AIDSWEEKLY Plus, 23 September 1996
Daniel J. DeNoon, Senior Editor

"While the basic research of HIV's immunopathogenesis is of critical importance and should be thoroughly and vigorously pursued, systematic HIV vaccine development should not be immobilized by our current ignorance of these data," said John G. McNeil of the Walter Reed Army Institute of Research, Rockville, Maryland.

McNeil spoke during a presentation to the XI International Conference on AIDS, held July 7-12, 1996, in Vancouver, British Columbia, Canada.

An HIV vaccine can only be developed via clearly defined collaboration between industry, government, and communities, McNeil argued. And the fundamental basis for this partnership must be the development of effective, affordable, and deployable vaccines.

"We must realistically accept the notion that after an efficacy trial, candidates may be demonstrated inefficacious: an unfortunate but not entirely uncommon - yet acceptable - result to biopharmaceutical developers," he said.

"Given these realities, if we are to have any hope for advancing HIV preventive vaccine development during this millennium, scientific and public health leaders must not be timid apologists for the fact that HIV vaccine development should proceed concurrently and interdependently with basic research - adhering, of course, to rigorous standards of science and ethics."

McNeil noted that candidate HIV vaccines evaluated to date have been safe, well tolerated, and capable of inducing a wide range of anti-HIV cellular and humoral immune responses. Moreover, several vaccines have been able to protect laboratory animals against infection with HIV, SIV, or chimeric SHIV.

"Through the concerted efforts of many agencies and individuals, knowledge of issues related to HIV vaccine development is becoming globally quite widespread," he said. "Preparations for vaccine evaluations and preliminary development of HIV vaccines is now occurring in virtually every corner of the world. Taken together these provide a potential for vaccine development that didn't exist two years ago and are reasons for optimism."

The Walter Reed researcher noted that there are also reasons for pessimism. Foremost among these is the fact that extensive research has so far failed to provide sufficient understanding of the correlates of immune protection against HIV to guide vaccine development.

"This unpalatable situation is companioned by the fact that we currently don't know if we have a valid animal model system for predicting in vivo human protection from HIV after vaccination," he said. "And this is further compounded by the fact that HIV has a prolonged clinical latency period, making the efficacy trials challenging to design and expensive to conduct."

McNeil decried the fact that very few candidate vaccine incorporate antigens from HIV strains outside clade B, which is most prevalent in North America and Western Europe.

"While in excess of 90 percent of new infections are occurring with non-B-clade HIV, mostly in less well developed regions of the world, vaccine prototypes are still largely B- virus-based because industrialized nations have been home to virtually all basic vaccine research and preliminary clinical development," he said.

"Since the need for preventive vaccines is greatest in the developing world, the prospects and likelihood of advanced clinical development of candidates is also greater there. Preventive vaccine approaches and candidates developed in these international sites should be optimized by matching the vaccine antigen with the predominant circulating phenotypes in those locations. This currently is not common, and the development time lost in making these changes - if, indeed, vaccine developers even choose to make them - is a reason for pessimism."

To move forward, McNeil recommends "thoughtful empiricism."

He noted that vaccine developers have historically turned to human clinical trials when they lacked an animal model of disease and were unable to validate the immune correlates of disease recovery.

"Thoughtful empiricism has been the rule rather than the exception in vaccine development," McNeil said. "I believe that the logic of thoughtful empiricism can and should be applied to HIV vaccine development, too. ... Vaccine development should be both interdependent and concurrent with basic research with each informing the other. Advanced development of vaccines must be viewed as critically important, hypothesis-testing clinical research providing scientific information every bit as important as basic in vitro and animal research data. Development should proceed with the best available scientific data and practices with the absolute highest regard for sound ethics and scientific rigor."

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