SYDNEY -- HIV vaccine research is poised to take a step into the unknown -- the use of live but attenuated viruses to create immunity.
SYDNEY, July 23 -- HIV vaccine research is poised to take a step into the unknown -- the use of live but attenuated viruses to create immunity.
"That train is leaving," said Wayne Koff, Ph.D., of the International AIDS Vaccine Initiative in New York, speaking at the 2007 International AIDS Society meeting.
He said researchers in academia and industry are trying to find ways to use so-called replication-competent viruses to carry HIV antigens into the body.
That would parallel some of the most effective vaccines in use today, including those used against polio, measles, and mumps, Dr. Koff told an IAVI-sponsored satellite session here.
The efficacy of such well-known vaccines is usually greater than 99%, Dr. Koff said.
Also, he said, research in animals shows that using a live attenuated virus is more effective than using viruses that can't replicate -- the approach used in most of the 30-odd HIV vaccines now in the clinical pipeline for human therapy.
Dr. Koff said there are two possible approaches -- using a weakened version of HIV itself or using another vector, such as vaccinia, engineered to carry HIV antigens.
But creating such vaccines is fraught with difficulties, he and other researchers said, including navigating them through the regulatory process and selling them to a public that is increasingly risk averse.
"This is a nightmare for us," said Keith Peden, Ph.D., of the FDA's Center for Biologics Evaluation and Research. He told the symposium that the FDA would essentially be "regulating the unpredictable."
But if researchers proceed, he suggested, regulators will be much happier if they avoid using a weakened HIV. "It will be easier if you don't go that route right now," he said.
That's because the highly variable nature of the HIV virus creates fears that even a weakened version -- engineered so it can't cause disease -- might one day mutate to become virulent again.
For that reason, Dr. Koff said, an HIV-based vaccine "is off the IAVI table for the time being."
That doesn't mean it's off everybody's table, said virologist Ben Berkhout, Ph.D., of the University of Amsterdam. Dr. Berkhout described a technique of creating a form of HIV that can only replicate in the presence of the antibiotic doxycycline (Doryx).
The so-called conditional live virus would be given with the antibiotic, allowed to replicate long enough to generate a robust immune response, and then be turned off by withdrawing the drug.
In cell cultures and in animal studies, Dr. Berkhout said, the system worked without a hitch, allowing researchers to turn the virus on and off at will.
"By switching off the replication, you will, of course, have no viral evolution," he said.
But he agreed with Dr. Peden that the key worry is a loss of control, the virus finding a way to replicate without the need of the antibiotic. But so far, he said, he and colleagues haven't seen any signs of that.
The other approach is to use another virus, genetically modified so that it expresses HIV antigens, according to Linqi Zhang, Ph.D., of the AIDS Research Center of the Chinese Academy of Medical Sciences in Beijing.
Dr. Zhang said he and colleagues have shown that a highly attenuated vaccinia virus, engineered to carry the HIV pol, gag, and env genes, can be given safely to mice and appears to generate an immune response.
And Christopher Parks, Ph.D., formerly with Wyeth Pharmaceuticals of Madison, N.J., said the company is pressing ahead with a vaccine program using vesicular stomatitis virus.
Dr. Parks, now with IAVI, said the safety of the viral vector is the big issue for the company, as it is likely to be for any pharmaceutical maker. "There is going to be some risk" with a live attenuated virus vaccine, he said, but exactly how much risk remains unclear.
"It's a developing technology," he said.