Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN 503/Phambili study

Abstract

Background The Phambili study, conducted in South Africa amongst a predominantly heterosexual population, evaluated the efficacy of the MRK Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine. Enrollment and vaccinations were stopped, participants unblinded, and follow-up extended when the Step study evaluating the same vaccine in the Americas, Caribbean and Australia was unblinded for non-efficacy with more HIV infections amongst vaccinee than placebo recipients [ZM1]. Extensive analyses over the complete follow-up period, most of which was unblinded, are reported. Methods Phambili participants were HIV-1 uninfected, sexually active men and women aged 18–35 years, followed for 3.5 years. HIV testing and risk reduction counseling occurred at weeks 0, 12, 30 and were switched to a 3 monthly schedule after unblinding. Cox proportional hazards models were used to estimate HIV-1 infection hazard ratios (HR) comparing vaccine to placebo recipients, overall and within subgroups. Long-term vaccine efficacy was evaluated in participants who were unblinded early in follow-up. Results Of the 801 participants enrolled (400 vaccine, 401 placebo), 112 (28%) received 1 vaccination, 259 (65%) 2 vaccinations and 29(7%) 3 vaccinations. More infections occurred in vaccinees (n=63) as compared to placebo (n=37) (adjusted HR (vaccine:placebo) 1.70, 95% CI 1.13–2.55, p = 0.01). We found no increase in infections with the number of vaccinations received and that the HRs did not differ by gender, circumcision, or Ad5 serostatus. Differences in risk behavior at baseline or during the study, or differential drop-out (p=0.40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccinees. Conclusion The increased HR of HIV-1 acquisition, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. Further use of the Ad5 vector for HIV vaccines is not warranted

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

“…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.…”

Polyvalent vaccine approaches to combat HIV‐1 diversity

“…A novel CMV vector developed by Louis Picker et al 31, 32, 33. has elicited unusual and protective T‐cell responses in rhesus macaques.…”

An update on human immunodeficiency virus vaccine preparedness studies

“…Due to the results of the STEP study, the Phambili study in South Africa, which used the same vaccine as the STEP study, was stopped in 2007 (Gray et al, 2014). The RV144 vaccine trial in Thailand in lower-risk heterosexuals utilized the HIV vaccines ALVAC HIV (vCP1521) and AIDSVAX B/E (RerksNgarm et al, 2009).…”