Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge

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.

Antibody Fab‐Fc properties outperform titer in predictive models of SIV vaccine‐induced protection

“…Here, protection was modeled with a multi‐dimensional, multi‐group CoxPH survival model, combining animals from all adjuvant groups and employing aggressive feature filtering, to incorporate only a small number of features. The use of a Cox modeling approach follows that used in recent studies (Bradley et al , ; Ackerman et al , ), so as to avoid having to discretize protection levels (Chung et al , ; Vaccari et al , ). We found that to avoid overfitting, it was necessary to perform feature pre‐filtering and employ greedy feature elimination methods to narrow down the number of features used by the Cox model (Frejno et al , ); regularization techniques (Simon et al , ) displayed substantially poorer performance, resulting in empty models (i.e., with no features selected), likely due to the semi‐parametric formulation of the Cox PH model and the small sample size of the study.…”

“…In order to enable “systems serology” studies (Chung et al , ; Ackerman et al , ), we have recently developed a platform, the “Fc Array”, to comprehensively dissect antibody profiles of serum samples (Brown et al , , ). By characterizing antibodies in terms of simultaneous Fab and Fc properties (i.e., both antigen specificity as well as subclass and ability to bind complement and different FcγR receptors), the Fc Array has provided a refined characterization of immune responses in a variety of vaccination and natural infection studies (Lai et al , ; Choi et al , ; Ackerman et al , , ; Vaccari et al , ; Bradley et al , ).…”

Prospects from systems serology research

“…17 More recently, partial protection from SHIV infection was observed in NHP when administered with a canary pox prime (ALVAC)/ recombinant pentavalent envelope protein vaccine. 18 Multiple humoral immune correlates were associated with decreased risk of infection, including plasma antibody binding to HIV-infected cells, ADCC antibody titres, natural killer cell-mediated ADCC and antibody-mediated activation of macrophage inflammatory protein-1b. 18 These recent human and NHP HIV vaccine studies have highlighted our limited understanding of humoral immune responses and challenges us to shift our analysis of potential humoral immune correlates from being a univariate or 'one component at a time' paradigm (e.g.…”

HIV/AIDS Vaccines: 2018

“…Gp120 is generally used as a boost for DNA‐primed or vector‐primed responses (see Figure ). It has, however, been used as a prime and boost in a preclinical trial of a pentavalent gp120 that showed some protection attributed to pnnAb . A canarypox‐expressed membrane‐anchored gp120 displayed on VLPs and bivalent gp120 protein were used in the partially successful RV144 trial and are being used in the ongoing HVTN 702 efficacy trial ( Figure and Table ).…”

“…Mixtures of immunogens are also being studied for their ability to broaden nAb responses (for examples, see Refs. 54,57,69). To date, such broadening has been achieved for pnnAb and tier 1 nAb (but not bnAb) responses.…”