Publications by Year: 2024

Messenger RNA (mRNA) vaccines were highly effective against the ancestral SARS-CoV-2 strain, but the efficacy of bivalent mRNA boosters against XBB variants was substantially lower. Here, we show limited durability of neutralizing antibody (NAb) responses against XBB variants and isotype switching to immunoglobulin G4 (IgG4) responses following bivalent mRNA boosting. Bivalent mRNA boosting elicited modest XBB.1-, XBB.1.5-, and XBB.1.16-specific NAbs that waned rapidly within 3 months. In contrast, bivalent mRNA boosting induced more robust and sustained NAbs against the ancestral WA1/2020 strain, suggesting immune imprinting. Following bivalent mRNA boosting, serum antibody responses were primarily IgG2 and IgG4 responses with poor Fc functional activity. In contrast, a third monovalent mRNA immunization boosted all isotypes including IgG1 and IgG3 with robust Fc functional activity. These data show substantial immune imprinting for the ancestral spike and isotype switching to IgG4 responses following bivalent mRNA boosting, with important implications for future booster designs and boosting strategies.

The COVID-19 Biorepository at Beth Israel Deaconess Medical Center in Boston was initiated in 2020 to address questions about COVID-19 infection and vaccination in a time of urgent need. From April 2020 through July 2024, we enrolled 1018 participants and collected thousands of biospecimens. We enrolled participants from the general population as well as from specific populations that were not well represented in clinical trials, including immunosuppressed, pregnant, and lactating individuals. Our observational study was designed to accommodate the rapidly changing landscape of the pandemic, including the introduction of new vaccines and boosters, breakthrough infections, and emerging variants. Reflecting on the past four years of this experience, we believe that teamwork, collaboration, and flexibility were key factors for the success of this effort, which generated data in real time about COVID-19 vaccine responses in multiple populations, hybrid immunity following breakthrough infections, immune evasion of emerging variants, and immune imprinting following booster immunizations. Rapid dissemination of data through preprints, peer-reviewed publications, and public communications allowed for the real time use of our findings to address public health issues and to inform vaccine policies. The dedication of the study participants, clinical investigators, and laboratory investigators made this research program possible.

Prior infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is typically measured by nucleocapsid serology assays. In this study, we show that the Simoa serology assay and T-cell intracellular cytokine staining assay are more sensitive than the clinical Elecsys assay for detection of nucleocapsid-specific immune responses. These data suggest that the prevalence of prior SARS-CoV-2 infection in the population may be higher than currently appreciated.

A new highly mutated Omicron subvariant BA.2.87.1 has recently been identified with over 30 amino acid mutations in the Spike protein compared with BA.2, BA.5, XBB.1.5, and JN.1 variants. Mutiple mutations in BA.2.87.1 are located in the N-terminal domain (NTD) rather than in the receptor binding domain (RBD) of the Spike protein. We evaluated neutralizing antibody (NAb) responses to BA.2.87.1 because of its highly mutated sequence and its unique NTD region. Our data show that NAb responses to BA.2.87.1 were lower than to BA.2 but higher than to JN.1, suggesting that BA.2.87.1 is not a further antibody escape variant compared with other currently circulating variants. Moreover, XBB.1.5 mRNA boosting increased NAb titers to all variants tested including BA.2.87.1.

Current COVID-19 vaccines provide robust protection against severe disease but minimal protection against acquisition of infection. Intramuscularly administered COVID-19 vaccines induce robust serum neutralizing antibodies (NAbs), but their ability to boost mucosal immune responses remains to be determined. In this study, we show that the XBB.1.5 messenger RNA (mRNA) boosters result in increased serum neutralization to multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in humans, including the dominant circulating variant JN.1. In contrast, we found that the XBB.1.5 mRNA booster did not augment mucosal NAbs or mucosal IgA responses, although acute SARS-CoV-2 XBB infection substantially increased mucosal antibody responses. These data demonstrate that current XBB.1.5 mRNA boosters substantially enhance peripheral antibody responses but do not robustly increase mucosal antibody responses. Our data highlight a separation between the peripheral and mucosal immune systems in humans and emphasize the importance of developing next-generation vaccines to augment mucosal immunity to protect against respiratory virus infections.

The replication-incompetent modified vaccinia Ankara-Bavarian Nordic vaccine (MVA-BN; Jynneos) was deployed during the 2022 clade IIb mpox outbreak. On August 14, 2024, the World Health Organization declared the mpox clade Ib outbreak in the Democratic Republic of the Congo a public health emergency of international concern, which has raised the question about the durability of vaccine immunity after MVA-BN vaccination. In this study, we show that the MVA-BN vaccine generated mpox serum antibody responses that largely waned after 6-12 months.