The National Institutes of Health fails to grasp the urgency of developing an AIDS vaccine, a leading AIDS researcher asserts.
Only an empirical approach and decisive leadership can produce an effective HIV vaccine, argued Mary Lou Clements-Mann of Johns Hopkins University.
"Now is the time for reassessment of government delegations of responsibility for AIDS vaccine development," Clements-Mann said. "A broad strategic plan has yet to be developed by the NIH. ... The [NIH] Division of AIDS has emphasized basic research over vaccine development."
Clements-Mann's comments came during an address to the First Annual Conference on Vaccine Research, held May 30-June 1, 1998, in Washington, D.C.
She said that the NIH does not have the expertise appropriate for real-world vaccine development and suggested that the U.S. Centers for Disease Control and Prevention (CDC) or the Army's Walter Reed Institute could do a better job.
"AIDS is a fatal disease," Clements-Mann said. "Ninety percent of the world can't afford drugs. Many populations - even in this country - are willing to volunteer. Is it ethical not to do a vaccine trial? If this epidemic occurred in 40,000 U.S. university students, wouldn't we be doing a Phase III study? ... When you get right down to it, what are the drawbacks of doing a [large-scale] study?"
CDC researcher Bruce Weniger, one of the conference organizers, asked Clements-Mann to comment on behind-the-scenes efforts by some well-known AIDS researchers to undermine trials of the VaxGen candidate HIV vaccine in Thailand.
"My own feeling is that it is well intended, but not well informed about the clinical development process," she replied. Later she explained that she believes much of the resistance to empirical trials of candidate HIV vaccine comes from basic researchers who have spent their entire careers on AIDS and have never seen a vaccine through the entire development process.
Whether due to lack of commitment or lack of high-quality vaccine candidates, progress toward an AIDS vaccine has been slow. Of the 23 candidate HIV vaccines tested in 47 federally funded Phase I trials to date, only two have proceeded to Phase II trials. There are still no national criteria to determine when a candidate vaccine is ready for Phase III testing.
Clements-Mann blames this situation on a number of prevalent misconceptions about HIV vaccines:
* That a vaccine must provide sterilizing immunity to infection: i.e., that it must prevent HIV from establishing an infection.
* That a vaccine must prevent all symptoms of HIV disease. "Recent treatment results show that a realistic goal of an AIDS vaccine would be to stimulate immunity that could reduce viremia and prevent or delay disease," Clements-Mann said.
* That vaccine-induced protection must be demonstrated in animals before large-scale human trials.
* That the correlates of HIV immunity must be known. "The observed correlates of immunity may be markers for disease rather than markers of protection," Clements-Mann said. "The correlates of effective immunity can never be known until there is a Phase III trial. ... The complex interactions of humoral, mucosal, and cellular immunity cannot be identified by a single assay."
* That a vaccine should induce long-lived immune responses. "So long as it remains intact, immunologic memory [would be sufficient]," Clements-Mann said.
* That the quality and quantity of vaccine-induced immune responses must be the same as those seen in natural HIV infection.
* Only one efficacy trial is usually needed to develop an effective vaccine. "Well designed, iterative Phase III trials may be needed to confirm vaccine efficacy in populations differing by age, genetics, or nutrition; in populations exposed to HIV by different routes of transmission; or in populations exposed to different HIV antigens," Clements-Mann said. "Iterative trials may be needed to determine how to redesign or reformulate vaccines to achieve optimal protection."
Clements-Mann noted that many vaccines have been successfully tested without each of these listed features.
"Collectively, all these misconceptions have led to the conclusion on the part of many basic scientists that all vaccines currently in development won't work," she said. "They fail to understand that well-designed Phase III trials [can provide crucial information]."
Clements-Mann listed what she believes to be the key components of an HIV development program:
* To recognize the urgent need for a vaccine;
* To establish a broad institutional base;
* To adopt well-defined missions and goals;
* To create a strategic plan;
* To find strong and sustained program leadership;
* To engage appropriate expertise;
* To forge effective partnerships with vaccine companies;
* To establish long-term international collaboration; and
* To marshal support - not necessarily consensus - for vaccine efficacy trials.
Clements-Mann argued that expanded trials of currently available HIV vaccine candidates would yield valuable information.
"We need to know if [HIV] envelope is safe," she said. "We need to know if a single envelope will protect against many clades. We need to get some indication of biologic relevance of different assays, and we hope that Phase III trials - even if they do not yield an effective vaccine - can answer these questions."
Clements-Mann can count on powerful support for her position. Maurice Hilleman, the director of Merck's Institute for Therapeutic Research and the developer of a number of vaccines, rose to speak at the conclusion of her presentation.
"Who could disagree with what you are saying?" Hilleman said. "I think you are right. Historically, in indefinable situations, the key ingredients are common sense and good faith."