Abstract
The RV144 Thai trial HIV-1 vaccine of recombinant poxvirus (ALVAC) and recombinant HIV-1 gp120 subtype B/subtype E (B/E) proteins demonstrated 31% vaccine efficacy. Here we design an ALVAC/Pentavalent B/E/E/E/E vaccine to increase the diversity of gp120 motifs in the immunogen to elicit a broader antibody response and enhance protection. We find that immunization of rhesus macaques with the pentavalent vaccine results in protection of 55% of pentavalent-vaccine-immunized macaques from simian–human immunodeficiency virus (SHIV) challenge. Systems serology of the antibody responses identifies plasma antibody binding to HIV-infected cells, peak ADCC antibody titres, NK cell-mediated ADCC and antibody-mediated activation of MIP-1β in NK cells as the four immunological parameters that best predict decreased infection risk that are improved by the pentavalent vaccine. Thus inclusion of additional gp120 immunogens to a pox-prime/protein boost regimen can augment antibody responses and enhance protection from a SHIV challenge in rhesus macaques.
Highlights
The RV144 Thai trial human immunodeficiency virus (HIV)-1 vaccine of recombinant poxvirus (ALVAC) and recombinant HIV-1 gp[120] subtype B/subtype E (B/E) proteins demonstrated 31% vaccine efficacy
Efforts to define the correlates of reduced infection risk in RV144 revealed that IgG antibody responses to the HIV-1 envelope (Env) variable loop 1 and variable loop 2 (V1–V2) epitopes were associated with a lower risk of infection, as were antibody-dependent cell-mediated cytotoxicity (ADCC)-mediating IgG antibodies with low IgA antibodies against Env subunit gp[120]
Is subtype E diversity represented by the RV144 trial samples better accounted for in the pentavalent vaccine, the pentavalent vaccine substantially improved potential epitope coverage of the C subtype simian–human immunodeficiency virus (SHIV) challenge virus used in this study in both the V2 and across the gp[120] (Fig. 1a)
Summary
The RV144 Thai trial HIV-1 vaccine of recombinant poxvirus (ALVAC) and recombinant HIV-1 gp[120] subtype B/subtype E (B/E) proteins demonstrated 31% vaccine efficacy. We design an ALVAC/Pentavalent B/E/E/E/E vaccine to increase the diversity of gp[120] motifs in the immunogen to elicit a broader antibody response and enhance protection. We find that immunization of rhesus macaques with the pentavalent vaccine results in protection of 55% of pentavalent-vaccine-immunized macaques from simian–human immunodeficiency virus (SHIV) challenge. Inclusion of additional gp[120] immunogens to a pox-prime/protein boost regimen can augment antibody responses and enhance protection from a SHIV challenge in rhesus macaques. In an effort to improve the RV144 vaccine regimen, we performed a nonhuman primate (NHP) study to compare the protective efficacy of a pentavalent (subtypes B/E/E/E/E) gp[120] protein boost to that of a RV144-like bivalent (B/E) gp[120] protein boost following ALVAC-AE prime against a heterologous neutralization-resistant (Tier-2) simian–human immunodeficiency virus (SHIV) challenge. We determined the immune correlates of delayed infection risk to inform future poxvectored prime, gp[120] boost vaccine designs
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