Antibody Responses Against HIV-1 Vaccine Candidates

Abstract

The elicitation of protective antibody responses is likely to be important in developing a successful human immunodeficiency virus type 1 (HIV-1) vaccine. As HIV-1 infection in humans is predominantly transmitted via the mucosal route, it is thus likely that a prophylactic vaccine will need to elicit protective antibody responses at mucosal sites of infection. While studies have shown that vaccine-elicited immunoglobulin G (IgG) responses are important in preventing simian/human immunodeficiency virus (SHIV) transmission in rhesus monkeys, IgA’s role and function in protection, and whether it is in fact beneficial or detrimental, remain poorly defined. In this thesis, we investigated the relationship between mucosal and systemic vaccine-elicited IgG and IgA antibody responses in rhesus monkeys that were intramuscularly immunized with candidate HIV-1 vaccine vectors. Systemic and mucosal antibody responses exhibited similar kinetics, and the isotype, functionality, and epitope specificity of mucosal IgG responses were further shown to be similar to those of systemic IgG responses. This suggests that mucosal and systemic responses are likely to be immunologically coordinated. IgG and IgA responses, in terms of magnitude of antibody responses and antibody specificities against linear HIV-1 epitopes, were also shown to be correlated and immunologically related. Mucosal and systemic antibody responses were similarly observed to be correlated in mice immunized with microspheres encapsulating the HIV-1 envelope protein (Env). Non-traditional vaccine delivery modalities have long been investigated as a way to improve vaccination coverage and immunogenicity. We developed multiple biodegradable poly(lactic-co-glycolic acid) (PLGA) microsphere formulations containing HIV-1 Env and different adjuvants, and evaluated their effects on the antibody response in a mouse model. Microspheres containing HIV-1 Env elicited comparable or higher antibody responses in both the systemic and mucosal compartments, and also generated a more diverse antibody response that targeted more linear Env epitopes, when compared to similar amounts of soluble Env. These data help to improve our understanding of mucosal and systemic antibody responses following immunization, and could help improve future vaccine design.