Polyfunctional Fc-effector profiles mediated by IgG subclass selection distinguish RV144 and VAX003 vaccines.

The human phase 2B RV144 ALVAC-HIV vCP1521/AIDSVAX B/E vaccine trial, held in Thailand, resulted in an estimated 31.2% efficacy against HIV infection. By contrast, vaccination with VAX003 (consisting of only AIDSVAX B/E) was not protective. Because protection within RV144 was observed in the absence of neutralizing antibody activity or cytotoxic T cell responses, we speculated that the specificity or qualitative differences in Fc-effector profiles of nonneutralizing antibodies may have accounted for the efficacy differences observed between the two trials. We show that the RV144 regimen elicited nonneutralizing antibodies with highly coordinated Fc-mediated effector responses through the selective induction of highly functional immunoglobulin G3 (IgG3). By contrast, VAX003 elicited monofunctional antibody responses influenced by IgG4 selection, which was promoted by repeated AIDSVAX B/E protein boosts. Moreover, only RV144 induced IgG1 and IgG3 antibodies targeting the crown of the HIV envelope V2 loop, albeit with limited coverage of breakthrough viral sequences. These data suggest that subclass selection differences associated with coordinated humoral functional responses targeting strain-specific protective V2 loop epitopes may underlie differences in vaccine efficacy observed between these two vaccine trials.

Mechanisms by which HIV envelope minimizes immunogenicity.

With many viruses, vaccines containing the appropriate envelope antigens have provided strong and long lasting immunity. Not so with HIV-1 envelope, despite two decades of experience with various envelope and core constituent vaccines, protection provided has been weak or absent. Our laboratory has been systematically investigating the characteristics of HIV-1 envelope gp140, the principle HIV-1 envelope protein heterodimer responsible for HIV infectivity. We have identified two properties of HIV-1 envelope gp140 that may be important factors in reducing immunogenicity. HIV envelope protein gp140 rejects complement binding. Such binding can be of vital importance, since an extensive literature suggests that complement binding markedly increases immunogenicity, and, more importantly, complement binding influences the type of immune response. For many antigens, C3 binding is required for normal transport of antigens into follicles to initiate a normal germinal center response, and in the absence of appropriate complement binding, the antibody response is reduced, short lived with short-lived memory cell formation, and for an unknown reason, the antibody response shows increased affinity maturation of antibody. These features are characteristic of the HIV-1 antibody response. Just as important is the finding that envelope gp140 is highly unstable on injection, is rapidly removed from the circulation, and is degraded into peptides. This short-lived antigen may be available on initial exposure to the immune system for too short a period of time, particularly in the absence of complement binding, to be an adequate immunogen.