The path of HIV vaccine research got even rockier on July 17 when the National Institute of Allergy and Infectious Diseases announced that it will not move forward with PAVE 100, the most ambitious trial yet envisioned.
"The vaccine regimen did not warrant a trial of this size and scope ... PAVE 100 will not proceed," NIAID director Anthony Fauci said in a written statement. However, the vaccine candidate is "scientifically intriguing and sufficiently different from previously tested HIV vaccine to consider testing it in smaller, more focused clinical studies."
NIAID "will entertain a proposal for an alternative study with one specific goal: to determine if the vaccine regimen significantly lowers viral load �" the amount of HIV in the blood of vaccinated individuals who may later become infected with HIV," Fauci added.
The last 10 months have been particularly disappointing for HIV vaccine development. The large STEP trial, using a vaccine developed by the pharmaceutical company Merck, was halted last September when it became clear that those receiving the vaccine were becoming infected with HIV at a higher rate than those who received the placebo.
The vaccine used in the PAVE trial has many similarities with the one used in the STEP trial. The PAVE study was supposed to have begun enrolling participants last October but that was put on hold while researchers tried to get a better understanding of what had happened in the STEP trial.
Preliminary analysis suggested that being uncircumcised and having high levels of antibodies from prior exposure to adenovirus 5, a cold virus used to deliver key parts of both vaccines, put trial participants at greater risk for becoming infected with HIV.
As a result, the PAVE trial was scaled back from an ambitious 8,500 participants on three continents to 2,400 circumcised gay men in the United States who screened negative for antibodies to adenovirus 5. At the end of May, NIAID's Vaccine Research Advisory Subcommittee overwhelmingly supported moving forward with the scaled down trial.
But now that trial is canceled.
A leading critic of the vaccines in the STEP and PAVE trials has been Ronald Desrosiers, director of the New England Primate Research Center. In a highlighted speech at the retroviral conference in February he said, "The fundamental question is whether an effective vaccine against HIV-1 is feasible at the current time."
Desrosiers said it was not. "We don't know how to elicit antibodies with broadly neutralizing activity. We don't know how to deal with the enormous sequence diversity present in the virus. And we don't know what constitutes immune protection," he said.
After the failure of STEP and through a series of meetings over the ensuing months, a consensus has emerged among researchers that HIV vaccine research must take a step back from trying to develop a product and put more effort into basic research to answer those questions. Fauci has since reprogrammed some of the agency's resources to accomplish that.
Reactions to cancellation of the PAVE trial generally have been positive and muted.
Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition, said, "After nearly a year of public hand-wringing and unproductive public attacks on the entire search for an AIDS vaccine, it is essential that this decision not be viewed as a vote of no confidence for the overall endeavor."
Dr. Seth Berkley, president of the International AIDS Vaccine Initiative, said, "The decision does not reflect paralysis in the AIDS vaccine field, or lack of direction forward. In fact, it reflects the opposite �" the dynamic learning that is the scientific process, that is pharmaceutical product development. The decision reflects leadership on the part of NIAID."