title: A Sequential Phase 2b Trial Design for Evaluating Vaccine Efficacy and Immune Correlates for Multiple HIV Vaccine Regimens.
abstract: Five preventative HIV vaccine efficacy trials have been conducted over the last 12 years, all of which evaluated vaccine efficacy (VE) to prevent HIV infection for a single vaccine regimen versus placebo. Now that one of these trials has supported partial VE of a prime-boost vaccine regimen, there is interest in conducting efficacy trials that simultaneously evaluate multiple prime-boost vaccine regimens against a shared placebo group in the same geographic region, for accelerating the pace of vaccine development. This article proposes such a design, which has main objectives (1) to evaluate VE of each regimen versus placebo against HIV exposures occurring near the time of the immunizations; (2) to evaluate durability of VE for each vaccine regimen showing reliable evidence for positive VE; (3) to expeditiously evaluate the immune correlates of protection if any vaccine regimen shows reliable evidence for positive VE; and (4) to compare VE among the vaccine regimens. The design uses sequential monitoring for the events of vaccine harm, non-efficacy, and high efficacy, selected to weed out poor vaccines as rapidly as possible while guarding against prematurely weeding out a vaccine that does not confer efficacy until most of the immunizations are received. The evaluation of the design shows that testing multiple vaccine regimens is important for providing a well-powered assessment of the correlation of vaccine-induced immune responses with HIV infection, and is critically important for providing a reasonably powered assessment of the value of identified correlates as surrogate endpoints for HIV infection.
authors.affiliation: Fred Hutchinson Cancer Research Center and University of Washington.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Gilbert
authors.forename: Douglas
authors.initials: D
authors.lastname: Grove
authors.forename: Erin
authors.initials: E
authors.lastname: Gabriel
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Glenda
authors.initials: G
authors.lastname: Gray
authors.forename: Scott M
authors.initials: SM
authors.lastname: Hammer
authors.forename: Susan P
authors.initials: SP
authors.lastname: Buchbinder
authors.forename: James
authors.initials: J
authors.lastname: Kublin
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.forename: Steven G
authors.initials: SG
authors.lastname: Self