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. 2014 Mar 19;6(228):228ra39.
doi: 10.1126/scitranslmed.3007730.

Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination

Nicole L Yates  1 , Hua-Xin Liao, Youyi Fong, Allan deCamp, Nathan A Vandergrift, William T Williams, S Munir Alam, Guido Ferrari, Zhi-yong Yang, Kelly E Seaton, Phillip W Berman, Michael D Alpert, David T Evans, Robert J O'Connell, Donald Francis, Faruk Sinangil, Carter Lee, Sorachai Nitayaphan, Supachai Rerks-Ngarm, Jaranit Kaewkungwal, Punnee Pitisuttithum, James Tartaglia, Abraham Pinter, Susan Zolla-Pazner, Peter B Gilbert, Gary J Nabel, Nelson L Michael, Jerome H Kim, David C Montefiori, Barton F Haynes, Georgia D Tomaras
Affiliations

Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination

Nicole L Yates et al. Sci Transl Med. .

Abstract

HIV-1-specific immunoglobulin G (IgG) subclass antibodies bind to distinct cellular Fc receptors. Antibodies of the same epitope specificity but of a different subclass therefore can have different antibody effector functions. The study of IgG subclass profiles between different vaccine regimens used in clinical trials with divergent efficacy outcomes can provide information on the quality of the vaccine-induced B cell response. We show that HIV-1-specific IgG3 distinguished two HIV-1 vaccine efficacy studies (RV144 and VAX003 clinical trials) and correlated with decreased risk of HIV-1 infection in a blinded follow-up case-control study with the RV144 vaccine. HIV-1-specific IgG3 responses were not long-lived, which was consistent with the waning efficacy of the RV144 vaccine. These data suggest that specific vaccine-induced HIV-1 IgG3 should be tested in future studies of immune correlates in HIV-1 vaccine efficacy trials.

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Conflict of interest statement

Competing interests: J.T. was employed by Sanofi when these studies were performed. G.J.N. and Z.-y.Y. have subsequently taken positions at Sanofi. M.D.A. is the founder of Immunathon Inc. A.P. consults for Avatar Biomedical. A.P. is listed as inventor on U.S. Patent 6,815,201 “HIV-1 gp120 V1/V2 domain epitopes capable of generating neutralizing antibodies.” A provisional patent application Ser. No. 61/884,038 “Correlates of protection against HIV-1 infection” was filed on 28 September 2013. The inventors listed on this patent application are B.F.H., G.D.T., H.-X.L., and S.Z.-P.

Figures

Fig. 1
Fig. 1. Higher HIV-1 Env IgG3 but lower HIV-1 Env IgG1, IgG2, and IgG4 antibody response rates in RV144 compared to VAX003 vaccinees
(A to D) HIV-1 Envelope antibody response rates for proteins from the vaccine strain immunogens in the prime (92Th023) and boost (A244, MN) as well as against group M and clade AE consensus proteins (ConS gp140 and AE Con gp140, respectively) (percent responders are shown for RV144 V8 and VAX003 V5 and V9) for IgG1 (A), IgG2 (B), IgG3 (C), and IgG4 (D). ***P < 0.0005; **P < 0.005; *P < 0.05. P values were calculated with the two-tailed Fisher’s exact test and adjusted with the Benjamini-Hochberg correction.
Fig. 2
Fig. 2. HIV-1 Env IgG subclass response magnitude: RV144 versus VAX003
(A) HIV-1 Env IgG1 antibody concentrations were lower in RV144 compared to VAX003. Antibody response magnitude in mean fluorescence intensity (MFI) is shown for positive responders only. (B) HIV-1 Env IgG2 antibody responses were higher in VAX003 than in RV144. (C) HIV-1 Env IgG3 antibody responses were elevated after two protein boosts (V5) in VAX003 and then declined after four protein boosts (V9). (D) HIV-1 Env IgG4 responses were lower in RV144 compared to VAX003. (E) IgG avidity to the vaccine strain antigen, A244, and also to the group M consensus gp140 was measured by surface plasmon resonance (SPR). ***P < 0.0005; **P < 0.005; *P < 0.05. P values for (A) to (D) were calculated with two-tailed t tests. P values for (E) and (F) were calculated with the Wilcoxon rank-based test.
Fig. 3
Fig. 3. V1–V2 IgG3 antibody responses differ between RV144 and VAX003 and correlate with a decreased HIV-1 infection risk in a RV144 case-control study
(A) Responders to V1–V2 antigens in RV144 and VAX003. (B and C) Magnitude of V1–V2 responses to RV144 at V8 and VAX003 at V5 and V9. (D and E) Magnitude of V1–V2 IgG3 responses in the RV144 case-control study. (F and G) Cumulative incidence plots for V1–V2 IgG3 responses. ***P < 0.0005; **P < 0.005; *P < 0.05. P values in (A) were calculated with the two-tailed Fisher’s exact test. P values in (B) and (C) were calculated with two-tailed t tests.
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