Reports for NATAP

AIDS Vaccine 2001 Conference

September 6, 2001 Philadelphia, PA

Skeptical About AIDS Vaccine / Testing method questioned
      Newsday - September 5, 2001
      Laurie Garrett, Staff Writer

Even as scientists searching for an AIDS vaccine convene today in Philadelphia, many leading researchers warn that newfound optimism in the field may rest on rocky, even dangerously misleading, science.

The optimism stems from three alleged breakthrough vaccines announced over the last year, and a fourth to be unveiled at this week's meeting.

One of the naysayers is Harvard Medical School scientist Dr. Ronald Desrosiers, director of the New England Primate Research Center. "I fail to understand where this optimism is coming from," Desrosiers said. "I find it totally astounding, to the point of it being irresponsible, in many cases. What are they thinking?"

At issue for Desrosiers and other top vaccine researchers is the way all these new products, which their developers hope to rapidly put into human clinical trials, were tested in monkeys. They argue that the test method has yielded false promises of success. It's possible, they say, that none of these vaccines could even protect monkeys that were infected with natural, wild forms of the simian AIDS virus, much less have any hope of working in human beings.

Among the loudest voices of enthusiasm and optimism is Dr. Norman Letvin of the Harvard Medical School, who says that now "there is a rational, data-driven approach to the epidemic here that cries out to be tested in humans. There are an awful lot of people that share in this optimism. And the big money is behind this."

All four potential vaccines were made and tested in monkeys and proved effective using an artificial monkey AIDS virus. Further, none of these products actually prevents the monkeys from getting infected or sparks production of effective antibodies. In their favor, they do seem to decrease the likelihood that infection will progress to AIDS and death, by virtue of boosting some non-antibody elements of the immune system.

Even that effect - boosting the monkey's ability to fight off AIDS - may be an artifact of the ways in which the vaccines were tested, critics charge. That's because the super-lethal, artificial monkey AIDS virus used in all of the experiments, called a SHIV, is so different from natural viruses that it produces a different disease, a different immune response and, therefore, "protection" against a totally artificial phenomenon.

At the AIDS Vaccine 2001 conference this week Letvin will defend the scientific basis for the optimism in a keynote speech. Desrosiers and many other doubters aren't attending.

The problem they see is the artificial AIDS virus, designated in scientific circles by the cumbersome moniker of SHIV89.6p. In each test, monkeys were given a vaccine, then exposed to this virus.

This artificial virus is made from the outer envelope of HIV, the human virus, along with the inner workings of a strain of SIV, the monkey form of AIDS. This SHIV was a fairly mundane AIDS virus until it was used to infect a series of monkeys; it underwent mutations, becoming so powerful that it kills rhesus macaques in weeks.

"It became terribly pathogenic," researcher David Watkins, of the University of Wisconsin in Madison, said. This SHIV can obliterate vital immune system cells, called CD4s, "and in two weeks, [there were] no CD4 cells. That's it. That doesn't occur with HIV in people."

In other words, the disease itself is different. Unlike AIDS, this virus produces a rapidly lethal immune system wipeout.

"Now, does SHIV89.6p represent a model for human disease?" asked Dr. Gary Nabel, director of the National Institutes of Health's Vaccine Research Center. "I think there's a lot of concern. It's a cloned [artificial] virus, it rapidly kills off CD4 cells. I think it's an open question, and I think it would be a mistake to assume too much."

Nevertheless, three years ago, in hopes of standardizing some aspects of vaccine research, the NIH convened a meeting to choose a "challenge virus" for all HIV monkey vaccine experiments. The designated virus would thereafter be given to every experimentally vaccinated monkey, to test whether the monkeys' immune systems could withstand infection.

Some scientists said the best way to challenge a candidate vaccine was with a virus that was identical to those spreading among wild primates in Africa. But Letvin argued successfully for this particular SHIV because "it's very pathogenic, and quickly produces disease. It provides a rapid readout for many vaccine concepts. Where an answer in a [normal] SIV model might take many animals, and many months, SHIV89.6p tells you what you need to know in a few animals, after weeks."

And given the high cost of obtaining and caring for research monkeys, coupled with humanitarian concerns about limiting the number used in experiments, saving time and money is important. The virus is now used as an AIDS vaccine challenge in all NIH-funded efforts.

In people, HIV first causes infection by attaching itself to bumps on the surfaces of immune system cells called macrophages. The bumps, called ccR5 receptors, have a special shape to which the virus must be able to lock itself. Once inside the macrophage cells, HIV rapidly replicates, floods the bloodstream with viruses and causes a brief flu-like illness. After that, HIV settles in for a years-long siege. Every day, billions more viruses are made, and immune system cells that bear those bumps are killed off.

Years later, new HIVs take over, using a different bump on cells, called cxcR4. Deterioration into AIDS and death usually follows.

If the ccR5-using viruses are nasty, the cxcR4-using HIVs are, by contrast, homicidal maniacs - and this developed SHIV is the ultimate: a cxcR4-using virus that obliterates the immune system's T- cells far faster than any natural AIDS virus, causing an acute disease, rather than the persistent, prolonged form seen with natural HIVs and SIVs.

"The kinds of viruses transmitted in humans are ccR5 viruses. So why would you use a cxcR4-using virus as a challenge? There's no good reason," argues HIV vaccine researcher John Moore, of the Weill Medical College of Cornell University, in Manhattan. "You're looking at an aberrant situation. I think the best of the vaccine concepts are going to do OK against other challenge viruses, but there are too many vaccines that are doing too well against the SHIV virus that didn't work against SIV."

Vaccine researcher Dennis Burton, of the Scripps Research Institute in La Jolla, Calif., calls the SHIV "a crash and burn monkey model." In a sense, he says, this SHIV is producing a disease that is like flu: an immediate high fever, acute fatigue, nausea and other symptoms.

And unvaccinated monkeys that survive go on to live for months without contracting AIDS - far longer than SIV-infected animals. This, Burton argues, proves that the immune response to SHIV is radically different from that which animals muster against natural SIV infections. Watkins has done experiments directly comparing animal responses to SHIV versus SIV and found they are very different, and vaccines that seem to work against SHIV do not usually work against SIV.

"And that, to me, is the most worrying thing," Burton says. "I think it would not surprise me if you used all the SHIV-tested vaccines in HIV and they did not protect. Hopes may have been raised too high, too quickly."

Even if future experiments testing these vaccines against natural SIVs proved promising, their actual effectiveness is limited. None of these vaccines produce the sorts of neutralizing antibody immunity that prevents infection. Rather, they stimulate the cellular arm of the immune system, boosting the body's ability to slow down the virus' otherwise relentless course toward AIDS.

"Right now we have what I would call different milestones that we could hope to achieve in a vaccine," Nabel explained. "What the monkey model shows us is that we can convert the disease from lethal to largely asymptomatic. How that translates to humans is largely theoretical."

John Shiver and a team of scientists at Merck Pharmaceutical are proceeding with development of their SHIV-tested candidate vaccine - the one that scientists, skeptics and optimists alike seem to agree has the best chances of success.

"I think there are justifications for optimism," Shiver said in an interview. "In these monkeys, in the absence of vaccine, whether you infect with SIV or SHIV, each of these viruses establish huge amounts of viral replication in the monkeys." But vaccinated monkeys get "dramatically lower numbers of viruses," he said, indicating their stimulated cellular immune systems are successfully battling the SIV or SHIV.

Before plunging into large-scale human trials, the company has experimentally vaccinated another batch of monkeys, and just before Labor Day injected those animals with challenge doses of natural SIV strains. Desrosiers insists that every potential vaccine should now be retested against wild type SIVs, and SHIV89.6p should no longer serve as a gold standard of vaccine development.

"If you look back to the early days when people started doing the first monkey trials, one of the things we learned was that you could get any results you wanted in your vaccine trial if you used the right challenge strain," Desrosiers, who has done more monkey AIDS vaccine research than anyone in the field, said. " ... If one accepts the notion that you can get anything you want out of a monkey trial, just by picking the right challenge virus, it's hard to know what we're seeing right now."

The website for the Vaccine Conference is:
http://www.AIDSvaccine2001.org