison Greaney, and their team at Fred Hutchinson Cancer Research Center, Seattle. In an earlier study, this same team focused on the receptor binding domain (RBD), a key region of the spike protein that studs SARS-CoV-2’s outer surface. This RBD is especially important because the virus uses this part of its spike protein to anchor to another protein called ACE2 on human cells before infecting them. That makes RBD a prime target for both naturally acquired antibodies and those generated by vaccines. Using a method called deep mutational scanning, the Seattle group’s previous study mapped out all possible mutations in the RBD that would change the ability of the virus to bind ACE2 and/or for RBD-directed antibodies to strike their targets.

In their new study, published in the journal Science Translational Medicine, Bloom, Greaney, and colleagues looked again to the thousands of possible RBD variants to understand how antibodies might be expected to hit their targets there [1]. This time, they wanted to explore any differences between RBD-directed antibodies based on how they were acquired.

Again, they turned to deep mutational scanning. First, they created libraries of all 3,800 possible RBD single amino acid mutants and exposed the libraries to samples taken from vaccinated individuals and unvaccinated individuals who’d been previously infected. All vaccinated individuals had received two doses of the Moderna mRNA vaccine. This vaccine works by prompting a person’s cells to produce the spike protein, thereby launching an immune response and the production of antibodies.

By closely examining the results, the researchers uncovered important differences between acquired immunity in people who’d been vaccinated and unvaccinated people who’d been previously infected with SARS-CoV-2. Specifically, antibodies elicited by the mRNA vaccine were more focused to the RBD compared to antibodies elicited by an infection, which more often targeted other portions of the spike protein. Importantly, the vaccine-elicited antibodies targeted a broader range of places on the RBD than those elicited by natural infection.

These findings suggest that natural immunity and vaccine-generated immunity to SARS-CoV-2 will differ in how they recognize new viral variants. What’s more, antibodies acquired with the help of a vaccine may be more likely to target new SARS-CoV-2 variants potently, even when the variants carry new mutations in the RBD.

It’s not entirely clear why these differences in vaccine- and infection-elicited antibody responses exist. In both cases, RBD-directed antibodies are acquired from the immune system’s recognition and response to viral spike proteins. The Seattle team suggests these differences may arise because the vaccine presents the viral protein in slightly different conformations.

Also, it’s possible that mRNA delivery may change the way antigens are presented to the immune system, leading to differences in the antibodies that get produced. A third difference is that natural infection only exposes the body to the virus in the respiratory tract (unless the illness is very severe), while the vaccine is delivered to muscle, where the immune system may have an even better chance of seeing it and responding vigorously.

Whatever the underlying reasons turn out to be, it’s important to consider that humans are routinely infected and re-infected with other common coronaviruses, which are responsible for the common cold. It’s not at all unusual to catch a cold from seasonal coronaviruses year after year. That’s at least in part because those viruses tend to evolve to escape acquired immunity, much as SARS-CoV-2 is now in the process of doing.

The good news so far is that, unlike the situation for the common cold, we have now developed multiple COVID-19 vaccines. The evidence continues to suggest that acquired immunity from vaccines still offers substantial protection against the new variants now circulating around the globe.

The hope is that acquired immunity from the vaccines will indeed produce long-lasting protection against SARS-CoV-2 and bring an end to the pandemic. These new findings point encouragingly in that direction. They also serve as an important reminder to roll up your sleeve for the vaccine if you haven’t already done so, whether or not you’ve had COVID-19. Our best hope of winning this contest with the virus is to get as many people immunized now as possible. That will save lives, and reduce the likelihood of even more variants appearing that might evade protection from the current vaccines.

Reference:

[1] Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection. Greaney AJ, Loes AN, Gentles LE, Crawford KHD, Starr TN, Malone KD, Chu HY, Bloom JD. Sci Transl Med. 2021 Jun 8.

Links:

COVID-19 Research (NIH)

Bloom Lab (Fred Hutchinson Cancer Research Center, Seattle)

NIH Support: National Institute of Allergy and Infectious Diseases


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