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Principal Investigator: Susan Moir
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $361,442
Funding agency: National Institute of Allergy and Infectious Diseases
In 2024, we conducted studies on COVID-19 by focusing on antibody and B-cell responses following multiple exposures to SARS-CoV-2 through infection and/or vaccination and contributed to studies addressing immune response to SARS-CoV-2 vaccination in people living with HIV (PLWH) or comparing responses to SARS-CoV-2 versus HIV vaccination. Our efforts have addressed: 1) 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; and 2) how B-cell and antibody responses to SARS-CoV-2 are affected by HIV infection.
In 2024, we completed one large multi-year longitudinal study on humoral immunity to repeated SARS-CoV-2 exposures through infection and/or vaccination. Since December of 2020, we have been collecting longitudinal blood samples to study immune responses to the SARS-CoV-2 mRNA vaccine. Our first organized cohort was established in late 2020 using an existing blood draw protocol, ClinicalTrials.gov identifier NCT00001281, where we enrolled participants who were eligible to receive their two-dose mRNA vaccine and designed a study with serial blood draws to characterize the primary immune response to the vaccine. As it became clear that booster vaccines would be needed, we wrote a broad-purpose protocol, ClinicalTrials.gov identifier NCT05078905, that would allow us to rapidly study vaccine responses to SARS-CoV-2 and other emerging pathogens. We eventually modified the protocol to include the ability to compare responses to vaccination and breakthrough infections. From October 2021 through March of 2022, we enrolled 100 participants, including 25 individuals from the first cohort, 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. These findings were published in Cell late 2022. The protocol was written in a way that reset study visits each time a participant received a booster vaccine, which by early 2023 ranged from 3-5 doses. Additional protocol visits were added after breakthrough infections, at timepoints which matched those post-vaccination. In August 2023, we decided to address the effect of multiple exposures to SARS-CoV-2 on the temporal dynamics of B-cell and antibody responses. To this end, we focused on 450 samples collected on 33 participants over 18 timepoints, from the beginning of dose 2 through to 6 months after the bivalent dose, which was either the fourth or fifth dose. By the last timepoint, 11 of 33 study participants remained uninfected and among those who became infected, 16 had provided 1-2 additional blood samples post-infection. We assessed B-cell responses to SARS-CoV-2 spike proteins by spectral flow cytometry as well as antibody responses by measuring binding antibodies against a panel of wild-type (WT) and eight variant receptor binding domain (RBD) proteins and antibody neutralizing titers against WT, BA.5 (to match the bivalent vaccine) and XBB.1.5 (to match the major variant in circulation at time of sample evaluation) with a pseudovirus-based assay. Using high-dimensional clustering and trajectory analyses, we identified five clusters with distinct B-cell phenotypes that were the main drivers of RBD reactivity, peaking at day 14 after the first booster vaccine (dose 3) in the absence of infection, and with overall frequencies that were similar to responses at 14-28 days after a breakthrough infection. While there were differences in the distribution of RBD-reactive clusters at peak of response post-vaccination versus post-infection, the overall outcomes at the end of study were similar between the two groups. RBD reactivity in a subset of B-cell clusters also correlated with neutralizing antibody titers, suggesting a role for these B cells in the generation and durability of humoral immunity, which is critical to preventing and curtailing symptomatic SARS-CoV-2 infection. A manuscript describing these findings is in the final stage of preparation for submission.
We continue to collaborate with intramural and extramural researchers, mainly by providing expertise that we have gained studying B cells in our various studies on SARS-CoV-2. In 2024, we helped other teams design immunophenotyping panels to interrogate the response of B cells to SARS-CoV-2. One such study with the University of Toronto, published over the past year, addressed the effect of HIV infection on B-cell and T-cell responses to SARS-CoV-2 vaccination. We contributed specimens and sample processing expertise in another recently published study led by Dr. Mark Connors in the LIR, showing that HIV vaccines elicit CD8 T-cell responses that are inferior to those elicited by SARS-CoV-2 vaccination and natural HIV infection. In addition, we continue to contribute to the efforts of NIAID collaborators on the persistence of the virus in the pharyngeal lymphoid tissues of children. The contribution of our group has been to help develop multiparameter B-cell panels for evaluating 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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