Immune-correlates analysis of an HIV-1 vaccine efficacy trial

Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, Evans DT, Montefiori DC, Karnasuta C, Sutthent R, Liao HX, DeVico AL, Lewis GK, Williams C, Pinter A, Fong Y, Janes H, DeCamp A, Huang Y, Rao M, Billings E, Karasavvas N, Robb ML, Ngauy V, de Souza MS, Paris R, Ferrari G, Bailer RT, Soderberg KA, Andrews C, Berman PW, Frahm N, De Rosa SC, Alpert MD, Yates NL, Shen X, Koup RA, Pitisuttithum P, Kaewkungwal J, Nitayaphan S, Rerks-Ngarm S, Michael NL, Kim JH. N Engl J Med. 2012 Apr 5;366(14):1275-86

In the RV144 trial, the estimated efficacy of a vaccine regimen against human immunodeficiency virus type 1 (HIV-1) was 31.2%. Haynes and colleagues performed a case-control analysis to identify antibody and cellular immune correlates of infection risk. In pilot studies conducted with RV144 blood samples, 17 antibody or cellular assays met prespecified criteria, of which 6 were chosen for primary analysis to determine the roles of T-cell, IgG antibody, and IgA antibody responses in the modulation of infection risk. Assays were performed on samples from 41 vaccinees who became infected and 205 uninfected vaccinees, obtained 2 weeks after final immunization, to evaluate whether immune-response variables predicted HIV-1 infection through 42 months of follow-up. Of six primary variables, two correlated significantly with infection risk: the binding of IgG antibodies to variable regions 1 and 2 (V1V2) of HIV-1 envelope proteins (Env) correlated inversely with the rate of HIV-1 infection (estimated odds ratio, 0.57 per 1-SD increase; P=0.02; q=0.08), and the binding of plasma IgA antibodies to Env correlated directly with the rate of infection (estimated odds ratio, 1.54 per 1-SD increase; P=0.03; q=0.08). Neither low levels of V1V2 antibodies nor high levels of Env-specific IgA antibodies were associated with higher rates of infection than were found in the placebo group. Secondary analyses suggested that Env-specific IgA antibodies may mitigate the effects of potentially protective antibodies. This immune-correlates study generated the hypotheses that V1V2 antibodies may have contributed to protection against HIV-1 infection, whereas high levels of Env-specific IgA antibodies may have mitigated the effects of protective antibodies. Vaccines that are designed to induce higher levels of V1V2 antibodies and lower levels of Env-specific IgA antibodies than are induced by the RV144 vaccine may have improved efficacy against HIV-1 infection.

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Editor’s note: These findings are so intriguing! And they are quite amazing, because the samples available from RV144, the trial that many thought should be stopped as probably futile, were so few in the end. This well designed study used samples from the vaccine regimen arm (see HIV This Week Issue 74 for details) and compared those who became infected with those who did not in a 5 to 1 ratio. The researchers narrowed down the search to 6 immune parameters and 2 proved significant: one of which was associated with decreased risk of HIV acquisition (IgG against the V1V2 variable loop) and one which appeared to be associated with a lack of protection without increasing the risk of HIV acquisition itself (Env-specific IgA antibodies). The latter counters the protective effects of other responses the body is mounting when exposed to HIV and it had been seen with exposure to other pathogens, in the regulation of autoantibody function, and in immune responses to cancer. These findings are exciting on at least two levels. First, they are hypothesis-generating with regard to immune responses required for protection and they can improve the selection of primary end-points in future HIV vaccine trials. Second, if the protection of V1V2 antibodies can be confirmed then vaccine efficacy might improve with vaccines specifically designed to induce high levels of V1V2 IgG antibodies and low levels of Env-specific antibodies.

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