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Principal Investigator: Susan Moir
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2021
Award: $82,447
Funding agency: National Institute of Allergy and Infectious Diseases
In 2021, we contributed to several clinical research studies on COVID-19. We evaluated B cells following infection and/or vaccination, as well as innate cells in patients hospitalized with COVID-19. Our efforts were focused on three general study groups: 1) individuals hospitalized at the NIH clinical center and enrolled in phase 2/3 interventional double-blind placebo-controlled clinical trials NCT04280705, NCT04401579, NCT04492475, and NCT04579393; 2) individuals who recovered from COVID-19 and close contacts enrolled in observational sequelae trial NCT04411147; and 3) individuals who were vaccinated with the Moderna mRNA-1273 vaccine and participated in the blood-draw observational trial NCT00001281.
In studies on the first group, we performed multiparameter phenotyping by spectral flow cytometry and high-dimensional analyses to evaluate innate and B-cell populations and virus-specific responses in patients who were hospitalized with COVID-19, as well as the effects of various interventional drugs on these populations and responses. The most striking observations during acute infection were the increased frequencies of antibody-secreting cells called plasmablasts and of low-density neutrophils, especially in patients with severe disease. Several interventional drugs were found to modulate these populations, albeit to varying degrees. The drug fostamatinib, an inhibitor of the tyrosine kinase SYK that is involved in intracellular signaling pathways of many different immune cells, was found to cause a shift from immature to more mature neutrophils, possibly the result of reducing the inflammatory conditions in severe acute infection that increase neutrophil production. The effects of fostamatinib on B cells are currently being evaluated phenotypically and by transcriptional and epitope profiling at the single-cell level.
In studies on the second group, we evaluated B-cell phenotypes and SARS-CoV-2 B-cell and antibody responses in individuals enrolled in a large longitudinal observational study of COVID-19 sequelae, with goal of identifying correlates of sustained immunity following infection and vaccination. Between June 2020 and August 2021, over 200 survivors and 130 close contacts have been enrolled in the study, with visits every 6 months. In addition, 50 of the enrolled participants provided additional blood after receiving their SARS-CoV-2 vaccine. Preliminary findings revealed that post recovery B-cell phenotypes in survivors did not significantly change between time of enrollment and month six visit, an indication there were no long-term B-cell perturbations in this cohort. However, B-cell responses to the virus varied within the survivor group, for reasons that remain under investigation, and were strongly increased following vaccination. As others have reported, antibody and B-cell responses were stronger in the survivor group than in the close contacts, although the differences between the groups were modest after the booster dose in individuals receiving two-dose mRNA vaccines. 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 a study on the third group, under revised review in a high-impact journal, we sought to delineate B-cell correlates of the antibody response to SARS-CoV-2 following vaccination. Accordingly, we evaluated early antibody and B cell responses 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 two months after the first vaccine dose. Among non-specific B-cell correlates, one was a pre-vaccination population of natural memory B cells that may represent lymphoid-tissue derived cells that are poised to rapidly respond to pathogens. 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 the SARS-CoV-2 mRNA vaccines and help monitor responses in people who are at risk of severe infection or re-infection.
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