Novel Vaccination Strategies With HIV-1 Envelope Trimeric Proteins for the Induction of Improved Neutralizing Responses

Abstract

In the course of human immunodeficiency virus type 1 (HIV-1) vaccine development, the HIV-1 Envelope (Env) trimer has been a major target for immunogen optimization. One of the goals for Env-based vaccine research is the production of stable, native-like, pre-fusion closed Env trimers for the induction of broadly neutralizing antibodies (bNAbs). Based on the structural mapping of Env across four different classes of bNAbs, a novel Signature-based Epitope Targeted (SET) vaccine design strategy has previously been reported. The SET vaccine design incorporates neutralization signatures into HIV-1 Env immunogens and exposes sequence diversity to the immune system, resulting in the induction of bNAbs of greater breadth and potency. It was shown that a trivalent vaccine with SET mutations in the variable loop 2 (V2) epitope region of clade C Env 459C increased neutralization breadth against heterologous tier 2 viruses in a guinea pig model. At present, we have successfully expressed and purified the next generation of SET vaccines with bNAb signatures in both the V2 and V3 epitope regions of a single Env 459C trimer. When being evaluated in a guinea pig model, preliminary results suggested that the novel V2V3-SET trivalent vaccine was comparable to the V2-SET trivalent vaccine in the induction of high binding antibody titers and moderate tier 2 heterologous neutralizing responses. We have also investigated different vaccine regimens incorporating a fusion peptide Env immunogen, Env proteins with repair-and-stabilize (RNS) modifications, as well as different classes of adjuvants that include 3M052 and Adjuplex. Preliminary results from early time points in these studies showed comparable elicitation of binding antibody titers and tier 2 heterologous neutralizing responses in guinea pigs by V2-SET trimers with RNS modifications, as compared with V2-SET trimers. By using the SET strategy to incorporate bNAb signatures in multiple Env epitopes, in addition to employing a combination of immunogens and adjuvants, we hope to optimize a vaccination strategy that enhances the breadth and magnitude of bNAbs against tier 2 heterologous viruses.