Bivalent gp120/mAb complex vaccines to induce broadly reactive antibody response against HIV-1 (VAC7P.987)

Abstract

Abstract HIV-1 envelope gp120 is a key target for neutralizing antibodies (NAbs) against the virus. Our work focuses on improving immunogenicity of cross-reactive neutralizing epitopes on gp120 antigen. We demonstrated that immunogenicity of gp120 and especially its neutralizing V3 epitopes was enhanced when gp120 was administered with the anti-CD4 binding site monoclonal antibody (mAb) 654 as immune complex (IC) vaccine. The enhanced V3 immunogenicity correlated with greater V3 antigenicity and was mediated mainly by the Fab activity of mAb 654. Here, we further explored the use of gp120/654 to elicit V3 Ab responses with greater breadth. A bivalent IC vaccine made of two gp120 proteins with immunogenically distinct V3 loops, gp120JRFL and gp120LAI-N448Q (a LAI derivative), were compared with the individual ICs. Individually, these ICs elicited V3 Abs with complementary reactivity: gp120JRFL/654 induced V3 Abs reactive with many subtypes B and subtype C viruses but not LAI, whereas gp120LAI-N448/654 induced V3 Abs specific for LAI. Administration of the ICs as a mixture or sequentially did not expand the breadth of Ab response. However, injection of the ICs s.c. at different sites resulted in induction of Abs reactive to LAI and the other subtype B viruses. Neutralization was also detected against Tier I subtype B HIV-1 pseudoviruses. These results demonstrate the potential of multi-valent vaccines and the importance of the delivery methods to broaden Ab responses against HIV-1.