The 31% efficacy seen in the RV144 Phase III trial prompted an examination of immune responses correlated with reduction in infection risk as well as sequence based examination of breakthrough viruses for "sieve" effects -sequence differences between vaccine and placebo breakthrough viruses attributed to vaccine-induced immune responses. The immune responses that appear to be inversely correlated with infection are antibody responses targeting the V1/V2 region of gp120. Interestingly, analysis of the breakthrough viruses by single genome analysis sequencing also suggests that breakthrough viruses from vaccine recipients differ from placebo recipients at two sites, 169 and 181; both of these sites are in V2. Further support comes from mAb isolated from subjects vaccinated with ALVAC-HIV and AIDSVAX B/E, which again appear to target V2, and mapping of the binding sites of two mAb (CH58 and 59) shows potential contact residues consistent with the sieve analysis. Information from these studies is being further developed in analysis of longitudinal samples from vaccine recipients and breakthrough viruses. Finally, the potential role of V2 as a correlate of risk was also explored in a rhesus study of Ad26 / MVA based SIV vaccines. V2 was also found to be a potential correlate in that study and ongoing analysis of SIVmac251 breakthrough viruses may suggest a similar V2 based sieve effect. While not definitive these data suggest that antibody responses against V2 may be important in protection against infection, and provide new hypotheses for the development of improved HIV vaccines.
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