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With HIV devastating parts of the developing world and continuing to gain hold in countries that once had a negligible HIV rate, researchers and governments around the world continue to hold out hope for a successful HIV vaccine that will signal the beginning of the end of the two-decade-old epidemic. However, the vaccine answer to AIDS has been as elusive as the Holy Grail, despite years of investigation and work that has taken many different approaches.
The good news is that there are 25 promising vaccine candidates that could enter Phase I human trials within the next six years, says Kay Marshall, director of communications for the International AIDS Vaccine Initiative (IAVI), a global, nonprofit organization founded in 1996 to bring leadership to the search for an AIDS vaccine. "We believe it is possible to have an AIDS vaccine of at least limited efficacy sometime in the next decade, if the world accelerates its vaccine development effort," Marshall says.
IAVI’s cornerstone program is its Vaccine Development Partnerships (VDPs), which are designed to move promising experimental vaccines into clinical trials as quickly as possible, Marshall says. "VDPs link researchers from academia or biotechnology companies with vaccine manufacturers and with clinical researchers in developing countries," Marshall says. "For each partnership, the candidate vaccine is tailored to match the predominant HIV strain in the VDPs’ developing country."
Four of the five VDPs are in Africa, and one is in India, although more are planned, including a VDP for China, Marshall adds. Two IAVI-sponsored vaccines based on the common HIV strain in East Africa, subtype A, have entered Phase I human safety trials, Marshall says. One of the first subtype A vaccines was tested on volunteers in Kenya and the United Kingdom.
IAVI makes financial contributions to each VDP and provides technical and management support. The organization also funds infrastructure improvements in developing countries, such as contributing to the University of Nairobi’s state-of-the-art laboratory for vaccine trials in Kenya, Marshall says. In exchange, IAVI secures unique intellectual property agreements from all parties. This way, if the vaccines prove effective, they will be made available to developing countries at a reasonable price, Marshall explains. "Meanwhile, developers are free to sell the vaccines sold in industrialized nations at the market price," Marshall adds.
The IAVI has filled a vacuum left by big pharmaceutical firms that, until this year, have largely stayed away from AIDS vaccine research, says Jon Cohen, correspondent with Science magazine and author of the new book Shots in the Dark: The Wayward Search for an AIDS Vaccine. (See "AIDS vaccine efforts have followed long, bumpy road," in this issue, which features Cohen’s discussion of the HIV vaccine research.)
"There are indications that a few big pharmaceutical companies are very serious about making an AIDS vaccine," Cohen says. "But a lot of time has been wasted, and I think that scientists and companies both have ducked behind the argument that the science was too complicated and that industry only gets involved once they know enough to do something."
Cohen calls the early AIDS vaccine efforts a market failure because IAVI and governments in North America and Europe have had to form consortiums and create industry rather than the usual scenario of industry creating a product to fill a need. The opposite occurred with HIV antiretroviral drug development, in which industry leaped to the rescue and created a wide variety of treatment options. Activists helped push the drugs to market more quickly by lobbying government and industry, Cohen says.
No such collaboration was seen between industry, government, activists, and researchers in the early years of HIV vaccine search, he explains. "It’s been a real cultural wake-up call to the scientific community about the limits of governments only funding basic research when industry doesn’t have the incentive to bring that fruit to market," Cohen says.
One of the more positive HIV vaccine announcements in recent months was the pledge of $100 million made by the Melinda and Bill Gates Foundation of Seattle to IAVI for vaccine research over the next five years. Philanthropic money has fewer constraints and therefore can be used for bolder research initiatives than government money, which is why the Gates Foundation donation is particularly helpful, Cohen says. Meanwhile, some important ethical considerations still need to be fully addressed by the scientific community, industry, governments, and the public, Cohen says. "I think that ethical dilemmas are going to complicate vaccine trials, and they are complicating them right now," Cohen says. "One of the issues is risk vs. benefit."
In communities where people have a higher risk of becoming infected, such as areas of South Africa, uninfected people have a greater incentive to try an experimental vaccine because they have more to gain from a successful vaccine. So they may be more willing to try vaccines that have both a greater risk of harm and a greater potential for protection than a person from an industrialized country, he points out.
Does this mean investigators should offer riskier vaccines to people in these high-HIV-risk populations? "Right now, I don’t think there is much thinking going on about the amount of risk the hardest-hit communities are willing to take," Cohen says. "It’s a tough, very tough question."
The other ethical issue involves whether HIV antiretroviral drugs should be offered to vaccine trial participants in developing nations, where such drugs are cost-prohibitive to most people. "There’s been a raging debate about whether people who sponsor vaccine trials should offer drugs to anyone who becomes infected during the trial, not because the vaccine infected them, but because the vaccine didn’t protect them," Cohen says. "That’s a real thorny issue if you want to evaluate whether a vaccine prevents or delays disease, because people who take the drugs are going to cloud the question."
Also, if a vaccine trial offered free HIV drugs to anyone who becomes infected, would that constitute undue influence on the individual participant’s decision of whether to volunteer for the trial? These are the kinds of issues an international group representing all interested parties needs to address, Cohen says.
IAVI’s position is that these difficult decisions are up to the countries themselves, Marshall says. "It must be up to the country in which a trial is conducted to decide whether it is ethical," Marshall says. "It must be up to the country to determine if, when, and to what extent those who become naturally infected during a trial are offered antiretroviral therapy."
The broader ethical consideration is how long can the world wait for an effective vaccine when there are 15,000 new HIV infections each day, Marshall adds. "The world cannot afford to wait until candidate vaccines are far along in development before key questions of safety and efficacy are identified and agreed on internationally," Marshall says. "As vaccine candidates proceed along the development continuum, companies will need to devise studies that are calculated to answer all relevant questions."
It’s important to remember that the best vaccine goal is not necessarily to find the most effective and safest vaccine before making it available to the public. The first polio vaccine was only 60% effective and it was used by 70% of the population, but it brought down the polio infection rate by 96% between 1955 and 1961, Cohen says. "There was a calculation done with HIV that said if you had a 60% effective vaccine today, then 10 years from now you would have prevented more infection than if you had a 90% effective vaccine introduced five years later," Cohen says.
IAVI is funding multiple vaccine efforts in hopes that one of these will prove efficacious within the next 10 years. While the first vaccine to make it to market probably won’t provide 100% protection, it could save lives while other vaccines are being prepared, Marshall says.
"And multiple vaccines may be needed for worldwide coverage, both because of different HIV strains and regional variation in immune systems," Marshall adds. "So while the first vaccine is within a decade’s reach, sadly the end of the epidemic is not."