Charting Vaccines

In an Era Tempered by an Optimistic but Realistic Research Community,
Larry Buhl Checks In on the State of HIV Vaccine Development

Soon after Dr. Robert Gallo announced the isolation of the virus that causes AIDS, Health and Human Services Secretary Margaret Heckler made the bold promise that there would be an AIDS vaccine ready for testing in two years. That was 1984.

On May 18, 1997, President Clinton called for a commitment to develop an AIDS vaccine within ten years; that date later became HIV Vaccine Awareness Day. Researchers admit that Clinton’s ten-year goal won’t be met and are making sure everyone knows that a vaccine is not around the corner. Still, there is guarded optimism.

Researchers have not given up on finding the holy grail—a vaccine that will prevent HIV infection in the uninfected—but they are broadening their definition of what a successful vaccine might look like.
Even the most optimistic scientists admit that a sense of realism has set in about the timeline for finding an effective vaccine. The difficulty in finding a vaccine, scientists say, lies in the slipperiness of the virus itself.

The protein on the outside of the virus, called the HIV envelope, is larger in diversity than any other virus known. That means researchers have to “teach” a body’s immune system to recognize the common features of a virus that wears many masks.

Furthermore, live attenuated vaccines are believed to be risky for HIV. In those vaccines, a body is given a piece of a virus—a taste of what’s to come—to inform the immune system how to fight the real thing. But HIV attacks the immune system, the very thing a live attenuated vaccine would boost.

“The three biggest obstacles to finding a vaccine are science, science, and science,” Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition (AVAC) tells A&U magazine. “Some sciences and approaches we have now, such as the human genome project and crystallization of the virus, were not there twenty-five years ago, but what we really have now is a sense of the questions we need to answer, if not the answers.”

Preventive and therapeutic vaccine researchers are taking several different approaches, including:

• Component vaccine, which uses structural pieces of HIV, such as the outer surface components or a regulatory protein, produced by genetic engineering.
• Live vector vaccine, which modifies a live bacterium or virus so it cannot cause disease but can transport into the body a gene or genes that makes one or more HIV proteins.
• Vaccine combination, commonly referred to as a prime-boost strategy, in which one vaccine primes the immune system and the other boosts it.
• Peptide vaccine, using chemically synthesized pieces of HIV proteins, or peptides known to stimulate HIV-specific immunity.
• Virus-like particle vaccine, a non-infectious HIV look-alike that has one or more, but not all, HIV proteins.
• DNA vaccine, involving direct injection of genes that code for HIV proteins.
Whole-killed virus vaccine, which uses HIV that has been inactivated by chemicals or irradiation.

Due to safety considerations, whole-killed HIV vaccines are not being tested in humans, nor are live attenuated vaccines. However, according to IAVI, the Live Attenuated Consortium (LAC) is using this type to study successful vaccination strategies against SIV, a virus that causes an AIDS-like disease in some non-human primates.

The unique nature of HIV is leading researchers toward new ways of thinking about how vaccines will work. To that end, researchers are expanding their understanding of a “cure” to include therapeutic as well as preventive vaccines, according to Dr. Howard Grossman, executive director of the American Academy of HIV Medicine.

“Unlike preventive vaccines—the type of vaccine we all know—researchers now see promise in therapeutic vaccines for HIV, where you take people already infected and try to generate an immune response,” Grossman said. “For the millions of people with HIV now, a preventive vaccine is a non-issue anyway.”

Warren uses the term “disease modification” rather than “cure.” “What we think will happen is a vaccine first might delay the degree of severity, or slow the progression of HIV to AIDS, or minimize the infectiousness of one individual to another. In public health terms any of those would be a tremendous benefit.”

Despite the scientific obstacles, progress has been made, although what constitutes progress has been redefined within the scientific community. One of the most positive developments, Warren explains, is the coalescing of the scientific community and its efforts to find a road map to a vaccine.

“For a long time scientists went off on their own, but now you see them working toward a common framework and consensus on what questions should be asked. You see this coalescing in the push to standardize laboratory assays, so that trial X results can easily be compared to trial Y results.”

This cooperation was underscored in 2005 when the NIH chose a group led by Barton Haynes of Duke University to form the Center for HIV/AIDS Vaccine Immunology. Other consortia include the On-line Collaborative Training for AIDS Vaccine Evaluation project to provide worldwide, standardized training on how to conduct trials, and the U.S. Government’s Partnership for AIDS Vaccine Evaluation (PAVE), which has designed a series of trials to be conducted on different sites by the U.S. Department of Defense and the International AIDS Vaccine Initiative (IAVI).

R&D efforts have become more global every year, and more than thirty human trials are underway. Most of these are concerned with finding the “road map,” or a framework for developing a preventive vaccine, rather than testing a vaccine.

One of the largest international trials is using a modified version of the cold virus Adenovirus 5 to spark the immune defense. Conducted by Merck and the NIH, the Adeno5 trial is a “proof-of-concept,” meaning that it will show whether this particular approach could be effective in developing a vaccine.

Dr. Peggy Johnston, director for vaccine research at NIAID’s AIDS division calls Adeno5 a “step trial,” because it could be a step to success. “Human trials for preventive vaccines take many years due to the need to provide constant counseling of uninfected participants,” she says. “Right now our key challenge is finding enough people to participate in these trials.”

Researchers say that even if today’s human trials are successful, there will be many steps to take before preventive or therapeutic vaccines can be developed. The most likely near-term scenario, according to Johnston, is a vaccine that could benefit the already infected. “For infected people we want it to boost the immune response to control the virus so fewer drugs are needed,” Johnston says. “In the uninfected we want it to give the immune system a ‘heads up’ so it can respond to the virus faster. Already we have vaccines that give infected animals a longer, healthier lifespan, and we plan to move those into human testing.”

When a vaccine for HIV does arrive—and researchers still say it will, eventually—it will have to be delivered in the context of a prevention package, not like a single shot in the arm for polio.

“Even after vaccines arrive, we will still have to focus on prevention,” Grossman said. “And in places like Africa and developing countries a vaccine will [initially] be too expensive when it comes, so prevention is all we’ve got.”

For more information on clinical trials of all diseases, including HIV/AIDS, log on to www.clinicaltrials.gov.

Larry Buhl is a freelance writer based in Los Angeles. He has written about politics, technology, healthcare, and culture.

May 2006