For the first time in the decade-long battle against AIDS, most scientists say they believe the development of an effective vaccine against the human immunodeficiency virus is likely, even if it is years off.
As recently as a year ago, leading AIDS experts said it would be impossible to develop a vaccine against HIV because it can insert itself in human genes, hiding for months, perhaps years, from the body's immune defenses. It also rapidly mutates, presenting an ever-changing target and making eradication of the virus extremely difficult.
But scientists in the past year have immunized animals against the AIDS virus, overcoming what had long been considered one of the "impossible" obstacles to vaccine development. That success and others have created a new optimism as an estimated 12,000 experts prepare to gather in San Francisco for the 6th International Conference on AIDS June 20.
"I do think a vaccine is possible. I think it is too many years away, though, to guess when we will have it," Dr. Clifford Lane of the National Institute of Allergy and Infectious Diseases' vaccine program said in an interview with Newsday.
"I am quite excited, and we are working like the dickens now," Duke University's Dr. Dani Bolognesi, long a skeptic, recently said.
"It's getting to be more and more visible that a vaccine is possible at this point," Johnson & Johnson vaccine researcher Dr. Yair Devash said recently.
But scientists are quick to add that the moment's euphoria is merely a celebration of learning that the impossible might be possible. Interviews with more than 50 of the world's top AIDS researchers and recent studies show that problems associated with the AIDS virus may not be insurmountable, but no obvious candidate for a safe, effective vaccine currently exists.
"I don't hold any hope for any of the vaccines that are in clincal trials right now," Dr. June Osborn, chair of the National Commission on AIDS, said in an interview. "I don't see the rationale for the clinical studies at the moment. Until we come up with a vaccine that is based on rational science we are not going to get anywhere.
"I think it is at least a decade away," she said.
Traditionally, vaccines are made from a virus. In some cases, a small sample of live viruses is injected into people. More commonly the virus is killed before being injected. In the past five years genetic engineers have invented ways to create harmless pieces of protein that mimic viruses for use as vaccines.
Regardless of the way the viral sample is prepared, the result is the same: the immune system sees the vaccine in the bloodstream and recognizes the presence of a foreign invader. Antibodies are made against the invader, and the ability to make a defense against the virus is memorized in the immune system.
Key to developing any vaccine is selecting the proper target, the correct virus. If, for example, Americans were vaccinated against the Hong Kong strain of the flu virus one year, but an entirely different strain from Argentina swept the nation, the vaccination effort would be useless.
All of the vaccines currently being used on hundreds of human volunteers in the United States are based on a strain of the human immunodeficiency virus called HTLVIIIb. Portions of that strain have been chopped up, killed, artificially replicated and manipulated in a host of ways to create a target.
But it's the wrong target.
The strain HTLVIIIb is one of the least common of what may be hundreds of AIDS viruses found in nature. In fact, HTLVIIIb may only still exist in laboratories, said Bolognesi, whose team is analyzing all the strains of HIV found in nature and looking for groups that share enough common features to make a vaccine possible. If such groupings exist, it might be possible to make a small number of vaccines - one against each group - providing protection against all the hundreds of AIDS strains in nature.
"It's still early," Bolognesi said, "but we think it may be possible there are just five major classes of HIV viruses," in North America, the largest of which, comprising more than 30 strains, is a group dubbed MN. "So there are a lot of viruses out there that could be neutralized by MN-specific antibodies," he said.
Johnson & Johnson's Devash and Dr. Ayre Rubinstein of the Albert Einstein College of Medicine in the Bronx recently discovered that HIV-infected pregnant women make antibodies against MN-class AIDS viruses. If women have high levels of anti-MN antibodies, their fetuses are protected from infection by a virus which, nevertheless, is slowly killing the mothers. In other words, the babies are vaccinated, Rubinstein said in an interview.
"This gives you a rationale for a vaccine for the first time. And we already have made a vaccine which I hope to produce for use in monkeys," Rubinstein said in an interview.
Lane heads several of the infectious disease institute's studies using human volunteers who are receiving a vaccine manufactured by MicroGeneSys of West Haven, Conn., and based on the HTLVIIIb strain. "I certainly wouldn't pick IIIb as the antigen to use today, but those trials were initiated three years ago. And at the time it was the only [completely analyzed] strain we had. I figured if that wasn't going to be 'it', it would help us find 'it,' " Lane said.
The national search for "it" is conducted out of an inauspicious office in a small building in suburban Rockville, Md., where the institute's Dr. Wayne Koff glances at a magnetic scoreboard on his wall. By shuffling the magnets, Koff can keep track of which of the 30-some vaccine candidates being studied in the United States, Europe and Africa have entered clinical trials. Ten magnets on his board have made it to the Phase I column, just two columns shy of being marketed products.
But those two columns represent hurdles all scientists agree will be hard to jump. Some insist it will be impossible.
Vaccines in Phase I are being tested on small groups of human volunteers. A serious adverse reaction would probably knock the candidate off Koff's board.
On the other hand, after several good performances - if the candidate vaccine was safe and seemed to offer some hope of efficacy - Koff would likely recommend that the developers ask the federal Food and Drug Administration for approval to go to Phase II: small human efficacy trials to see if the vaccine actually works. The tests are conducted by drawing blood from the vaccinated volunteers and then challenging that blood with live HIV in the laboratory. If the vaccine works, the virus is killed off. At some point, volunteers would have to be exposed to live virus, though there is no consensus on how to do this without violating medical ethics. For example, one suggestion is to conduct trials among people who are at very high risk for infection, such as Central Africans, and observing over time how many get infected.
If any AIDS vaccine candidate ever reaches Phase III, it will be tested on tens of thousands of volunteers, Koff said. As the size of the test group grows, it offers scientists a way to study different dosages and to discover side effects.
"We're almost at the point now where we can begin to weed these down to a finite number of candidate AIDS vaccines, and what that is going to take now is a couple of years of animal experimentation," Koff said.
Until this year it was unthinkable that any AIDS vaccine effort would pause to consider how the product performed in animals. The first hint that an animal model for testing AIDS vaccines might work came from Dr. Michael Murphey-Corb's Laboratory at Tulane University in New Orleans. Murphey-Corb injected a group of rhesus monkeys with a vaccine against SIV, the monkey form of AIDS. She then injected the monkeys with live virus and saw that nearly all the animals mustered an immune response against SIV.
Murphey-Corb said she was once all alone in believing that a monkey could be used as a test animal for possible vaccines. "So they moved ahead into humans. I think they did it out of desperation," Murphey-Corb said. "In Washington you will now see far more reservation about going forward into people without first getting a trial in rhesus. Otherwise, you're just using people as experimental subjects - as substitutes for rhesus and chimpanzees."
But the Murphey-Corb model is far from conclusive, critics say. It is based on SIV, not the human AIDS virus. And because the monkeys were challenged with the same SIV strain with which they were immunized, Murphey-Corb said she does not know if the animals have been protected against a realistic range of SIV strains. Harvard's Harry Kestler led a team of scientists at the New England Regional Primate Research Center that recently created a special ultra-lethal strain of SIV that kills monkeys in less than a year. Further refinements, they predict, will provide a strain that kills 100 percent of infected rhesus within six months, greatly speeding up animal research.
Perhaps more encouraging was a May announcement from France's Pasteur Institute that scientists had succeeded in vaccinating two chimpanzees against HIV, the human virus. The French team immunized chimps with what Koff called "The Kitchen Sink Vaccine," giving the animals exposure to a very broad range of HIV-related targets and the smallpox vaccine. Genentech, Inc., a California biotechnology company, announced this month that it, too, had successfully vaccinated two chimpanzees, using a genetically engineered form of a part of the outer shell of the HIV virus. It is unclear how this approach would work for humans.
Any testing system based on chimpanzees, the animal genetically closest to humans, is unlikely to be put into widespread use because the animals are on the endangered species list, limiting their importation and use, Koff said.
Which is fine with Dr. Don Mosier of the University of California in San Diego. Mosier says mice, not monkeys or chimps, should be used to test vaccines.
Mosier is working with a genetically bizarre type of mouse, called SCID, which has virtually no immune system. Mosier transplanted cells from the immune systems of people into SCID mice and found the human cells thrived. In his pivotal experiment, Mosier removed immune system cells from volunteers who had received an experimental AIDS vaccine at the University of Washington or Johns Hopkins School of Medicine. Four weeks later he injected the mice with a huge dose of live HIV virus.
Five out of six mice that got cells from people vaccinated at the University of Washington were "well protected against the virus," and no HIV could be found in their bodies a month after challenge, Mosier said. The mice that got cells from Johns Hopkins donors were unable to fight off the virus.
A month after the challenge, Mosier found "high levels of virus" in control mice that had received cells from unvaccinated people.
"This [SCID) model allows us to take parts of the human immune system, transfer it to the mouse and ask what's going on. It may not be perfect, but it certainly is going to move us much, much faster," Mosier said.
The FDA's Janet Woodcock, who oversees the agency's response to AIDS vaccine development, said in an interview that because of this year's breakthroughs in animal research, "people should explore their candidate vaccines in the animal models that are available, before moving to human studies, unless the strategy they are exploring involved 'uniquely human molecules.' "
Dr. Anthony Fauci, director of NIAID, said in an interview that the new evidence in animal models has changed the vaccine picture throughout the federal research establishment, and "there is a reluctance to go into efficacy testing [Phase II] in man unless you've proven a candidate is safe in an animal model." If potential manufacturers are required to perform animal tests before moving to clinical trials, the time required to develop an AIDS vaccine could be lengthened by at least a year, Koff said.
"How do you test a vaccine against a sexually transmitted disease," Col. Edmund Tramont, head of the U.S. Army's vaccine effort, asked. Gazing about his office at the Walter Reed Medical Center in Washington, Tramont pointed out that vaccine development was the hallmark of Army medicine. But even the Army, he said, can't figure out how to test an AIDS vaccine's efficacy without animal studies.
"I understand how desperate people are, but I can't ethically give something to someone without having some idea what I'm doing. I mean, that's unethical. In fact, that's unethicism in the worst way. I may be killing you. I may be making it worse. We may see a transient protection and then a big crash," Tramont said.
But Tramont plans to expand the Army's studies of the MicroGeneSys vaccine to include "hundreds" of volunteers this summer. The infectious diseases institute's Lane also plans to expand vaccine trials of current candidates and said he would gladly try other products in people before they are tested in animals.
"People will say you shouldn't do a vaccine trial because we haven't shown it's a system that works in the monkeys with SIV or the SCID mice or whatever. I'll ask from now until that happens how many hundreds or thousands of people will be infected with HIV while we do animal studies," he said.
"What do we lose? If the vaccine is toxic, we made a major mistake, we hurt a lot of people. Well, that's a danger of clinical research. People who volunteer accept that risk - that's what it's all about."
One reason to move ahead with human trials, Lane said, is to resolve the puzzles surrounding the way people's immune systems have responded in some of the clinical trials. Some candidate vaccines boost antibody production, but these appear to be "useless" antibodies that cannot neutralize the virus. Huge boosts in other components of the immune system have resulted from candidate vaccines but nobody is sure what they mean.
"The resources are being poured into those experiments now, to try and find out," what parts of the immune system fight off HIV, Koff said. "Until now, we could just sit around a table and one person would say, 'I think T cells are important.' And another person would say, 'Antibodies are important,' and so on. We just didn't have any idea," Koff said.
The confusion arises largely from what Koff calls "the V3 problem."
Peter Nara of the National Cancer Institute has found that when neutralizing antibodies are made by either humans or monkeys they are directed toward a very tiny loop of the virus called V3. Nara showed that people can make effective anti-V3 antibodies when first infected, but within "a matter of days" the virus mutates to create a change in the shape of V3. People continue to make antibodies, but they no longer work, Nara explained in an interview, because the antibodies don't fit over the newly mutated V3 loop.
Even more troubling, Nara said, is the finding that once the immune system starts making one type of anti-V3 antibody, it seems to be unable to change, to adapt to viral mutations. So the entire immune system is "locked into a futile exercise," he said.
Dr. Robert Gallo said the V3 problem is so immense that, "it means that if AIDS is ever solved with a vaccine there will be a lot of other viruses conquered, too. It means a major new thing will have occurred in science." No traditional vaccine, he said, will ever conquer HIV.
The Army's Col. Tramont thinks the viral variation problem can be conquered, and predicted, "we will have a vaccine, by the year 2000." But because of the virus' ability to hide inside human genes, he said, "I don't think we'll have a blockbuster. I think we will have something that we will inject that will change the status of the disease process," but the virus will remain hidden inside their genes, he said.
Tramont's view is shared by AIDS experts from Jonas Salk to Robert Gallo, all of whom now believe the ability of the virus to go latent - becoming a "provirus" - means no vaccine will ever eradicate the AIDS virus from the human population.
"It all comes back to how we deal with latency. Are we going to prevent the proviral stage? If that's what you mean by a vaccine then I don't think we'll ever have it. But to prevent clinical disease, I think we'll get there. But you've got to think about that. Do you want a piece of provirus running around in your body?" Tramont asked.
Finally, few pharmaceutical companies are enthusiastic about AIDS vaccine work, Koff said, because "the total amount of revenue on all vaccines last year was under $200 million. And if the estimation now is $100 million to bring a product into the marketplace, even if it's only $80 million, you're not looking at a major return," he said.
The demographics of who is getting AIDS is changing, shifting throughout the world to poorer populations. Vaccine manufacturers know that within 10 years the major purchasers of an AIDS vaccine will be the World Health Organization and governments, not individuals. And that means, Koff said, there will be strong pressure to keep costs low.
So, Tramont said, while many scientists are newly optimistic this spring about the future of AIDS vaccines, "we're just getting out of the batter's box," he said. "Yet you hear all these people talking about a breakthrough, like we had a home run already. Baloney. We haven't. You know, let's keep it in perspective, folks."
How a Vaccine Works
1. A solution containing live viruses, killed whole viruses, or pieces of virus is injected into a healthy person
2. White blood cells, called B cells, see the vaccine-viruses and make antibodies that attach to the viruses.
3. Other white blood cells, called macrophages or killer T cells, engulf the virus-antibody complexes.
4. Booster injections of the vaccine help the B cells "remember" the viral enemy so that if the person is ever infected with the virus in the future, antibodies are released quickly and the virus is destroyed.
2. White blood cells, called cytolytic T cells, see the vaccine virus.
3. The T cells attach themselves to the viruses, eventually engulfing and destroying them.
4. Booster injections ensure these T cells "remember" the enemy, so they will be ready to attack in force if the person becomes infected in the future.