Special Bulletin

'Stopping a steam train'

Immunizations and enrollment in a second trial in South Africa testing Merck’s vaccine have now been stopped permanently in light of the STEP trial results

by Andreas von Bubnoff*

On October 23, immunizations and enrollment were stopped permanently in a second National Institute of Allergy and Infectious Diseases (NIAID)-sponsored trial called Phambili, or HVTN 503, following the recommendation by the trial's data safety monitoring board (DSMB). The trial was a companion study to the STEP trial testing the same clade B MRKAd5 vaccine at sites in South Africa (see A STEP back?). The decision was based on a review of STEP trial data. The Phambili DSMB also recommended that the study investigators unblind all participants, telling them whether they received vaccine or placebo, and counsel them that they might have an increased susceptibility to HIV infection due to the vaccine.

The Phambili trial's immunizations and enrollment had already been suspended on September 21 in response to the futility analysis by the DSMB of the STEP trial. Phambili was at a much earlier stage than the STEP trial—it had only started enrollment earlier this year and when it was suspended in September, it had enrolled 801 volunteers of a planned total of 3,000, only 58 of whom had received all three vaccinations.

As news of the suspension reached the Phambili trial sites in September, it felt like "stopping a steam train," says Glenda Gray, of the Perinatal HIV Research Unit at the University of Witwatersrand and the principal investigator of the Phambili trial. At that time, the trial sites were enrolling as many as 50 volunteers a day.

One goal of the Phambili trial was to see if the candidate vaccine would be effective in areas with HIV subtype C, the most common clade circulating in South Africa. The Phambili trial was also conducted for the most part in heterosexual volunteers and was to enroll 60% women, far more than in the STEP trial, which aimed for one quarter of the volunteers to be women. Women are at a very high risk of contracting HIV in South Africa, and while the STEP trial involved primarily men who have sex with men (MSM), the Phambili trial could have helped researchers determine the efficacy of this candidate in women.

When Phambili was suspended it had enrolled about 45% women, compared with 38% in STEP. But the HIV incidence rates among women in the STEP trial were very low—only one of the 83 HIV infections through October 17 occurred in a female volunteer. The reasons for this discrepancy are currently unclear, researchers say. "We don't have enough data from this study to say anything about vaccine effects in women," says Susan Buchbinder of the University of California in San Francisco and principal investigator of the STEP trial.

The process of unblinding the Phambili trial was started immediately after the DSMB's decision was released on October 23. Gray says it took only 16 days to unblind all participants after the initial announcement. In what she compared to a "military operation," the volunteers were contacted by radio, cell phone short message service (SMS), and phone. All volunteers are still being encouraged to return for study visits. Gray says unblinding volunteers in the Phambili trial made sense because it was at such an early stage it would not have yielded any substantial information, even if it the participants who were already enrolled had been kept blinded. Keith Gottesdiener, of Merck Research Laboratories, agrees. "I think the [STEP and Phambili] trials were at different stages of development," he says, adding that the only additional information the Phambili DSMB used to make its decision to unblind was eight additional HIV infections in the STEP trial that had accumulated by October 17 in the low Ad5 titer group. The additional infections, four in the vaccine and four in the placebo group, did not make much of a difference in the overall outcome, he says.

The decision to unblind the STEP trial will come in about 10 days, researchers said on November 7. This decision won't be easy, says Peggy Johnston, from NIAID's division of AIDS. She says the best way to learn the long-term effects of the vaccine may be to follow the volunteers in a blinded manner. Still, Johnston adds, "we don't know if and how people's behaviors will change when they learn whether they got the vaccine or placebo. [There are] an infinite number of hypotheticals here." Safety of the volunteers is another concern. "If there's any reason to believe the safety of participants will be better after unblinding, then we have to unblind," says Mitchell Warren of the AIDS Vaccine Advocacy Coalition (AVAC).

But the STEP trial volunteers can always ask to be unblinded, and at some sites, that's already happening. Theresa Wagner, principal investigator at the HVTN site in San Francisco, says volunteers are now asking to be unblinded, as well as to know their Ad5 antibody titers. She expects most volunteers at her site will eventually choose to be unblinded. Peter Gilbert of the Statistical Center for HIV/AIDS Research and Prevention (SCHARP) in Seattle calculated that if at least 40% of all the STEP trial volunteers remain blinded, the statistical power of the trial will still be intact.

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*Andreas von Bubnoff, PhD, is senior science writer of IAVI Report.
Kristen Jill Kresge contributed reporting to this article.