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Statistical Communications in Infectious Diseases

Editor-in-Chief: Evans, Scott

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Mathematical Citation Quotient (MCQ) 2014: 0.12

A Sequential Phase 2b Trial Design for Evaluating Vaccine Efficacy and Immune Correlates for Multiple HIV Vaccine Regimens

Peter B. Gilbert1 / Douglas Grove2 / Erin Gabriel3 / Ying Huang4 / Glenda Gray5 / Scott M. Hammer6 / Susan P. Buchbinder7 / James Kublin8 / Lawrence Corey9 / Steven G. Self10

1Fred Hutchinson Cancer Research Center and University of Washington

2Fred Hutchinson Cancer Research Center

3University of Washington

4Fred Hutchinson Cancer Research Center

5University of the Witwatersrand

6Columbia University Medical Center

7San Francisco Department of Public Health and University of California, San Francisco

8Fred Hutchinson Cancer Research Center

9Fred Hutchinson Cancer Research Center and University of Washington

10Fred Hutchinson Cancer Research Center and University of Washington

Citation Information: Statistical Communications in Infectious Diseases. Volume 3, Issue 1, ISSN (Online) 1948-4690, DOI: 10.2202/1948-4690.1037, October 2011

Publication History

Published Online:

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.

Keywords: HIV vaccine efficacy clinical trial; immune correlate of protection; one-way crossover design; surrogate endpoint for HIV infection; two-phase sampling

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Ying Huang, Peter B. Gilbert, and Julian Wolfson
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