Understanding vaccine-induced memory responses to develop the next generation of pertussis vaccines

Abstract

Bordetella pertussis is a Gram-negative respiratory pathogen that can infect individuals of all ages and is notably responsible for infant fatalities. Pertussis (whooping cough) is a vaccine-preventable respiratory disease for which vaccines have been available in the United States since the 1940s. Whole cell pertussis vaccines kept incidence of pertussis under 5,000 cases per year, but were associated with reactogenicity issues. Following the introduction of less reactogenic acellular pertussis vaccines in the late 1990s, there have been noteworthy outbreaks of pertussis. For example, in 2012 there were over 50,000 reported cases of pertussis and 20 deaths in the U.S. The reemergence of pertussis raises concern for the development of next generation pertussis vaccines that can outlast current acellular vaccines and elicit long-term vaccine induced memory. There are several hypotheses for resurgence of pertussis, including more sensitive testing, increased reporting, bacterial evolution, and lack of vaccine-induced memory responses. The overall objective of this work is to better understand the murine model of pertussis vaccination and challenge to aid in the development and selection of improved acellular pertussis vaccine candidates that induce long-term protection. For these studies, a B. pertussis murine vaccination and challenge model was utilized. We sought to understand the vaccine-induced memory responses by focusing on follicular responses and comparing whole cell pertussis vaccination to acellular pertussis vaccination. In this dissertation, we evaluated components of germinal center formation, including cytokines, T follicular helper cells, B memory responses, and antibody secreting cells. We identified that while protection from challenge and serological responses are similar in both whole cell and acellular vaccinated mice, increases in CXCL13, T follicular helper cells, and B memory cells are associated with whole cell pertussis vaccination. This information was utilized to design studies in which we aimed to improve acellular pertussis vaccine-induced memory responses by the addition of adjuvant to DTaP. When measuring bacterial burden and IgG antibody titers, protection studies showed no significant differences between DTaP and DTaP supplemented with adjuvant. The groups with the highest antibody titers and lowest bacterial loads were selected to move forward with (SWE and MPLA). Taking a closer look into the adaptive immune response, it is clear that addition of adjuvant alters T cell responses as observed by measuring the IgG1/IgG2 ratio paired with cytokine levels in the sera. Addition of adjuvant also leads to increases in CXCL13, follicular dendritic cells, and T follicular helper cells compared to PBS and