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Posted: 10 Nov 2011
30 years in 30 weeks, 2008

The Step trial (HVTN 502/Merck 023) was the third efficacy trial of an HIV vaccine. The trial began in 2005 and preliminary results stopped the trial in 2007, resulting in widespread pessimism about the feasibility of developing an HIV vaccine. Still, as Dr. Susan Buchbinder explains in her commentary, the trial provided valuable knowledge that could not be obtained in any other way. Results of this trial, together with the results of the RV144 trial in Thailand, released two years later, highlight the unpredictability of the path to vaccine discovery, which can only be traveled by taking risks and conducting crucial experiments.

Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial.
Lancet. 2008 Nov 29;372(9653):1881-93. Epub 2008 Nov 13.
Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D, Gilbert PB, Lama JR, Marmor M, Del Rio C, McElrath MJ, Casimiro DR, Gottesdiener KM, Chodakewitz JA, Corey L, Robertson MN; Step Study Protocol Team.

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Commentary by Dr. Susan Buchbinder

Dr. Susan Buchbinder
This paper, and the companion paper by Julie McElrath in the 13 November 2008 online edition of the Lancet, describes results of the first interim efficacy analysis of the Step Study. These results were unexpected and disappointing, but paradoxically reinforced the importance of clinical trials to move HIV vaccine science forward.

Because earlier HIV-1 vaccines had failed to elicit neutralizing antibody to primary isolates, the focus of HIV vaccine science from the mid-1990’s to mid-2000’s concentrated heavily on vaccines that could elicit strong cellular immune responses. Non-human primate studies suggested that vaccines that elicited CD8+ T cell responses would not prevent infection, but could control viral replication, in essence turning vaccinees into long-term non-progressors. Observational studies of HIV-infected non-progressors reinforced the importance of CD8+ CTL and suppressive activity in control of viral replication and avoidance of clinical disease. At that time, the replication deficient adenovirus type 5 (Ad5) vectors were among the most immunogenic of all vaccines. Merck’s trivalent gag/pol/nef vaccine consistently generated HIV-specific CD8+ T cell responses in more than half of participants with pre-existing immunity to Ad5, and much higher proportions in vaccinees with low or no neutralizing antibody to Ad5. The HIV Vaccine Trials Network (HVTN) collaborated with Merck to develop the Step Study, a Phase IIB efficacy study of 3 doses of the MRKAd5 gag/pol/nef vaccine. Our goal was to confirm the safety of this vaccine, and to test the concept that this vaccine would protect against HIV infection and/or provide early control of HIV-1 viral replication.

We were eager to get an early read on the promise of this approach, and built into the protocol planned interim analyses to indicate the potential promise or futility of this vaccine approach. HVTN and Merck clinical trial sites enrolled 3000 HIV uninfected men and women at risk of sexually acquired HIV-1 infection in clade B regions of the world (North and South America, the Caribbean and Australia). Our Data and Safety Monitoring Board (DSMB) conducted their first interim efficacy analysis in September 2007, only 33 months after the launch of our trial. To our surprise and great disappointment, efficacy results for the Ad5 negative and low-titer strata (the groups specified for the primary analysis) crossed the pre-determined futility boundaries. We worked with the site investigators to ensure a simultaneous release of information to the participants and general public within 72 hours of that DSMB meeting.

Even more surprising and disturbing were the patterns that emerged as we examined efficacy data for the entire trial. We found an overall trend toward an increased risk of HIV infection that appeared limited to men who entered the study either with pre-existing Ad5 neutralizing antibody or who were uncircumcised. Men who had both risk factors and were vaccinated were more than 3 times more likely to become HIV infected than men with these risk factors who received placebo.
A number of valuable lessons emerged from this study. Among the most important was the critical nature of clinical trials in moving HIV vaccine science forward, as we would not have anticipated the increased risk of HIV acquisition, the role of pre-existing Ad5 immunity or the importance of foreskin in vaccine-induced responses from previous basic or pre-clinical studies. Follow-up studies have generated hypotheses for increased risk associated with vaccination, which are being explored in more depth. Additional studies also pointed to potential immune pressure on early viral variants, suggesting potentially positive but inadequate immune responses due to vaccination. These highlight the complementary strengths of the non-human primate models to more intensively study mucosal immune responses and events early after HIV exposure than is possible in clinical trials.

Good science and clinical equipoise demand that research focus on important, unanswered questions. Such studies often yield surprising results. Even disappointing results are fruitful if they are timely, advance the field and create new and important insights. I believe the Step Study did all of these things, while creating a structure to further widespread scientific and community collaborations to understand and communicate results from HIV vaccine trials.

About the Author: Susan Buchbinder is the Director of the HIV Research Section in the San Francisco Department of Public Health and an Associate Clinical Professor of Medicine, Epidemiology and Biostatistics at the University of California, San Francisco.

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