AIDSWEEKLY Plus, 23 September 1996
Daniel J. DeNoon, Senior Editor

And through its UNAIDS organization, the U.N. is preparing to begin such trials in Brazil, Thailand, and Uganda.

"It is impractical, if not unethical, to leave developing countries out of the HIV vaccine development process," said UNAIDS executive Saladin Osmanov.

Osmanov spoke during a presentation to the XI International Conference on AIDS, held July 7-12, 1996, in Vancouver, British Columbia, Canada.

The UNAIDS representative noted that the 6 million people who have died of AIDS represent only a fraction of the 22 million people currently living with HIV infection. Each day brings 8,500 new infections.

More than 90 percent of HIV infections occur outside of the developed world. Sub-Saharan Africa has 65 percent of these cases, but as many as 20 percent of the world's HIV infections have occurred in south and southeast Asia.

Osmanov listed several compelling reasons why HIV vaccines should be tested in the developing world:

• The eventual vaccine would be used most frequently in these areas.
• Phase III trials will yield the best and quickest results if tested in areas of high HIV incidence.
• The genetic variability of HIV requires testing vaccines in diverse geographic areas.
• The effects of various routes of HIV transmission and/or various cofactors must be evaluated for their effects on vaccine protection.

"Although there is little argument that a safe and effective AIDS/HIV vaccine is urgently needed to bring the epidemic under control, there is little agreement on what should be the characteristics of such a vaccine and how to proceed," Osmanov said. "This lack of consensus is the result of uncertainties regarding the immunological correlates of protection, the significance of genetic variability on biological characteristics of the virus and vaccine-induced protection, and the meaning of animal protection with experimental HIV vaccines."

Osmanov noted that there are two basic sides in the debate over how soon to begin advanced clinical trials of candidate HIV vaccines: theorists and empiricists.

"The theorists, usually represented by basic researchers, create a model or theory from which they predict how to move forward with HIV vaccine development," he said. "On the other hand, the empiricists, usually represented by clinicians and public health officials, take a practical approach and make progress through the trial and error method.

"These labels are in fact generalizations, because most people are in both camps. However, on one point everyone agrees: in order to achieve our overall objective ... Phase III clinical trials must be done. The theorists must eventually submit to empiricism in order to test their conceptual model."

Regardless of how the decision to proceed with advanced trials is made, Osmanov listed several "overriding requirements" that must be in place:

• Availability of a well-characterized population with a high incidence of HIV infection despite available interventions.
• Cohorts of volunteers willing to participate and to be followed for three to five years.
• Adequate research and clinical infrastructures.
• Independent review bodies must be present or established.
• Strong community and political support must be present before and during the trials.

In cooperation with UNAIDS, preparation work is already underway in Brazil, Thailand, and Uganda. Preparations include:

• Isolation and characterization of circulating HIV strains.
• Identification of populations appropriate for and willing to participate in vaccine trials.
• Ongoing Phase I and Phase II clinical trials.
• Establishment of institutional review boards.

The UNAIDS official noted that while the primary endpoint of Phase III trials will be prevention of infection, it will be important to evaluate other endpoints. These endpoints would include measurements, such as viral load, to assess whether the vaccine impacts the course of infection, and clinical endpoints, measuring the rates of disease progression in the event that infection is not prevented.

"Multiple efficacy trials conducted in parallel or sequentially in different national sites may be necessary because of the worldwide genetic variability of HIV and the presence of cofactors and routes of transmission in different geographical areas," Osmanov said. "It will be necessary to test and compare different vaccine concepts. ... With 8500 new infections each day there is urgency to proceed."

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