Safety and efficacy of the HVTN 503/Phambili Study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study

Abstract

Summary We report the primary analysis of the safety and efficacy of the MRKad5 gag/pol/nef HIV-1 sub-type B vaccine in South Africa (SA), where the major circulating clade is sub-type C. Methods This phase IIb double-blind, randomized test-of-concept study was conducted in sexually active HIV-1 sero-negative participants in SA. The co-primary endpoints were a vaccine-induced reduction in HIV-1 acquisition or viral-load setpoint. These were assessed independently in the modified intent-to-treat (MITT) cohort with two-tailed significance tests stratified by gender. Immunogenicity was assessed by interferon-gamma (IFNγ) ELISPOT in peripheral blood mononuclear cells. Following the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrollment and vaccination in this study was halted, treatment unblinding occurred and follow-up continued. This study is registered with the SA National Health Research Database (DOH-27-0207-1539) and ClinicalTrials.gov (NCT00413725). Results 801 of a scheduled 3000 participants were enrolled, of whom 360 (44.9%) were women, more than half (55.6%) had Ad5 titres > 200, and almost a third (29.3%) of men were circumcised. 62 MITT participants were diagnosed with HIV-1, 34 in the vaccine arm and 28 in the placebo arm, with infection rates of 4.54 and 3.70 per 100 person-years, respectively. There was no evidence of vaccine efficacy (VE); the hazard ratio adjusted for gender was 1.25 (95% CI: 0.76, 2.05). VE did not differ by Ad5 titre, gender, age, HSV-2 status, or circumcision. The geometric mean viral load setpoint was 20,483 copies/ml (N=33) in vaccinees and 34,032 copies/ml (N=28) in placebo recipients (p=0.39). The vaccine elicited IFNγ-secreting T cells recognizing both clade B (89.2%) and C (77.4%) antigens. Conclusion The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint however early stopping likely compromised our ability to draw conclusions. The high incidence rates seen in SA highlight the critical need for intensified efforts to develop an efficacious vaccine.

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

“…78). The increased risk correlated with prevaccination antibody titers to Ad5 in uncircumcised men who have sex with men (13)(14)(15)48). Subsequently, the HVTN-505 trial was designed to control for these factors, and the vaccine also included Env to enable the production of potentially protective antibodies (16).…”

“…These central features distinguish the path to an HIV vaccine from the traditional design principles that led to successful vaccines against other infectious agents. The inability of these principles to yield an HIV vaccine became abundantly clear in six large HIV vaccine trials, where efficacy was not observed (11)(12)(13)(14)(15)(16) (Table 1). Strikingly, vaccination increased the risk of infection in two of these studies that selectively targeted T-cell immunity (13)(14)(15), providing a stark contrast between the development of conventional and HIV vaccines.…”

“…CD4 + T-cell lineage commitment is determined by the cytokine composition of the microenvironment in which the CD4 + T cells are primed and boosted via transcriptional regulation of lineage-specific cytokine gene families (38,39,45). This observation leads to the sobering possibility that CD4 + CCR5 + T cells (i.e., Th17 cells) responding to an HIV vaccine designed to elicit a persistent and protective antibody response could blunt protection or, worse, increase susceptibility to infection, as suggested in the adenovirus serotype 5 (Ad5) vaccine trials (13)(14)(15)(16). This finding was presaged by an earlier study in nonhuman primates vaccinated with an attenuated varicella zoster vaccine (VZV) encoding SIV gp120 (46).…”

“…The increased transmission associated with unappreciated immune activation in Ad5-HIV efficacy trials is abundantly apparent in the follow-up to the HIV Vaccine Trials Network 503 (HVTN-503; Phambili) (14,15) and HVTN-504 (Step) (13,48) trials, in which vaccinees experienced a higher and sustained increased risk of infection compared with placebo recipients (15,48). Because the vaccines tested in these trials did not include the HIV envelope, any impact of T-cell activation would be relatively unbridled.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Education, identification and treatment of infected persons with antiretroviral drugs, male circumcision, condoms, and needle exchange programs have been effective at curtailing the epidemic, but declines in the rate of new infections have plateaued, and it appears unlikely that the goal of <500 000 new adult infections per year will be achieved by 2020. An effective HIV‐1 vaccine could contribute to further reductions of infections as part of a coordinated prevention strategy,2 but to date, testing of candidate vaccines in efficacy trials has been disappointing 3, 4, 5, 6, 7 with only one trial showing any degree of vaccine efficacy 8…”