Differential shaping of T cell responses elicited by heterologous ChAd68/self-amplifying mRNA SIV vaccine in macaques in combination with αCTLA4, αPD-1, or FLT3R agonist

Abstract

While therapeutic vaccines are a promising strategy for inducing human immunodeficiency virus (HIV) control, HIV vaccines tested to date have offered limited benefit to people living with HIV. The barriers to success may include the use of vaccine platforms and/or immunogens that drive weak or suboptimal immune responses, immune escape and/or immune dysfunction associated with chronic infection despite effective antiretroviral therapy. Combining vaccines with immune modulators in a safe manner may address some of the challenges and thus increase the efficacy of therapeutic HIV vaccines. We evaluated the immunogenicity of a ChAd68/samRNA-based simian immunodeficiency virus (SIV) vaccine regimen alone and in combination with a series of immune modulators in a preclinical rhesus macaque (M. mulatta) model. The vaccine was co-delivered with the checkpoint inhibitors αPD-1 or αCTLA-4, or with a FLT3 receptor agonist (FLT3Ra) shown to differentiate and expand dendritic cells and improve T cell priming. We demonstrate that the magnitude, breadth and functionality of SIV-specific vaccine-elicited CD8+ T cell responses were enhanced by combination with either αPD-1, αCTLA-4, or FLT3Ra. Combination with FLT3Ra also expanded polyfunctional CD4+ T cell responses. Our data demonstrate enhanced and distinct shaping of vaccine-elicited immune responses by immune modulators with implications for developing a functional HIV cure.