By Rick Weiss
Washington Post Staff Writer
Wednesday, September 3, 1997
ST. LOUIS -- Inside a small and nearly windowless downtown medical clinic, Tim Lynch rolls up one sleeve of his T-shirt and looks straight ahead, trying not to notice the stainless steel needle being unsheathed beside him.
Lynch, who is 35 and gay, is not infected with HIV, the virus that causes AIDS. But if all goes well in the next few weeks his body will behave very much as though it were.
St. Louis University vaccine researcher Robert Belshe leans forward, slides the needle into Lynch's arm and pushes the plunger on the syringe, propelling about a million specially modified viruses into the man's muscle.
They are canarypox viruses, which cause disease in birds but are harmless in people. Each one has been genetically engineered to contain three extra genes that are normally found only in HIV. The goal is to introduce some of the hallmarks of HIV to Lynch's immune system, so he can build up a SWAT team of antibodies and white blood cells capable of fighting off a real infection, should one ever occur.
Lynch is one of thousands of healthy people in the United States who have agreed to lease their immune systems to science for a period of months or years, as part of the quest to develop an AIDS vaccine. It is a quest that has proven exceedingly and unexpectedly difficult.
AIDS vaccine researchers have endured so many disappointments in the past decade that some began to think their mission was impossible. HIV has shrugged off dozens of experimental formulations that almost certainly would have felled lesser viruses. Meanwhile, progress has been hampered by a lack of investment from private vaccine developers and a federal research program criticized as lacking in leadership.
Yet a new, if cautious, optimism has emerged among many AIDS vaccine researchers in the past year or so. Using salvaged bits of information from otherwise failed experiments, scientists have been developing a picture of what a successful AIDS vaccine would look like -- then building and testing vaccines along those lines and getting them into human trials. Increasingly, the results of those trials have been offering up more good news than bad.
Political and economic will may also be on the rise. This summer, President Clinton declared a national goal of producing an effective AIDS vaccine within 10 years. He also called for the quick creation of a vaccine research center at the National Institutes of Health.
"It's still not going to be easy," said Patricia Fast, associate director of the vaccine and prevention research program of the National Institute for Allergy and Infectious Diseases, the NIH branch that holds primary responsibility for the federal war against AIDS. "But the idea that it's impossible," Fast said, "is gone."
The need for an AIDS vaccine has never been greater. Although new and potent drugs are proving remarkably effective in many patients, scientists are concerned that those benefits may not last forever. And the new drugs are largely unavailable or unaffordable in developing countries, where 95 percent of the world's new cases are emerging.
"We'll never end this epidemic unless we have a vaccine," said Sandra Thurman, chairman of the White House Office of National AIDS Policy.
Recent progress notwithstanding, the art and science of making a vaccine remains frustratingly inexact -- and the testing process remains fraught with dangers. In Lynch's case, for example, no one knows whether the engineered bird virus might someday make him or his fellow volunteers ill. Also worrisome: Animal studies have suggested that AIDS vaccines may in some cases speed, rather than slow, the progression of AIDS in vaccinated people who eventually become infected with HIV.
Moreover, any experimental AIDS vaccine worth its sting will leave volunteers awash in HIV antibodies, which means they will test positive on an AIDS test even if they do not have AIDS. That could wreak havoc with efforts to gain employment, insurance, or visas for travel to countries that demand evidence of HIV status.
Even Lynch, who works as a case manager at a local agency that distributes emergency financial aid to people with AIDS, had second thoughts when he came in for the first of three scheduled inoculations. "There was a brief moment of anxiety," he conceded. "But I've had a couple of very close friends who have contracted HIV in the past few years," he said softly. "If it helps get us even one step closer to a vaccine, then it's well worth it."
In his office overlooking the St. Louis University campus, Belshe recalled his involvement in previous vaccine efforts, which ultimately led to the development of highly effective vaccines for measles, whooping cough and a fatal kind of childhood influenza. The challenge of creating an AIDS vaccine is unlike any other he has faced, he said.
HIV's uncanny knack for mutation makes it a constantly moving target, said Belshe, who heads the AIDS Vaccine Evaluation Group, an NIH-funded network of research sites in six U.S. cities. Making matters worse, the virus infects the very immune system cells that are meant to attack it -- the cells a vaccine is designed to rally.
Then there is the still unanswered question of what, exactly, a vaccine ought to do to elicit a state of protective immunity. Is it enough, for example, that a vaccine produce anti-HIV antibodies in the blood? Doubts seem justifiable; HIV-positive people make antibodies by the billions without any obvious therapeutic benefit.
Some scientists believe that the problem with antibodies is mostly one of timing; antibodies made in response to an infection may appear too late to do much good, while a vaccine-induced arsenal of antibodies, ready to strike at the very first sign of infection, might protect a person from AIDS.
Then again, antibodies may simply not be up to the task of tackling HIV. In that case, scientists may have to concentrate on vaccines that stimulate the other major branch of the body's armed forces: fierce immune system cells called killer T-cells.
"It's going to require several field trials of different types of vaccines to find out," Belshe said.
The usual approach to answering such basic scientific questions is to conduct studies in animals. But here, too, HIV has been uncooperative. The virus does not infect mice or monkeys, the workhorses of basic biological research. And although chimpanzees can be infected with HIV, they do not become sick for at least a decade -- making them only marginally more useful than human beings in studies of vaccine efficacy.
So it is that researchers have called upon an ever growing number of human volunteers to help them test experimental AIDS vaccines. To date, more than 2,000 healthy volunteers in the United States have participated in about 40 small clinical trials.
The process has been a study in disappointment, and AIDS vaccine researchers repeatedly have had to lower their expectations. The idea of creating a vaccine that would not only prevent new infections but would also be therapeutic in people already infected with HIV has mostly dropped by the wayside, for example. With the exception of one or two companies banking on the long shot of therapeutic vaccination, everyone trying to develop an AIDS vaccine is now focusing on prevention.
Even the goal of completely preventing HIV infection -- what scientists call "sterilizing immunity" -- is not considered achievable, at least for now. The current aim is to make a vaccine that can muffle the normally rampant viral multiplication that occurs soon after infection -- the "viremia" through which a small platoon of viruses in a few drops of semen or blood blossoms into a florid infection. The hope is that the body will be able to keep the few remaining viruses suppressed, and symptoms at bay, for many years and perhaps indefinitely.
"In the past we maybe inappropriately said we'll judge a vaccine primarily on the basis of being able to prevent infection completely," said NIAID chief Anthony S. Fauci. "Now we're thinking maybe it's enough if you get infection but not disease. Until recently we never considered that."
Increasingly, these more modest goals are coming within reach. Chimpanzees and monkeys inoculated with experimental vaccines and then challenged with big doses of HIV (or SIV, the monkey equivalent of HIV) have in several cases been able to block the initial viremia, with virus levels dropping quickly to near zero -- although in some cases infection reappears later, evidence that the virus was simply suppressed for a time.
It would be unethical, of course, to expose human volunteers to HIV deliberately. But in recent tests in volunteers, several different vaccines have elicited responses similar to those seen in animals.
In early human tests of the canarypox vaccine given to Lynch, for example, the bird virus and its Trojan horse cache of HIV genes stimulated a potent blend of both killer T-cells and antibodies. Moreover, researchers found they could boost HIV antibody levels in these volunteers even higher by following up with additional shots of gp120, a laboratory-grown protein identical to one found on the outer envelope of HIV.
In an especially inspiring result reported in May, killer T-cells induced by the canarypox vaccine fought off multiple strains of HIV in test tubes -- including strains from Africa and Asia -- even though the vaccine is made from genes taken from a single North American strain of HIV. That provided the first solid hope that researchers may not have to develop separate vaccines for each of the eight major known strains of HIV that infect people in different parts of the world.
In June, the NIH gave the nod to try this "prime-boost" approach -- modified canarypox followed by gp120 -- in a phase II test of 420 people in 14 cities, including St. Louis. If the vaccine still looks safe and stimulates reasonable numbers of antibodies and T-cells in these people, then it may become the first AIDS vaccine ever to be promoted to a full-scale testing to determine its effectiveness.
That trial would be unprecedented in size, scope and significance, involving 5,000 to 10,000 HIV-negative men and women deemed at high risk of getting AIDS, and would go on for several years. Out of such a trial, the world's first marketable AIDS vaccine would emerge.
The canarypox vaccine, made by Pasteur-Merieux/ Connaught, is only the second AIDS vaccine to have made it even to phase II testing in the United States. The other, a genetically engineered version of gp120 given alone, gave mixed results a few years ago that some interpreted as hopeful and others as too equivocal to justify the expense of a phase III study. In June 1994, citing gp120's inability to stimulate T-cells, the failure of gp120 antibodies to neutralize some strains of HIV, and a lack of support from the gay community -- where the vaccine would be tested -- NIAID director Fauci decided against large-scale testing.
It was a decision that haunts Fauci to this day -- not because he thinks it was wrong, but because he will never know whether he was right. Others, like Belshe, are more certain.
"It was the worst decision the NIH ever made in terms of vaccine development," Belshe said. "We knew it was safe. We knew it induced antibodies. I have no idea how well it might have worked, but now we never will know because they pushed a negative decision too fast."
Moreover, Belshe argues, that controversial decision had repercussions beyond gp120 that can still be felt today. "It showed uncertain support from the government. It said to manufacturers, 'We're not going to back this effort.' "
Corporate reticence has persisted ever since, according to a December 1996 analysis by the nonprofit AIDS Vaccine Advocacy Coalition (AVAC). "Of the five leading global vaccine manufacturers, only two (Pasteur-Merieux-Connaught and Chiron) have broad-based HIV vaccine programs that are pursuing a number of approaches," the group found.
Two other global companies (SmithKline Beecham and Wyeth Lederle) have no significant AIDS vaccine effort, while the remaining large company (Merck & Co.), and several smaller biotech companies, are focused on a single approach each -- meaning that if a company's particular idea fails, then that company's participation in AIDS vaccine research will abruptly end.
Why aren't companies battling to dominate the potentially huge AIDS vaccine market? AVAC found that corporate officers were intimidated by the scientific difficulty of the task and were concerned about potential liability. A recent analysis by the Washington-based International AIDS Vaccine Initiative confirmed a "low level of commitment from private industry," and blamed it in part on corporate fears that the vaccine would not prove profitable since it would be marketed mostly in developing countries.
A lack of coordination in the government's own basic research program has also slowed progress, according to a March 1996 report commissioned by the NIH. In response to that report, NIH chief Harold E. Varmus set up an AIDS Vaccine Research Committee, headed by Nobel laureate David Baltimore, to help coordinate the government's support of basic AIDS vaccine research.
NIH's budget for HIV vaccine research is scheduled to increase next year to about $ 117 million, or 17 percent of the total NIAID budget. That's up from 11 percent this year but still lags significantly behind the proportions going to basic AIDS research (23 percent) and AIDS therapies (45 percent).
Most of this attention will be focused on three types of vaccines: genetically engineered proteins and peptides such as gp120, live virus vaccines such as the canarypox formulation, and "naked DNA" vaccines made from raw pieces of HIV genetic material that mimic a real HIV infection. A fourth approach -- more radical and controversial than any other -- could also start to get renewed attention: vaccination with a strain of weakened but living HIV itself.
The prospect of injecting healthy HIV-negative people with live AIDS viruses is seen by many people as irrational and unethical, since even weakened viruses can turn deadly. In two recent experiments, monkeys inoculated with a weakened version of SIV quickly came down with an AIDS-like disease, apparently as a result of the vaccine itself.
Moreover, HIV belongs to a family of viruses known for their ability to cause cancer many years or even decades after infection. "How long are you going to wait before you determine that a live HIV vaccine is safe?" asked Robert C. Gallo, chief of the Institute of Human Virology in Baltimore and co-discoverer of HIV. "What if you wait 10 years, and then after 20 or 30 years you find out it causes leukemia?"
Yet proponents of a "live attenuated" HIV vaccine note that the most effective viral vaccines today -- including those directed at smallpox, yellow fever, measles, mumps and rubella -- are made from weakened viruses. And despite some failures, animal studies of live attenuated AIDS vaccines have mostly been extremely encouraging.
Human trials have also been done, through accidents of nature. In Australia, scientists have been studying about a dozen men who became infected with a strain of HIV that naturally lacks a gene called nef, which normally helps the virus replicate. These men have remained healthy since becoming infected many years ago, even though at least one of them has apparently had multiple exposures to virulent strains of HIV since then.
Recently, Ronald DesRosiers of the New England Regional Primate Research Center in Southborough, Mass., created a version of HIV that lacks not only the nef gene but also three other chunks of HIV DNA, as an added safety margin. Now scientists are starting to ask whether the time is right to test this vaccine in people -- and if so, who should be the first to accept such a potentially dangerous mission?
Last month, in a bold move, the Chicago-based International Association of Physicians in AIDS Care called for doctors to volunteer as test subjects for a proposed trial of the DesRosiers vaccine to start by the year 2000. "It is time to follow in the tradition of Louis Pasteur, Walter Reed, and hundreds of our other colleagues who made the commitment to be the first human subjects in critical clinical trials," wrote Charles F. Farthing, a member of the 5,500-member organization. More than 25 volunteers signed up in the first two weeks.
But even if testing of a live HIV vaccine someday passes muster with regulators, it will be well into the next millennium before it progresses to efficacy testing, experts said. By contrast, a decision to conduct wide-scale testing of the canarypox vaccine could come as early as a year from now, when data from the current studies come together.
Then, as in 1994, Fauci will face the unenviable task of weighing the many risks and potential benefits of injecting thousands of people with the experimental product. He and his advisers will have far more information about AIDS and immunology than they had three years ago and will face a much more receptive audience of potential volunteers. They will also feel the heat of Clinton's call for progress, and the weight of the world's growing need for a vaccine.
At the same time, Fauci will be burdened by many of the same unknowns that plagued him in 1994 -- questions about safety and efficacy that can never be fully answered without going forward, and uncertainties about whether it is wiser to wait for the next best product or to move ahead with what is in hand.
For Fauci, who has devoted so much of his professional life to battling AIDS, and for the millions of people in the world who today walk the precipice between health and infection with HIV, it may be the most important decision he ever makes.
"You hope the data will be so strong that it becomes a no-brainer," Fauci said. But he's been in the trenches long enough to know that nothing about HIV is that simple. "You hope it will be a slam dunk, but it's unlikely that will be the case."