AIDSWEEKLY Plus, Monday, 27 October 1997
Daniel J. DeNoon, Senior Editor

The U.S. intends to build a centralized laboratory for AIDS vaccine development, announced Nobel laureate David Baltimore, chair of the U.S. AIDS Vaccine Research Committee (AVRC)

The laboratory will be a joint project of the National Cancer Institute and the National Institute of Allergy and Infectious Diseases, Baltimore said. It will be built on the National Institutes of Health (NIH) campus in Bethesda, Maryland, by the year 2000. In the meantime, the project will get underway as a "laboratory without walls." According to Baltimore, the search for the director of the laboratory already has begun and the AVRC is serving an advisory role.

He suggested that the laboratory symbolizes the governments approach to finding a global solution to AIDS. "The commitment of the U.S. government to find an AIDS vaccine is as strong as it can be," said Baltimore.

He spoke in a plenary address to the American Society for Microbiology's 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 28 to October 1, 1997, in Toronto, Ontario, Canada.

He was introduced by David Ho of Aaron Diamond Aids Research Center as the "U.S. czar for AIDS vaccines," but Baltimore declined the title. "I am not a czar. We [AVRC] are just an advisory group," Baltimore said. "But our advice is listened to at the highest levels.

He noted that NIH funding of AIDS vaccine research is now $100 million per year. "If there was a need for more funds, more funds would be found," he said.

Baltimore said that AVRC has three major accomplishments under its belt:

* It has developed a new, targeted grant program to address specific questions relative to AIDS vaccine research. Development of animal models for HIV vaccines and exploration of HIV envelope protein structure have been two main foci for these grants.

* It has held workshops to find new approaches to AIDS vaccines by bringing together scientists representing different disciplines, particularly those related to virology and immunology.

* It is creating a "focused" AIDS vaccine research laboratory at the NIH.

This ground-up approach, Baltimore stressed, is because finding an HIV vaccine is a unique effort. Successful viral vaccines stimulate development of immunologic memory rather than maintain high levels of antibodies and cytotoxic lymphocytes (CTL). But as most viral vaccines were discovered by empiricism, researchers are blazing a new trail in seeking to achieve this immunologic effect by a rational approach.

Baltimore said that the best models for virus vaccines have been live attenuated virus or whole killed virus.

"Against that background we have to look at HIV vaccines," Baltimore said. "Over 15 years of vaccine trials we have developed few candidates for clinical trials. Because of the novelty of using viral subunits, it is not surprising that we are not very far along."

The gold standard for a vaccine is sterilizing immunity. But an AIDS vaccine could fall short of this goal and still be effective.

"A vaccine could reduce the initial multiplication of HIV so we get more long-term nonprogressors and fewer AIDS cases," Baltimore said. "Such a vaccine must reduce transmission. Reducing transmission is the most important thing for an HIV vaccine to do."

New insights into HIV pathogenesis suggest how this kind of vaccine could work. Soon after infection, HIV and the immune system establish a so-called "setpoint" viral load level. High levels are associated with rapid disease progression, low levels are associated with a relatively long period once incorrectly known as latency. A person with a setpoint below a hypothetical threshold would theoretically never develop AIDS.

"A vaccine should reduce the setpoint, and a good vaccine should reduce the setpoint to a level at which many people could have a normal lifespan despite infection," Baltimore said.

There is one experimental vaccine that apparently accomplished this feat in the rhesus monkey/SIV model: a live, multiply attenuated virus vaccine. A year after receiving this vaccine (but not before), animals resist challenge with even the most virulent strains of SIV.

"If we could transfer all of that to humans, we would be very excited," Baltimore said.

Support for a human version of the vaccine - once considered unthinkable due to safety concerns - has been growing. A group of AIDS physicians has even volunteered for the first human trial.

But Baltimore signalled that the flirtation with a live HIV vaccine may be coming to an end. He announced that as- yet-unpublished studies show that the multiply attenuated SIV vaccine causes progressive disease in some vaccinated animals.

"We are worried that when an individual becomes immunocompromised for some reason, the virus may no longer be attenuated," he said. "In my opinion, we should use this model to learn more about protective immunity rather than to develop a human version. ... A live vaccine is of dubious acceptability on an international scale."

He suggested that virus-vector or pseudovirus-particle vaccines may be safer alternative approaches.

Whichever approach eventually emerges, Baltimore said that the vaccine development program must integrate the latest knowledge about HIV.

"We began [the search for an AIDS vaccine] when much less was known," he said. "We are still testing out-of-date materials."

He acknowledged that human testing should be an integral part of development, yielding short-term results that can be used in the laboratory to develop better vaccines.

Building the joint NCI/NIAID Vaccine Research Center, he said, will permit researchers:

* to explore new approaches for development of new tools for immunomodulation;

* to develop new insights into key components of HIV proteins;

* to improve HIV DNA vaccines;

* to identify promising vaccine candidates and move them forward rapidly; and

* to explore the mechanics of immune protection by attenuated virus.

With regard to this latter point, Baltimore offered his own insights.

"We do not understand how the attenuated virus stimulates immunity," he said. "How can attenuated virus induce immunity that fails to clear the immunogen but protects against virulent virus?"

He proposed an answer: perhaps there are two possible compartments of the viral reservoir, a "deep" compartment and a "peripheral" compartment. If the attenuated virus occupies the deep compartment, perhaps it keeps new pathogenic virus on the periphery where it can be controlled by the immune system.

"We have been working on an AIDS vaccine for a long time, but the information we needed is just becoming available today," Baltimore concluded. "We have seen what will happen if we don't succeed: it is not a pretty picture. We have to redouble our efforts to make an AIDS vaccine work."

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