Stalled vaccine effort gets new boost in U.S.

Top vaccine expert cites lack of scientific knowledge as hurdle

While President Clinton has pledged support for development of an HIV vaccine within 10 years, AIDS experts who gathered in Boston last month criticized the United States for not making vaccine development a higher priority, and the man in charge of the U.S. AIDS vaccine effort says Clinton’s timetable seems optimistic.

"We are currently paralyzed in the global effort to develop an AIDS vaccine by the perception of pessimism, if not defeatism," said Jonathan Mann, MD, MPH, director of the International AIDS Center at Harvard University AIDS Center and author of AIDS Around the World. Mann spoke at a conference on modern plagues, sponsored by Massachusetts General Hospital in Boston and the Cambridge, MA-based Whitehead Institute, a leading biomedical research organization. "If the same standards and criteria had been applied to drug development for AIDS that are currently being applied to vaccine development, none of the drugs currently available to treat HIV would be around."

Mann blamed the lack of a concerted AIDS vaccine effort on complacency, driven in part by successes for new HIV drugs, and a belief among the public and many health officials that the epidemic, at least in the United States, will be eradicated without a vaccine. Mann also pointed out that the majority of the 50,000 or more people who will be infected in the United States this year are disenfranchised and voiceless. In contrast, a vaccine for Lyme disease, which afflicts a much smaller but more affluent population, has progressed from Phase I to Phase II and III trials in only a few years, he added.

"While we applaud President Clinton’s recent call for AIDS vaccine development and the appointment of David Baltimore as AIDS vaccine research committee chair at the National Institutes of Health, we must have international collaborative vaccine field trials. They are the critical, urgent next step around which there are no insurmountable ethical and human rights issues," said Mann.

A vaccine can make the crucial difference in defeating an epidemic in which 98% of new infections take place in developing countries and in people who will never be able to afford HIV treatments, Mann said. While acknowledging legitimate scientific controversy over the correlates of immunity to the virus, Mann said there is a strong impression in the vaccine research community that field trials are necessary to discover those correlates.

"When one considers that this year there may be 4 million people newly infected worldwide, a vaccine of only partial efficacy has tremendous potential use," Mann said.

Three years ago, presented with the first vaccine candidate (GP-120) ready to be tested in the field, the National Institutes of Health nixed the trial because its efficacy was so indeterminate and several people in smaller trials had become infected despite having been vaccinated. That setback in vaccine development came at the same time that drug companies were developing protease inhibitors, which have captured the attention of the medical and scientific community.

Baltimore, a Nobel laureate and soon-to-be president of California Institute of Technology, said in an update on vaccine research that Clinton’s initiative calls for $150 million a year (or 10% of the federal AIDS budget) to be spent on AIDS vaccine research, and that financial resources are not the problem. Hindered by a lack of precise scientific knowledge about HIV, researchers could take at least 10 years to develop a vaccine and several more years to make it available to the public, he said.

Nonetheless, he said, new drug treatments, while promising, are only halfway measures, similar to putting polio patients in iron lungs. "A vaccine that really works would be a clean and effective matter," he said. "That is how we conquer viruses, and in much of the world it is the only hope."

While drug manufacturers have said a vaccine could be developed in five years once the scientific barriers are overcome, health officials are saddled with a host of social, legal, and ethical issues surrounding testing of an AIDS vaccine. Baltimore pointed out some of the unique features of AIDS vaccine development and the problems they present.

Vaccines traditionally stimulate immunity before the virus enters the body and buy time for the immune system to stay ahead of the virus, thereby indefinitely delaying the onset of symptoms. In other words, the vaccine protects against the disease and not the virus, Baltimore explained. But in cases of HIV infection, optimal immune response is not enough. In nearly all people, ultimately the virus gets ahead of the immune system and decimates it.

"That is fundamentally why it has been so hard to design an HIV vaccine: We don’t have natural immunity on our side and are trying to design something dramatically better than nature," Baltimore said, adding that scientists still don’t know why the virus gets ahead of the immune system.

HIV is a unique virus in other ways. For example, once a person is infected with HIV, antibodies are slow to develop, and antibody titers (the amount of antibodies that can neutralize the infectivity of the virus) are low. Moreover, the body has difficulty inducing antibodies against the "wild type" strains of virus, and researchers don’t even know if antibodies can protect against the virus.

Because the virus often takes 10 years to manifest as disease, some aspect of the immune system must be naturally effective against the virus. However, one problem with AIDS vaccine research is that it has targeted humoral immunity rather than cell-based immunity, which appears to correlate better to the course of infection.

"Something is very effective and many people think it is cell-based immunity, but again we don’t know for sure," he said.

Another problem is that vaccine researchers use virus that has been cultured in the laboratory, rather than the wild-type strains found in the real world, Baltimore said. "That virus changed a lot in the process, and in ways we only now understand. So the laboratory strains are much easier to neutralize with antibodies than the wild-type strains," he explained. "If we had recognized that 15 years ago, we may not be where we are now, so there still is no vaccine candidate based on wild-type virus."

Choosing the cellular vehicle for delivering a vaccine also has been a problem unique to HIV. All virus vaccines, except for hepatitis B, take one of two forms: live attenuated virus (taking a strain out of nature and weakening it so it loses its ability to cause disease), and a killed virus vaccine (taking the virus and physically killing it with formaldehyde). For safety reasons, neither approach has been deemed suitable for an AIDS vaccine. As a result, researchers have taken a revolutionary approach through development of subunit vaccines — taking the HIV envelope, reproducing it in mammalian cells, purifying it, and injecting it into the virus.

More recently, researchers have developed vectors that deliver the genes needed to make the virus protein, rather than putting the genes themselves in the protein which has the advantage of inducing cellular immunity, he said. The most exciting and advanced candidate of this type is a recombinant canarypox virus combined with a booster strategy, which is now in Phase II of testing.

"We are only just starting to make [HIV] vaccines. We have not yet given it a reasonable shot," he said. "Nobody has tried any of the historic vaccines — the killed virus or the live attenuated virus."

While there are reasons not to use those approaches, live attenuated HIV vaccines work in protecting monkeys. If researchers can develop a wild type to make either a vector or a protein preparation that has a natural configuration, the odds of developing an effective vaccine will improve, he added.

NIH seeks ‘multiple opportunities’

Consequently, the NIH vaccine committee has taken an open-ended approach to choosing the best candidates, considering any product that has even the slightest possibility. "Because we don’t know what will work, what we need is multiple opportunities to test materials that have a good chance of working," Baltimore said.

One exciting discovery that could change the approach to vaccines was presented at the conference. In research headed by the Whitehead Institute, molecular biologists have mapped out for the first time the mechanism by which the virus binds to CD4 cells. The protein responsible for this fusion, gp41, could offer a new target for a vaccine, said Whitehead biologist Peter Kim, PhD, professor of biology at Massachusetts Institute of Technology.

"Although it is speculative, since this is the first time we have had a structure of part of the HIV envelope, we are also considering that this could be used to develop new candidates for vaccine trials," he said.