Characterization of immune responses induced by N. meningitidis PorB and its us as a vaccine adjuvant
Platt, Andrew Philip
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Vaccines play an essential role in public health. Adjuvants increase immunogenicity for many of these vaccines by stimulating the innate immune system: driving cytokine secretion to induce local and systemic pro-inflammatory states, upregulating costimulatory molecules on antigen presenting cells (APCs), and increasing antigen uptake and presentation to better engage T cell responses. Neisseria meningitidis porin PorB is a Toll-Like Receptor 2 (TLR2) ligand with broad immune stimulating functions and can act as a vaccine adjuvant. Our lab is interested in characterizing how PorB activates the immune system and how these effects relate to its adjuvant activity. An understanding of adjuvant functions will allow for the rational, rather than empiric, design of future vaccines. Here we further investigate the effects of PorB on the innate immune system as it may apply to the adjuvant activity of the porin. In a direct test of adjuvanticity we show that without the presence TLR2 the adjuvant activity of PorB, measured by antigen-specific IgG production, is diminished in immunized mice while loss of MyD88 entirely ablates PorB adjuvant activity. We demonstrate costimulatory molecule upregulation in response to PorB stimulation and its dependence on TLR2. We show that stimulation with PorB increases antigen uptake by APCs and drives APC migration to draining lymph nodes, which appears to be dependent on TLR2 and not on MyD88. Finally, we use systems vaccinology to uncover complex regulatory networks and dynamics. The inclusion of PorB as an adjuvant in a multi-injection vaccine formulation has two major effects on expression profiles in murine splenocytes. Vaccine preparations containing PorB as an adjuvant induce expression in inflammatory and immune signaling networks, in agreement with previous work, and accelerate the kinetics of the immune response, as demonstrated by induction of expression of cell cycle and proliferative genes and regulatory networks at earlier time points as compared to preparations not containing PorB. This systems biology approach reveals previously unappreciated aspects of reaction of the immune system to PorB. Together, these findings deepen our understanding of the immune response to PorB and offer potential insight into the mechanisms behind its adjuvanticity.
Thesis (Ph.D.)--Boston University