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
"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
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."