IAVI REPORT 11(4)
DSMB STEPs in
On September 21, Merck and the National Institute of Allergy and Infectious Diseases (NIAID) announced that a Phase IIb clinical trial of MRKAd5, an adenovirus serotype 5 (Ad5)-based AIDS vaccine candidate developed by the company to induce cellular immune responses against HIV, failed to show any effect. Immunizations in the so-called STEP trial were discontinued because the vaccine did not lower the infection rates or the viral loads in the vaccine group compared with the placebo group. Immunizations in another trial, known as Phambili, which was testing the same vaccine in South Africa, were also suspended.
The STEP trial—also known as HVTN 502 and Merck V520-023—was co-sponsored by Merck and NIAID, a division of the US National Institutes of Health (NIH). It was the first Phase IIb test-of-concept trial for a candidate that primarily induces cell-mediated immunity (CMI) and it involved 3000 healthy volunteers at high risk of HIV infection at sites in North and South America, the Caribbean, and Australia. All volunteers were scheduled to receive three shots of placebo or vaccine, which contains a mix of Ad5 vectors carrying one of three different HIV genes, gag, pol, or nef. The inserts were from HIV clade B, matching the predominantly circulating clade in the areas where the trial took place. At the time vaccinations were stopped only about a dozen of the 3000 volunteers had not received all of their shots, says Susan Buchbinder of the University of California in San Francisco and principal investigator of the trial.
The trial started enrollment in December 2004 and vaccinations were stopped prematurely after the data safety monitoring board (DSMB) carried out its first scheduled interim analysis in half of the 3000 trial volunteers with low pre-existing antibody immunity to Ad5. It found that the vaccine was unlikely to show any effect. Merck and NIAID researchers will now carefully analyze the trial data and make them publicly available as soon as possible. They will also continue to follow the volunteers in an attempt to gain insight into how the vaccine failed to show an effect, which might aid future vaccine design. Buchbinder says that the exact length of the follow-up is still to be determined.
Due to their low levels of pre-existing immunity to Ad5, the approximately 1500 volunteers included in the DSMB's interim analysis had been expected to have the best response to the vaccine. "The infection rates were essentially identical in all the participants who had become infected in this first half of the study," Buchbinder says, adding that the viral loads were virtually identical in the vaccine and placebo groups as well. "The two groups looked so similar that it was unlikely that we were going to see a beneficial effect."
The interim analysis looked at two overlapping groups. One included volunteers who had received at least one shot of the vaccine or placebo; volunteers who didn't adhere to the protocol; and volunteers who became infected by week 12, possibly too soon for the vaccine to have had any effect, according to Merck. In this group there were HIV infections in 24 of 741 vaccinees, compared with 21 of the 762 placebo recipients. The second group, a subset of the first, included volunteers who had received at least two shots but did not contain volunteers who didn't adhere to the protocol or those with early infections. In this group there were 19 HIV infections in the 672 volunteers who had received vaccine, compared with 11 HIV infections in the 691 volunteers who had received placebo. These differences between the vaccine and placebo groups were not statistically significant, the trial investigators say. "The data shows a trend, but these things often turn out to be noise," says Tony Fauci, director of NIAID.
The DSMB for the Phambili trial in South Africa has not yet decided if vaccinations and enrollment in this other trial with MRKAd5 will continue. At the time both were suspended 800 of the intended 3000 volunteers were already recruited. Glenda Gray of the Perinatal HIV Research Unit in Soweto and principle investigator of the study says there was a lot of national pride in this trial and "people are very keen to understand why this vaccine didn't work."