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What immediate implications does the cessation of immunizations in the STEP trial have for the AIDS vaccine field?

Merck and the US National Institute of Allergy and Infectious Diseases (NIAID) recently announced that a Phase IIb clinical trial of MRKAd5, an adenovirus serotype 5 (Ad5)-based AIDS vaccine candidate developed by the company, was not effective. The vaccine candidate did not lower HIV infection rates in individuals who received the vaccine compared to those who received an inactive placebo, nor did it successfully reduce the amount of virus in the blood of those who became HIV infected through exposure to the virus, despite vaccination.

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, rather than neutralizing antibodies which is how most licensed vaccines work. Phase IIb trials are smaller than traditional Phase III efficacy trials but still allow researchers to collect information about whether or not the vaccine is effective (see VAX September 2005 Primer on Understanding Test-of-Concept Trials).

The STEP trial involved 3000 healthy volunteers at high risk of HIV infection at sites in North and South America, the Caribbean, and Australia. Each volunteer received three shots of either placebo or the vaccine candidate, which uses a virus—in this case one that in its natural form causes the common cold—as a vector to carry three different fragments of HIV. The vaccine candidate can not cause HIV infection because it only contains some components of HIV. These fragments, known as immunogens, are shuttled into human cells by the viral vector and are then presented to the immune system. This triggers an immune response against HIV that then enables the immune system to recognize and attack HIV in the future.

The STEP trial started enrolling volunteers in December 2004 and was scheduled to end late next year, but was stopped early when the data safety monitoring board (DSMB), an independent group assigned to review clinical trials while in progress, performed a scheduled analysis of the data in half of the volunteers (see VAX June 2007 Primer onUnderstanding Data Safety Monitoring Boards). The DSMB concluded that based on the data collected so far, it was unlikely the vaccine would show any effect if the trial continued.

The interim analysis by the DSMB showed that in a subset of volunteers who received one injection of either placebo or the vaccine candidate, there were 24 new HIV infections amongst the 741 volunteers who received the vaccine, compared with 21 infections in the 762 volunteers who received placebo. Another analysis of people who had two injections showed that there were 19 new HIV infections out of the 672 volunteers given the vaccine, and 11 new infections in 691 volunteers given placebo. The differences between the vaccine and placebo groups were not statistically significant, the trial investigators say, which means that the difference in the number of infections was due merely to chance. There was also no significant difference between the amount of virus in the blood of individuals who received vaccine or placebo.

Based on this information, Merck and NIAID decided to discontinue further immunizations. At the time the trial was ended, all but about a dozen of the 3000 volunteers had received all three vaccinations. Another trial testing the same Ad5-based vaccine in South Africa, called the Phambili trial or HVTN 503, was suspended at the same time by that trial's DSMB. Even though the injections in the STEP study were discontinued researchers are still continuing to follow the trial volunteers in an attempt to gather clues about how the vaccine failed. This information could be incredibly valuable to researchers whose efforts are focused on improving future vaccine candidates.

Other trials

Following the news about the STEP trial, NIAID quickly announced that it would delay the start of its 8500-person Phase IIb test-of-concept trial, known as PAVE 100, which was scheduled to start in October. This trial tests a combination of two different vaccine candidates, a DNA and an Ad5 vector-based candidate, administered sequentially in what is known as a prime-boost combination. Both of these candidates were developed at the Vaccine Research Center (VRC), which is part of NIAID.

IAVI also delayed the start of its Phase II trial, known as V002, in Rwanda, Kenya, Uganda, and Zambia with these same candidates, which was scheduled to begin enrolling volunteers just three days after the announcement from Merck.

Although these trials also involve candidates that use an Ad5 vector, "there are substantial differences," says Gary Nabel, director of the VRC. He says the VRC's strategy of using two different candidates in combination induces different types of immune responses. The candidates also contain different HIV immunogens.

The population of volunteers that are involved in the STEP study and the proposed PAVE 100 trial are also different. The STEP study volunteers were primarily men who have sex with men (MSM). In the South Africa Phambili trial, NIAID was testing MRKAd5 in a population where HIV is mainly transmitted through heterosexual sex. In this study over half of the volunteers recruited so far are women, compared to one third of the volunteers in the STEP trial. Researchers think that the route of infection—whether the virus is transmitted vaginally or rectally—may partly determine whether or not the immune responses induced by a vaccine candidate are capable of protecting against HIV infection (see VAX October 2003 Primer on Understanding Routes of Transmission). Like the Phambili study, the PAVE 100 trial will also involve a large number of women who are at risk of HIV infection through heterosexual sex.

New start dates for the PAVE 100 or V002 trials have not been decided yet, but Nabel says he is hopeful PAVE 100 will begin by early next year.

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All articles written by Kristen Jill Kresge