Posted on by Lawrence Tabak, D.D.S., Ph.D.
Do you feel as if you or perhaps your family members are constantly coming down with illnesses that drag on longer than they should? Or, maybe you’re one of those lucky people who rarely becomes ill and, if you do, recovers faster than others.
It’s clear that some people generally are more susceptible to infectious illnesses, while others manage to stay healthier or bounce back more quickly, sometimes even into old age. Why is this? A new study from an NIH-supported team has an intriguing answer . The difference, they suggest, may be explained in part by a new measure of immunity they call immune resilience—the ability of the immune system to rapidly launch attacks that defend effectively against infectious invaders and respond appropriately to other types of inflammatory stressors, including aging or other health conditions, and then quickly recover, while keeping potentially damaging inflammation under wraps.
The findings in the journal Nature Communications come from an international team led by Sunil Ahuja, University of Texas Health Science Center and the Department of Veterans Affairs Center for Personalized Medicine, both in San Antonio. To understand the role of immune resilience and its effect on longevity and health outcomes, the researchers looked at multiple other studies including healthy individuals and those with a range of health conditions that challenged their immune systems.
By looking at multiple studies in varied infectious and other contexts, they hoped to find clues as to why some people remain healthier even in the face of varied inflammatory stressors, ranging from mild to more severe. But to understand how immune resilience influences health outcomes, they first needed a way to measure or grade this immune attribute.
The researchers developed two methods for measuring immune resilience. The first metric, a laboratory test called immune health grades (IHGs), is a four-tier grading system that calculates the balance between infection-fighting CD8+ and CD4+ T-cells. IHG-I denotes the best balance tracking the highest level of resilience, and IHG-IV denotes the worst balance tracking the lowest level of immune resilience. An imbalance between the levels of these T cell types is observed in many people as they age, when they get sick, and in people with autoimmune diseases and other conditions.
The researchers also developed a second metric that looks for two patterns of expression of a select set of genes. One pattern associated with survival and the other with death. The survival-associated pattern is primarily related to immune competence, or the immune system’s ability to function swiftly and restore activities that encourage disease resistance. The mortality-associated genes are closely related to inflammation, a process through which the immune system eliminates pathogens and begins the healing process but that also underlies many disease states.
Their studies have shown that high expression of the survival-associated genes and lower expression of mortality-associated genes indicate optimal immune resilience, correlating with a longer lifespan. The opposite pattern indicates poor resilience and a greater risk of premature death. When both sets of genes are either low or high at the same time, immune resilience and mortality risks are more moderate.
In the newly reported study initiated in 2014, Ahuja and his colleagues set out to assess immune resilience in a collection of about 48,500 people, with or without various acute, repetitive, or chronic challenges to their immune systems. In an earlier study, the researchers showed that this novel way to measure immune status and resilience predicted hospitalization and mortality during acute COVID-19 across a wide age spectrum .
The investigators have analyzed stored blood samples and publicly available data representing people, many of whom were healthy volunteers, who had enrolled in different studies conducted in Africa, Europe, and North America. Volunteers ranged in age from 9 to 103 years. They also evaluated participants in the Framingham Heart Study, a long-term effort to identify common factors and characteristics that contribute to cardiovascular disease.
To examine people with a wide range of health challenges and associated stresses on their immune systems, the team also included participants who had influenza or COVID-19, and people living with HIV. They also included kidney transplant recipients, people with lifestyle factors that put them at high risk for sexually transmitted infections, and people who’d had sepsis, a condition in which the body has an extreme and life-threatening response following an infection.
The question in all these contexts was the same: How well did the two metrics of immune resilience predict an individual’s health outcomes and lifespan? The short answer is that immune resilience, longevity, and better health outcomes tracked together well. Those with metrics indicating optimal immune resilience generally had better health outcomes and lived longer than those who had lower scores on the immunity grading scale. Indeed, those with optimal immune resilience were more likely to:
- Live longer,
- Resist HIV infection or the progression from HIV to AIDS,
- Resist symptomatic influenza,
- Resist a recurrence of skin cancer after a kidney transplant,
- Survive COVID-19, and
- Survive sepsis.
The study also revealed other interesting findings. While immune resilience generally declines with age, some people maintain higher levels of immune resilience as they get older for reasons that aren’t yet known, according to the researchers. Some people also maintain higher levels of immune resilience despite the presence of inflammatory stress to their immune systems such as during HIV infection or acute COVID-19. People of all ages can show high or low immune resilience. The study also found that higher immune resilience is more common in females than it is in males.
The findings suggest that there is a lot more to learn about why people differ in their ability to preserve optimal immune resilience. With further research, it may be possible to develop treatments or other methods to encourage or restore immune resilience as a way of improving general health, according to the study team.
The researchers suggest it’s possible that one day checkups of a person’s immune resilience could help us to understand and predict an individual’s health status and risk for a wide range of health conditions. It could also help to identify those individuals who may be at a higher risk of poor outcomes when they do get sick and may need more aggressive treatment. Researchers may also consider immune resilience when designing vaccine clinical trials.
A more thorough understanding of immune resilience and discovery of ways to improve it may help to address important health disparities linked to differences in race, ethnicity, geography, and other factors. We know that healthy eating, exercising, and taking precautions to avoid getting sick foster good health and longevity; in the future, perhaps we’ll also consider how our immune resilience measures up and take steps to achieve or maintain a healthier, more balanced, immunity status.
 Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection. Ahuja SK, Manoharan MS, Lee GC, McKinnon LR, Meunier JA, Steri M, Harper N, Fiorillo E, Smith AM, Restrepo MI, Branum AP, Bottomley MJ, Orrù V, Jimenez F, Carrillo A, Pandranki L, Winter CA, Winter LA, Gaitan AA, Moreira AG, Walter EA, Silvestri G, King CL, Zheng YT, Zheng HY, Kimani J, Blake Ball T, Plummer FA, Fowke KR, Harden PN, Wood KJ, Ferris MT, Lund JM, Heise MT, Garrett N, Canady KR, Abdool Karim SS, Little SJ, Gianella S, Smith DM, Letendre S, Richman DD, Cucca F, Trinh H, Sanchez-Reilly S, Hecht JM, Cadena Zuluaga JA, Anzueto A, Pugh JA; South Texas Veterans Health Care System COVID-19 team; Agan BK, Root-Bernstein R, Clark RA, Okulicz JF, He W. Nat Commun. 2023 Jun 13;14(1):3286. doi: 10.1038/s41467-023-38238-6. PMID: 37311745.
 Immunologic resilience and COVID-19 survival advantage. Lee GC, Restrepo MI, Harper N, Manoharan MS, Smith AM, Meunier JA, Sanchez-Reilly S, Ehsan A, Branum AP, Winter C, Winter L, Jimenez F, Pandranki L, Carrillo A, Perez GL, Anzueto A, Trinh H, Lee M, Hecht JM, Martinez-Vargas C, Sehgal RT, Cadena J, Walter EA, Oakman K, Benavides R, Pugh JA; South Texas Veterans Health Care System COVID-19 Team; Letendre S, Steri M, Orrù V, Fiorillo E, Cucca F, Moreira AG, Zhang N, Leadbetter E, Agan BK, Richman DD, He W, Clark RA, Okulicz JF, Ahuja SK. J Allergy Clin Immunol. 2021 Nov;148(5):1176-1191. doi: 10.1016/j.jaci.2021.08.021. Epub 2021 Sep 8. PMID: 34508765; PMCID: PMC8425719.
COVID-19 Research (NIH)
HIV Info (NIH)
Sepsis (National Institute of General Medical Sciences/NIH)
Sunil Ahuja (University of Texas Health Science Center, San Antonio)
Framingham Heart Study (National Heart, Lung, and Blood Institute/NIH)
“A Secret to Health and Long Life? Immune Resilience, NIAID Grantees Report,” NIAID Now Blog, June 13, 2023
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute on Aging; National Institute of Mental Health; National Institute of General Medical Sciences; National Heart, Lung, and Blood Institute
Posted on by Lawrence Tabak, D.D.S., Ph.D.
More than 215 million people in the United States are now fully vaccinated against the SARS-CoV-2 virus responsible for COVID-19 . 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 . 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 . 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.
 COVID-19 vaccinations in the United States. Centers for Disease Control and Prevention. February 27, 2022.
 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.
 COVID-19 vaccine booster shots. Centers for Disease Control and Prevention. Feb 2, 2022.
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
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Since joining NIH, I’ve held a number of different leadership positions. But there is one position that thankfully has remained constant for me: lab chief. I run my own research laboratory at NIH’s National Institute of Dental and Craniofacial Research (NIDCR).
My lab studies a biochemical process called O-glycosylation. It’s fundamental to life and fascinating to study. Our cells are often adorned with a variety of carbohydrate sugars. O-glycosylation refers to the biochemical process through which these sugar molecules, either found at the cell surface or secreted, get added to proteins. The presence or absence of these sugars on certain proteins plays fundamental roles in normal tissue development and first-line human immunity. It also is associated with various diseases, including cancer.
Our lab recently joined a team of NIH scientists led by my NIDCR colleague Kelly Ten Hagen to demonstrate how O-glycosylation can influence SARS-CoV-2, the coronavirus that causes COVID-19, and its ability to fuse to cells, which is a key step in infecting them. In fact, our data, published in the journal Proceedings of the National Academy of Sciences, indicate that some variants, seem to have mutated to exploit the process to their advantage .
The work builds on the virus’s reliance on the spike proteins that crown its outer surface to attach to human cells. Once there, the spike protein must be activated to fuse and launch an infection. That happens when enzymes produced by our own cells make a series of cuts, or cleavages, to the spike protein.
The first cut comes from an enzyme called furin. We and others had earlier evidence that O-glycosylation can affect the way furin makes those cuts. That got us thinking: Could O-glycosylation influence the interaction between furin and the spike protein? The furin cleavage area of the viral spike was indeed adorned with sugars, and their presence or absence might influence spike activation by furin.
We also noticed the Alpha and Delta variants carry a mutation that removes the amino acid proline in a specific spot. That was intriguing because we knew from earlier work that enzymes called GALNTs, which are responsible for adding bulky sugar molecules to proteins, prefer prolines near O-glycosylation sites.
It also suggested that loss of proline in the new variants could mean decreased O-glycosylation, which might then influence the degree of furin cleavage and SARS-CoV-2’s ability to enter cells. I should note that the recent Omicron variant was not examined in the current study.
After detailed studies in fruit fly and mammalian cells, we demonstrated in the original SARS-CoV-2 virus that O-glycosylation of the spike protein decreases furin cleavage. Further experiments then showed that the GALNT1 enzyme adds sugars to the spike protein and this addition limits the ability of furin to make the needed cuts and activate the spike protein.
Importantly, the spike protein change found in the Alpha and Delta variants lowers GALNT1 activity, making it easier for furin to start its activating cuts. It suggests that glycosylation of the viral spike by GALNT1 may limit infection with the original virus, and that the Alpha and Delta variant mutation at least partially overcomes this effect, to potentially make the virus more infectious.
Building on these studies, our teams looked for evidence of GALNT1 in the respiratory tracts of healthy human volunteers. We found that the enzyme is indeed abundantly expressed in those cells. Interestingly, those same cells also express the ACE2 receptor, which SARS-CoV-2 depends on to infect human cells.
It’s also worth noting here that the Omicron variant carries the very same spike mutation that we studied in Alpha and Delta. Omicron also has another nearby change that might further alter O-glycosylation and cleavage of the spike protein by furin. The Ten Hagen lab is looking into these leads to learn how this region in Omicron affects spike glycosylation and, ultimately, the ability of this devastating virus to infect human cells and spread.
 Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation. Zhang L, Mann M, Syed Z, Reynolds HM, Tian E, Samara NL, Zeldin DC, Tabak LA, Ten Hagen KG. PNAS. 2021 Nov 23;118(47).
COVID-19 Research (NIH)
Kelly Ten Hagen (National Institute of Dental and Craniofacial Research/NIH)
Lawrence Tabak (NIDCR)
NIH Support: National Institute of Dental and Craniofacial Research
Posted on by Dr. Francis Collins
With Omicron now on so many people’s minds, public health officials and virologists around the world are laser focused on tracking the spread of this concerning SARS-CoV-2 variant and using every possible means to determine the effectiveness of our COVID-19 vaccines against it. Ultimately, the answer will depend on what happens in the real world. But it will also help to have a ready laboratory means for gauging how well a vaccine works, without having to wait many months for the results in the field.
With this latter idea in mind, I’m happy to share results of an NIH-funded effort to understand the immune responses associated with vaccine-acquired protection against SARS-CoV-2 . The findings, based on the analysis of blood samples from more than 1,000 people who received the Moderna mRNA vaccine, show that antibody levels do correlate, albeit somewhat imperfectly, with how well a vaccine works to prevent infection.
Such measures of immunity, known as “correlates of protection,” have potential to support the approval of new or updated vaccines more rapidly. They’re also useful to show how well a vaccine will work in groups that weren’t represented in a vaccine’s initial testing, such as children, pregnant women, and those with certain health conditions.
The latest study, published in the journal Science, comes from a team of researchers led by Peter Gilbert, Fred Hutchinson Cancer Research Center, Seattle; David Montefiori, Duke University, Durham, NC; and Adrian McDermott, NIH’s Vaccine Research Center, National Institute of Allergy and Infectious Diseases.
The team started with existing data from the Coronavirus Efficacy (COVE) trial. This phase 3 study, conducted in 30,000 U.S. adults, found the Moderna vaccine was safe and about 94 percent effective in protecting people from symptomatic infection with SARS-CoV-2 .
The researchers wanted to understand the underlying immune responses that afforded that impressive level of COVID-19 protection. They also sought to develop a means to measure those responses in the lab and quickly show how well a vaccine works.
To learn more, Gilbert’s team conducted tests on blood samples from COVE participants at the time of their second vaccine dose and again four weeks later. Two of the tests measured concentrations of binding antibodies (bAbs) that latch onto spike proteins that adorn the coronavirus surface. Two others measured the concentration of more broadly protective neutralizing antibodies (nAbs), which block SARS-CoV-2 from infecting human cells via ACE2 receptors found on their surfaces.
Each of the four tests showed antibody levels that were consistently higher in vaccine recipients who did not develop COVID-19 than in those who did. That is consistent with expectations. But these data also allowed the researchers to identify the specific antibody levels associated with various levels of protection from disease.
For those with the highest antibody levels, the vaccine offered an estimated 98 percent protection. Those with levels about 1,000 times lower still were well protected, but their vaccine efficacy was reduced to about 78 percent.
Based on any of the antibodies tested, the estimated COVID-19 risk was about 10 times lower for vaccine recipients with antibodies in the top 10 percent of values compared to those with antibodies that weren’t detectable. Overall, the findings suggest that tests for antibody levels can be applied to make predictions about an mRNA vaccine’s efficacy and may be used to guide modifications to the current vaccine regimen.
To understand the significance of this finding, consider that for a two-dose vaccine like Moderna or Pfizer, a trial using such correlates of protection might generate sufficient data in as little as two months . As a result, such a trial might show whether a vaccine was meeting its benchmarks in 3 to 5 months. By comparison, even a rapid clinical trial done the standard way would take at least seven months to complete. Importantly also, trials relying on such correlates of protection require many fewer participants.
Since all four tests performed equally well, the researchers say it’s conceivable that a single antibody assay might be sufficient to predict how effective a vaccine will be in a clinical trial. Of course, such trials would require subsequent real-world studies to verify that the predicted vaccine efficacy matches actual immune protection.
It should be noted that the Food and Drug Administration (FDA) would need to approve the use of such correlates of protection before their adoption in any vaccine trial. But, to date, the totality of evidence on neutralizing antibody responses as correlates of protection—for which this COVE trial data is a major contributor—is impressive.
Neutralizing antibody levels are also now being considered for use in future coronavirus vaccine trials. Indeed, for the EUA of Pfizer’s mRNA vaccine for 5-to-11-year-olds, the FDA accepted pre-specified success criteria based on neutralizing antibody responses in this age group being as good as those observed in 16- to 25-year-olds .
Antibody levels also have been taken into consideration for decisions about booster shots. However, it’s important to note that antibody levels are not precise enough to help in deciding whether or not any particular individual needs a COVID-19 booster. Those recommendations are based on how much time has passed since the original immunization.
Getting a booster is a really good idea heading into the holidays. The Delta variant remains very much the dominant strain in the U.S., and we need to slow its spread. Most experts think the vaccines and boosters will also provide some protection against the Omicron variant—though the evidence we need is still a week or two away. The Centers for Disease Control and Prevention (CDC) recommends a COVID-19 booster for everyone ages 18 and up at least six months after your second dose of mRNA vaccine or two months after receiving the single dose of the Johnson & Johnson vaccine . You may choose to get the same vaccine or a different one. And, there is a place near you that is offering the shot.
 Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial.
Gilbert PB, Montefiori DC, McDermott AB, Fong Y, Benkeser D, Deng W, Zhou H, Houchens CR, Martins K, Jayashankar L, Castellino F, Flach B, Lin BC, O’Connell S, McDanal C, Eaton A, Sarzotti-Kelsoe M, Lu Y, Yu C, Borate B, van der Laan LWP, Hejazi NS, Huynh C, Miller J, El Sahly HM, Baden LR, Baron M, De La Cruz L, Gay C, Kalams S, Kelley CF, Andrasik MP, Kublin JG, Corey L, Neuzil KM, Carpp LN, Pajon R, Follmann D, Donis RO, Koup RA; Immune Assays Team§; Moderna, Inc. Team§; Coronavirus Vaccine Prevention Network (CoVPN)/Coronavirus Efficacy (COVE) Team§; United States Government (USG)/CoVPN Biostatistics Team§. Science. 2021 Nov 23:eab3435.
 Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group. N Engl J Med. 2021 Feb 4;384(5):403-416.
 A government-led effort to identify correlates of protection for COVID-19 vaccines. Koup RA, Donis RO, Gilbert PB, Li AW, Shah NA, Houchens CR. Nat Med. 2021 Sep;27(9):1493-1494.
 Evaluation of the BNT162b2 Covid-19 vaccine in children 5 to 11 years of age. Walter EB, Talaat KR, Sabharwal C, Gurtman A, Lockhart S, Paulsen GC, Barnett ED, Muñoz FM, Maldonado Y, Pahud BA, Domachowske JB, Simões EAF, Sarwar UN, Kitchin N, Cunliffe L, Rojo P, Kuchar E, Rämet M, Munjal I, Perez JL, Frenck RW Jr, Lagkadinou E, Swanson KA, Ma H, Xu X, Koury K, Mather S, Belanger TJ, Cooper D, Türeci Ö, Dormitzer PR, Şahin U, Jansen KU, Gruber WC; C4591007 Clinical Trial Group. N Engl J Med. 2021 Nov 9:NEJMoa2116298.
 COVID-19 vaccine booster shots. Centers for Disease Control and Prevention. Nov 29, 2021.
COVID-19 Research (NIH)
Combat COVID (U.S. Department of Health and Human Services)
Peter Gilbert (Fred Hutchison Cancer Research Center)
David Montefiori (Duke University, Durham, NC)
Adrian McDermott (National Institute of Allergy and Infectious Diseases/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases
Posted on by Dr. Francis Collins
The winter holidays are approaching, and among the many things to be grateful for this year is that nearly 200 million Americans are fully vaccinated for COVID-19. That will make it safer to spend time with friends and family, though everyone should remain vigilant just to be on the safe side. Though relatively uncommon, breakthrough infections are possible. That’s why the Centers for Disease Control and Prevention (CDC) recommends booster shots for several at-risk groups, including folks 65 years and older, those with underlying medical conditions, and people whose occupations place them at high risk of exposure.
One of the main studies providing the evidence for CDC’s recommendation was recently published in the New England Journal of Medicine . It found that vaccine-induced immunity, while still quite protective against infection and severe illness from COVID-19, can wane after several months.
The study is yet another highly informative report from Israel, where public health officials launched a particularly vigorous national vaccination campaign in December 2020. More than half of adult Israelis received two doses of the Pfizer vaccine within the first three months of the campaign. By May 2021, Israel had extremely small numbers of confirmed COVID-19 cases—just a few dozen per day.
But the numbers crept back up in June 2021. The rise also included a substantial number of breakthrough infections in vaccinated individuals. The vast majority of those cases in June—98 percent—were caused by the emerging Delta variant.
Researchers led by Yair Goldberg, Technion-Israel Institute of Technology, Haifa, wondered whether this resurgence of COVID-19 could be fully explained by the rise of the more infectious Delta variant. Or, they wondered, did the waning of immunity over time also play a role?
To find out, the researchers looked to over 4.7 million fully vaccinated Israeli adults, more than 13,000 of whom had breakthrough infections from July 11 to 31, 2021 with SARS-CoV-2. The researchers looked for an association between the rate of confirmed infections and the time that had passed since vaccination. Without any significant waning of immunity, one shouldn’t see any difference in infection rates among people who were fully vaccinated at the earliest opportunity versus those vaccinated later.
The results were clear: the rate of confirmed COVID-19 infection revealed a slow but steady waning of immunity over time. Among individuals 60 years or older who were fully vaccinated last January, the number of confirmed breakthrough infections was 3.3 per 1,000 people during the three weeks of the study. Those who were vaccinated in February and March had lower infection rates of 2.2 per 1,000 and 1.7 per 1,000, respectively. The data revealed a similar pattern in those aged 40 to 59 and those aged 16 to 39.
An important question is whether these breakthrough infections were serious enough to require hospitalization. While such cases were much less common, more than 400 of those with confirmed COVID-19 breakthroughs went on to develop severe illness. And, again, the data show a similar pattern of waning immunity. The rate of severe COVID-19 among adults 60 years of age or older who were fully vaccinated in January was 0.34 cases per 1,000 persons. The rate of severe illness dropped to 0.26 cases per 1,000 among those vaccinated in February and 0.15 cases per 1,000 for those vaccinated in March. The researchers report that the number of severe COVID-19 cases among the younger fully vaccinated groups were too small to draw any conclusions.
While the Delta variant surely has played a role in the resurgence of COVID-19 in recent months, these findings suggest that waning immunity also is an important factor. Understanding these dynamics is essential for making critical policy decisions. In fact, these data were a key factor in the decision by the Israeli Ministry of Health in July 2021 to approve administration of COVID-19 booster shots for individuals who’d been vaccinated at least 5 months before.
Back in the U.S., if you were among those who got your vaccine on the early side—good for you. If it’s been more than six months since your original shots, and if you are in one of the risk groups, you should consider a COVID-19 booster shot to remain optimally protected in the months ahead. I’ll be getting my Moderna booster this week. While you’re at it, consider getting your annual flu shot taken care of, too. The CDC guidelines state that it’s perfectly OK to get your COVID-19 and flu shots at the same time.
 Waning immunity after the BNT162b2 vaccine in Israel. Goldberg Y, Mandel M, Bar-On YM, Bodenheimer O, Freedman L, Haas EJ, Milo R, Alroy-Preis S, Ash N, Huppert A. N Engl J Med. 2021 Oct 27.
COVID-19 Research (NIH)
COVID-19 Vaccine Booster Shots (Centers for Disease Control and Prevention)
Posted on by Dr. Francis Collins
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 .
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 . 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.
 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]
 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]
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
Posted on by Dr. Francis Collins
One of the best ways to learn how something works is to understand how it’s built. How it came to be. That’s true not only if you play a guitar or repair motorcycle engines, but also if you study the biological systems that make life possible. Evolutionary studies, comparing the development of these systems across animals and organisms, are now leading to many unexpected biological discoveries and promising possibilities for preventing and treating human disease.
While there are many evolutionary questions to ask, Brenda Bass, a distinguished biochemist at University of Utah, Salt Lake City, has set her sights on a particularly profound one: How has innate immunity evolved through the millennia in all living things, including humans? Innate immunity is the immune system’s frontline defense, the first responders that take control of an emerging infectious situation and, if needed, signal for backup.
Exploring the millennia for clues about innate immunity takes a special team, and Bass has assembled a talented one. It includes her Utah colleague Nels Elde, a geneticist; immunologist Dan Stetson, University of Washington, Seattle; and biochemist Jane Jackman, Ohio State University, Columbus.
With a 2020 NIH Director’s Transformative Research Award, this hard-working team will embark on studies looking back at 450 million years of evolution: the point in time when animals diverged to develop very distinct methods of innate immune defense . The team members hope to uncover new possibilities encoded in the innate immune system, especially those that might be latent but still workable. The researchers will then explore whether their finds can be repurposed not only to boost our body’s natural response to external threats but also to internal threats like cancer.
Bass brings a unique perspective to the project. As a postdoc in the 1980s, she stumbled upon a whole new class of enzymes, called ADARs, that edit RNA . Their function was mysterious at the time. It turns out that ADARs specifically edit a molecule called double-stranded RNA (dsRNA). When viruses infect cells in animals, including humans, they make dsRNA, which the innate immune system detects as a sign that a cell has been invaded.
It also turns out that animal cells make their own dsRNA. Over the years, Bass and her lab have identified thousands of dsRNAs made in animal cells—in fact, a significant number of human genes produce dsRNA . Also interesting, ADARs are crucial to marking our own dsRNA as “self” to avoid triggering an immune response when we don’t need it .
Bass and others have found that evolution has produced dramatic differences in the biochemical pathways powering the innate immune system. In vertebrate animals, dsRNA leads to release of the immune chemical interferon, a signaling pathway that invertebrate species don’t have. Instead, in response to detecting dsRNA from an invader, and repelling it, worms and other invertebrates trigger a gene-silencing pathway known as RNA interference, or RNAi.
With the new funding, Bass and team plan to mix and match immune strategies from simple and advanced species, across evolutionary time, to craft an entirely new set of immune tools to fight disease. The team will also build new types of targeted immunotherapies based on the principles of innate immunity. Current immunotherapies, which harness a person’s own immune system to fight disease, target infections, autoimmune disorders, and cancer. But they work through our second-line adaptive immune response, which is a biological system unique to vertebrates.
Bass and her team will first hunt for more molecules like ADARs: innate immune checkpoints, as they refer to them. The name comes from a functional resemblance to the better-known adaptive immune checkpoints PD-1 and CTLA-4, which sparked a revolution in cancer immunotherapy. The team will run several screens that sort molecules successful at activating innate immune responses—both in invertebrates and in mammals—hoping to identify a range of durable new immune switches that evolution skipped over but that might be repurposed today.
Another intriguing direction for this research stems from the observation that decreasing normal levels of ADARs in tumors kickstarts innate immune responses that kill cancer cells . Along these lines, the scientists plan to test newly identified immune switches to look for novel ways to fight cancer where existing approaches have not worked.
Evolution is the founding principle for all of biology—organisms learn from what works to improve their ability to survive. In this case, research to re-examine such lessons and apply them for new uses may help transform bygone evolution into a therapeutic revolution!
 Evolution of adaptive immunity from transposable elements combined with innate immune systems. Koonin EV, Krupovic M. Nat Rev Genet. 2015 Mar;16(3):184-192.
 A developmentally regulated activity that unwinds RNA duplexes. Bass BL, Weintraub H. Cell. 1987 Feb 27;48(4):607-613.
 Mapping the dsRNA World. Reich DP, Bass BL. Cold Spring Harb Perspect Biol. 2019 Mar 1;11(3):a035352.
 To protect and modify double-stranded RNA – the critical roles of ADARs in development, immunity and oncogenesis. Erdmann EA, Mahapatra A, Mukherjee P, Yang B, Hundley HA. Crit Rev Biochem Mol Biol. 2021 Feb;56(1):54-87.
 Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Ishizuka JJ, Manguso RT, Cheruiyot CK, Bi K, Panda A, et al. Nature. 2019 Jan;565(7737):43-48.
Bass Lab (University of Utah, Salt Lake City)
Elde Lab (University of Utah)
Jackman Lab (Ohio State University, Columbus)
Stetson Lab (University of Washington, Seattle)
Bass/Elde/Jackman/Stetson Project Information (NIH RePORTER)
NIH Director’s Transformative Research Award Program (Common Fund)
NIH Support: Common Fund; National Cancer Institute
Posted on by Dr. Francis Collins
For the millions of Americans now eligible to receive the Pfizer or Moderna COVID-19 vaccines, it’s recommended that everyone get two shots. The first dose of these mRNA vaccines trains the immune system to recognize and attack the spike protein on the surface of SARS-CoV-2, the virus that causes COVID-19. The second dose, administered a few weeks later, boosts antibody levels to afford even better protection. People who’ve recovered from COVID-19 also should definitely get vaccinated to maximize protection against possible re-infection. But, because they already have some natural immunity, would just one shot do the trick? Or do they still need two?
A small, NIH-supported study, published as a pre-print on medRxiv, offers some early data on this important question . The findings show that immune response to the first vaccine dose in a person who’s already had COVID-19 is equal to, or in some cases better, than the response to the second dose in a person who hasn’t had COVID-19. While much more research is needed—and I am definitely not suggesting a change in the current recommendations right now—the results raise the possibility that one dose might be enough for someone who’s been infected with SARS-CoV-2 and already generated antibodies against the virus.
These findings come from a research team led by Florian Krammer and Viviana Simon, Icahn School of Medicine at Mount Sinai, New York. The researchers reasoned that for folks whose bodies have already produced antibodies following a COVID-19 infection, the first shot might act similarly to the second one in someone who hadn’t had the virus before. In fact, there was some anecdotal evidence suggesting that previously infected people were experiencing stronger evidence of an active immune response (sore arm, fever, chills, fatigue) than never-infected individuals after getting their first shots.
What did the antibodies show? To find out, the researchers enlisted the help of 109 people who’d received their first dose of mRNA vaccines made by either Pfizer or Moderna. They found that those who’d never been infected by SARS-CoV-2 developed antibodies at low levels within 9 to 12 days of receiving their first dose of vaccine.
But in 41 people who tested positive for SARS-CoV-2 antibodies prior to getting the first shot, the immune response looked strikingly different. They generated high levels of antibodies within just a few days of getting the vaccine. Compared across different time intervals, previously infected people had immune responses 10 to 20 times that observed in uninfected people. Following their second vaccine dose, it was roughly the same story. Antibody levels in those with a prior infection were about 10 times greater than the others.
Both vaccines were generally well tolerated. But, because their immune systems were already in high gear, people who were previously infected tended to have more symptoms following their first shot, such as pain and swelling at the injection site. They also were more likely to report other less common symptoms, including fatigue, fever, chills, headache, muscle aches, and joint pain.
Though sometimes it may not seem like it, COVID-19 and the mRNA vaccines are still relatively new. Researchers haven’t yet been able to study how long these vaccines confer immunity to the disease, which has now claimed the lives of more than 500,000 Americans. But these findings do suggest that a single dose of the Pfizer or Moderna vaccines can produce a rapid and strong immune response in people who’ve already recovered from COVID-19.
If other studies support these results, the U.S. Food and Drug Administration (FDA) might decide to consider whether one dose is enough for people who’ve had a prior COVID-19 infection. Such a policy is already under consideration in France and, if implemented, would help to extend vaccine supply and get more people vaccinated sooner. But any serious consideration of this option will require more data. It will also be up to the expert advisors at FDA and Centers for Disease Control and Prevention (CDC) to decide.
For now, the most important thing all of us can all do to get this terrible pandemic under control is to follow the 3 W’s—wear our masks, wash our hands, watch our distance from others—and roll up our sleeves for the vaccine as soon as it’s available to us.
 Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine. Krammer F et al. medRxiv. 2021 Feb 1.
COVID-19 Research (NIH)
Krammer Lab (Icahn School of Medicine at Mount Sinai, New York, NY)
Simon Lab (Icahn School of Medicine at Mount Sinai)
NIH Support: National Institute of Allergy and Infectious Diseases
Posted on by Dr. Francis Collins
More than 8 million people in the United States have now tested positive for COVID-19. For those who’ve recovered, many wonder if fending off SARS-CoV-2—the coronavirus that causes COVID-19—one time means their immune systems will protect them from reinfection. And, if so, how long will this “acquired immunity” last?
The early data brought hope that acquired immunity was possible. But some subsequent studies have suggested that immune protection might be short-lived. Though more research is needed, the results of two recent studies, published in the journal Science Immunology, support the early data and provide greater insight into the nature of the human immune response to this coronavirus [1,2].
The new findings show that people who survive a COVID-19 infection continue to produce protective antibodies against key parts of the virus for at least three to four months after developing their first symptoms. In contrast, some other antibody types decline more quickly. The findings offer hope that people infected with the virus will have some lasting antibody protection against re-infection, though for how long still remains to be determined.
In one of the two studies, partly funded by NIH, researchers led by Richelle Charles, Massachusetts General Hospital, Boston, sought a more detailed understanding of antibody responses following infection with SARS-CoV-2. To get a closer look, they enrolled 343 patients, most of whom had severe COVID-19 requiring hospitalization. They examined their antibody responses for up to 122 days after symptoms developed and compared them to antibodies in more than 1,500 blood samples collected before the pandemic began.
The researchers characterized the development of three types of antibodies in the blood samples. The first type was immunoglobulin G (IgG), which has the potential to confer sustained immunity. The second type was immunoglobulin A (IgA), which protects against infection on the body’s mucosal surfaces, such as those found in the respiratory and gastrointestinal tracts, and are found in high levels in tears, mucus, and other bodily secretions. The third type is immunoglobulin M (IgM), which the body produces first when fighting an infection.
They found that all three types were present by about 12 days after infection. IgA and IgM antibodies were short-lived against the spike protein that crowns SARS-CoV-2, vanishing within about two months.
The good news is that the longer-lasting IgG antibodies persisted in these same patients for up to four months, which is as long as the researchers were able to look. Levels of those IgG antibodies also served as an indicator for the presence of protective antibodies capable of neutralizing SARS-CoV-2 in the lab. Even better, that ability didn’t decline in the 75 days after the onset of symptoms. While longer-term study is needed, the findings lend support to evidence that protective antibody responses against the novel virus do persist.
The other study came to very similar conclusions. The team, led by Jennifer Gommerman and Anne-Claude Gingras, University of Toronto, Canada, profiled the same three types of antibody responses against the SARS-CoV-2 spike protein, They created the profiles using both blood and saliva taken from 439 people, not all of whom required hospitalization, who had developed COVID-19 symptoms from 3 to 115 days prior. The team then compared antibody profiles of the COVID-19 patients to those of people negative for COVID-19.
The researchers found that the antibodies against SARS-CoV-2 were readily detected in blood and saliva. IgG levels peaked about two weeks to one month after infection, and then remained stable for more than three months. Similar to the Boston team, the Canadian group saw IgA and IgM antibody levels drop rapidly.
The findings suggest that antibody tests can serve as an important tool for tracking the spread of SARS-CoV-2 through our communities. Unlike tests for the virus itself, antibody tests provide a means to detect infections that occurred sometime in the past, including those that may have been asymptomatic. The findings from the Canadian team further suggest that tests of IgG antibodies in saliva may be a convenient way to track a person’s acquired immunity to COVID-19.
Because IgA and IgM antibodies decline more quickly, testing for these different antibody types also could help to distinguish between an infection within the last two months and one that more likely occurred even earlier. Such details are important for filling in gaps in our understanding COVID-19 infections and tracking their spread in our communities.
Still, there are rare reports of individuals who survived one bout with COVID-19 and were infected with a different SARS-CoV-2 strain a few weeks later . The infrequency of such reports, however, suggests that acquired immunity after SARS-CoV-2 infection is generally protective.
There remain many open questions, and answering them will require conducting larger studies with greater diversity of COVID-19 survivors. So, I’m pleased to note that the NIH’s National Cancer Institute (NCI) recently launched the NCI Serological Sciences Network for COVID19 (SeroNet), now the nation’s largest coordinated effort to characterize the immune response to COVID-19 .
The network was established using funds from an emergency Congressional appropriation of more than $300 million to develop, validate, improve, and implement antibody testing for COVID-19 and related technologies. With help from this network and ongoing research around the world, a clearer picture will emerge of acquired immunity that will help to control future outbreaks of COVID-19.
 Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients. Iyer AS, Jones FK, Nodoushani A, Ryan ET, Harris JB, Charles RC, et al. Sci Immunol. 2020 Oct 8;5(52):eabe0367.
 Persistence of serum and saliva antibody responses to SARS-CoV-2 spike antigens in COVID-19 patients. Isho B, Abe KT, Zuo M, Durocher Y, McGeer AJ, Gommerman JL, Gingras AC, et al. Sci Immunol. 2020 Oct 8;5(52):eabe5511.
 What reinfections mean for COVID-19. Iwasaki A. Lancet Infect Dis, 2020 October 12. [Epub ahead of print]
 NIH to launch the Serological Sciences Network for COVID-19, announce grant and contract awardees. National Institutes of Health. 2020 October 8.
Coronavirus (COVID-19) (NIH)
Charles Lab (Massachusetts General Hospital, Boston)
Gingras Lab (University of Toronto, Canada)
Jennifer Gommerman (University of Toronto, Canada)
NCI Serological Sciences Network for COVID-19 (SeroNet) (National Cancer Institute/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; National Cancer Institute