AIDS vaccine researchers meeting in Atlanta expressed renewed optimism that they might finally be on the path to creating a product that can prevent the deadly HIV infection.
"A few years ago I wasn't even sure that it was possible," said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases ( NIAID ) . But last year the RV144 trial in Thailand, a trial that many researchers thought was doomed to fail and they tried to stop, showed a surprising 31-percent protection.
Fauci called that an important "proof of concept" of the principle that such a vaccine is possible. "But we still don't know what the correlates of protection are." Correlates are those specific components of the innate and adaptive immune systems that provide that protection.
Colonel Nelson Michael, the U.S. Army researcher who led the Thai study, said collaborators at twenty academic centers are submitting the remaining blood samples from the trial to different analyses, trying to tease out exactly what was going on among those who were protected from infection.
The Army, with the support of NIAID, is planning to begin two mid-sized follow on studies in 2013 in populations with high rates of infection. The study in Thailand will focus on men who have sex with men and female sex workers; the other, in southern Africa, will be among high-risk heterosexual couples.
They hope to use information they gleaned from the initial trial to tweak the components of the vaccine, and perhaps add a second booster shot, to try to generate an improved immune response and level of protection.
Michael is particularly excited about a new combination vaccine that has shown greater protection in a small group of monkeys than has ever been seen before in that animal model.
Neutralizing antibodies
Earlier failures to develop a vaccine that could protect against initial infection led researchers to turn their attention of the T-cell component of the immune system. Several species of monkeys are able to live with the simian version of HIV infection and control the virus quite nicely and live a normal lifespan. The hope was to create a vaccine for humans that might do the same thing.
But the STEP trial of a vaccine made by Merck was stopped in late 2007 when it appeared that the vaccine made people more susceptible to becoming infected with HIV rather than less. It also did not slow disease progression in those who became infected. That put a damper on a T-cell focus on vaccine design.
Then last July, a team at the NIH Vaccine Research Center ( VRC ) announced the discovery of two potent neutralizing antibodies that worked against 91 percent of the different strains of HIV worldwide. Other researchers have since added to that list of antibodies. It had been a dozen years since the last, weaker antibodies had been identified.
John Mascola, one of the team leaders at the VRC, said, "We need to understand not just the final product but how it got there." His work has found that the two antibodies are structurally similar but their amino acid sequences are quite different. It suggests that there may be more than one pathway to the maturation of these neutralizing antibodies.
The developments were made possible by new technologies that allowed researchers to work backwards from potential binding sites on the virus and use reverse engineering to identify the structure of antibodies that could fit into those binding sites, and then isolate the antibodies themselves. These tools have sparked a renaissance of interest in antibody research.
More trials
Lawrence Corey, the University of Washington researcher who heads NIAID's international HIV Vaccine Trials Network, said the field has conducted a major vaccine trial about once every five years. That simply isn't enough; "The pace of conduct is slow by any standard."
He pushed for a modification of the traditional approach that favors large phase 3 trials that lead to approval by regulators such as the FDA. Given that correlates of protection for an HIV vaccine are still unknown, he argued for the use of trials designed to learn things rather than immediately seek regulatory approval.
Corey favors wider use of adaptive trial designs that are smaller, allow for modifications along the way, and are quicker to carry out. He wants to see the research community initiate one to four trials a year for the next four years.
One of his fears is that evolving new ways of preventing HIV infection will have to be incorporated into a trial beginning in about five years, and that will make vaccine studies more difficult and expensive to conduct.
Among those new tools are microbicides, which had its first trial success this summer, and pre-exposure prophylaxis ( PrEP ) , or the use of anti-HIV drugs such as tenofovir and Truvada, to prevent infections.
Either or both will mean that the incidence of new HIV infections will go down, and vaccine trials will have to enroll more participants and run longer in order obtain sufficient new infections to evaluate differences between those who did and did not receive the vaccine. Dr. Fauci said he anticipates that the size and cost of such trials will double.
As an example, the Thai trial initially proposed to enroll 2,000 participants in the study. But that country began a strong prevention program based primarily around condom use, and the incidence of new infections plummeted. The study eventually had to enroll 16,000 participants.
Money
More than a billion dollars a year is being put into HIV-vaccine research worldwide, with NIH and the Bill and Melinda Gates Foundation contributing about 80 percent of that. Fauci said getting other developed countries involved in this research is not as easy as getting their support for treatment.
Brazil, China, India and South Africa are among those nations that recently have stepped up their vaccine research efforts. It is no coincidence that they also are countries with their own large epidemics.
