Identifying the cellular mechanisms that promote effective meningococcal vaccine responses in infants

[Truncated abstract] The introduction of glyco-conjugate vaccines has led to a significant reduction in the prevalence of diseases caused by polysaccharide-encapsulated bacteria, including Haemophilus influenzae b, Neisseria meningitidis and Streptococcus pneumoniae. The inclusion of a carrier protein, a T cell antigen, in glyco-conjugate vaccines induces a Tdependent antibody response leading to increased immunogenicity, which is particularly imperative in infants who are most susceptible to these infections. There are still a number of questions regarding the exact mechanisms of glyco-conjugate vaccines that remain unanswered, such as how they influence the generation of memory B cells and a persistent, high-quality antibody response, in particular the role of antigen-specific CD4+ T cells in these processes. In order to undertake these investigations, we developed sensitive assays capable of detecting rare carrier protein-specific functional memory CD4+ T cells and polysaccharide-specific memory B cells in the peripheral blood. Using these tools, we studied an infant cohort who had received a combined Haemophilus influenzae B, Meningococcal C and Y (HibMenCY-TT) vaccine where all polysaccharides were conjugated to tetanus toxoid (TT) as a carrier protein, in a 2-4-6 month primary schedule with a 12 month HibMenCY-TT booster. We determined whether memory B cells induced post-priming correlated with polysaccharide-specific IgG pre- and postboosting, whether type of conjugate and timing of prime could influence the B cell response, and whether TT-specific CD4+ T cells induced post-priming had any influence over the nature of the B cell response. In a small pilot cohort of infants vaccinated with HibMenCY-TT, the assays developed for this thesis were for the first time able to detect TT-specific CD4+ T cells, and Men C-, Y- and Hib PRP- specific memory B cells following HibMenCY-TT vaccine.