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Principal Investigator: Susan Moir
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2022
Award: $82,612
Funding agency: National Institute of Allergy and Infectious Diseases
In 2022, we conducted and contributed to several clinical research studies on COVID-19. We evaluated antibody and B-cell responses following infection and/or vaccination and contributed to the analysis of innate responses in patients hospitalized with COVID-19. Our efforts focused on three types of studies: 1) investigating the role of therapeutic interventions in reducing the severity of COVID-19 disease in patients hospitalized at the NIH clinical center; 2) investigating the long-term immunity and outcomes of COVID-19; and 3) investigating the immune response to SARS-CoV-2 mRNA vaccines.
In studies on hospitalized patients, our efforts focused on clinical protocol NCT04579393, involving the administration of the drug fostamatinib, an inhibitor of the tyrosine kinase SYK that is involved in intracellular signaling pathways of many different immune cells. Our group performed multiparameter immunophenotyping by spectral flow cytometry to help show that fostamatinib had a potent normalizing effect on low density neutrophils and myeloid cells which are increased by acute severe COVID-19. Both neutrophils and myeloid cells are thought to contribute the inflammatory dysregulation caused by COVID-19 and thus treatment with fostamatinib may offer a new avenue of treatment against severe disease. A manuscript describing these findings is under preparation.
In studies on COVID-19 sequelae and immunity, we have helped conduct a large longitudinal observational protocol, NCT04411147. We have contributed to the evaluation of the host response to infection, both in terms of immunity and biomarkers that may help understand why some people suffer long-term effects of the disease. The preliminary findings were recently published in Ann Intern Med. Efforts are currently underway to compare the potency and longevity of antibody and B-cell responses following vaccination in the two groups of participants. These analyses are being conducted in parallel with efforts to evaluate other immunologic markers associated with COVID-19, including those that may predict full recovery and protection from re-infection.
In studies on the immune response to SARS-CoV-2 vaccination, we delineated B-cell correlates of the antibody response to the two-dose Moderna mRNA-1273 vaccine in a cohort of 21 COVID-19-unexposed adults. We performed antibody binding and neutralization assays from frequent serial blood draws, in parallel with phenotypic and antigen-specific profiling of peripheral blood B cells. The latter was performed using spectral flow cytometry with integrated and unbiased high-dimensional clustering approaches. Our findings revealed several antigen non-specific and specific B-cell populations that were correlated with the antibody response measured up to six months after the first vaccine dose. Early post dose one non-specific and dose two antigen-specific plasmablasts were also found to correlate with the endpoint antibody responses. Finally, a population of memory B cells that we and others have shown previously to be associated with long-lived memory capacity, was found to correlate at the antigen-specific level with endpoint antibody responses. Collectively, these findings established populations of B cells that can serve as early predictors the antibody response to SARS-CoV-2 mRNA vaccines and help monitor responses in people who are at risk of severe infection or re-infection. These findings were published in Proc Natl Acad Sci U S A. We recently developed a new protocol, NCT05078905, to further understand antibody and B-cell responses to SARS-CoV-2 vaccines and to prepare for similar studies as other pandemic-causing pathogens emerge. From October 2021 through March of 2022, we enrolled 100 participants in the new protocol for the purpose of evaluating antibody and B-cell responses to SARS-CoV-2 booster vaccines and to determine whether these responses were affected by prior or post-boost SARS-CoV-2 infections. We found that recent SARS-CoV-2 infection abrogated antibody and B-cell responses to the booster vaccine. A manuscript describing our findings in final stages of preparation.
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