"Designing vaccines specifically for developing countries has been uppermost in the minds and agendas of many of us for years, ever since we recognized critical differences between the epidemics in the developing and industrialized worlds," said Max Essex, chairman of the Harvard AIDS Institute, which sponsored the conference. "Not only are far greater numbers of people infected in many developing countries, but subtypes and transmission routes also vary, which has tremendous implications for vaccine development."

A major dilemma in the search for vaccines, according to Essex, is that while most of the technology resides in industrialized countries, the greatest need exists in developing countries. "We run the risk of AIDS becoming another malaria, where expertise is not mobilized, despite a tremendous need in the developing world, because industry has no obvious incentive," Essex said.

The Harvard conference participants agreed that collaborations between developing and industrialized countries are the best and perhaps the only way to ensure the realization of an effective vaccine. "Scientists from developing countries should play an equal and meaningful role at every step of AIDS vaccine research," said Subhash Hira, director of the AIDS Research and Control Centre in Bombay.

Balancing Risks
The participants--who included representatives from more than a dozen developing and industrialized countries--expressed optimism that safe, effective, and affordable vaccines could be devised for use around the world provided enough researchers, funding, and political will were committed to the effort. While acknowledging safety as their top priority, participants agreed that, given the epidemic's continued escalation in the developing world, an accelerated response is crucial. Speed will dictate, however, that carefully considered risks be taken.

Human efficacy trials, for example, must begin as soon as a viable vaccine is developed. Participants agreed that even when trials fail, they still yield critical information about viral antigen preparations, immune correlates of protection, and vaccine adjuvants--information that researchers can use to refine successive vaccine preparations. The group further recommended that human trials proceed even in the absence of animal model data. Moreover, they argued, animal models often have limited applicability and results from them can sometimes be misleading.

Participants agreed that when a vaccine is ready for widespread testing, the rules may need to be eased for Phase III trials, in which vaccine efficacy is tested in thousands of people. While basic guidelines for safety and effectiveness would still be followed, other standards might require modification. For example, a high rate of efficacy--70 percent or more--is usually necessary for vaccine acceptance. In a country devastated by HIV, however, a prevention rate of 50 or even 30 percent might be considered acceptable.

Considerations for a Trial
During the conference, participants identified a number of criteria essential to a trial's success. First, they said, the epidemic in the host country must be properly characterized in terms of viral subtypes, transmission routes, seroprevalence rates, and risk factors. The vaccine prototype should then be tailored to match the predominant subtypes and transmission routes found in the host country. Such customization may increase the likelihood of achieving direct and substantial benefits for the host country which can then be extrapolated to other developing countries.

The group agreed that the population tested must have an HIV seroincidence rate of at least 2 percent to guarantee reliable results, and trials should take place in populations at high risk for HIV infection--such as female sex workers--to provide quick and accurate data on both efficacy and immune correlates of protection. Participants further recommended that the vaccine trials be randomized, placebo-controlled, double-blind designs that emphasize both safety and scientific accuracy. Other important considerations include the host country's political stability and the commitments of participating governments and communities. Ethical issues should be factored in from the outset.

Ensuring Appropriateness and Availability
Participants urged host countries to contribute to all stages of vaccine design. They stated that the final formulation must be useful in the host country, and that production technology must be appropriate to developing countries. As far as possible, vaccines should be inexpensive, heat stable, and able to be taken orally. The ideal vaccine could be administered in a single dose and would confer long-lasting protection.

Moreover, as more than 20 million people are already infected with HIV worldwide, participants advocated the development of vaccines that are not only preventive, but also therapeutic. "It would be best if some configuration could be designed so that the vaccine would be useful after someone has been exposed to or infected with HIV," said Natth Bhamarapravati, professor at the Center for Vaccine Development at Mahidol University in Thailand.

The group placed particular weight on establishing mechanisms to make vaccines available to developing countries. "Although the hepatitis B vaccine was researched in Senegal and approved for use, we have yet to obtain it," said Souleymane Mboup, professor of bacteriology and virology at University Cheikh Anta Diop in Dakar. "It is too expensive. This is a lesson we must pay attention to as we develop an HIV vaccine."

Bhamarapravati concurred: "If a vaccine happens to be successful, will it be available to poor people in developing countries, when there is a more profitable market in industrialized countries? Based on our experience with vaccine manufacturers, developing countries must negotiate from the very start. Some developing countries may want to be involved in the manufacturing process, to ensure quality control and availability."

Building Partnerships
In light of Senegal's experience with the hepatitis B vaccine and other historical problems with vaccine development, conference participants stressed the importance of collaboration. They stated that developing and industrialized countries both have critical contributions to make: a developing country, for example, may have a population in which the seroincidence rate is high enough for reliable testing, while an industrialized country may be able to provide technical assistance.

Participants agreed that ground rules negotiated in advance are essential to the success of such partnerships. The host country should define vaccine policy, and the partner countries should maintain equal ownership of all data culled from the trials. During the course of the trial, the host country's scientific infrastructure should also be strengthened. "These trials should be regarded as a major opportunity for the host country to gain scientific expertise," Bhamarapravati said.

Enlisting a Global Response
While participants were able to agree on a general blueprint for vaccine development and use, they acknowledged that questions of commitment still loomed. They expressed concern, for example, that the pharmaceutical and biotechnology industries in developed countries have not been more active in AIDS vaccine research. Some participants speculated that this reluctance may derive from the perception that, with the epidemic's apparent slowing in the United States and Europe, the market for a vaccine in those regions is not significant.

In response, researchers from developing countries emphasized their willingness to help ensure the development of an HIV vaccine for use throughout the world. "The Indian pharmaceutical industry must help pave the way toward indigenous manufacture of an AIDS vaccine," Hira said. Similarly, Zheng Yi, president of the Chinese Academy of Preventive Medicine in Beijing, spoke to his country's need and capabilities: "China is an ideal place to use such a vaccine before infection with HIV becomes severe, and we have the technical capacity to produce it ourselves."

Essex concluded the conference with a call for worldwide commitment to vaccine development. "By testing vaccines designed specifically for developing countries," he said, "we will not only target vaccines where they are most needed, but we will likely speed vaccine development in general. And the faster we can move, the more lives we can save."

The Fogarty International Center of the National Institutes of Health provided major support for this conference; the Rockefeller Foundation provided additional funding.