HIV-1 Vaccine Sequences Impact V1V2 Antibody Responses: A Comparison of Two Poxvirus Prime gp120 Boost Vaccine Regimens

Abstract

Nonhuman primate studies conducted after RV144 supported the importance of non-neutralizing antibodies to V2 for protection from experimental challenge. Vaccine-elicited V2 IgG correlated with delayed SIV 9-13 and SHIV acquisition 14 , and with viremia control after SIV infection 13. Passive transfer of 830 A, a V2-specific monoclonal antibody (mAb), resulted in improved viremia control in nonhuman primates 15. Many studies have reported antiviral functions that include antibody Fc effector functions and direct neutralization mediated by antibodies that recognize V2 7,16-22. V2-specific mAbs recognizing aa169, which were isolated from RV144 vaccine recipients, were shown to mediate tier 1 neutralization, bind to infectious virions 23 , and mediate killing of primary HIV-1 isolate infected cells 16. Aa169 is located within the linear epitope sequence bound by RV144 vaccine-elicited antibodies that correlated with decreased HIV-1 risk 4. The other known site of RV144-induced immune pressure in V2, aa181, is also part of the leucine-aspartic acid-isoleucine/valine (LDI/V) aa179-181 sequence motif reported to mediate HIV-1 envelope interaction with the gut mucosal homing integrin receptor α4β7 to facilitate cell-to-cell spread 19,20. It has been postulated that V2-specific antibodies may block or interfere with the interaction between α4β7 and the HIV-1 envelope to prevent viral transmission 19,20. In participants from the RV144 trial and the RV305 trial, in which delayed boosters were given to RV144 participants, a group of V2-specific mAbs were shown to be capable of blocking AE.92TH023 V2 peptide binding to α4β7 24. The α4β7-blocking antibodies included both those targeting the linear V2 hotspot and those targeting the conformational epitopes 25. V2-specific antibodies can mediate phagocytosis 18,26,27 and can synergize with C1-C2 specific IgG for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) 28. Furthermore, quaternary epitopes involving the V2 loop were identified as a target for broadly neutralizing antibodies 21,29. The Pox-Protein Public-Private Partnership (P5) program was established to develop a subtype C-directed vaccine based on the RV144 regimen 30. As part of this program, two phase 1/2 trials were designed in South Africa: HIV Vaccine Trials Network (HVTN) 097 31 (ClinicalTrials.gov NCT02109354) determined immune responses of an African population to the RV144 regimen, and HVTN 100 32 (ClinicalTrials.gov NCT02404311) investigated the immunogenicity of the regimen adapted to subtype C. The selection criteria for the subtype C envelope immunogens included binding and affinity by V2-specific mAbs 33,34. The HVTN 100 primary immunological data were evaluated against prespecified immunological criteria and guided the decision to proceed with the vaccine regimen into an efficacy trial, HVTN 702. Vaccine-elicited responses in HVTN 100 met all four prespecified go/no-go criteria for the continuation of the HVTN 702 trial, including the envelope-binding and V1V2-binding IgG response 32. Our stu...

Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines

“…The breadth of IgG responses amongst vaccine recipients to the gp120, gp140, and V1V2 antigen panels was significantly higher at month 12.5 than month 6.5 (all P < 0.001) and also higher at month 18 than at month 12 (P < 0.001, P < 0.001, and P = 0.001, respectively) ( Fig 4), indicating that IgG envelope breadth was boosted. In addition to conformational V1V2 antibody responses, linear V2 IgG responses, a correlate of decreased HIV-1 risk in the RV144 trial [19], were also elicited in HVTN 100 [20]. IgG3 bAb response rates were significantly higher at month 6.5 than at month 12.5 for 1086.C gp120 and TV1c8.2.C gp120 (P = 0.016 and P = 0.011, with estimates and 95% CIs in S4 Table), and were similar at month 18 compared to month 12 for all 3 vaccine-matched gp120 antigens (P = 0.75, 1.00, and 0.63, with estimates and 95% CIs in S4 Table; S1 Fig) and for all 4 V1V2 antigens at all timepoints (vaccine-matched antigens shown in S1 Fig) (all P > 0.50).…”

Polyfunctional Fc Dependent Activity of Antibodies to Native Trimeric Envelope in HIV Elite Controllers

“…Efforts to replicate RV144 vaccine-mediated protection in South Africa using a regimen analogous to the one used in the RV144 trial but with a vaccine regimen based on clade C HIV, the HVTN702 vaccine trial, failed to protect against HIV infection (66,67). Companion phase II safety and immunogenicity vaccine trials showed that levels of anti-Env Abs induced by the clade C based vaccine regimens were as high if not higher than the levels induced by the RV144 vaccine regimen (3,62,68,69). These Abs responses were tested using cells coated with monomeric rgp120 and thus, the immune monitoring strategy preferentially detected Abs to CD4i epitopes.…”

Review of preventative HIV vaccine clinical trials in South Africa

“…The results were compared to those of another phase I trial, HVTN 100, which investigated the subtype C ALVAC and MF59-adjuvanted gp120 regimen. The immunological profiles of the two regimens were different, and it was found that the selected vaccine inserts contributed to these differences [32]. The RV144/ HVTN 097 regimen induced greater magnitude and breadth of V2 responses than the HVTN 100/HVTN 702 regimen, but the HVTN 100/HVTN 702 regimen induced higher gp120 and ADCC responses [31].…”

“…However, when the subtype B/E and subtype C vaccines were compared in terms of the IgG antibody response against the V1V2 loop region of the 1086C HIV envelope, a lower proportion of participants responded to the subtype C vaccine. The difference in responses between the RV144/HVTN 097 and HVTN 100/HVTN 702 regimens suggest that the choice of viral sequences inserted into prime-boost vaccine regimens influences the elicitation of V2-specific antibodies [32]. V2-specific IgG antibodies had been observed as one of the correlates of protection in the RV144 vaccine trial in Thailand.…”