How does the immune system remember and recognize viral invaders it has encountered in the past? A trio of newly published studies in people infected with SARS-CoV-2, vaccinated against the virus, or both provide tantalizing new clues about the factors affecting the speed and magnitude of the immune system’s response to subsequent infection with SARS-CoV-2. affect variants. CoV-2.
These findings could help researchers work backwards to further improve vaccines, with the ultimate goal of developing either a multi-variant vaccine that could protect people from multiple strains, or even a pan-coronavirus vaccine that could protect against could offer variants that have yet to emerge.
The three studies published in science immunology and led by researchers from Brigham and Women’s Hospital, Harvard Medical School, Massachusetts General Hospital and the Ragon Institute of MGH, MIT and Harvard, are providing intriguing answers as to how long COVID-19 immunity lasts and how Immune system is recalled after infection or vaccination, or both.
“If we’re going to demand more of our immune system, we need to know what it’s capable of,” said Duane Wesemann, associate professor of immunology HMS and researcher in Brigham’s Division of Allergy and Clinical Immunology. Wesemann is a senior author on two of the papers and a co-author on the third.
Our results suggest that there are differences between people -; Some people have antibody responses that are relatively more sustained and broader than others, and this may help provide better protection against future infection. If we can understand and harness what gives some people an immunological advantage, we may be able to trick the immune system into giving a little more through improved vaccination strategies.”
Duane Wesemann, associate professor of immunology HMS and researcher in Brigham’s Division of Allergy and Clinical Immunology
In a study, Wesemann and colleagues examined immunity after infection with the original SARS-CoV-2 strain, first identified in Wuhan, China. The team evaluated 73 antibodies produced in response to infection with the ancestral strain to determine which, if any, were effective against five variants -; Alpha, Beta, Gamma, Delta and Omicron. They found that certain antibodies generated by infection with the original strain could neutralize worrisome variants -; Results that confirm why vaccines formulated against the original strain can still provide protection against variants.
With the help of sophisticated imaging techniques, the researchers were able to follow how the changing structure of the mutating virus interacts with the immune system. They located mutation-prone sites on the viral spike protein, which the pathogen uses to enter human cells, and to visualize how these sites interact with sites on antibodies that neutralize the virus and prevent it from entering cells.
In a second publication, researchers examined immune retrieval -; the process of triggering memory cells to fight repeated invasions by the same pathogen. The team analyzed the response of the immune system after infection, vaccination and booster by examining blood samples from people with different disease trajectories -; those who recovered from SARS-CoV-2 infection but were not vaccinated, those who recovered from infection and then were vaccinated against COVID-19, or those who were never infected but were vaccinated and have been refreshed. The team found evidence that people who had been infected and vaccinated, as well as people who had been vaccinated and boosted, could achieve a strong and broad response across variants, including Omicron. In addition, the researchers found evidence that remembering a previous infection with cold coronaviruses -; mild viruses that circulated before SARS-CoV-2 -; may be responsible for the robust, sustained immune response in a small subset of unvaccinated individuals recovering from COVID-19. Known as “sustainers,” these individuals experience rapid resolution of COVID-19 symptoms and have a prolonged, sustained antibody response.
“We’re very excited about this idea that some people get their antibodies and have memory B cells that can respond across variants — it opens up some interesting possibilities as we think about a pan-coronavirus vaccine,” Wesemann said.
In a third study, led by Andrew Luster, MD, PhD, and James Moon, PhD, both from the Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy and Immunology at MGH, researchers tried to better understand the role of CD4 to understand+ T cells in COVID-19 immunity by directly identifying those that recognize SARS-CoV-2. Analyzing blood samples from patients recovering from infection in Boston during the first wave of the pandemic, they found that certain CD4+ T cell subsets -; circulating follicular helper T (Tfh) cells and helper T-1 (Th1) cells -; were more common in people who had milder disease and did not require hospitalization. This cellular response appeared to persist for several months, potentially giving the immune system an advantage for later exposure to SARS-CoV-2, including variants. In addition, it was found that follicular T helper cells specific for SARS-CoV-2 are more common in the same group of antibody “conservators” observed in the Wesemann study, suggesting an association between these T cells and longer-lasting antibody responses.
“Our study shows that the quality of the CD4+ The T cell response to SARS-CoV-2 was better in patients with less severe infections and this was reflected in the presence of persistent antibodies. This supports the general immunological theory that optimal antibody responses require robust CD4+ T cells help and that vaccines should be designed to maximize responses from this component of the adaptive immune system as well,” Luster said.
Brigham and Mass General’s groups have received one of four federally funded program project grants from the National Institute of Allergy and Infectious Diseases to conduct research to develop vaccines that can protect against multiple types of coronaviruses and virus variants. Wesemann, Luster, Moon and their collaborators continue to analyze samples from people infected with or vaccinated against COVID-19 to identify immunological characteristics that may confer the broadest possible immunity to coronaviruses and variants.
Brigham and Women’s Hospital
- Windsor, IW et al. “Antibodies induced by the SARS-CoV-2 ancestral strain can cross-neutralize variants from Alpha to Omicron BA.1.” science immunology DOI: 10.1126/sciimmunol.abo3425
- Chen, Y et al. “Immune recall improves durability and breadth of antibodies against SARS-CoV-2 variants” science immunology DOI: 10.1126/sciimmunol.abp8328
- Nelson, RW et al. “SARS-CoV-2 epitope-specific CD4+ memory T cell responses across COVID-19 disease severity and antibody persistence” science immunology DOI: 10.1126/sciimmunol.abl9464