Virus World

During the COVID-19 pandemic it was widely described that certain individuals infected by SARS-CoV-2 experience persistent disease signs and symptoms, Long COVID, which in some cases is very severe with life changing consequences. To maximize our chances of identifying the underpinnings of this illness, we have focused on 121 of the most severe cases from >1000 patients screened in specialized clinics in Sweden and Belgium. We restricted this study to subjects with objective measures of organ damage or dysfunction, >3 months following a verified, but mild- to-moderate SARS-CoV-2 infection.

By performing systems-level immunological testing and comparisons to controls fully convalescent following a similar mild/moderate COVID-19 episode, we identify elevated serological responses to SARS-CoV-2 in severe Long COVID suggestive of chronic antigen stimulation. Persistent viral reservoirs have been proposed in Long COVID and using multiple orthogonal methods for detection of SARS-CoV-2 RNA and protein in plasma we identify a subset of patients with detectable antigens, but with minimal overlap across assays, and no correlation to symptoms or immune measurements. Elevated serologic responses to SARS-CoV-2 on the other hand were inversely correlated with clonally expanded memory CD8+ T cells, indicating that restrained clonal expansion enables viral persistence, chronic antigen exposure and elevated IgG responses, even if antigen-detection in blood is not universally possible.

Preprint in medRxiv (Feb. 13, 2024):

 https://doi.org/10.1101/2024.02.11.24302636 

SARS-CoV-2-reactive T cells are detected in some healthy unexposed individuals. Human studies indicate these T cells could be elicited by the common cold coronavirus OC43. To directly test this assumption and define the role of OC43-elicited T cells that are cross-reactive with SARS-CoV-2, we develop a model of sequential infections with OC43 followed by SARS-CoV-2 in HLA-B*0702 and HLA-DRB1*0101 Ifnar1−/− transgenic mice. We find that OC43 infection can elicit polyfunctional CD8+ and CD4+ effector T cells that cross-react with SARS-CoV-2 peptides. Furthermore, pre-exposure to OC43 reduces subsequent SARS-CoV-2 infection and disease in the lung for a short-term in HLA-DRB1*0101 Ifnar1−/− transgenic mice, and a longer-term in HLA-B*0702 Ifnar1−/− transgenic mice. Depletion of CD4+ T cells in HLA-DRB1*0101 Ifnar1−/− transgenic mice with prior OC43 exposure results in increased viral burden in the lung but no change in virus-induced lung damage following infection with SARS-CoV-2 (versus CD4+ T cell-sufficient mice), demonstrating that the OC43-elicited SARS-CoV-2 cross-reactive T cell-mediated cross-protection against SARS-CoV-2 is partially dependent on CD4+ T cells. These findings contribute to our understanding of the origin of pre-existing SARS-CoV-2-reactive T cells and their effects on SARS-CoV-2 clinical outcomes, and also carry implications for development of broadly protective betacoronavirus vaccines. The origin of SARS-CoV-2 cross-reactive T cells in unexposed humans is unclear. Here, the authors use HLA transgenic mouse models of sequential infections with human coronavirus OC43 and SARSCoV-2 and show that OC43 elicits cross-protective immunity against SARS-CoV-2, which partially depends on CD4 + T cells.

Published in Nature Communications (Jan. 26, 2024):

https://doi.org/10.1038/s41467-024-45043-2 

Study published in Nature Immunology reveals that repeated mRNA COVID-19 vaccinations enhance immune response, especially in previously infected individuals, leading to a diversified and increased number of immune cell clones and a stronger ability to combat various virus strains. In a recent study published in the journal Nature Immunology, researchers investigated how repeated mRNA vaccinations improve COVID-19 immunity in SARS-CoV-2-naïve and priorly infected individuals. Focusing on the latter cohort, the study evaluated the diversity and concertation in tandem with multiple sequencing analyses of immune cells isolated from the patient’s peripheral blood mononuclear cells. Study findings reveal that sequential vaccination promotes heterogeneous immune cell clonal expansions, with the third mRNA vaccination resulting in almost two times the number of clones as the first vaccination dose. Parallelly, populations of CD8+ T cells substantially increase, thereby better preparing an individual’s immune system to cope with multiple COVID-19 strains. Surprisingly, the presence and severity of COVID-19 infection were directly associated with post-vaccination immunity.

Does infection prevent infection?

First, a disclaimer – under no circumstances are the authors of the publication or the author of this article recommending that you allow yourself to become infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a means of improving your future immunity against the Coronavirus disease 2019 (COVID-19) pandemic. However, a number of previous studies have established the improved anti-COVID-19 capabilities of ‘hybrid immunity.’ Hybrid immunity arises from the combined effects of both a previous COVID-19 infection and vaccination, which have been consistently found to confer better protection than either alone. Two main mechanisms for this improved observed immunity have been proposed – an increase in the abundance and diversity of virus-specific memory T (Tm) cells and an increased diversity of spike (S) proteins in the Tm cell pool. Hitherto, however, these hypotheses have never been scientifically tested. Understanding the mechanisms underpinning observed immune responses to COVID-19 in hybrid individuals may allow for improved and personalized vaccination regimes, thereby improving global resistance against the pandemic, which has hitherto infected more than 770 million individuals and cost humanity almost 7 million lives.

About the study

In the present study, researchers used peripheral blood mononuclear cells (PBMCs) to identify and quantify the variations in T and B cell populations across individuals exposed to multiple vaccination doses in tandem with COVID-19 infections of varying severity. They then focused their efforts on evaluating the kinetics and diversity of T spike (Ts) cells, thereby verifying both proposed hypothesized mechanisms underpinning previously observed immunity improvements. The study cohort comprised 54 (28 female) self-reported COVID-19 survivors recruited from Seattle, USA, between April and August 2020. All participants had their demographic and medical data recorded and were subjected to convalescent plasma donation for PBMC isolation. The cohort consisted of 35 individuals with mild to moderate COVID-19, 19 with severe illness (hospital and oxygen support required), and eight with critical COVID-19 (intensive care unit [ICU] admission required). Participants ranged from 31 to 74 years of age, with 60.3 presenting the median value. Participants presented a diverse array of comorbidities, including cancer (n = 8), renal disease (n = 4), heart ailments (n = 9), hypertension (n = 9), and diabetes (n = 9).

From preserved PCMBs, selective staining was used to identify and isolate live CD3+ single cells, single positive CD4−CD8+, and CD4+CD8−, excluding all double positive and negative CD cells from further experiments. Gating and Boolean analyses with PBMC stimulation were used to identify and study AIM assay combinations of antigen-specific (in this case, SARS-CoV-2 Wu-1 strain) T-cell frequency. Intracellular cytokine staining (ICS) was used to identify and quantify the production of cytokines following SARS-CoV-2 stimulation. Genomic DNA isolated from PBMCs was used for T-cell Receptor Sequencing (TCR-Seq), a method used to identify and track specific T cells and their clones. TCR-Seq was carried out independently for bulk repertoire analyses (bulk TCR-Seq) and antibody feature barcode library generation (single-cell TCR-Seq). The library generated above was used for CD4+ and CD8+ assignments using unique molecular identifier (UMI) counts. SARS-CoV-2 Wu-1 strain-transfected Cos-7 cells were used to evaluate the specificity of assigned CD8+ T cells. Finally, next-generation Human Leukocyte Antigen (HLA) Typing was carried out to identify class 1 and class 2 allotypes.

Study findings

Results from the above tests revealed divergent vaccine response kinetics, both between CD4+ and CD8+ TS cells and between individuals with differing COVID-19 disease severity. “In persons with previous SARS-CoV-2 infection, mRNA vaccines induced profound, albeit variable, expansion of preexisting circulating TM cell clones.” These results were amplified based on the number of mRNA vaccines received following COVID-19 disease, with the first two vaccine doses observed to augment S-reactive clonotypic diversity in the blood, resulting in substantial expansion in CD8+ TS clonotypes. A similar expansion in CD8+ TS clonotypes has been reported in COVID-19-naïve individuals following their first vaccination dose, albeit to a much lower extent. This study further revealed that while not as substantial as CD8+ TS clonotype expansion, CD4+ clonotypes also expanded following the second vaccination dose.

Published in Nat. Immunology (Dec. 6, 2023):

https://doi.org/10.1038/s41590-023-01692-x

NIH-funded study suggests need to boost CD8+ T cell response after infection. The magnitude and quality of a key immune cell’s response to vaccination with two doses of the Pfizer-BioNTech COVID-19 vaccine were considerably lower in people with prior SARS-CoV-2 infection compared to people without prior infection, a study has found. In addition, the level of this key immune cell that targets the SARS-CoV-2 spike protein was substantially lower in unvaccinated people with COVID-19 than in vaccinated people who had never been infected. Importantly, people who recover from SARS-CoV-2 infection and then get vaccinated are more protected than people who are unvaccinated. These findings, which suggest that the virus damages an important immune-cell response, were published today in the journal Immunity. The study was co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and led by Mark M. Davis, Ph.D. Dr. Davis is the director of the Stanford Institute for Immunity, Transplantation and Infection and a professor of microbiology and immunology at Stanford University School of Medicine in Palo Alto, California. He is also a Howard Hughes Medical Institute Investigator. Dr. Davis and colleagues designed a very sensitive tool to analyze how immune cells called CD4+ T cells and CD8+ T cells respond to SARS-CoV-2 infection and vaccination. These cells coordinate the immune system’s response to the virus and kill other cells that have been infected, helping prevent COVID-19.

The tool was designed to identify T cells that target any of dozens of specific regions on the virus’s spike protein as well as some other viral regions. The Pfizer-BioNTech vaccine uses parts of the SARS-CoV-2 spike protein to elicit an immune response without causing infection. The investigators studied CD4+ and CD8+ T-cell responses in blood samples from three groups of volunteers. One group had never been infected with SARS-CoV-2 and received two doses of the Pfizer-BioNTech COVID-19 vaccine. The second group had previously been infected with SARS-CoV-2 and received two doses of the vaccine. The third group had COVID-19 and was unvaccinated. The researchers found that vaccination of people who had never been infected with SARS-CoV-2 induced robust CD4+ and CD8+ T-cell responses to the virus’ spike protein. In addition, these T cells produced multiple types of cell-signaling molecules called cytokines, which recruit other immune cells—including antibody-producing B cells—to fight pathogens. However, people who had been infected with SARS-CoV-2 prior to vaccination produced spike-specific CD8+ T cells at considerably lower levels—and with less functionality—than vaccinated people who had never been infected. Moreover, the researchers observed substantially lower levels of spike-specific CD8+ T cells in unvaccinated people with COVID-19 than in vaccinated people who had never been infected. Taken together, the investigators write, these findings suggest that SARS-CoV-2 infection damages the CD8+ T cell response, an effect akin to that observed in earlier studies showing long-term damage to the immune system after infection with viruses such as hepatitis C or HIV. The new findings highlight the need to develop vaccination strategies to specifically boost antiviral CD8+ T cell responses in people previously infected with SARS-CoV-2, the researchers conclude.  

Research published (March 15, 2023) in Immunity:

https://doi.org/10.1016/j.immuni.2023.03.005 

The adaptive immune response is under circadian control, yet, why adaptive immune reactions continue to exhibit circadian changes over long periods of time is unknown. Using a combination of experimental and mathematical modeling approaches, we show here that dendritic cells migrate from the skin to the draining lymph node in a time-of-day-dependent manner, which provides an enhanced likelihood for functional interactions with T cells.

Rhythmic expression of TNF in the draining lymph node enhances BMAL1-controlled ICAM-1 expression in high endothelial venules, resulting in lymphocyte infiltration and lymph node expansion. Lymph node cellularity continues to be different for weeks after the initial time-of-day-dependent challenge, which governs the immune response to vaccinations directed against Hepatitis A virus as well as SARS-CoV-2. In this work, we present a mechanistic understanding of the time-of-day dependent development and maintenance of an adaptive immune response, providing a strategy for using time-of-day to optimize vaccination regimes. Circadian rhythms have been shown to influence immune responses, but it is unclear whether this influences responses to vaccines. Here the authors show that dendritic cells migrate in a circadian rhythm meaning that interactions with T cells are altered leading to differential vaccine responses.

Published in Nature Communications (Jan. 30, 2023):

https://doi.org/10.1038/s41467-023-35979-2 

Inhaled particulates from environmental pollutants accumulate in macrophages in lung-associated lymph nodes over years, compromising immune surveillance via direct effects on immune cell function and lymphoid architecture. These findings reveal the importance of improved air quality to preserve immune health against current and emerging pathogens.

The question

Study of triple vaccinated people also says Omicron infection does little to reduce chance of catching variant again.  People who caught Covid during the first wave of the pandemic get no boost to their immune response if they subsequently catch Omicron, a study of triple vaccinated people reports. Experts say that while three doses of a Covid jab help to protect individuals against severe outcomes should they catch Omicron, previous infections can affect their immune response. “If you were infected during the first wave, then you can’t boost your immune response if you have an Omicron infection,” said Prof Rosemary Boyton, of Imperial College London, a co-author of the study. The team also found an Omicron infection offered little extra protection against catching the variant again. “When Omicron started flying around the country, people kept saying that’s OK, that will improve people’s immunity,” said Boyton. “What we’re saying is it’s not a good booster of immunity.”  The team said the findings may help to explain why reinfections with Omicron over a short time period have been so frequent, adding the findings were also important for vaccine development.

Writing in the journal Science, the researchers reported how they followed the vaccination and infection experiences of 731 triple vaccinated healthcare workers in the UK from March 2020 to January 2022. The team then used blood samples collected from participants in the weeks after their third dose of vaccine to explore their antibody and T-cell responses towards the Omicron variant, BA.1. The participants varied considerably in terms of their Covid history, including whether they had had a previous Covid infection and, if so, the variant involved. The results suggested that, regardless of the participants’ previous infection history, a few weeks after their third Covid jab their levels of T-cells against Omicron proteins were poor, while levels of antibodies against Omicron proteins were lower than against other variants. But previous infections also mattered. Among other findings the team reported infection with Omicron increased protection against future infection with other variants. However, it only offered a limited boost to protection against another Omicron infection – a response that was actually weakened among those who had also previously had the original strain of the virus.  The team said the results held for both antibody and T-cell responses, and suggested those who caught Covid in the first wave of the pandemic did not gain a boost to their immune response should they subsequently catch Omicron.

The researchers said the finding was a surprise as it was typically assumed that a prior infection, even of a different variant, would act to boost an individual’s immune response. Prof Danny Altmann, another author of the study, said that while it had previously been thought Covid variants such as Omicron had developed mutations in their spike protein that helped them to evade immune responses, the situation was more complex.

“It’s actually worse than that, because the adaptations that the spike [protein] has now are actually inducing a kind of regulation or shutdown of immune response,” he said, adding that while the study looked at responses to the BA.1, similar findings were likely for other subvariants of Omicron. The team added that with people in the UK having had very different histories of Covid infections and vaccinations, the study was important as it suggested this “immune imprinting” would shape subsequent immunity against the next variant. Altmann said that while the continued low levels of hospitalisation and deaths from Covid in the UK, despite high levels of infection, suggested Covid jabs continued to offer protection against death and severe disease, the findings could be important for the development of new vaccines. But he added the findings raised other concerns. “We’re not getting herd immunity, we’re not building up protective immunity to Omicron,” he said. “So we face not coming out the other end of infections and re-infections and breakthrough infections.”

Published in Science (June 14, 2022):

https://doi.org/10.1126/science.abq1841 

Findings from Brazil, Sweden and the United Kingdom show that before the advent of Omicron, vaccination benefited even those who had had a bout of COVID-19.  Even people who have had COVID-19 receive long-lasting benefits from a full course of vaccination, according to three recent studies1–3. What's more, one of the studies3 found that the ‘hybrid’ immunity caused by vaccination and infection is long-lasting, conferring highly effective protection against symptomatic disease for at least six to eight months after vaccination. The data were collected before the Omicron variant emerged, casting some doubt on the studies’ relevance today. But if the findings hold up, they could inform vaccination schemes and vaccine passports, which some countries require for entry to places such as restaurants. The work also counters high-profile claims that people who have had COVID-19 don’t benefit from vaccination. Just such a claim helped to launch some of the research. Brazilian President Jair Bolsonaro “said that he already had COVID-19, and for this reason, it is not necessary to take a vaccination”, says Julio Croda, an infectious-disease doctor and epidemiologist at the Oswaldo Cruz Foundation in Rio de Janeiro, Brazil. Croda and his colleagues drew on Brazilian vaccination and infection databases to test such assertions. The researchers found that between February 2020 and November 2021, people who had previously been infected with SARS-CoV-2 and then received one vaccine dose — made by either Pfizer–BioNTech, Oxford–AstraZeneca, SinoVac or Johnson & Johnson — avoided as many as 45% of the COVID-19 cases that the group would have been expected to contract without vaccination1. Full courses of two-dose vaccines prevented as many as 65% of expected infections and more than 80% of expected cases of severe COVID-19. “The big message is this: you need to have a full vaccination scheme for COVID-19,” Croda said.

‘Immunity’ passports?

Some authorities consider previous infections when deciding who should have entry to public places such as concerts and restaurants, but others consider only vaccination status. Peter Nordström, an epidemiologist at Umeå University in Sweden, says this dichotomy prompted him and his colleagues to perform another of the studies. Using records collected by the Public Health Agency of Sweden between March 2020 and October 2021, the researchers showed that Swedish residents who had been infected with SARS-CoV-2 had a 95% reduction in their risk of contracting COVID-19 compared with people who had no immunity — and protection grew over the three months following infection and lasted until at least 20 months after infection2. One dose of vaccine reduced the risk of infection by about an additional 50%, and a second dose stabilized the additional protection over the six months following vaccination. Although vaccination increases protection, Nordström thinks the immunity offered by infection alone is worthy of consideration. “Perhaps we should have immunity passports instead of vaccination passports. So you are considered immune — and less likely to transmit the disease — if you have been fully vaccinated, or you have had a documented previous infection,” he says.  Epidemiologist Victoria Hall at the UK Health Security Agency in London and her colleagues performed the third study by tracking infections in thousands of health-care workers from March 2020 to September 2021. The researchers found that previous infections prevented more than 80% of the COVID-19 cases that otherwise would have been expected in the year after infection, but protection waned to around 70% after a year3. Study participants who received two doses of the Pfizer–BioNTech or Oxford–AstraZeneca vaccine after an infection had near 100% protection for at least six to eight months following the second dose. “Protection declined over time after vaccination, and also after infection, but remained persistently high in those with hybrid immunity,” Hall wrote in an e-mail to Nature. Miguel Hernan, an epidemiologist at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, says the studies show the near-universal benefit of full vaccination. Some nations have issued guidelines that encourage people who have had COVID-19 to receive only a single vaccine dose: a move that “may be justified in a setting of vaccine scarcity, but not otherwise”, Hernan wrote in an e-mail to Nature.

Variant might change the game

Dan Barouch, a virologist at the Beth Israel Deaconess Medical Center in Boston, Massachusetts, says the findings are in line with previous research. “Vaccination following infection, or infection following vaccination, results in particularly robust antibody responses” he wrote in an e-mail to Nature. But Barouch notes that all three studies draw on data collected before the Omicron variant emerged. He and others caution that past infections will provide imperfect protection against emerging strains. Dan Kelly, an infectious-disease epidemiologist at the University of California, San Francisco, underscores that concern. Omicron is so different from the strains analysed in the studies that the findings might not apply to people who were infected with Omicron after being vaccinated. His advice to people who fall into this category: “Just be really careful.”

Published in Nature (April 6, 2022):

https://doi.org/10.1038/d41586-022-00961-3

The term ‘fully vaccinated’ needs to be redefined. It’s time for the United States and the CDC to see natural immunity as a partial path to protection. The US Centers for Disease Control and Prevention (CDC) has failed to recognize that people with confirmed Covid infections, also known as “natural immunity,” have achieved some level of protection against subsequent infections and severe disease. This has unnecessarily fueled divisiveness, particularly when vaccines are mandated without acknowledgement that prior Covid is an alternate path, albeit with some limitations, for protection of the individual and helping to build the population’s immunity wall. While there has been a body of data supporting a robust immune response to Covid infections, that evidence has recently been substantially bolstered. In the very large trial on the Johnson and Johnson vaccine single shot compared with placebo, among over 2,000 participants with prior infections, as documented by positive antibody status, their protection against moderate or severe disease was 90%. That’s much higher than the vaccine efficacy of 56%, yet the CDC recognizes 2-shot of this vaccine as “fully vaccinated” but ignores these data, and many other proof points, of natural immunity protection.

A recent CDC report for Covid in California that included the Delta wave, the cumulative hospitalization rate for the vaccinated was 0.7% among vaccinated and 0.3% unvaccinated with prior infection. Notably, a 10-fold lower risk of subsequent infection was found in the people with natural immunity compared with those vaccinated in the Cleveland Clinic health system’s study of over 52,000 employees. These reports convey a high level of protection of natural immunity, at times comparable to 2-shot vaccines. Multiple studies following people at least 15 months out from Covid infections have shown persistent antibody levels and memory B cells. Reinfections among those with natural immunity throughout the pandemic, until the recent Omicron wave, have been very low, less than 1%. A United Kingdom study of about 9,000 people with prior infections demonstrated higher than 90% protection against subsequent infections, even among those who had Covid more than 18 months previously. If there is good protection from infections, then why is one-shot of a vaccine necessary and sufficient? A new report of nearly 150,000 people with Covid infections in Israel, with about half vaccinated, compared to the others left unvaccinated, there was an 82% lower risk of reinfection for people aged 16 to 64 years, and 60% for age 65 or older. There was no difference for the protection with more than 1-dose of vaccine. The same was found in another study. Both of these were performed during the Delta wave, but now we have data with Omicron, the strain of the virus with the most substantial evasion of our immune system. Substantiating that, In Qatar, while the protection of natural immunity was about 90% for previous Alpha, Beta and Gamma variants, it dropped to 56% for Omicron. In the United Kingdom, the risk of reinfection for people with prior Covid spiked to a level 16-fold what had been seen previously. Yet an Omicron wave study from Cleveland Clinic in about 8,000 people with natural immunity, 1-shot of vaccine markedly reduced the risk of infection and 2 or 3-shots had no incremental protective benefit. That same finding was consistent in the Israel and UK studies: 1-shot did the trick, no added protection from 2 or 3-shots. Indeed, the waning of protection after 1-year in the UK study was averted with one dose of vaccine.

Past critique of natural immunity protection is still relevant. These studies have survivor bias—they only include people who survived their infections. We know that the symptoms of Long Covid can be reduced by vaccines, which is an important added feature of the controlled vaccine approach compared with the unpredictable chronic duration sequalae of an infection, which can be disabling, even when they are mild. Although about 90% of people with infections develop antibodies and memory B an T cells, that leaves some without an immune response, which appears to be more of an issue when a person did not have symptoms, or they were very mild. Since we do not assess antibody levels, especially those capable of neutralizing of the virus, and do not measure T cell responses, there is a blind spot in knowing about an individual’s level of protection, be it by infection or vaccination. Which brings us to hybrid immunity. It would be reckless to ever recommend someone get purposely infected with Covid. However, for those who have sustained an infection their immune response was directed to the whole virus whereas our vaccines are specific to the spike-protein. The result of combining the different immune responses is synergy, more than additive, a powerful and durable protection, 25 to 100 times more antibody response and broader against variants of the virus. Note that we do not have the same evidence for the opposite order: vaccination prior to breakthrough infections.

It is now clearly overdue for the United States and the CDC to acknowledge natural immunity as a partial path to protection, as has been previously done in several countries. The term “fully vaccinated” needs to be redefined. For people who have received 2 mRNA vaccine shots, without prior infection, a third shot, booster, is needed to protect against symptomatic and severe disease. On the other hand, for people with natural immunity, with proof of a positive PCR test, one-shot is all that is necessary to be considered “fully vaccinated.” By providing immunity certification in this way, the polarization between natural and vaccine-induce immune camps will be bridged, at least to some extent. The evidence has become overwhelming and its adoption as policy will likely help get the low American vaccination rate of 64% , ranked worse than 60 countries in the world, to a much higher level, further building the immunity wall for the whole population. It’s also about sticking to the science when a large and ever-increasing body of data can no longer be ignored. One can fully understand why vaccine mandates would be repudiated when there was evidence of protection conferred by infection. Now, as the virus evolved, we are at a time when natural immunity alone is not sufficient, but with a single shot it’s as good as three.

• Eric Topol is the founder and director of the Scripps Research Translational Institute, professor of molecular medicine, and executive vice-president of Scripps Research

Hope for a future without fear of COVID-19 comes down to circulating antibodies and memory B cells. Unlike circulating antibodies, which peak soon after vaccination or infection only to fade a few months later, memory B cells can stick around to prevent severe disease for decades. And they evolve over time, learning to produce successively more potent "memory antibodies" that are better at neutralizing the virus and more capable of adapting to variants. Vaccination produces greater amounts of circulating antibodies than natural infection. But a new study suggests that not all memory B cells are created equal. While vaccination gives rise to memory B cells that evolve over a few weeks, natural infection births memory B cells that continue to evolve over several months, producing highly potent antibodies adept at eliminating even viral variants.  The findings highlight an advantage bestowed by natural infection rather than vaccination, but the authors caution that the benefits of stronger memory B cells do not outweigh the risk of disability and death from COVID-19. "While a natural infection may induce maturation of antibodies with broader activity than a vaccine does—a natural infection can also kill you," says Michel C. Nussenzweig, the Zanvil A. Cohn and Ralph M. Steinman professor and head of Rockefeller's Laboratory of Molecular Immunology. "A vaccine won't do that and, in fact, protects against the risk of serious illness or death from infection."

Your body on COVID-19

When any virus enters the body, immune cells immediately churn out hordes of circulating antibodies. Foot soldiers of the immune system, these antibodies burn bright but decay at variable rates depending on the vaccine or infection—they may protect us for months or years but then dwindle in number, allowing possible reinfection. The immune system has a backup plan: an elite cadre of memory B cells that outlive circulating antibodies to produce so-called memory antibodies that provide long-term protection. Studies suggest that memory B cells for smallpox last at least 60 years after vaccination; those for Spanish flu, nearly a century. And while memory B cells don't necessarily block reinfection, they can prevent severe disease. Recent studies have suggested that within five months of receiving a vaccine or recovering from a natural infection, some of us no longer retain sufficient circulating antibodies to keep the novel coronavirus at bay, but our memory B cells stand vigilant. Until now, however, scientists did not know whether the vaccines could be expected to provide the sort of robust memory B cell response seen after natural infection.

The convalescent advantage

Nussenzweig and colleagues resolved to tease out any differences in memory B cell evolution by comparing blood samples from convalescent COVID-19 patients to those from mRNA-vaccinated individuals who had never suffered natural infection. Vaccination and natural infection elicited similar numbers of memory B cells. Memory B cells rapidly evolved between the first and second dose of the Pfizer and Moderna vaccines, producing increasingly potent memory antibodies. But after two months, progress stalled. The memory B cells were present in large numbers and expressed potent antibodies, but the antibodies were not getting any stronger. Also, although some of these antibodies were able to neutralize Delta and other variants, there was no overall improvement in breadth. With convalescent patients, on the other hand, memory B cells continued to evolve and improve up to one year after infection. More potent and more broadly neutralizing memory antibodies were coming out with every memory B cell update.

To boost or not to boost

There are several potential reasons that memory B cells produced by natural infection might be expected to outperform those produced by mRNA vaccines, the researchers say. It is possible that the body responds differently to viruses that enter through the respiratory tract than those that are injected into our upper arms. Or perhaps an intact virus goads the immune system in a way that the lone spike protein represented by the vaccines simply cannot. Then again, maybe it's that the virus persists in the naturally infected for weeks, giving the body more time to mount a robust response. The vaccine, on the other hand, is flushed out of the body mere days after triggering the desired immune response. Regardless of the cause, the implications are clear. We can expect memory B cells to undergo limited volleys of evolution in response to mRNA vaccines, a finding that may have significant implications for the design and rollout of booster shots. A booster with the currently available mRNA vaccine would be expected to engage memory cells to produce circulating antibodies that are strongly protective against the original virus and somewhat less so against the variants, Nussenzweig says. "When to administer the booster depends on the object of boosting," he says. "If the goal is to prevent infection, then boosting will need to be done after 6 to 18 months depending on the immune status of the individual. If the goal is to prevent serious disease boosting may not be necessary for years."

See findings published in Nature (October 7, 2021):

https://doi.org/10.1038/s41586-021-04060-7

A new study from La Jolla Institute for Immunology (LJI) scientists helps answer the question: how long does immunity against COVID-19 last in vaccinated people?  As they report in Science, a low dose of the Moderna vaccine lasts for at least six months, and there is no indicator that vaccinated people will need a booster shot. "This time point is critical because that is when true immune memory has formed," says LJI Research Assistant Professor Daniela Weiskopf, Ph.D., who co-led the study with LJI Professors Alessandro Sette, Dr.Biol.Sci., and Shane Crotty, Ph.D. In fact, while the Moderna COVID-19 vaccine (mRNA-1273) led to strong CD4+ (helper) T cell, CD8+ (killer) T cell and antibody responses for at least six months after clinical trial participants were fully vaccinated, it is likely that the immune response could last much longer. The researchers also show that this strong immune memory lasted in all age groups tested, including in people over age 70, a demographic especially vulnerable to severe COVID-19.  "The immune memory was stable, and that was impressive," adds Crotty. "That's a good indicator of the durability of mRNA vaccines."

Comparing Moderna vaccine to natural immunity

The researchers compared recovered COVID-19 patients to vaccine trial participants who received a 25-microgram dose of the Moderna vaccine during the phase 1 clinical trials (supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health).  "We wanted to see if a quarter of the dose is able to induce any immune response," says study first author Jose Mateus Triviño, Ph.D., a postdoctoral fellow at LJI. "We had the opportunity to receive the samples from the original Moderna/ NIH phase 1 trial participants who had received two 25-microgram injections of the vaccine, 28 days apart." This vaccine dose is a quarter of the 100-microgram Moderna dose given emergency authorization by the Food and Drug Administration (FDA). While researchers don't know whether this smaller dose is as effective as the standard dose, this new study shows that the T cell and antibody response in the smaller dose group is still strong. In fact, the researchers found that the Moderna vaccine spurs an adaptive immune response to the SARS-CoV-2 spike protein (a key target) nearly identical to the immune system's response to a natural SARS-CoV-2 infection. "The response is comparable," says Weiskopf. "It's not higher and it's not lower." The new study does not show that a lower dose of the Moderna vaccine provides the same protection as the standard dose. "It would take a clinical trial to tell you how protective the lower dose is," says Crotty.

Common cold viruses do prep the immune system

The new research also shows the power of "cross-reactive" T cells. In a 2020 Science study, the LJI team showed that T cells in people who had recovered from common cold coronaviruses could respond to the novel coronavirus, SARS-CoV-2. At the time, they didn't know whether this cross-reactivity could actually protect against COVID-19.  "Understanding the role of cross-reactive T cells is important because T cells play an important role in the control and resolution of COVID-19 infections," says Sette. For the new study, the researchers found that people with cross-reactive T cells had significantly stronger CD4+ T cell and antibody responses to both doses of the vaccine. "If you have this immune reactivity, your immune system may kick in faster against the virus," says Sette. "And multiple studies have shown that how quickly the immune system reacts is key."

Moderna vaccine activates "killer" T cells 

The team also filled in an important gap in COVID-19 vaccine research. Until now, many studies had shown an effective CD4+ T cell response to the Moderna vaccine, but CD8+ T cell data was lacking.  "We know naturally infected and recovered people develop excellent CD8+ T cell responses against SARS-CoV-2; however, there was concern about the generation of CD8+ T cells by mRNA vaccines," says Mateus Triviño.  The new study shows a strong CD8+ T cell response to the low dose Moderna vaccine, similar to the response after a patient fights a natural SARS-CoV-2 infection, says Sette, a renowned T cell expert. "We see a robust CD8+ T cell response—and we showed that using multiple assays," adds Weiskopf.

Coming up:

Will this same vaccine durability hold true for the other types of COVID-19 vaccines? Weiskopf and her colleagues are investigating. In the meantime, Weiskopf says real-world data suggest immune memory does last.  "The people in the hospitals are the ones not vaccinated," she says. The researchers are also interested in how the durability of the Moderna vaccine compares with other COVID-19 vaccines in use.

Research cited published in Science (Sept. 14, 2021):

https://doi.org/10.1126/science.abj9853 

While all participants in the control group displayed a positive antibody response to spike protein, only 51 of the 136 (37.5%) organ transplant recipients had positive serology. Researchers have found that organ transplant recipients may remain at high risk for COVID-19 even after being fully vaccinated against the novel coronavirus. The Israeli study analyzed the humoral responses of 139 kidney transplant recipients after receiving both shots of the Pfizer-BioNTech vaccine, benchmarking their results against a control group of 25 healthy participants. Across the board, the mean antibody levels "were significantly lower" in comparison to the control participants, the researchers said. Transplant recipients who did in fact display a positive serology were typically younger than those without. Additionally, the longer period of time between transplantation and vaccination was "significantly associated" with positive serological response to mRNA vaccines.

"The most significant predictors of failure to mount a humoral response in our cohort of kidney transplant recipients were advanced age, need for high dose corticosteroids during the last (pre-vaccination) year, maintenance with three immunosuppressive medications, and a regimen that includes [Mycophenolate mofetil] MMF," the study authors wrote. Researchers added that MMF is known to have a "suppressive effect on the immune system, including inhibition of antibody production," noting that "the greater the degree of immunosuppression, the less likely the patient will respond to immunization."  Out of the 139 study participants, only two developed severe COVID-19 infections following a full vaccination. One required severe hospitalization 12 weeks after being vaccinated, and the other died, nine weeks after receiving the second dose of the Pfizer vaccine.

Sage says majority were likely infected shortly before or soon after jab, before immunity had time to develop.  One in 25 people hospitalised with Covid-19 since December have had at least one dose of vaccine, with the majority infected shortly before or soon after vaccination – before immunity would have had time to develop. However, few of those who developed symptoms, did so more than 2 weeks after receiving a first dose – indicating that the vaccines do help to prevent serious disease once they’ve had time to take effect. The data, presented to the government’s Scientific Advisory Group for Emergencies (Sage), could be a further indication that people are dropping their guard once they’ve received a jab, wrongly assuming that they are immediately protected. Alternative explanations include the possibility that they were infected shortly before vaccination, during the vaccine appointment itself, or that vaccination triggered symptoms in infected people who were previously asymptomatic. In minutes from its 83rd meeting on 11 March Sage said:“The observation that a significant number of people developing symptoms within a few days of a first dose may suggest some behaviour change following vaccination. It is important therefore that communications around vaccination reinforce the need for safe behaviours to be maintained.” Almost 29 million people in the UK have received at least one dose of a coronavirus vaccine so far, with some degree of immune protection thought to develop around two weeks after receiving the first jab – although a second dose is needed to achieve the highest levels of protection.

According to data submitted to Sage by the Covid-19 Clinical Information Network (CO-CIN), there were 1,802 recorded cases of vaccinated patients hospitalised with Covid-19 in the UK as of 5 March. This accounted for 4.2% (1,802/42,788) of all Covid-related hospital admissions since 8 December – the date when the first people in the UK were vaccinated. The median time between vaccination and symptom onset for these patients was five days, indicating that most of them were infected shortly before or around the time of vaccination, with the remainder infected after vaccination but before immunity had developed. “Elderly and vulnerable people who had been shielding, may have inadvertently been exposed and infected either through the end-to-end process of vaccination, or shortly after vaccination through behavioural changes where they wrongly assume they are immune,” the CO-CIN report said.  Data from previous vaccine rollouts, national surveys and evidence from Israel have also indicated that people may be less likely to abide by social distancing rules once they’ve been vaccinated. In its 11 March meeting, Sage emphasised the need for better government communication about how long it takes for the jab to work, and that although the Covid-19 vaccines in use in the UK are highly effective, no vaccine is 100% effective. Minutes from the meeting said: “Some people will be hospitalised with Covid-19 even after completing their full vaccination schedule. It will be particularly important to monitor the prevalence of different variants present in this group by sequencing to understand any potential immune escape. This is under way by Public Health England.” A separate document released by Sage on Friday suggested there has been a four-fold increase in confirmed cases of the Brazilian P1 variant during the fortnight of 10 March to 24 March from 5 to 21, while cases of the South African variant have increased from 190 to 305.

Research into bacteriophages adds to evidence that gut and brain interactions influence our behaviour. Viruses are widely regarded as harmful to our health, but a subset of viruses living in the gut could play a crucial role in regulating stress, research suggests. The discovery adds to mounting evidence that interactions between the gut and brain influence people’s behaviours, and could eventually lead to new treatments for stress-related conditions that target the vast community of viruses living inside us. While previous studies have suggested that the composition of microbes living in the gut changes in response to stress, these have largely focused on bacteria, rather than on this “virome”. “The way the virome interacts with bacteria, and how they affect stress-related health and disease status is largely unexplored,” said Dr Nathaniel Ritz, of the APC Microbiome Ireland research centre at University College Cork. “Our research opens up the potential to target the virome to treat and reduce the effects of stress.”

Ritz and his colleagues focused on a subset of viruses called bacteriophages, which infect bacteria and replicate alongside them. They studied what happened to these viruses when the mice they inhabited were exposed to chronic social stresses, such as being housed alone or in overcrowded conditions, and found that stress exposure led to changes in the composition of the viruses and the bacteria in the animals’ guts. Next, they harvested viruses from the droppings of unstressed healthy animals, and transplanted some of them back in, once the mice had been exposed to chronic social stress. The research, published in Nature Microbiology, suggested these transplants reduced levels of stress hormones and curbed depression- and anxiety-like behaviour in the mice. While further studies are needed to assess whether virus transplants are beneficial to humans suffering from stress-related conditions, the research provides some of the first evidence that gut viruses are involved in the response to stress, and that manipulating them could have therapeutic benefits. “Given that the virome composition varies greatly among individuals, it may open the door for personalised medicine approaches for stress-related disorders in the future,” said Prof John Cryan at APC Microbiome Ireland, who led the research. “One thing for certain, we must acknowledge that not all viruses are bad and they can play a key role in keeping the bad bacteria in our gut at bay especially in times of stress.”

Cited research published in Nature Microbiology (Feb.5, 2024):

https://doi.org/10.1038/s41564-023-01564-y 

IMPORTANCE

Children have largely avoided severe COVID-19 symptoms because they have a strong initial 'innate' immune reaction that quickly defeats the virus. And now, researchers led by scientists at the Garvan Institute of Medical Research have uncovered what this might mean for the immune system. Unlike those of adults, children's immune systems don't remember the virus and don't adapt, so when they're next exposed to SARS-CoV-2, their body still treats it as a new threat, the scientists found. "Because children haven't been exposed to many viruses, their immune system is still 'naive'. And because they don't develop memory T cells, they are at risk of getting sick when they become reinfected. With each new infectious episode as they get older, there is a risk of their T cells becoming 'exhausted' and ineffective, like the T cells in older people. This is why we think it's important to vaccinate children," he says. The immune system has two modes. The innate immune system is the first line of defense, comprising physical barriers such as skin and mucosal surfaces that block viruses from entering. It is also composed of cells that make chemicals to signal to other cells and ward off the viruses. The innate immune system does not distinguish between one type of virus or another.

The second line of defense comprises B and T cells of the adaptive immune system. These cells have specific receptors that can recognize and distinguish different parts of a virus and generate a rapid response to neutralize or limit it. Infants start with an immune system blank slate, which has a much higher proportion of naïve T cells, the researchers found. As they move through childhood into adulthood and become exposed to more viruses, the naïve T cells are replaced by memory T cells that are locked in to making responses to viruses they have seen before. "Over time, as you get infections, your immune system becomes more 'educated', allowing you to make a faster immune response that's tightly matched to the viruses that have infected you before," says Associate Professor Philip Britton, pediatric infectious diseases physician at the Children's Hospital at Westmead, and clinical lead in the study. "Children's immune systems move from relying mostly on the innate system, to needing the adaptive system as a backup as they grow older and are unable to clear viruses as rapidly." In the new study, published in the journal Clinical Immunology, Professor Phan, Associate Professor Britton and colleagues took a deep dive to investigate T cells and cellular immune responses of a small group of children and their household family contacts who had mild or no symptoms from coronavirus (SARS-CoV-2) infection.

The researchers sequenced white blood cell samples to analyze T cells in children and adults at the time of acute infection and one month later. Because they studied household family contacts who were infected, researchers could control for the impact of genetic or environmental influences on the immune response. They found that children had many different naive T cells to fight SARS-CoV-2 and made poor memory T cell responses to the virus after they had recovered, whereas the adults had few naïve T cells but made good memory T cell responses after recovery. Interestingly, the findings point to why older adults can have a kind of immune over-reaction to SARS-CoV-2. "When adults are infected for the first time with SARS-CoV-2, their memory T cells recognize only what they've seen before – like a familiar part of the coronavirus that is shared with the common cold coronaviruses," Professor Phan says. "This may lock the immune system in to a misdirected response that is not specific to SARS-CoV-2. It provides an opportunity for the virus to escape and multiply unchecked to cause more severe symptoms as the immune system ramps up to try and fix the problem."

Cited research published in  Clinical Immunology (jan. 2023):

https://doi.org/10.1016/j.clim.2022.109209

Vaccination, infection with SARS-CoV-2 infection and a combination of both provide varying degrees of protection against infection. Three years into the pandemic, the immune systems of the vast majority of humans have learnt to recognize SARS-CoV-2 through vaccination, infection or, in many cases, both. But just how quickly do these types of immunity fade? New evidence suggests that ‘hybrid’ immunity, the result of both vaccination and a bout of COVID-19, can provide partial protection against reinfection for at least eight months1. It also offers greater than 95% protection against severe disease or hospitalization for between six months and a year after an infection or vaccination, according to estimates from a meta-analysis2. Immunity acquired by booster vaccination alone seems to fade somewhat faster. But the durability of immunity is much more complex than the numbers suggest. How long the immune system can fend off SARS-CoV-2 infection depends not only on how much immunity wanes over time but also on how well immune cells recognize their target. “And that has more to do with the virus and how much it mutates,” says Deepta Bhattacharya, an immunologist at the University of Arizona College of Medicine in Tucson. If a new variant finds ways to escape the existing immune response, then even a recent infection might not guarantee protection.

Omicron era

Omicron has presented just such a scenario. In late 2021 and early 2022, the main Omicron subvariants that were causing infections were BA.1 and BA.2. By mid-2022, the BA.5 wave was gathering strength in some countries, raising the prospect that those who’d already had one round of Omicron could soon be exposed to another. Data are now providing a sense of the risk of reinfection over time. In one study1, researchers looking at Portugal’s national database of infections studied vaccinated people who became infected during the BA.1/BA.2 wave. Analysis showed that 90 days after an infection, this population had high immune protection — their risk of becoming infected with BA.5 was just one-sixteenth that of people who had been vaccinated but never infected. After that, hybrid immunity against infection declined steeply for a few months and then stabilized, ultimately providing protection for eight months after infection, the duration of the study. Another study3 looked at 338 vaccinated health-care workers in Sweden, some of whom had also had a prior SARS-CoV-2 infection. The authors found that workers with hybrid immunity had some level of protection against infection with BA.1, BA.2 and BA.5 for at least eight months. Swabbing of these workers’ noses revealed high levels of ‘mucosal’ antibodies, which are thought to be a better shield against infection than antibodies that circulate in the blood. A study4 in Qatar compared the infection risks of people who had never caught SARS-CoV-2 with those of people who’d had a previous infection with Omicron or an earlier variant. Both groups included vaccinated and unvaccinated individuals. The results show that more recent infections provide greater protection than older ones in all cases. But because the virus kept evolving, the authors couldn’t untangle whether those differences were because of waning immunity, the virus’s growing ability to evade the immune response or, more likely, a combination of the two.

Infection reprieve

Taken together, the studies suggest that hybrid immunity provides some protection against infection for at least seven or eight months, and probably longer. “That’s pretty good,” says Charlotte Thålin, an immunologist at the Karolinska Institute in Stockholm and an author of the Swedish study. Other data suggest that in people whose immunity arises only from vaccination, a booster dose provides relatively short-lived protection against infection. Researchers in Israel studied more than 10,000 health-care workers who had not previously been infected; all received either three or four doses of the vaccine made by Pfizer and BioNTech5. The authors found that the fourth dose’s efficacy against infection fell rapidly. In fact, after four months, the fourth dose was no better than three doses at preventing infection. However, “we are talking just about what we call relatively mild disease”, says study co-author Gili Regev-Yochay, an epidemiologist at Sheba Medical Center Tel Hashomer in Ramat Gan, Israel. None of the people in the study developed severe COVID-19. What about those who haven’t been vaccinated? Another study6 in Qatar suggests that if the virus doesn’t change, infection-based immunity against reinfection can last up to three years. But that immunity can fade faster if the virus mutates. The authors studied data from unvaccinated people who were infected with a pre-Omicron variant. Fifteen months later, those infections were less than 10% effective at protecting against Omicron infection. And it is much riskier to rely on immunity from infection than to get immunized. But it’s nearly impossible to apply the study results to predict an individual’s risk of becoming infected in future. Immunity depends on a variety of factors, including genetics, age and sex. And past risk of infection isn’t necessarily a good predictor of the risk of future infection, because new variants are continually arising.

Publiished in Nature (Feb. 2, 2023)

https://doi.org/10.1038/d41586-023-00124-y 

Infection with a pre-Omicron SARS-CoV-2 variant protects against reinfection with a second, although the effect fades almost completely after three years.  Natural immunity induced by infection with SARS-CoV-2 provides a strong shield against reinfection by a pre-Omicron variant for 16 months or longer, according to a study1. This protection against catching the virus dwindles over time, but immunity triggered by previous infection also thwarts the development of severe COVID-19 symptoms — and this safeguard shows no signs of waning. The study1, which analyses cases in the entire population of Qatar, suggests that although the world will continue to be hit by waves of SARS-CoV-2 infection, future surges will not leave hospitals overcrowded with people with COVID-19. The research was posted on the medRxiv preprint server on 7 July. It has not yet been peer reviewed. The study is “solid”, says Shane Crotty, an immunologist at the La Jolla Institute for Immunology in California. “The data make sense and are in line with multiple other studies and previous work by this group.”

Better late than never

But scientists also warn that the study’s results do not mean that infected people can skip vaccination. A separate study2 by many of the same authors found that “people who had both natural immunity and vaccine immunity were substantially more protected against the virus than people who had only natural immunity alone or vaccine immunity”, says Laith Abu-Raddad, an infectious-disease epidemiologist at Weill Cornell Medicine–Qatar in Doha and a co-author of both studies. “It was very clear-cut.” Studies3,4 on the effectiveness of COVID-19 vaccines suggest that protection against the virus SARS-CoV-2 decreases over time, waning considerably after six months. To learn about the course of naturally acquired immunity, the authors examined COVID-19 data gathered in Qatar between 28 February 2020 and 5 June 2022. “Our study is the first to have such a long time of follow-up,” says co-author Hiam Chemaitelly, an epidemiologist also at Weill Cornell Medicine–Qatar. The researchers compared COVID-19 cases in unvaccinated individuals who’d had one previous SARS-CoV-2 infection with cases in unvaccinated people who’d never previously caught the virus. They found that infection with a pre-Omicron variant prevented reinfection by another pre-Omicron variant with an average effectiveness of 85.5% for the period covering the 4th through the 16th month following the initial infection. Effectiveness peaked at 90.5% in the 7th month after the first infection and fell to about 70% at 16 months (see ‘Immunity fades away’). By extrapolating this trend, the authors predict that effectiveness against reinfection will fall to less than 10% 32 months after the first infection. Pre-Omicron infection was only 38% effective at preventing infection by an Omicron variant in the first 6 months after Omicron emerged. Modelling suggests that the number will drop to 10% at 15 months. All the same, infection with any SARS-CoV-2 variant is highly effective at combating severe, critical or fatal COVID-19 after reinfection: effectiveness was around 100% up to the 14th month after primary infection and showed no signs of declining.

Published  in Nature July 15, 2022

 https://doi.org/10.1038/d41586-022-01914-6 

Recent emergence of SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.2. The new variants' receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we showed that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 shows the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization escape from the plasma of 3-dose vaccinees and, most strikingly, from vaccinated BA.1 convalescents.

To delineate the underlying evasion mechanism, we determined the escaping mutation profiles, epitope distribution and Omicron sublineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype (WT) induced humoral memory and elicits antibodies that neutralize both WT and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure of Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to WT SARS-CoV-2, due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths.

As for therapeutic NAbs, LY-CoV1404 (Bebtelovimab) and COV2-2130 (Cilgavimab) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.

Preprint available in bioRxiv (May 02, 2022):

 https://doi.org/10.1101/2022.04.30.489997 

Background

Methods

Findings

Interpretation

They remain susceptible to the virus for longer after the first vaccination, but achieve a mostly normal response after the second, a study says.  Pregnant and breastfeeding women respond to the first dose of the coronavirus vaccines more slowly than other women, and mount a less potent defense against the virus, according to a new study. After the second dose, however, their response looks almost normal. The results, published this month in the journal Science Translational Medicine, suggest that pregnant and breastfeeding women remain susceptible to the virus for longer after vaccination. The study underscores the importance of giving these women the second dose in time, and monitoring them closely in the meantime for signs of infection. During pregnancy, the immune system is modified to tolerate the fetus — effectively a foreign entity — leaving pregnant women particularly susceptible to pathogens like the coronavirus. Because of this, pregnant women are more likely to become severely ill and to die from Covid than other women of the same age.

BACKGROUND

Despite high vaccine coverage and effectiveness, the incidence of symptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been increasing in Israel. Whether the increasing incidence of infection is due to waning immunity after the receipt of two doses of the BNT162b2 vaccine is unclear.

METHODS

We conducted a 6-month longitudinal prospective study involving vaccinated health care workers who were tested monthly for the presence of anti-spike IgG and neutralizing antibodies. Linear mixed models were used to assess the dynamics of antibody levels and to determine predictors of antibody levels at 6 months.

RESULTS

The study included 4868 participants, with 3808 being included in the linear mixed-model analyses. The level of IgG antibodies decreased at a consistent rate, whereas the neutralizing antibody level decreased rapidly for the first 3 months with a relatively slow decrease thereafter. Although IgG antibody levels were highly correlated with neutralizing antibody titers (Spearman’s rank correlation between 0.68 and 0.75), the regression relationship between the IgG and neutralizing antibody levels depended on the time since receipt of the second vaccine dose. Six months after receipt of the second dose, neutralizing antibody titers were substantially lower among men than among women (ratio of means, 0.64; 95% confidence interval [CI], 0.55 to 0.75), lower among persons 65 years of age or older than among those 18 to less than 45 years of age (ratio of means, 0.58; 95% CI, 0.48 to 0.70), and lower among participants with immunosuppression than among those without immunosuppression (ratio of means, 0.30; 95% CI, 0.20 to 0.46).

CONCLUSIONS

Six months after receipt of the second dose of the BNT162b2 vaccine, humoral response was substantially decreased, especially among men, among persons 65 years of age or older, and among persons with immunosuppression.

Published in NEJM (Oct. 6, 2021):

https://doi.org/10.1056/NEJMoa2114583 

Important immune cells survive in the bone marrow of people who were infected with the virus or were inoculated against it, new research suggests.  Immunity to the coronavirus lasts at least a year, possibly a lifetime, improving over time especially after vaccination, according to two new studies. The findings may help put to rest lingering fears that protection against the virus will be short-lived. Together, the studies suggest that most people who have recovered from Covid-19 and who were later immunized will not need boosters. Vaccinated people who were never infected most likely will need the shots, however, as will a minority who were infected but did not produce a robust immune response. Both reports looked at people who had been exposed to the coronavirus about a year earlier. Cells that retain a memory of the virus persist in the bone marrow and may churn out antibodies whenever needed, according to one of the studies, published on Monday in the journal Nature. The other study, posted online at BioRxiv, a site for biology research, found that these so-called memory B cells continue to mature and strengthen for at least 12 months after the initial infection.  “The papers are consistent with the growing body of literature that suggests that immunity elicited by infection and vaccination for SARS-CoV-2 appears to be long-lived,” said Scott Hensley, an immunologist at the University of Pennsylvania who was not involved in the research. The studies may soothe fears that immunity to the virus is transient, as is the case with coronaviruses that cause common colds. But those viruses change significantly every few years, Dr. Hensley said. “The reason we get infected with common coronaviruses repetitively throughout life might have much more to do with variation of these viruses rather than immunity,” he said.

In fact, memory B cells produced in response to infection with SARS-CoV-2 and enhanced with vaccination are so potent that they thwart even variants of the virus, negating the need for boosters, according to Michel Nussenzweig, an immunologist at Rockefeller University in New York who led the study on memory maturation. “People who were infected and get vaccinated really have a terrific response, a terrific set of antibodies, because they continue to evolve their antibodies,” Dr. Nussenzweig said. “I expect that they will last for a long time.” The result may not apply to protection derived from vaccines alone, because immune memory is likely to be organized differently after immunization, compared with that following natural infection. That means people who have not had Covid-19 and have been immunized may eventually need a booster shot, Dr. Nussenzweig said. “That’s the kind of thing that we will know very, very soon,” he said.  Upon first encountering a virus, B cells rapidly proliferate and produce antibodies in large amounts. Once the acute infection is resolved, a small number of the cells take up residence in the bone marrow, steadily pumping out modest levels of antibodies. To look at memory B cells specific to the new coronavirus, researchers led by Ali Ellebedy of Washington University in St. Louis analyzed blood from 77 people at three-month intervals, starting about a month after their infection with the coronavirus. Only six of the 77 had been hospitalized for Covid-19; the rest had mild symptoms. Antibody levels in these individuals dropped rapidly four months after infection and continued to decline slowly for months afterward — results that are in line with those from other studies. Some scientists have interpreted this decrease as a sign of waning immunity, but it is exactly what’s expected, other experts said. If blood contained high quantities of antibodies to every pathogen the body had ever encountered, it would quickly transform into a thick sludge. Instead, blood levels of antibodies fall sharply following acute infection, while memory B cells remain quiescent in the bone marrow, ready to take action when needed.

Dr. Ellebedy’s team obtained bone marrow samples from 19 people roughly seven months after they had been infected. Fifteen had detectable memory B cells, but four did not, suggesting that some people might carry very few of the cells or none at all.  “It tells me that even if you got infected, it doesn’t mean that you have a super immune response,” Dr. Ellebedy said. The findings reinforce the idea that people who have recovered from Covid-19 should be vaccinated, he said. Five of the participants in Dr. Ellebedy’s study donated bone marrow samples seven or eight months after they were initially infected and again four months later. He and his colleagues found that the number of memory B cells remained stable over that time. The results are particularly noteworthy because it is difficult to get bone marrow samples, said Jennifer Gommerman, an immunologist at the University of Toronto who was not involved in the work. A landmark study in 2007 showed that antibodies in theory could survive decades, perhaps even well beyond the average life span, hinting at the long-term presence of memory B cells. But the new study offered a rare proof of their existence, Dr. Gommerman said. Dr. Nussenzweig’s team looked at how memory B cells mature over time. The researchers analyzed blood from 63 people who had recovered from Covid-19 about a year earlier. The vast majority of the participants had mild symptoms, and 26 had also received at least one dose of either the Moderna or the Pfizer-BioNTech vaccine. So-called neutralizing antibodies, needed to prevent reinfection with the virus, remained unchanged between six and 12 months, while related but less important antibodies slowly disappeared, the team found.  As memory B cells continued to evolve, the antibodies they produced developed the ability to neutralize an even broader group of variants. This ongoing maturation may result from a small piece of the virus that is sequestered by the immune system — for target practice, so to speak. A year after infection, neutralizing activity in the participants who had not been vaccinated was lower against all forms of the virus, with the greatest loss seen against the variant first identified in South Africa. Vaccination significantly amplified antibody levels, confirming results from other studies; the shots also ramped up the body’s neutralizing ability by about 50-fold.

Senator Rand Paul, Republican of Kentucky, said on Sunday that he would not get a coronavirus vaccine because he had been infected in March of last year and was therefore immune. But there is no guarantee that such immunity will be powerful enough to protect him for years, particularly given the emergence of variants of the coronavirus that can partially sidestep the body’s defenses. The results of Dr. Nussenzweig’s study suggest that people who have recovered from Covid-19 and who have later been vaccinated will continue to have extremely high levels of protection against emerging variants, even without receiving a vaccine booster down the line. “It kind of looks exactly like what we would hope a good memory B cell response would look like,” said Marion Pepper, an immunologist at the University of Washington in Seattle who was not involved in the new research. The experts all agreed that immunity is likely to play out very differently in people who have never had Covid-19. Fighting a live virus is different from responding to a single viral protein introduced by a vaccine. And in those who had Covid-19, the initial immune response had time to mature over six to 12 months before being challenged by the vaccine. “Those kinetics are different than someone who got immunized and then gets immunized again three weeks later,” Dr. Pepper said. “That’s not to say that they might not have as broad a response, but it could be very different.”

The BNT162b2 vaccine was shown to have 95% efficacy against coronavirus disease 2019 (Covid-19).1 To date, the two-dose vaccine protocol has not been approved in Israel for persons previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, administration of a single dose is now being considered. In addition to the original virus first identified in Wuhan, China, SARS-CoV-2 variants first identified in the United Kingdom (B.1.1.7), South Africa (B.1.351), and Brazil (P.1) have been detected in recent months.2 Samples from persons who had been vaccinated or previously infected with the original virus or the B.1.1.7 variant were shown to have significantly less neutralizing activity against the B.1.351 variant than against the other variants.3,4 In this study, we investigated whether one dose of the BNT162b2 vaccine would increase neutralizing activity against the B.1.1.7, B.1.351, and P.1 variants in persons previously infected with SARS-CoV-2. 

A microneutralization assay with isolates of the original virus (sublineage B.1) and the B.1.1.7, B.1.351, and P.1 variants was performed on 18 serum samples from six health care workers previously infected with SARS-CoV-2, with a sample obtained from each patient at three time points: 1 to 12 weeks after natural infection, immediately before vaccination, and 1 to 2 weeks after vaccination (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). All six health care workers were women (32 to 67 years of age) and had been infected with the original virus (sublineage B.1), as determined by sequencing of SARS-CoV-2 performed at the time of diagnosis. Samples obtained at the first time point had neutralizing activity against the original virus and the B.1.1.7 and P.1 variants, with geometric mean titers of 456, 256, and 71, respectively, but had little or no neutralizing activity against the B.1.351 variant, with a geometric mean titer of 8. At the second time point, geometric mean titers were 81, 40, 36, and 7 for the original virus and the B.1.1.7, P.1, and B.1.351 variants, respectively. Of note, at the third time point, geometric mean titers were 9195, 8192, 2896, and 1625 for the original virus and the B.1.1.7, P.1, and B.1.351 variants, respectively — that is, the titers after vaccination were 114, 203, 81, and 228 times as high as the titers immediately before vaccination (Figure 1 and Table S2).

This study showed that, in our small cohort, one vaccine dose substantially increased neutralizing activity against all variants tested, with similar titers detected across patients for each variant. This highlights the importance of vaccination even in previously infected patients, given the added benefit of an increased antibody response to the variants tested. Limitations of the study include the small cohort of only women and the lack of evaluation of T-cell response. However, we think the fact that all six patients responded similarly to vaccination supports our conclusions. Further studies could investigate the effects of a second vaccine dose on neutralizing activity against variants of concern in persons who have and persons who have not been previously infected.

Published in New England J. Medicine (April 7, 2021):

https://10.1056/NEJMc2104036