Project Summary Vaccines are powerful tools for combating infectious diseases yet vaccination may fail to induce robust antibody responses, even after multiple doses. Yet 2-10% of all vaccinations in healthy people fail to result in protective immunity, and, in the specific example of hepatitis B virus (HBV) vaccine, chronic inflammatory states such as obesity are associated with 10-30% of individuals having poor antibody responses, leaving them unprotected. Moreover, the prevalence of chronic inflammatory states such as obesity is steadily increasing worldwide, at a time where we more than ever depend on vaccines to prevent infectious diseases such as COVID-19. Better understanding of mechanisms of poor humoral responses to vaccines are urgently needed. Vaccine responses involve induction of affinity-matured antibodies by B cells, which requires help from T follicular helper (Tfh) CD4 cells in germinal centers. We previously identified circulating Tfh, termed cTfh, which provided help to B cells in vitro and had transcriptional and phenotypic similarities to lymphoid Tfh, and responded to influenza vaccination in an antigen-specific way, giving us a “window” into lymphoid state and activity. However, understanding of how cTfh and B cell responses to HBV vaccine are established and change over time are limited, particularly in humans. Here, we propose to study the HBV vaccine response to understand factors associated with the strength of the protective antibody response, using a systems immunology approach in a prospective clinical study of HBV vaccination in the setting of chronic inflammation induced by obesity. In Aim 1, we will evaluate the effect of repeated antigen exposure by studying the Tfh-B cell axis longitudinally for phenotype and repertoire, in order to determine which characteristics are most predictive of the final antibody response. In Aim 2, we will compare subjects receiving adjuvanted HBV vaccine to those receiving traditional HBV vaccine to determine how the cTfh and B cell responses differ due to adjuvant, using multi-modality single cell profiling. Finally, in Aim 3, we will test mechanisms of how chronic inflammation in the host affects the HBV vaccine response by performing direct lymph node biopsies for multiplex immunofluorescence studies. Together, these experiments will explore the effects of repeated antigen exposure, adjuvants, and chronic inflammation on the cTfh-B cell axis and suggest future strategies for improved vaccine design.

Project Narrative Vaccines are a major tool to prevent infection, yet many who receive hepatitis B vaccination do not respond and are not protected. The goal of this proposal is to understand the qualities of the T and B cell responses that enable early prediction of who might have a weak vaccine response by focusing on the immune cells relevant to the antibody response, in order to decipher mechanisms that can be addressed with future vaccine strategies.