‘A LONG WAY TO GO’ IN VACCINE WORK

Merck’s announcement in October that its investigational HIV vaccine, the furthest along in clinical trials, appeared to actually increase risk for infection was yet another blow to the two-decade-long search for an AIDS vaccine. NIAID Director Anthony Fauci said that until key questions are answered, NIAID’s own vaccine trial, PAVE-100, has been put on hold.

Like nearly every vaccine currently being investigated in clinical trials, PAVE-100 is a T-cell vaccine. Though each vaccine is unique, all are based on the general premise that protecting these critical immune cells, a subgroup of which HIV targets first, could halt the virus’s eventual stranglehold on the immune system. The Merck vaccine’s “rather abrupt failure,” as Fauci called it, may challenge that premise, although it is not yet clear why the vaccine failed.

The cold virus that was used as a vector to deliver the HIV DNA into the bodies of study participants is a primary culprit at the moment, because volunteers who had higher “baseline” immunity to the cold virus at the beginning of the study had a higher HIV infection rate. Fauci’s lab is among those looking into this link. But this association may merely be a marker for some other demographic or socioeconomic factor, rather than a “true biological effect,” he said.

While the cold-virus connection gets sorted out, Fauci and other AIDS vaccine experts are re-emphasizing the need to think beyond T cells. “Although a lot of the effort and activity has been directed toward the T-cell vaccine—and we are still presuming this [to be a target]—it is clear that we will have to somehow get a neutralizing antibody effect from the vaccine,” he said, referring to the goal of broadly activating immune proteins to recognize the offending virus and attack it. This fundamental immune defense system fails in HIV infection.

“Right now, none of the vaccines that are in clinical trials are specifically directed toward inducing neutralizing antibodies,” he said. “The bottom line is, we have a long way to go.”
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Rethinking AIDS Prevention

A conversation with Anthony Fauci of the National Institutes of Health
By Brenda Patoine
 December 17, 2007

As science takes stock of what went wrong with the most promising HIV vaccine in clinical development (see sidebar), researchers are realizing that “we may have to settle for a less-than-perfect vaccine,” in the words of the nation’s top AIDS expert, and refocus attention on efforts to prevent AIDS, not treat it.

Head shot of Anthony Fauci - NIAID - Thumbnail 

Anthony FauciCourtesy: NIAID

“There is not going to be one single preventive measure that is going to be the home run in HIV,” Anthony Fauci, the director of the National Institute for Allergy and Infectious Disease (NIAID), said in an interview on Nov. 28. “Even when we get a vaccine, it’s clear that you will still have to practice other preventive measures, because it is not projected at all that a vaccine would be 100 percent effective.”

Any vaccine will be part of a “prevention toolbox” tailored to each high-risk group, he said. It would include already proven but poorly adopted measures such as using condoms, supplying clean needles for intravenous drug users and modifying high-risk behaviors.

Such measures are notoriously underused by people most at risk. In a symposium at the annual meeting of the American Neurological Association in October, Fauci showed United Nations data that document dismal rates of accessibility to preventive services. Worldwide, less than 20 percent of people who are at risk for HIV have access to basic prevention services, and accessibility is less than 10 percent for many high-risk groups.

“Already, we’re missing 80 to 90 percent of the people at greatest risk,” Fauci said. Robust, effective preventive strategies could avert half of the 60 million new HIV infections that are projected by 2015, Fauci said—but only with big improvements in access, education and adoption of preventive measures.

 “We have not fully pulled out all the stops in trying to make these preventive measures accessible to the people who can benefit from them. We need to put more resources into it, nationally and internationally, and we just have to keep hammering away at it.”

New Avenues to Prevention

Science has also opened new avenues for stopping HIV in its tracks by teasing apart the molecular mechanisms by which the virus replicates and inundates the immune system. For example, there is a small “window of vulnerability,” Fauci says, after HIV transmission but before the virus has spread fully in the body. This may represent the one real chance to hit the virus with early interventions that might blunt the critical first events in HIV replication and prevent its spiraling course.

Preventive use of antiretroviral drugs, the drugs currently used to treat HIV/AIDS, is one strategy that might nip HIV in the bud. It is clear from studies of healthcare workers who have been exposed to HIV through needle sticks on the job that HIV risk is dramatically decreased if they take AIDS drugs prophylactically. Two studies are now under way to examine if treating HIV with antiretroviral drugs before infection decreases infection risk.

Circumcision is another example where recent findings can be applied to prevention, potentially on a large scale. “We now know clearly from studies in Africa that if you have adult, medically supervised circumcision you can decrease the acquisition of HIV infection upon exposure to an infected partner by a minimum of 53 percent, and possibly as much as 65 percent,” Fauci said.

In the future, topical treatments that serve as a physical barrier to HIV infection or otherwise inhibit or neutralize the virus will be available. More than a dozen such therapies are currently in clinical development, including several in late-stage clinical trials. Such treatments would be particularly important to women, who otherwise must depend on male-controlled methods of protection, such as condoms, Fauci said.

Increasing circumcision rates among men and making topical preventions available to women face formidable cultural barriers in countries where such practices run against traditional practices and customs. Overcoming these kinds of hurdles will take bold leadership from the moral, political and community leaders at the local level, Fauci said.