Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine in low-risk, HIV-uninfected, South African adults: a phase 1/2 trial

Abstract

SummaryBackgroundModest efficacy was reported for the HIV vaccine tested in the RV144 trial, which comprised a canarypox vector (ALVAC) and envelope (env) glycoprotein (gp120). These vaccine components were adapted to express HIV-1 antigens from strains circulating in South Africa, and the adjuvant was changed to increase immunogenicity. Furthermore, 12-month immunisation was added to improve durability. In the HIV Vaccine Trials Network (HVTN) 100 trial, we aimed to assess this new regionally adapted regimen for advancement to efficacy testing.MethodsHVTN 100 is a phase 1/2, randomised controlled, double-blind trial at six community research sites in South Africa. We randomly allocated adults (aged 18–40 years) without HIV infection and at low risk of HIV infection to either the vaccine regimen (intramuscular injection of ALVAC-HIV vector [vCP2438] at 0, 1, 3, 6, and 12 months plus bivalent subtype C gp120 and MF59 adjuvant at 3, 6, and 12 months) or placebo, in a 5:1 ratio. Randomisation was done by computer-generated list. Participants, investigators, and those assessing outcomes were masked to random assignments. Primary outcomes included safety and immune responses associated with correlates of HIV risk in RV144, 2 weeks after vaccination at 6 months (month 6·5). We compared per-protocol participants (ie, those who completed the first four vaccinations and provided samples at month 6·5) from HVTN 100 with stored RV144 samples assayed contemporaneously. This trial is registered with the South African National Clinical Trials Registry (DOH-27-0215-4796) and ClinicalTrials.gov (NCT02404311).FindingsBetween Feb 9, 2015, and May 26, 2015, 252 participants were enrolled, of whom 210 were assigned vaccine and 42 placebo. 222 participants were included in the per-protocol analysis (185 vaccine and 37 placebo). 185 (100%) vaccine recipients developed IgG binding antibodies to all three vaccine-matched gp120 antigens with significantly higher titres (3·6–8·8 fold; all p<0·0001) than the corresponding vaccine-matched responses of RV144. The CD4+ T-cell response to the ZM96.C env protein in HVTN 100 was 56·4% (n=102 responders), compared with a response of 41·4% (n=79 responders) to 92TH023.AE in RV144 (p=0·0050). The IgG response to the 1086.C variable loops 1 and 2 (V1V2) env antigen in HVTN 100 was 70·5% (95% CI 63·5–76·6; n=129 responders), lower than the response to V1V2 in RV144 (99·0%, 95% CI 96·4–99·7; n=199 responders).InterpretationAlthough the IgG response to the HVTN 100 vaccine was lower than that reported in RV144, it exceeded the predicted 63% threshold needed for 50% vaccine efficacy using a V1V2 correlate of protection model. Thus, the subtype C HIV vaccine regimen qualified for phase 2b/3 efficacy testing, a critical next step of vaccine development.FundingUS National Institute of Allergy and Infectious Diseases (NIAID), and Bill & Melinda Gates Foundation.

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

“…HVTN 097 and HVTN 100 vaccine trial designs. The HVTN 097 (phase 1) 31 and HVTN 100 (phase 1-2) 32 clinical trials both evaluated vaccine regimens consisting of a canary pox virus vector prime and a bivalent envelope gp120 protein boost in South Africa. Differences between the two regimens include: (1) the envelope vaccine strain was 92TH023 for the ALVAC prime and A244 and MN for the gp120 boost in HVTN 097, whereas HVTN 100 contained the ZM96 sequence for the ALVAC prime and 1086 and TV1 for the gp120 boost; (2) the adjuvant was aluminum hydroxide for HVTN 097 compared to MF59 for HVTN 100; (3) the protein dose in HVTN 097 was 3 times higher than that in HVTN 100; (4) the actual dose of ALVAC-HIV in HVTN 097 was 2.7 times more than that in HVTN 100 (ref.…”

Clade C HIV-1 Envelope Vaccination Regimens Differ in Their Ability To Elicit Antibodies with Moderate Neutralization Breadth against Genetically Diverse Tier 2 HIV-1 Envelope Variants

“…The authors assessed the strength of positive serum neutralization responses in immunized guinea pigs and found that 1086.C ranked as the second most effective immunogen. Because of its favorable antigenicity profile, it was included as one part of the bivalent clade C gp120 boost for the HVTN-100 phase I/II randomized, double-blind, clinical vaccine trial carried out in South Africa (47) and is also included in the subsequent ongoing phase IIb/III efficacy trial, HVTN-702 (26,48). Overall, the subtype C bivalent gp120 immunogen has exhibited differences in antigenicity from the gp120s used in the RV144 regimen, in particular, for elicitation of responses directed at V1V2 (47).…”

“…Because of its favorable antigenicity profile, it was included as one part of the bivalent clade C gp120 boost for the HVTN-100 phase I/II randomized, double-blind, clinical vaccine trial carried out in South Africa (47) and is also included in the subsequent ongoing phase IIb/III efficacy trial, HVTN-702 (26,48). Overall, the subtype C bivalent gp120 immunogen has exhibited differences in antigenicity from the gp120s used in the RV144 regimen, in particular, for elicitation of responses directed at V1V2 (47). The 1086.C Env gp120 protein, when produced in CHO cells, also exhibited an unusually high occupancy of high-mannose glycans, which could favorably impact its antigenicity (26).…”

The search for an HIV vaccine, the journey continues

“…Rather than perform a direct repeat of RV144 in Thailand, where the epidemic is driven by viruses from clades AE and B, a clade C‐specific regimen was developed for testing in Southern Africa. When evaluated in the HVTN100 trial, the relevant correlate responses were detected and shown to be longer lasting than those of RV144 [5‐7]. With the go‐no‐go criteria for advancement met, the HVTN702 study moved ahead.…”