PURPOSE OF THE STUDY.
A recently completed Phase III vaccine trial demonstrated a 32% estimated efficacy. An earlier analysis suggested that envelope (Env)-specific antibody responses were associated with a lower risk of infection. Of particular interest, anti-HIV Env immunoglobulin A (IgA) antibodies correlated with increased infection risk. The purpose of this study was to evaluate potential mechanisms of this phenomenon.
Phase III controlled evaluation of the RV144 HIV vaccine to prevent HIV infection was conducted in Thailand. The current study represents a substudy in which all participants provided written consent to have plasma and cellular samples stored and subsequently tested.
The levels and affinities of IgA and immunoglobulin G (IgG) antibodies for HIV Env proteins were measured. The ability of patient IgA as well as patient-derived IgA monoclonal antibodies to inhibit natural killer cell–mediated, antibody-dependent cell-mediated cytotoxicity (ADCC) was measured.
The Env-specific IgA/IgG ratio directly correlated with infection risk, suggesting that the presence of IgA antibody directly inhibited ADCC function. Furthermore, IgA monoclonal antibodies derived from vaccines inhibited binding and blocked ADCC function. The phenomenon of interference of IgG function by IgA antibodies has been reported previously in other settings.
Postvaccination polyclonal antibody responses vary among individuals. Those generating an excess of Env-specific IgA seem to be at increased risk for infection secondary to reduced ADCC effector function of natural killer cells.
HIV has evolved multiple mechanisms to evade immune detection and elimination. These include impairment of neutralizing antibody generation, emergence of escape mutants, and Env glycosylation and conformational shielding. The vaccine studied in this article resulted in “blocking IgA antibodies” in a number of recipients and thus adds another level of complexity to vaccine design.
- Copyright © 2013 by the American Academy of Pediatrics