BANGKOK- A trial with the gp120 AIDS vaccine now underway in the capital of Thailand should provide the long sought answers regarding the utility of this vaccine candidate.

The vaccine is being administered to high-risk volunteers who have not tested positive for HIV. The study group comprises recovering intravenous drug users recruited from Bangkok clinics. Volunteers will receive a primary injection followed by follow-up boosters at one, six and 12 month intervals.

The initial trial is designed to confirm the safety of the vaccine, after which a larger trial will be conducted to more fully evaluate the potential efficacy of the vaccine candidate in preventing the transmission of HIV, the virus that causes AIDS. All volunteers will receive regular follow-up and counseling.

The gp120 vaccine has already been tested in 1,000 volunteers in the U.S.. Those trials confirmed that the vaccine was safe and that is stimulated an immune response. However, in June of 1995, the National Institutes of Allergic and Infectious Diseases Research Advisory Committee recommended that federal support not be extended for planned, large scale trials of AIDS candidate gp120 vaccines.

One reason for discontinuing the trials cited by the advisory committee was that such trials would take longer and require more participants if conducted in the U.S., because of the nature of the epidemic in this country. Not everyone agreed with that judgment.

"It is a matter of will," notes Dr. Don Francis, formerly of the Centers for Disease Control and prevention, and now at Genentech. "When we decided that we wanted to cure polio in this country, we were able to come up with the resources to test the Salk vaccine in hundreds of thousands of people. We can come up with an effective vaccine for AIDS, but only if we have the necessary will to do so."

The US decision to discontinue vaccine trials was based on the results of preliminary studies with several recombinant vaccine candidates. While the candidate vaccines could neutralize laboratory HIV isolates, none appeared to neutralize wild virus isolates. Confusing the issue, it appeared that protection against HIV was achieved in chimpanzees, but in the absence of neutralizing antibodies. Finally, some seronegative volunteers receiving the vaccines became HIV positive, although none had finished the complete immunization schedule.

"This last point in particular was distorted by the media," noted Dr. Francis. "This is a recombinant vaccine made from portions of the envelope protein. It is not made from live virus and cannot possibly cause AIDS," he emphasized.

Dr. Francis complimented the Thai health ministry for its understanding of the need to test available candidate vaccines and its willingness to act promptly. A few years ago Thailand had only a handful of AIDS cases. But now, in some areas as many as one in ten of the population are infected with HIV.

The current trial is being overseen by the World Health Organization. In addition to Thailand the WHO has proposed three other potential sites for vaccine trials, Brazil, Uganda and Rwanda- all areas with a large and growing incidence of HIV infection.

While public health campaigns face considerable logistic obstacles in the developing world, there are success stories. For example, in India, a country considered at high risk for an AIDS epidemic, a concerted public health effort successfully eradicated small-pox, noted Dr. Francis.

The proposed trials must overcome a number of hurdles before they can begin. Scientific questions include which strains of HIV should be used to make the vaccines The gp 120 vaccines are based on virus isolates that are prevalent in North America and Europe. However, the HIV subtype prevalent in the U.S. and Europe is different from strains encountered in Africa and Asia.

Another important question is how should the effectiveness of the candidate vaccines be measured. Reliable correlates of immunity for AIDS vaccines have yet to be established. More understanding is also need regarding which immune responses to pathogen are salutary and which are not. It was partly debate about these issues which stymied the U.S. trials. Levels of CD4 t-cells, currently the surrogate marker of immunity used in most AIDS studies, will be measured in all participants in the Bangkok trial, and will be monitored regularly.

"It is important to remember that it would be difficult to create a situation worse than AIDS. Virtually all HIV positive patents will become sick and will die. Considering this, the most important endpoint of vaccine trials is simply whether they prevent the transmission of the disease," noted Dr. Francis.

Other problems facing AIDS vaccine developers include overcoming the genetic variability of HIV; the problem of immunity enhancement in monocytes and macrophages; and the fact that intracellular HIV would not be eliminated by neutralizing antibodies generated by current vaccine candidates.

Even if a vaccine capable of preventing AIDS were available today, huge obstacles would remain regarding the widespread testing and eventual application of immunization programs. If a vaccine were developed that was 90% effective for a 20 year period 75% of all adolescents and adults in endemic countries in the developing world would require immunization, according to CDC projections. This raises practical questions regarding administration of the vaccines and follow-up of study participants.

"Over the past year several events have shaken the HIV vaccine field and left it in a rather unsettled state. Depending on one's vantage point, these revelations have either been confusing and troubling or logical and comforting," noted Dani Bolognesi, M.D., Director of AIDS Research, Duke University, Durham, N.C., at the 10th International AIDS Conference last year in Yokohama, Japan.

"These events illustrate the difficulties that HIV vaccines must face in order to proceed to large clinical trials. They also highlight the continuing struggle to establish standards that a vaccine must meet that are acceptable to scientists, vaccine developers, government officials and representatives of communities affected by such trials. There is a sizable gulf of uncertainty as to the best way to proceed," said Dr. Bolognesi.

Researchers will continue to focus on vaccines based on the hypothesis that neutralizing antibodies correlate with protection against HIV. Other approaches are also being pursued including cellular immunity and mucosal immunity, combination vector approaches and DNA vaccination, he said.

"The biomedical establishment cannot become passive or discouraged over these recent developments. It has little alternative but to redouble its efforts and be prepared to maintain a long term solid commitment until an effective vaccine against this devastating pathogen is achieved," he emphasized.

Transmitted: 95-05-08 22:49:23 ED

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