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Principal Investigator: Susan Moir
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2023
Award: $327,723
Funding agency: National Institute of Allergy and Infectious Diseases
In 2023, 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 humoral immunity to SARS-CoV-2 mRNA vaccines and the effects of SARS-CoV-2 infection on B-cell and antibody responses to the virus; 2) investigating the long-term immunity and outcomes of COVID-19; and 3) investigating the role of therapeutic interventions in reducing the severity of COVID-19 disease in patients hospitalized at the NIH clinical center.
In 2023, we conducted two major studies on antibody and/or B-cell responses to SARS-CoV-2 vaccination. The first study drew from a protocol developed in the fall of 2021, NCT05078905, to investigate immune responses to repeated SARS-CoV-2 vaccination and to prepare for similar studies as other pandemic-causing pathogens emerge. From October 2021 through March of 2022, we enrolled 100 participants to evaluate antibody and B-cell responses to the first SARS-CoV-2 mRNA booster vaccine (third dose) and to determine whether these responses were affected by prior or post-boost SARS-CoV-2 infection. A first interim analysis was performed through day 60 post-vaccination on 66 participants, 11 of whom had been infected prior to and another 11 after vaccination. We found that recent SARS-CoV-2 infection abrogated antibody and B-cell responses to the booster vaccine. Antibody binding and neutralizing titers to the ancestral spike protein as well as several variants of concern increased significantly following vaccination in the uninfected and post-infected but not in the prior-infected group. Notably, baseline titers were highest in the prior-infected group, consistent with effects of hybrid immunity, but only modestly increased after vaccination. A similar pattern was observed for spike-specific B cells and spike-specific antibodies secreted from cultured B cells, where induction of secreted antibodies was particularly muted in the prior-infected group at day 60 post vaccination. However, we also observed that responses within the prior-infected group were not uniform: participants who were most recently infected (< 6 months from vaccination) had the lowest response to the vaccine while those whose interval between infection and vaccination was longer had a response similar to that of the other two groups. This dichotomous response within the prior-infected group reflected intrinsic B-cell properties, as measured by proliferation and B-cell receptor (BCR) signaling following stimulation ex vivo. We found that the interval between infection and vaccination was directly correlated with the fold induction in BCR signaling of spike-specific B cells between baseline and day 60 post-vaccination, suggesting that the shorter the time between infection and vaccination, the less B cells were able to respond to the vaccine.
In a second major study, we performed multi-omic analyses on SARS-CoV-2 spike-specific B cells isolate from PBMCs after the second dose of the mRNA-1273 vaccine in three infection-nave healthy adults. This was a follow-up study to the one published in 2022 that established B-cell correlates of the antibody response to primary immunization. Using a single-cell approach involving transcriptome, surface protein and BCR repertoire analyses of samples collected serially through six months after the first dose, we traced the development vaccine-specific B-cell responses and identified B-cell populations involved in the generation of long-lasting B-cell memory. This integrated approach enabled us to identify two trajectories in the development of IgG spike-specific memory B cells. Both were rooted in a CXCR3-expressing common population that then bifurcated over time: one lead to the generation of atypical MBCs that expand following vaccination and infection but do not correlate with the antibody response, and the other branch developed from CD71+ activated precursors to resting MBCs, the dominant population at month 6 post-vaccination. These resting MBCs have been associated with long-lasting memory to infection and vaccination and have been found to correlate with the antibody response.
In collaborative studies on hospitalized patients, our efforts in 2023 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.
To address adaptive immunity to SARS-CoV-2 at the site of infection, we contributed to a study performed by NIAID collaborators on the persistence of the virus in the pharyngeal lymphoid tissues of children. The contribution of our group was to help develop multiparameter B-cell panels to evaluate the antigen- and non-antigen-specific responses to the virus in tonsil and adenoid lymphoid tissues. These results lay the groundwork for new studies on the persistence of tissue-specific immunity to SARS-CoV-2 and the effects of imprinting and multiple exposures on these responses.
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