The most persistent critic of the program the National Institutes of Health has laid out for developing an HIV vaccine was given the spotlight on February 5 at the premier meeting on HIV science, the 15th Conference on Retroviruses and Opportunistic Infections, taking place this week in Boston.

"The fundamental question is whether an effective vaccine against HIV-1 is feasible at the current time," said Ronald Desrosiers, director of the New England Primate Research Center at Harvard University. After reviewing the evidence, his answer was a resounding no.

"First and foremost we need to remember the defining hallmark of AIDS: HIV is the undisputed champion of persistent viral replication ... Not only is the natural immune response unable to control the virus and stop this continuous replication, it is not even able to protect against superinfection by different strains of HIV."

HIV mutates rapidly and has a huge genetic diversity. Desrosiers used a scattergram developed by others to illustrate the point. It visually compared the genetic diversity of the flu - a virus that changes so rapidly that a new version of the protective vaccine must be developed each year - and HIV.

If the flu worldwide has a diversity the size of the nail on your little finger, the genetic diversity of the HIV infecting a single patient is the size of the nail on a larger finger, maybe even your thumb. And the genetic diversity of all of the HIV circulating throughout the world is about the size of your fist.

The shell of the virus is coated with carbohydrates that block antibodies from binding to it; it produces proteins that neutralize immune responses; and all the while it is destroying CD4 cells. The human immune system can cope with some of this but "HIV is constantly spitting out [genetic] sequence variations" and the body can't defend against them all, Desrosiers said.

"None of this should be news to people in this room. But sometimes, I think that many forget, or choose to overlook, how daunting the task of a vaccine really is," Desrosiers added.

"We're batting 0 for 3 in the efficacy trials in human. We don't know how to elicit antibodies with broadly neutralizing activity. We don't know how to deal with the enormous sequence diversity present in the virus. And we don't know what constitutes immune protection," he said.

All of the other HIV vaccine candidates currently in the development pipeline depend upon the same general approach as the failed vaccines. He said there is no need for further human trials of that "me, too" approach.

Desrosiers lamented the sums of money being spent by NIH "to manufacture and test products with little reasonable hope of efficacy" - so far $189 million on phase 1-2-3 trials and more on product development and manufacturing - that could have been spent on basic research. And he warned that continued failure runs the risk of funder fatigue and volunteer backlash.

He asked if NIH "has lost its way" in picking up the slack for a pharmaceutical industry that largely has not been interested in HIV vaccine development. He answered affirmatively. "Pharma has gauged that given the current state of knowledge, a vaccine for HIV is not scientifically feasible at this time to warrant the dollars to develop one."

But he was encouraged by "some indications that NIH is ready to change the 'products in the pipeline philosophy' that has largely driven HIV vaccine development." A summit is being planned for this spring, perhaps as early as March, as part of that process.

Desrosiers said the NIH should return to its primary focus of funding basic research. He urged focusing on broadly neutralizing antibodies; more aggressive pursuit of novel vaccine concepts; identifying what constitutes effective immune response in monkeys and human long term slow progressors; and "comparative head-to-head testing in rhesus monkeys for protective efficacy."

Desrosiers has raised many of these points at various meetings over the years, including at a smaller session of CROI when it met four years ago in San Francisco. The number of people coming around to his views has increased dramatically since last September when the Merck vaccine trial was stopped because more people who received the vaccine became infected with HIV than those who got a placebo.

At a news conference later that day, CROI co-chair John Mellors said, "The path forward is not clear. I think there is agreement on that. Anybody who talks about a timeline for a vaccine is being silly and uninformed. It will require an incremental process of knowledge, and experimentation, and testing of ideas."