Dartmouth Events

Optional ZOOM LINK
Meeting ID: 958 3910 9566
Passcode: 141016

Abstract: The antibodies produced in response to respiratory viruses are a key component of protective immunity. Nowhere has this been more clearly demonstrated than in the development of effective COVID-19 vaccines, which have played a central role in reducing transmission and preventing severe disease. While large clinical trials have validated vaccine efficacy in the general population, the precise features of the antibody responses that mediate protection remain incompletely understood—especially in individuals with altered immunological backgrounds, such as those with hereditary disease or prior SARS-CoV-2 infection.

To investigate how immune history shapes the circulating antibody repertoire after COVID-19 vaccination, we applied an integrated approach combining high-resolution proteomic profiling of serum IgG against SARS-CoV-2 Spike with high-throughput sequencing of peripheral B cells. In infection-naïve individuals with cystic fibrosis (pwCF), mRNA vaccination elicited strong binding and neutralizing serum responses against ancestral Spike. The majority of the circulating IgG repertoire was directed against the receptor-binding domain (RBD), and many abundant antibodies showed convergent features—shared gene usage and similar CDRH3 sequences—with antibodies found in other pwCF and in published antibodies from non-CF individuals. These convergent antibodies tended to exhibit high affinity to the vaccine strain but were less likely to bind emerging variants such as Delta or Omicron.

In previously infected individuals, post-vaccine repertoires were compositionally distinct from post-infection responses. A subset of highly mutated, cross-reactive antibodies was no longer detected after vaccination. Among antibodies sustained from infection through vaccination, one vaccine dose diversified the repertoire and boosted antibodies that were more potent binders of Spike. Vaccine-induced antibodies, which dominated the post-vaccine repertoire, were more frequently reactive to the Omicron variant than sustained antibodies.
Together, these findings reveal how distinct immune histories shape antibody specificity and breadth and provide insights to guide future vaccine design for SARS-CoV-2 and other rapidly evolving respiratory pathogens.

Thesis Committee: Jiwon Lee (chair), Margaret Ackerman, Jennifer Bomberger (MCB), Camila Coelho (Mt. Sinai School of Medicine, External)