Eureka! Success of combo HIV vaccine raises hopes, should revitalize research
Eureka! Success of combo HIV vaccine raises hopes, should revitalize research
An HIV vaccine shows surprising efficacy in human trials
When news erupted in late September that a combination of two previously-failed HIV vaccines — the Sanofi Pasteur's Alvac and Global Solutions for Infectious Diseases' AIDSVAX — was successful with 31.2% of people vaccinated in a phase III Thailand clinical trial, a great deal changed for the HIV vaccine research world.
"It came as a big surprise to everyone," says Phillip Berman, PhD, chair of the department of biomolecular engineering in the school of engineering at the University of California - Santa Cruz. Berman also is the Jack Baskin professor of biomolecular engineering, and he was a cofounder of VaxGen, the company which carried out the first large-scale, phase III clinical trial of AIDSVAX.
"It's very exciting news," says Pat Fast, MD, chief medical officer for the International AIDS Vaccine Initiative in New York, NY.
"This isn't the final answer, but we think it's going to give us some really important clues about how to proceed," Fast says. "It's very hard to solve a problem when you don't know which direction to go in."
Both government and corporate sponsors had given up on AIDSVAX after its failed phase III trial results were published in 2003, says Don Francis, MD, DSc, executive director of Global Solutions for Infectious Diseases of South San Francisco, CA.
"So we started a nonprofit, and the Gates Foundation funded us," Francis says.
The nonprofit organization which inherited AIDSVAX has pursued various new vaccines, but had not changed or worked on AIDSVAX in the past six years.
"It was the same vaccine getting older and older in the bottle," Francis says.
Although the results suggested that AIDSVAX might work with an African American population in the earlier trials, there was no interest among funders to pursue that lead, Francis says.
The data were not strong enough so most observers did not think this was a real effect, Fast says.
The Thai trial was a landmark event in the 26-year battle against HIV, says Alan Bernstein, OC, PhD, executive director of the Global HIV Vaccine Enterprise in New York, NY.
"It's cause for modest optimism and some delight," Bernstein says. "This is the very first time that a vaccine against HIV has shown any efficacy in human trials."
The vaccine trials did not show any benefit in lowering viral load among trial participants who had received vaccination and still became infected with HIV.
Global cooperation
Skeptics have doubted scientists would find a vaccine that is effective in preventing HIV infection because it's a difficult virus to deal with, Bernstein says.
"My attitude as a scientist is this is a tough problem, and because of that we need to attract the very best scientists to this problem, and we need to cooperate on a global scale," he says. "This is all about global cooperation, and the Thai trial was a perfect example of global cooperation."
The Thai trial had 16,000 volunteers in Thailand. It was conducted as a collaboration of the Thai Ministry of Public Health and the U.S. Army.
"It took heroic efforts to get so many people to volunteer for a trial and to have the kinds of retention rates they did for three years," Bernstein says. "No one scientific team or country could solve this problem."
Experts in the HIV vaccine world hope the positive Thai trial results will help researchers understand what the problem has been with previous vaccines, as well as which problems with the successful agents could be improved, Fast says.
"This is probably the most important clue we have right now," Fast says.
The key is to build a better HIV vaccine step by step, she notes.
"There are a couple of potential ways we might need to improve the vaccine," Fast says. "One would be to make vaccines stronger, and another would be to make them broader."
Since there's considerable variability in HIV viruses, it's possible an HIV vaccine might protect against only a small fraction of viruses circulating in a population, Fast explains.
"If that's true, then we'll focus our efforts on making vaccines broader so that a person in the highest risk situation who might be exposed to lots of viruses would be protected," she says.
"We still need to learn more about what the risks were in this Thai population," Fast says. "It was a general population, and if they came in and said they wanted to be in the trial, they were in the trial."
One of the more enlightening analyses would be a description of who became infected and who didn't, she adds.
The Thai trial volunteers were given four vaccine injections over 24 weeks, Francis says.
The first injection and the second at four weeks were with Alvac-HIV. Then at 12 weeks and at 24 weeks, they received a combination of the two vaccines, he adds.
Trial volunteers were followed for three years after their last vaccine dose, and the results were based on three years post-vaccination.
"We were fascinated that the protection was most profound after the first year," Francis says. "It started waning after the first year, which had a 50% protection."
A vaccine booster shot?
This might suggest any HIV vaccine would require booster shots, he adds.
"The concept here was you want cell immunity to be stimulated by this prime, nonreplicating virus that stimulates cytotoxic T lymphocytes, providing cell-mediated immunity," Francis explains. "Our vaccine stimulated antibody cells."
Researchers hoped the combination of vaccines would provide both protection from infection and also would abort infection in those who did seroconvert, he adds.
"Interestingly, all the protection looks like it was antibody protection because once people got infected they looked like everyone else who got infected and there was no aborting of the infection," Francis says.
This is what has made HIV infection extremely rare. While viruses like the polio virus cause disease in only one out of 100 or 200 people, the HIV virus appears to cause disease and kill 99% of people who become infected and are not treated with antiretrovirals, he adds.
The next step will be to begin manufacturing more AIDSVAX for additional clinical trials, Francis says.
"Hopefully, as we analyze the response it will give us a roadmap of how to make it better," he says.
There are several alternative explanations for why the vaccine in the Thai trial worked at least in nearly one-third of participants, while the earlier clinical trial of VAXGEN showed no protection against HIV infection in general populations, Berman says.
"A first theory is that it's necessary for the vaccine to stimulate both cellular and antibody-mediated responses," Berman says. "So the French vaccine (Alvac) stimulated cellular response, and VAXGEN stimulated antibody response."
Another possibility is that the Thai trial's cohort was a much lower-risk cohort than either cohort in which VAXGEN was tested, Berman says.
"If VAXGEN was partially effective, we'd never see it in our results because our cohort was so high risk," he adds.
And a third possibility is that the Thai trial looked primarily at heterosexual transmission, and based on animal models and epidemiological data, it's easier to protect from heterosexual transmission than from intravenous drug use or male homosexual transmission, Berman says.
"I'd like to see a lot more clinical trials to try to understand the results," Berman says. "I think there's a tendency to get bogged down in laboratory assays, doing more and more lab assays, and what we need is more clinical data and clinical results to analyze."
Researchers have many ideas for ways to improve both components of the vaccine, he adds.
"I'd like to see those move into a clinical trial as quickly as possible," Berman says. "And I think the private industry is going to have to be involved to manufacture the different components and test them in a way that accelerates drug approval, which is very expensive and probably beyond the resources that any one organization can provide."
When news erupted in late September that a combination of two previously-failed HIV vaccines the Sanofi Pasteur's Alvac and Global Solutions for Infectious Diseases' AIDSVAX was successful with 31.2% of people vaccinated in a phase III Thailand clinical trial, a great deal changed for the HIV vaccine research world.Subscribe Now for Access
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