AIDS vaccine efforts move forward, but full prevention is elusive goal

Experts talk about what is possible soon

As HIV prevention strategies plod ahead and often falter, scientists and the international medical community continue to hold out hope that there will one day be a vaccine available to prevent HIV infection.

But how close are we to realizing that dream?

Not near enough, according to HIV vaccine experts and recent reports on the status of the vaccine pipeline.

The mood among HIV vaccine scientists is that developing a vaccine to prevent HIV infection remains a tough problem, says Pat Fast, MD, PhD, executive director of medical affairs for the International AIDS Vaccine Initiative (IAVI) of New York, NY.

"On the clinical side, we're making progress in that we have vaccines with good immune responses," Fast says. "In a few years, we'll know if that's enough to achieve this limited goal of trying to achieve HIV replication suppression."

Also, there's some optimism over ongoing basic science studies involving work with antibodies, but a true preventive vaccine remains elusive, she adds.

"People are guardedly optimistic, but that will take longer," Fast says.

It might be 2011 before an answer is available for the current antibody vaccine work, she adds.

The recent AIDS Vaccine 2007 conference, held in Seattle, WA, Aug. 20-23, 2007, brought together various HIV vaccine organizations under the umbrella of the Global HIV Vaccine Enterprise, says Barton F. Haynes, MD, director of the Duke Human Vaccine Institute at Duke University Medical Center in Durham, NC. Haynes spoke at the conference about the challenges of finding a path to development of an HIV vaccine.

The Global HIV Vaccine Enterprise is an alliance of various global organizations that are working to develop a preventive HIV vaccine. The Enterprise's goals include sharing scientific plans, mobilizing new funding sources, and encouraging greater collaboration to promote more efficient research and faster outcomes.

"Some of the best minds in vaccine research are now working together in a collaborative way in order to increase the chance of developing an efficacious vaccine as soon as possible," says Ruth Macklin, PhD, professor of bioethics in the department of epidemiology and population medicine at the Albert Einstein College of Medicine in the Bronx, NY. Macklin also is on the World Health Organization's HIV Vaccine Advisory Committee.

"The Global HIV Vaccine Enterprise is a world-wide effort working toward that end," Macklin says.

Vaccine efforts remain strong and experts believe a preventive vaccine is the only real hope of mitigating or even ending the HIV pandemic, Macklin notes.

There was a lot of discussion at the conference about why it's so difficult to induce broadly reactive neutralizing antibodies, Haynes says.

"If we had a vaccine that could induce broadly reactive neutralizing antibodies then that would give us a chance at having a preventive vaccine that either prevents infection or extinguishes infection in the early stages," Haynes says.

HIV vaccine experts say a successful vaccine will need to do two things: First it will have to induce broadly-neutralizing antibodies, which will block HIV from infecting cells, and then it will have to have a cell-mediated immune response, which would destroy infected cells and close the viral factories.

The VAXGEN 120 trials that were unsuccessful taught the field a lesson about what would not work in an HIV vaccine, Haynes says.

"I believe the field will be successful in making a vaccine that will ultimately control the virus, but it remains to be seen if we can solve the neutralizing antibody issue," says Haynes, who has been working on an HIV vaccine since 1985.

"This vaccine is an extremely difficult vaccine to make because of the nature of the virus," Haynes says. "What is being asked of this vaccine is different from other vaccines."

Other vaccines produce an antibody that produces the effects of the organism's disease, but HIV is an extremely fast mutating virus that inserts itself into the host's genetic material, Haynes explains.

"Once it gets in, thus far it has been impossible to eradicate by the person's own immune system and drugs," Haynes says.

The same immune cells that human bodies use to fight off viruses are what HIV uses to infect the body, he says.

"It's a triple whammy that we haven't been able to overcome yet," Haynes says. "The hope of this Enterprise is that by bringing together different components of the vaccine field it will speed up the process."

What looks promising so far is using a vaccine to slow HIV disease progression.

"There is now quite a bit of work going on with clinical trials," Fast says.

Trials in Thailand, the United States, South Africa, and elsewhere are focusing on the principle of inducing an immune response that would prevent virus replication, Fast explains.

"So they might not stop the first few cells in the body from being infected, and they may not block the establishment of infection, but the vaccine might make it very difficult for HIV to replicate," Fast says. "It could allow HIV to be under tight control for many years, turning the average person into a long-term nonprogressor."

While that's not the ultimate desired destination for an AIDS vaccine, everyone feels it's a big step forward, Fast says.

"All of these vaccines are trying to utilize t-cell immunization to achieve that end," Fast says.

For example, one study involves a pox virus-based vaccine that is combined with GP120 as a booster, and it's designed to fight HIV in Thailand, Fast says.

"That trial is ongoing right now," she says. "It was reviewed by the data safety monitoring board (DSMB) this year, and the trial will continue for another year or so."

Another trial involves an adenovirus, the Trivalent Ad5 Vaccine from Merck, which has shown some success in phase 1 trials. (See chart of phase I trials involving HIV vaccines.)

One of the challenges HIV vaccine researchers face is building health research infrastructure from scratch in the areas hardest hit by the pandemic, Fast says.

The International AIDS Vaccine Initiative, which was founded 11 years ago to focus on developing a vaccine that would work for people in the less developed countries, including India, and sub-Saharan African nations, has initiated some creative enterprises to build new infrastructure.

"We've been trying to set up not just vaccine trials, but capability in those countries for trials to go on," Fast explains. "So we've built or renovated space, put in standardized equipment, trained people in good clinical practice (GCP), set up laboratories, clinical labs, and immunology labs."

IAVI's goal has been to establish the foundations and standards that would be expected in the United States, she notes.

"We have a team called the Good Clinical Laboratory Practices team, and all of the sites have become accredited, including two in Kenya, two in Uganda, and one in Zambia," Fast says. "Our focus has been on setting up sites in places where there's not that much medical infrastructure."

For instance, IAVI conducted a study that enrolled 2,400 people for the purpose of finding out what was normal in terms of lab values in Africa, Fast says.

"If you apply the kind of standard test you'd find in a clinical lab in Manhattan, there would be certain lab standards, and they'd be similar to each other based on what they'd find in healthy people in their environment," she explains. "We wanted to find out more about healthy people in the African environment."

So each person enrolled in the study was given a physical exam, an HIV test, a hepatitis test, and women were tested for pregnancy, she says.

"We looked at the lab values for hemoglobin and white blood count, kidney function, bilirubin, and we tried to establish normal values," Fast says.

The Centers for Disease Control and Prevention (CDC) of Atlanta, GA, and the U.S. military reached the same conclusion that new lab values needed to be established for these non-western areas, and so the three groups set up a satellite meeting to discuss the project, Fast says.

What they found is that the normal lab values in parts of Africa look different from the normal lab values in the United States, she says.

For example, the hemoglobin values are higher, as are the bilirubin values, and the white blood cell counts are lower, she says.

These differences could be related to the infection burden many Africans carry because of malaria infection, or they could be genetic differences, Fast says.

If this groundwork had not been done, then clinical trial investigators and sponsors might have miscalculated in setting exclusion/inclusion criteria for vaccine trials, leading to people being excluded from trials when they're lab values are normal for their region of the world, she explains.

"We hope this will lead to a more realistic set of values about who can be included in a clinical trial," Fast adds.