Vaccine-Induced Env V1-V2 IgG3 Correlates with Lower HIV-1 Infection Risk and Declines Soon After Vaccination

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.

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

“…This finding is shown in Fig. 2A, where data from Yates et al (26) and Robb et al (30) are replotted in a single graph. Protection reached levels as high as ∼60% early but declined to undetectable levels by 18 mo.…”

“…The most probable answer is that the antigp120 responses linked with efficacy did not persist, as shown by Yates et al (26). In this light, had the antibody titers responsible for 59.9% protection in the RV144 trial been maintained, the vaccine could be licensable theoretically, at least for use in Thailand.…”

“…The contrast between the two vaccines is even more striking when it is considered that the RV144 V1/V2 curve is seropositivity, whereas the anti-HPV curve is titers, where the vast majority of vaccinees remain seropositive for decades (60). The t 1/2 estimate for the putatively protective IgG anti-V1/V2 response in the RV144 trial is estimated to be from 11.7 to 23.7 wk depending on the assay antigen (26). This estimate stands in stark contrast to the t 1/2 s of licensed vaccines listed in Table 1, which range from nearly 10 y to more than 100 y, particularly for replication-competent vectors and particle-based vaccines with potent adjuvants (i.e., the HPV vaccine).…”

“…Extensive analyses have been carried out seeking correlations between immune responses and reduced risk of infection (25,26,28,29,54,(74)(75)(76). The strongest correlation with reduced risk of infection was binding antibodies to the V1/ V2 region of gp120 (25,26,29,76).…”

“…24). Protection correlated with antibodies against the V1/V2 region of gp120 (25), particularly those antibodies of the IgG3 subclass that mediate potent antibody-dependent cellular cytotoxicity (ADCC) (26), in addition to other aspects of anti-gp120 humoral immunity (25)(26)(27)(28)(29). Importantly, efficacy in the RV144 trial was temporally dependent, peaking at ∼59.9% early in the study and waning to background by the end of the 3-y postvaccination follow-up, thus producing an overall efficacy of 31.2% (30).…”