In the last 12 years, approximately 15 million new HIV infections occurred. During those 12 years, five double-blind, placebo-controlled preventative HIV vaccine trials have been conducted to measure the efficacy of a vaccine regimen. One of these trials, the RV144 trial, reported a partially efficacious HIV vaccine that showed vaccine efficacy of 31 percent. The HIV vaccine field was not prepared for success, and the clinical trial pipeline thus has lagged in building upon the results from RV144 to test similar, improved vaccines. A common timeline for an HIV vaccine clinical trial is approximately 4-6 years between the first administration of vaccine to recipients and the first publication of results; this does not include years spent on trial design and follow-up data analyses. With approximately 2.7 million new HIV infections occurring last year, the speed of clinical trial completion must be increased without reducing the ability to detect harmful or ineffective vaccines or those with promising efficacy.
One type of vaccine clinical trial is two-stage, multi-arm. This type of trial is intended to accelerate the pace of answering key biological questions by analyzing multiple vaccine regimens simultaneously in the same population compared to the same placebo. In a recent publication, VIDD members Drs. Peter Gilbert and Steve Self, VIDD assistant member Dr. Ying Huang, VIDD principal staff scientist Dr. James Kublin and Center president and director Dr. Larry Corey and colleagues designed a sequential phase IIb vaccine trial for expeditiously assessing vaccine efficacy and immune correlates, immunological markers of vaccine effectiveness that can be measured earlier than infection status. The four main objectives of this study were to rapidly evaluate vaccine efficacy against HIV infection within 18 months of immunization, analyze durability of vaccine efficacy for each regimen that showed evidence of protection over the first 18 months, assess immune correlates of protection and compare efficacy among the vaccine regimens.
The study design included three vaccine arms and one placebo arm and was designed to achieve high enough power to detect large but not moderate differences in efficacy between the vaccine arms from 0-18 months. Frequent HIV testing and sampling for gathering and identifying potential immune correlates over the three vaccine arms will be invaluable for ascertaining reliable, accurate immune correlates for measuring vaccine efficacy and detecting potentially harmful sequelae of vaccination. Based on 10,000 simulated trials, the authors found probabilities of weeding out or carrying to completion regimens with different levels of efficacy. For example, a regimen with 0% efficacy would be weeded out with a probability of 50% within the first 17 months and 99% within the first 20 months. By estimating the likelihood of a vaccine trial’s outcome in an expeditious manner, this study has provided the field with a model for increasing the chance of finding an efficacious HIV vaccine. – MDM
Gilbert P, Grove D, Gabriel E, Huang Y, Gray G, Hammer S, Buchbinder S, Kublin J, Corey L, & Self S. A Sequential Phase 2b Trial Design for Evaluating Vaccine Efficacy and Immune Correlates for Multiple HIV Vaccine Regimens. Stat Commun Infect Dis. 2011 Oct; 3(1):1-86.