Vaccine and Infectious Disease Division

HVTN 505 phase 2b HIV vaccine trial showed no efficacy to reduce HIV infection risk

The research community has developed several biomedical and behavioral interventions for the prevention of HIV in the last six years. However, other than the RV144 Thai trial, which provided 31% protection from HIV acquisition, HIV vaccine efforts have thus far failed to show efficacy. The large reservoir of HIV-infected persons and the high frequency of asymptomatic acquisition and carriage all point to the requirement of an effective vaccine to provide the durable protection required for widespread reduction of HIV-1 on a global basis.

From 2009-2013, the HVTN conducted a phase 2b efficacy trial, HVTN 505, vaccinating at weeks 0, 4 and 8 with a DNA adenovirus 5-vectored vaccine platform containing epitopes from Gag (clade B), Pol (clade B), Nef (clade B), and Env (clades A, B, C) followed by a vector boost at 24 weeks containing a clade B Gag-Pol fusion protein and Env glycoproteins (clades A, B, C) in gay men and transgender women in the U.S. with one of the primary endpoints being the reduction of HIV acquisition in immunized individuals. 

HIV incidence, vaccine versus placebo

The cumulative incidences of HIV-1 infection diagnosed from week 28 through month 24 (week 28+ infection). Initial Analysis is on the left and Subsequent Analysis, referring to the analyses calculated in September, is on the right. These data show that the late separation of the estimated cumulative HIV-1 incidence curves after month 21 was not sustained. Figure adapted from Hammer, et al.

A total of 2,496 participants were enrolled and randomized to receive the vaccine (1,251 subjects) or placebo (1,245 subjects). The study team identified 27 HIV-infected participants who received the vaccine and 21 of the placebo subjects during follow-up between the period after the last vaccination (week 28) to 2 years; yielding a hazard ratio (HR) of infection of 1.25 (95% CI 0.71-2.21; P = 0.44) (see Figure, left panel). Vaccinations were discontinued and the study participants were informed of whether they were assigned vaccine or placebo in April of 2013 (two thirds of the trial timeline) by the trial’s safety monitoring board due to failure to demonstrate efficacy. The apparent increase in transmission risk of HIV in the vaccinated group was not statistically significant. In fact, a recent follow-up analysis (September 2013) showed no difference in infection risk between the vaccinated and unvaccinated groups (HR 1.09, 95% CI 0.64-1.84; P = 0.76) (see Figure, right panel).

In vaccinated individuals, the authors found HIV-specific lymphocyte response rates of 61.5% (CD4 T cells) and 64.1% (CD8 T cells). HIV-stimulated CD4 T cells producing cytokines IFNγ and IL-2 mainly targeted Gag and Env antigens, while the majority of CD8 T cells expressed cytokines targeting Env epitopes. Sexual behavior pre-trial enrollment had a striking impact on infection risk, with a HR of 6.01 (95% CI 3.15-11.48; P = 0.001) for subjects who had sex with > 3 male partners and unprotected anal receptive sex compared to those lacking these risk factors. This HIV infection risk was not dependent on arm assignment.
 

The HVTN 505 trial was designed, developed, conducted and analyzed by a multitude of investigators and scientists from over 15 universities, institutions, biotechnology corporations and governmental departments. On behalf of the 505 team, the study was authored by VIDD Associate Members Drs. Holly Janes and Nicole Frahm; Staff Physician Dr. Shelly Karuna; Principal Staff Scientists Drs. John Hural and Jim Kublin; and Members Drs. Julie McElrath, Larry Corey and Peter Gilbert.
 


Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Grove D, Koblin BA, Buchbinder SP, Keefer MC, Tomaras GD, Frahm N, Hural J, Anude C, Graham BS, Enama ME, Adams E, DeJesus E, Novak RM, Frank I, Bentley C, Ramirez S, Fu R, Koup RA, Mascola JR, Nabel GJ, Montefiori DC, Kublin J, McElrath MJ, Corey L, Gilbert PB; HVTN 505 Study Team. Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N Engl J Med. 2013 Nov 28;369(22):2083-92.
 

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