A 'Center without Walls'
Intramural HIV Vaccine Work Moves Forward
By Rich McManus
On the Front Page...
The metaphor of a "center without walls," born 2 years ago in Wilson Hall when NIH director Dr. Harold Varmus apprised the intramural community of President Clinton's challenge to create an HIV vaccine within a decade, has acquired a new adherent in Dr. Gary Nabel, who became VRC director Apr. 11.
During his first week on the job, Nabel convened a 1 ½-day strategic planning meeting at a hotel in Chevy Chase for 34 authorities in the field. Topics included initial scientific strategies, informatics and genomics applications to a vaccine, composition of labs, and the scope and mission of the VRC. Three weeks later, the AIDS vaccine research committee, chaired by Dr. David Baltimore, met at the Natcher Center to review the current state of HIV vaccine science and hear a summary of Nabel's retreat. These events have returned momentum to an effort that has waxed and waned in the past 2 years as scientific trends and personalities, budgets and research interests varied within intramural NIH.
"Committees never can move things forward the way you'd like to see them go," said Dr. Larry Arthur, director of the AIDS Vaccine Research Program at the Frederick Cancer Research and Development Center, and member of the 7-person VRC steering committee appointed by Varmus 2 years ago. "You need a central focus, which Gary can provide."
Dr. Larry Arthur works in his laboratory at Frederick.
The hope some may have initially had for a "Manhattan Project" type of effort was never realistic, explains Arthur. "In the Manhattan Project, the scientists knew what they wanted to do; it was just a matter of assembling them to do it. We're not sure we have the science yet to build a (HIV) vaccine." He assures, "If we had a vaccine that would work, there would be a major activity to get that into human trials. But it's not an easy task. HIV varies its envelope protein to a high level, and we know that even a slight variation in the influenza virus's envelope protein lets you get the flu year after year. But I feel certain that we will eventually prevail."
Another optimist is VRC steering committee member Dr. Genoveffa Franchini, chief of the animal models and retroviral vaccines section in NCI's Basic Research Laboratory. A feisty, energetic alumna of Dr. Robert Gallo's old NCI laboratory, in which HIV research flourished, she declares, "I am not a pessimist that's my nature.
"The encouragement (Varmus) gave for the center without walls fostered more thinking together," said Franchini, a 19-year NIH veteran and native of Modena, Italy.
After the May 28, 1997, meeting in Wilson Hall, the wall-less VRC met monthly at the Cloisters to discuss, informally, ideas and approaches to vaccine work. Both intramural scientists and distinguished guests contributed their ideas and suggestions to these parleys. "It was more personable than a seminar series," recalls Franchini, "less formal. They were very useful meetings. Then a little vaccine club began." Franchini, NIAID's Dr. Malcolm Martin and others would meet meet regularly in Bldg. 4 to discuss what each other was up to. Attendance varied from 15 to 20 people, and outside speakers invited on the basis of expertise were welcome.
"We asked each other what we were doing here at NIH, and challenged one another," Franchini remembers. "It was very useful in terms of suggestions."
"Overall," she concludes, "I think Dr. Varmus' message fostered communication."
Arthur recollects that Varmus participated in a number of the talks, peppering speakers with germane questions. "(Varmus) gave (the meetings) a high profile, which was very important," said Arthur, who served on two of several subcommittees Varmus established: one to provide scientific input on the construction of Bldg. 40, the actual VRC, and another committee charged with identifying gaps in the HIV vaccine endeavor, and to encourage more intramural investigators to get involved in such research. "Certainly he was scientifically enthusiastic about it."
"We brought in outside speakers every other Tuesday night at the Cloisters for a long time," Arthur continues. "We'd meet informally, then go out to dinner together." The Cloisters sessions petered out about the time that Dr. William Paul, former director of the Office of AIDS Research, left that post to return to intramural NIAID in November 1997. By the time OAR tried to reinstitute the series, the feeling was that a VRC director was so close to being named that renewal ought to be left to him.
"It's a difficult task to encourage people informally into other areas of research," notes Arthur. "Once you see something tangible, like a VRC, it will be a lot easier to do that. I'm encouraged by the approach how we're moving forward."
Franchini, who has been working for 10 years on an HIV vaccine that takes advantage of an avian poxvirus as a vector the work is now in preclinical trials lists what she's learned thus far: "We can't protect people from infection with HIV (through vaccine), but we might be able to control it. Our goal is no longer sterilizing immunity" which, she allows, doesn't exist for any vaccine-treatable disease. "HIV might reside in the host, but it could be controlled. We don't know the long-term effect of low-level viral infection that's a mystery. But we suspect that low viremia (burden of virus in the host) equals a low level of infectivity to naive hosts."
Arthur says scientists have learned that "HIV is very difficult to transmit sexually in humans. On average it takes between 200 and 500 unprotected sexual acts with an HIV-positive person to get a positive transmission. So we may not need that effective a vaccine to stem the tide of the epidemic. But you certainly need some effectiveness."
Reflecting on scientific trends in the past 2 years, he observed, "Scientists become very passionate about their areas of research, and this is how it should be because your passion is what gets things accomplished. We're not all on one horse, trying to ride it to a vaccine."
He said the gp120 vaccine, now in human trials, "probably won't work as a protective vaccine. It generates an ineffective response to primary (HIV) isolates, and offers no substantial neutralization. It also hasn't protected nonhuman primates."
A current hot topic is the "prime-boost strategy," wherein the host is immunized with a viral vector that expresses an HIV envelope protein, which is then boosted with a multimeric protein. No matter what the approach, Arthur cautioned, immunological testing will be a very critical process. "It's very difficult to set those types of experiments up," he said.
Arthur says the "center without walls" concept is still alive and useful (Bldg. 40 isn't expected to open until August 2000). "Dr. Nabel is still encouraging the center without walls. And its not just HIV that is targeted. We need to involve the (Dr. Robert) Chanocks, and (Dr. Robert) Purcells, and Brian Murphys, who have all been successful in moving vaccines into clinical trials. We also need to know more about structural biology, specifically the transmembrane outer surface glycoprotein we need to know this structure. There are some excellent structural biologists at NIH who can help this effort. I think Dr. Nabel will enhance collaborations on campus."
Arthur is already working more closely with NIAID's Dr. Malcolm Martin, with whom he had done some chimpanzee work in the past. For her part, Franchini says she intends to keep working on her vaccine, as well as maintain her collaborative efforts with Drs. Jay Berzofsky and Gene Shearer of NCI and NIAID's Dr. Warren Strober. But, she adds, "if a common motif emerges, I would be happy to participate. I am very open."
Concludes Arthur, "Everyone clearly wants to come up with a vaccine that would be efficacious. I like the idea of a center and a director to really focus on the problem. (Nabel) is fostering a team approach, which is very important."
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