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Hopes for AIDS Vaccine Still Alive Despite Setbacks
Date:12/1/2008

The lesson from 2 failed trials: The science must be more vigorous, experts say

MONDAY, Dec. 1 (HealthDay News) -- Nobody said HIV would give up without a fight.

As World AIDS Day arrives Dec. 1, scientists are taking a sobering look back at what went wrong in recent, high-profile failures of two human trials of candidate AIDS vaccines.

The consensus: A viable vaccine is still very possible, and with it comes the potential to wipe out HIV/AIDS. But the science behind any new candidate vaccine must be much stronger than it has been in the past before testing begins in humans.

"We are going to be better served to try and find out the basics of what the immune response is to HIV, what the limitations are, and how we can tweak or change that, or come up with something entirely new," said Rowena Johnston, vice president of research at the Foundation for AIDS Research (amFAR) in New York City. "And only then can we start to think about a product that could be taken into humans."

Just two potential HIV vaccines have made it so far to human clinical trials: VaxGen's AIDSVAX, tested in Thailand, until the trial was stopped in 2003; and Merck & Co.'s HIV vaccine, which was tested in North and South America, the Caribbean and Australia, until it proved a failure in 2007.

In the Merck case, the trial results have also been shadowed by speculations that the vaccine somehow tweaked some recipients' immune systems to make them slightly more vulnerable to HIV infection.

Some experts in the field now believe that both vaccines were rushed too soon into human trials. One big flaw: Primate trials matched the vaccine to the strain of HIV the monkey was exposed to. That's unlike "real world" human infections, where people may be randomly confronted with any number of strains, experts said.

"What you want to do is have evidence in primates that you can block completely, or nearly completely, a challenge with at least one, if not two or three challenges with heterologous [varied] strains of virus," said U.S. AIDS pioneer Dr. Robert Gallo, who is credited (along with French researcher Luc Montagnier) of pinpointing HIV as the cause of AIDS back in the early 1980s.

A broadly protective vaccine would be tested against "very different strains than the strains used to make the vaccine," Gallo explained. "None of that had been done before the clinical trials that have been in the press."

Still, it's a daunting task considering that the variety of viral strains circulating in a single infected human body exceeds the variety of flu strains circulating globally each year, according to Wayne Koff, senior vice president of research and development at the International AIDS Vaccine Initiative (IAVI), based in New York City.

According to Koff, a good AIDS vaccine's reach "needs to be broad to be able to tackle whatever isolate of HIV the individual happens to be exposed to."

Vaccines work in two key ways. First, they prime the body's immune cells to recognize proteins on the virus' surface so they can be identified and destroyed. This "neutralizing antibody" effect typically eliminates all but a fraction of invading virus.

But a remnant of virus will still get through, infecting human cells. That's where a second arm of vaccination, called the "cell-mediated" response, comes in. This involves the mobilization of immune T-cells that seek out and destroy infected cells.

Any viable vaccine must wipe out the virus quickly and completely, Koff explained, "So, we need each of these two arms primed and ready for when you get exposed to HIV."

But there's yet one more hurdle unique to HIV. Unlike standard flu or cold viruses, HIV -- a more primitive retrovirus -- actually inserts a piece of its DNA into the genome of the human host cell.

This "integration" begins within hours or days of infection, mainly in the lymphoid tissues of the gut, and lasts a lifetime. Using these cells as a base, HIV can then amplify and mount an attack at any time.

"This means that both antibodies and activated T-cells will have to be [targeted] to where the virus is amplifying early," Koff said. "If we don't get it then, and it seeds other lymphoid organs in the body, then from a vaccine point of view, the party's over."

So, those are the main components of any viable vaccine: a broad immunity against a variety of strains; a two-pronged immune attack that involves antibodies and T-cells; and a "hit-hard, hit-early" approach that stops HIV from setting up it's stronghold in the gut.

And, as Gallo, stressed, "any immune response must last, because we can't vaccinate every couple of months."

The task ahead seems daunting, but progress is being made, the experts said.

According to Gallo, his lab at the University of Maryland's Institute of Human Virology has one promising candidate. In primate trials, the vaccine has fulfilled most of the criteria -- except that immunity seems to fade with time.

"If we can solve the problem of keeping immunity going long-term, I'd say it's a candidate-rational vaccine," Gallo said.

Over at the University of Wisconsin, Madison, a group led by pathologist David Watkins has successfully tested a vaccine that has provided monkeys with protection from up to 20 different strains of the simian equivalent of HIV, using only T-cell mediated immunity.

Similar experiments have panned out well in pathologist Louis J. Picker's lab at the Oregon Health & Science University, Koff noted.

At the same time, money continues to pour into HIV vaccine research, either from private industry or from nonprofit sources such as the Bill and Melinda Gates Foundation, IAVI, and the U.S. National Institutes of Health.

The failures of the past have also toughened the science, the experts said.

"Over the past year or two, there have been a lot of calls for a return to basic science, rather than [quickly] testing candidates in people," Johnston said. "It all comes back to a question of doing our homework in basic research, so that we can really come up with a strong candidate that we can have a lot more optimism for."

Gallo agreed.

"There were a number of people in the past who were thinking naively that anything was going to work," he said. HIV has proven much tougher than that, of course. "However, I still believe that a vaccine is do-able, or I wouldn't be working on it," he said.

More information

Find out more about the search for an AIDS vaccine at IAVI.



SOURCES: Wayne Koff, Ph.D., senior vice president, research and development, International AIDS Vaccine Initiative, New York City; Robert Gallo, M.D., director, Institute of Human Virology, University of Maryland School of Medicine, Baltimore; Rowena Johnston, Ph.D., vice president, research, Foundation for AIDS Research (amFAR), New York City


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