Multivalent Vaccination Strategies With Novel HIV-1 Trimeric Envelope Proteins Elicit Improved Neutralizing Antibody Responses Compared to Monovalent Vaccination Regimens

Abstract

Elicitation of neutralizing antibodies (NAbs) remains a major goal in the generation of a successful vaccine against human immunodeficiency virus type 1 (HIV-1). One of the major obstacles in generating such NAbs is the vast sequence diversity of their target, the HIV-1 envelope (Env) protein. This dissertation will describe multiple vaccination strategies utilizing a soluble form of Env (gp140) to address the sequence diversity of HIV-1 Env and to improve the NAb responses elicited through vaccination in the guinea pig model. A bioinformatically optimized mosaic gp140, designed as a single sequence to cover global HIV-1 sequence diversity, was utilized in combination with a clade C gp140, resulting in a complementary repertoire of NAbs when compared to vaccination with each single protein. Additionally, a quadrivalent mixture of four novel clade C gp140s with distinct antigenic properties was found to elicit a greater magnitude of NAbs when compared to any single protein in the mixture. Furthermore, longitudinal, heterologous prime/boost vaccination regimens resulted in binding antibodies to a greater number of distinct sequences within a single epitope of variable loop 2, and NAb of a greater magnitude, than a homologous prime/boost regimen. Finally, a panel of rationally designed variable loop 2 and 3 sequence modified trimers was designed. When utilized in a mixture, the variable loop 2 modified trimers elicited a greater magnitude and breadth of NAbs than the single, unmodified wild type protein alone. These data show that multivalent vaccination strategies with HIV-1 Env trimers result in improved NAb responses compared to single Env protein vaccinations and may help to guide the development of future vaccination regimens.