AIDSWEEKLY Plus, Monday, 8 September 1997
Daniel J. DeNoon, Senior Editor

An AIDS physicians' organization is organizing a clinical trial of a live HIV vaccine - and its leaders are the first to volunteer.

The International Association of Physicians in AIDS Care (IAPAC) has established a subcommittee to organize and recruit subjects for a trial of a live, attenuated HIV vaccine. IAPAC hopes to begin the 1,000-person trial by the year 2000.

The first to volunteer for the trial were Charles Farthing, chair of the vaccine subcommittee; Gordon Nary, editor of the IAPAC journal; and Jose Zuniga, IAPAC deputy director.

Farthing and Nary issued a call to AIDS physicians, researchers, and other HIV negative members of the AIDS community to join them as volunteers.

"It is time to follow in the tradition of Louis Pasteur, Walter Reed, and hundreds of our other colleagues who made the commitment to be the first human subjects in critical clinical trials," Farthing wrote. "I am asking those of you who might qualify to join me by registering as potential candidates for a live-attenuated vaccine trial that could help bring us closer to an effective vaccine. Each day we delay in moving aggressively ahead in the development of such a vaccine will result in the unnecessary deaths and suffering of thousands of people, many of whom are in resource-poor countries and do not have access to the promising drugs that many of us can now give to our patients."

Farthing's appeal appeared in the Journal of the International Association of Physicians in AIDS Care ("A Call to Physicians," J IAPAC, August 1997. Retrieved August 11, 1997 from the World Wide Web: http://www.iapac.org/vaccines/augeditorial.html and /vaccineform.html).

Safety concerns have to date prevented human tests of live candidate HIV vaccines. There is the theoretical chance that attenuated HIV could cause AIDS after a very long period of latency, or that the vaccine virus could mutate into a virulent form.

A more pressing concern is that unlike other live attenuated vaccines such as the Sabin polio vaccine, a live HIV vaccine would not go away after stimulating immunity. Like pathogenic wild strains, the vaccine strain would become integrated into a recipient's DNA, where, via insertional mutagenesis, it could one day initiate a chain of events leading to a malignancy.

"We're really concerned with what happens when you vaccinate 20 million people and 10 years later, 5 or 10 percent get lymphoma," Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told Science magazine writer Jon Cohen ("Novel Campaign To Test Live HIV Vaccine," Science, 1997;277(5329):1035).

Despite Fauci's concern, it appears that policymakers have at least begun to reconsider their safety-based objections to human tests of a live attenuated HIV vaccine.

Prototype vaccines based on simian immunodeficiency virus (SIV) can protect primates against infection with AIDS-causing SIV strains, including strains not used in the vaccine. Animals that do become infected have much lower viral loads and, so far, have not developed AIDS symptoms.

None of the more than 40 candidate HIV vaccine strategies evaluated in human trials have shown such broad protection in primate studies. But neither is any of these strategies potentially as risky.

Reversion to wild type has never yet been seen in monkey studies of prototype vaccines, but the possibility remains.

"Live attenuated HIV vaccines would move forward if it weren't for one thing: safety," said National Cancer Institute researcher Larry Arthur during a press conference at the 1997 meeting of NIAID's National Cooperative Vaccine Development Groups for AIDS (NCVDG, see AIDS Weekly Plus, May 19, 1997).

Despite these concerns, Arthur hinted that he would favor testing of a live attenuated HIV vaccine if there were a study population in which the risk of HIV infection might outweigh vaccine risks.

"I've always been in favor of attenuated virus and I continue to be so," Arthur said.

Arthur noted that of all antiviral vaccines currently in widespread human use, only one (the hepatitis B subunit vaccine) does not use a live attenuated or whole killed virus. And when sufficiently attenuated live vaccines become available, Arthur said, they usually replace the killed-cell vaccines.

NIAID Director Fauci suggested in his plenary address to the 1997 NCVDG meeting that his agency is no longer firmly opposed to human tests of a live attenuated HIV vaccine.

"For safety reasons we have stayed away, but this may be something we might reconsider," he said.

And David Baltimore, Nobel laureate and chair of the NIH AIDS Vaccine Research Committee, called a live attenuated vaccine the "most exciting [approach] today."

The trick to making a live HIV vaccine is to remove genetic elements that make it pathogenic while leaving just enough of the genome to permit it to be weakly infectious.

Harvard researcher Ronald C. Desrosiers first accomplished this in 1993 by removing the nef regulatory gene from the SIV genome (HIV also has a nef gene). Desrosiers and colleagues have gone on to develop a triply deleted SIV vaccine (SIVdelta3) that lacks the viral nef, vpr, and LTR gene sequences.

The vaccine was licensed by Harvard to Therion Biologics Corp., which is developing it in cooperation with Harvard and TSI Mason Laboratories, TSI Corporation, Worcester, Massachusetts.

Optimism over live attenuated SIV vaccines is tempered by the finding that the vaccines are protective only when animals are challenged more than a year after inoculation.

Also dimming enthusiasm over these vaccines is the finding that they can be pathogenic in neonatal monkeys, although it appears that such effects depend on oral administration of a huge dose of the vaccine (see AIDS Weekly Plus, March 18, 1996).

Finally, there is the question of how long one should wait before deciding that the vaccines are safe enough for human tests. Critics of live attenuated HIV vaccines suggest that pathogenic effects might become apparent only a decade or more after vaccination.

But a bizarre twist of fate may already have provided the first human test of a nef-attenuated HIV vaccine. Between 1981 and 1984, seven people were infected with HIV via blood transfusions from a single donor in Sydney, Australia (see AIDS Weekly Plus, February 19, 1996; January 20, 1997; and March 17, 1997).

All of the infected individuals have been asymptomatic for more than a decade, with low viral load and normal CD4 counts (one elderly cohort member died in 1995 of causes unrelated to HIV disease). Analysis of virus isolated from the donor and the seven infected recipients showed that it fortuitously contained a truncated nef gene (the C-terminal 43 amino acids are missing).

These events "suggest a reasonable safety profile in human subjects along with a beneficial immune response that may protect against subsequent exposure to HIV," Farthing suggested in his call to the 5,500 IAPAC members.

Those interested in the IAPAC trial may contact the organization via its web site at http://www.iapac.org/vaccines/vaccineform.html.

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