AIDS vaccine trials - Copyright The Wall Street Journal

January 17, 2002 12:36 p.m. EST

FROM THE ARCHIVES: January 17, 2002

Monkey's Death Muddles HIV Vaccine Hunt
As Researchers Keep Focus on Inoculations


Dan Barouch was almost getting bored.

A young researcher at Harvard Medical School, Dr. Barouch had helped lead one of the most prominent AIDS vaccine trials in recent years. Starting in 1999, he and his mentor -- veteran HIV scientist Norman Letvin, also at Harvard -- immunized eight monkeys with an experimental vaccine and then tested it by injecting a lethal AIDS virus into the animals. The vaccinated monkeys got infected, but they didn't get sick. Most unvaccinated monkeys in the experiment's control group quickly got AIDS and died.

These results, published in a scientific journal and widely reported in the press last October, represented a major advance. Though the vaccine didn't block infection, it did appear to keep the virus in check.

After the initial good news, Dr. Barouch had to monitor the vaccinated monkeys to see how long the vaccine held the disease at bay. Every time Dr. Barouch analyzed the lab results, usually late at night after finishing his hospital rounds, the results were always the same: no change.

Until one night. In the early summer of 2000, blood tests indicated changes in the way the immune system of monkey 798 was responding to the AIDS virus. At first, Dr. Barouch didn't know what was happening, but over the next few months, an astonishing account -- to be published in Thursday's issue of the journal Nature -- emerged of how the AIDS virus evaded the vaccine-boosted immune system, causing the monkey to sicken and die. [graphic of t-cells and AIDS virus - copyright WSJ 2002]

The fate of monkey 798 highlights the scientific gamble that some of the world's foremost research institutions and pharmaceutical companies are taking on the AIDS crisis. As the epidemic sweeps through the poorest regions of the world, infecting more than a fifth of adults in some sub-Saharan African countries, many researchers are betting on the development of a "partial protection" vaccine, which would allow the virus to secure a toehold in the body rather than repel it completely.

If partial-protection vaccines prevent AIDS or delay it for a long time, they would give HIV-infected individuals a longer life. And because they suppress the amount of virus in the body, they could also reduce transmission of the disease. But if they postpone the onset of disease for only a short time, as in monkey 798, they might actually worsen the epidemic. People might well let their guard down on safer sex and pass on a virus they thought was under control.

Among the institutions pursuing the partial-protection strategy are the National Institutes of Health; the International AIDS Vaccine Initiative; the Aaron Diamond AIDS Research Center in New York; Emory University; Yale University; Wyeth Lederle Vaccines, a unit of American Home Products Corp.; and Merck & Co.

In fact, in the very same issue of Nature in which Dr. Letvin and Dr. Barouch report their results, Merck reports what is widely believed to be the strongest monkey results yet seen with a partial-protection AIDS vaccine. Merck is also conducting early-stage human trials of its vaccine but hasn't released any results. Any partial-protection vaccine remains years away from approval for widespread use.

Unorthodox Approach

Scientists have been forced to settle for partial-protection vaccines because the classical approach to immunization -- inducing the production of antibodies that block the virus from infiltrating cells -- has proved devilishly difficult for HIV. So researchers are trying to stimulate a different arm of the immune system, called killer T-cells. Squadrons of these cells can prevent or delay the onset of symptoms, but not, apparently, bar the virus from infecting the body.

"This is a wholly new way of making a vaccine," says David Baltimore, a Nobel laureate in medicine, president of the California Institute of Technology and chairman of the AIDS Vaccine Research Committee of the National Institutes of Health.

A new kind of vaccine may be needed because HIV is a new kind of virus. HIV has evolved an array of tactics to elude the immune system. Indeed, the most disturbing revelation in the study published Thursday is how easily the virus overcame the vaccine-strengthened immune system. Apparently, all the virus needed to regain the upper hand was one tiny mutation leading to a slight change in its structure.

"It is sobering to find that a single point mutation within the virus can initiate a cascade of events resulting in clinical vaccine failure and death," the researchers write.

Dr. Barouch insists that the study "is not the death knell for these kinds of vaccines." Indeed, seven of the eight vaccinated monkeys remain perfectly healthy. "The cup is 7/8ths full, not 1/8th empty," Dr. Letvin says.

What's more, other prominent researchers conducting similar experiments -- Emilio Emini of Merck, Harriet Robinson of Emory and John Rose of Yale -- say none of their monkeys that received similar vaccines have shown signs of AIDS. In the end, partial-protection vaccines may well tip the balance in favor of the immune system and curtail the epidemic.

Still, the demise of monkey 798 suggests that the path to an effective vaccine won't be an easy one, and it illuminates the contest between one of nature's most fearsome viruses and the human immune system.

Paradoxically, many strengths of the AIDS virus evolved to compensate for some basic weaknesses. The influenza virus is more rugged, able to survive outside the body. It can move from host to host by floating in the wake of a cough or settling on surfaces. The polio virus survives in contaminated water and food. But HIV soon dies once it leaves the blood or other bodily fluids, such as semen.

HIV isn't even very good at spreading through sex. In the developed world, the odds of a woman's acquiring the virus through one act of intercourse have been estmated to be slightly less than one in a thousand. In Africa and other poor parts of the world, the virus has spread rapidly among heterosexuals in part because lesions on the genitals -- caused by poor hygiene and other sexually transmitted diseases -- open portals to the blood.

For the virus to survive long enough to move from one person to another, it had to evolve strategies to elude the immune system. Chief among these tricks is that HIV attacks the immune system itself, infecting and killing the white blood cells, called CD4 cells, that orchestrate the immune response. That, in essence, means that the immune system is forced to fight with one hand tied behind its back.

HIV has other tricks, too. It often outsmarts antibodies, which snare and neutralize a virus before it enters cells. HIV is sheathed in an envelope that mutates as the virus reproduces, yielding strains that antibodies can't latch onto.

There are a few parts of HIV's exterior that the virus needs to infiltrate cells. If these critical parts mutated, they wouldn't work properly, and the virus would die. These unchanging parts make perfect antibody targets, but in recent years, scientists have found that the virus cloaks them in carbohydrate molecules. The immune system doesn't make antibodies to carbohydrates, and so these large molecules shield the important parts of the virus.

Researchers haven't abandoned the quest for effective antibodies. VaxGen Inc., in Brisbane, Calif., has an anitbody-based vaccine in final large-scale human trials. Among other companies and research institutions working on the problem are Chiron Corp., Merck, the NIH, Cornell University, the Dana-Farber Cancer Institute, and the Institute of Human Virology, run by the co-discoverer of HIV, Robert Gallo. But driven by frustration at the difficulty of generating potent antibodies, many HIV scientists began focusing several years ago on another arm of the immune system, killer T-cells.

Mobilizing T-Cells

These special cells circulate in the body, seeking out and destroying other cells that have been infected by viruses. Partly because of his own studies, Dr. Letvin long ago became convinced that a vaccine mobilizing these cells might be able to work against HIV.

Vaccines train the immune system by using a harmless dummy virus to mimic a real infection. Jonas Salk's polio vaccine was simply a dead polio virus. Drs. Letvin and Barouch started with a vaccine, developed by Merck, consisting of two genes from the AIDS virus, and added interleukin-2, an immune-system molecule that revs killer T-cells into high gear.

Their experiment was guided by an emerging understanding of how killer T-cells work. When a virus enters a cell, it commandeers the cell's machinery -- its DNA and proteins and enzymes -- in order to replicate. David Watkins, who worked under Dr. Letvin at Harvard and has gone on to make important contributions in T-cell research as a professor of pathology at the University of Wisconsin at Madison, suggests thinking of cells as factories. "The virus wants to take over the factory and make bombs instead of shoes," he says. When that happens, the cell has to be destroyed if the body is to be protected.

How do the killer T-cells know which cells to destroy?

When a virus hijacks a cell's inner machinery, it starts churning out viral segments, called proteins, that it later assembles into full-fledged new viruses. But the cell counterattacks by asking for help in an intricate way. It cuts up some of those unassembled viral segments into tiny fragments, called epitopes. A special molecule in the infected cell then displays some of these epitopes on the cell's surface. As Dr. Watkins puts it, the molecule is "sticking the epitopes out the window and saying, 'Hey, guys, we've been turned into a bomb factory.' "

The immune system has billions of killer T-cells, but each one recognizes only a single epitope. Studies suggest that an individual's immune system usually has killer T-cells that recognize only a limited number of epitopes from the AIDS virus. As soon as a killer cell comes across its epitope, it furiously clones itself to produce a platoon of killer cells that then patrol the body hunting for cells displaying that epitope and then destroying them.

Soon after Drs. Barouch and Letvin first vaccinated their monkeys in January 2000, the researchers found that the animals generated high levels of killer T-cells directed against several epitopes of the AIDS virus. When the researchers then injected the monkeys with a live AIDS virus, the killer T-cells did what they were supposed to do: They found and destroyed infected cells displaying their particular epitopes before the cells could produce a lot of new viruses. In this way, the killer T-cells apparently held the AIDS virus to very low levels, and the monkeys stayed healthy.

In the summer of 2000, though, the researchers noticed that in monkey 798, the number of killer T-cells directed against one particular epitope -- called p11C -- had started to wane.

Dr. Letvin was pretty sure he knew what was happening, and he was eventually proved right by tests that took almost a year to complete. Analyzing the DNA of the virus, Steven Wolinsky, a professor of medicine at Northwestern University, showed that the virus had made a single mutation that took the "Help!" sign out of the factory window by shifting the shape and other properties of the epitope. The researchers couldn't rule out the possibility of other mutations affecting other parts of the virus, but they were able to prove that because of the one known mutation, infected cells were no longer able to display the epitope. Even if they could, the killer T-cells were no longer able to recognize it.

In less than six weeks, the entire virus population in the monkey changed to the mutant type. "To see complete replacement of the virus in such a short period of time just took my breath away," Dr. Letvin says.

For reasons no one yet understands, the monkey's immune system had deployed more killer T-cells against the p11C epitope than against any other. Now, all those T-cells were rendered useless, and they atrophied away.

Meanwhile, the number of T-cells that recognized other epitopes was surging to carry on the fight. Based on previous research, Dr. Letvin felt confident that the backup killer cells would control the mutated virus.

"I was wrong," he says now. As data came in during the summer and fall of 2000, "you could see the immune system was trying to keep up," he says, "but it couldn't." Monkey 798 lost its appetite, stopped moving around in its cage, and got sick.

The failure of the second-string killer T-cells is particularly disturbing. Vaccine labs around the world are trying to broaden the number of epitopes that the killer cells target. The goal is to force the virus to mutate several epitopes, rather than just one, in order to escape from the T-cells. "The more the better," says Merck researcher Dr. Emini.

But Dr. Baltimore, the Nobel laureate, notes that evidence is accumulating that the immune system tends to concentrate its killer T-cells on just one or two epitopes, as happened in monkey 798. So if the virus mutates to change the main epitope targeted by the largest squadron of killer T-cells, having more backup killer T-cells may not make a difference.

It's "a new problem," Dr. Baltimore says. "I'm so used to HIV turning around and biting you when you think you've got it that I'm not surprised."

Despite the study published Thursday, much of the field remains optimistic. Dr. Letvin and Dr. Barouch tried several vaccines on their animals, and monkey 798 got the second-best one. Vaccines that induce a stronger immune response would almost certainly work better, and Dr. Letvin has said that the best Merck vaccine reported today looks more potent than any that he has used.

And monkey 798 might be just a fluke. "It's one monkey," says Seth Berkley, president of the International AIDS Vaccine Initiative, a New York-based nonprofit agency geared toward developing an AIDS vaccine. "I would not get that alarmed."

Still, research suggests that the same problem occurs in people, and other scientists had doubts even before Thursday's obituary for monkey 798.

Ronald Desrosiers, a veteran AIDS vaccine researcher at Harvard, says the current optimism "almost borders on irresponsibility."

Real-World Scenario

He and other researchers point out that the vaccines were made from the same strain of the virus that was used to test them -- an extremely unrealistic scenario, given that HIV is one of the most mutable viruses ever. In the real world, a vaccine might train the immune system to recognize epitopes that don't exist in the strain that eventually infects the patient. That would render the vaccine less effective, or even useless.

Some researchers, including Dr. Watkins and Dr. Desrosiers, also argue that the strain of the virus used to test the vaccines might be easy to protect against, compared with others. In fact, Merck is now testing its vaccine in monkeys against a different strain. Timing is an issue, too. In the major studies, vaccines were tested no more than seven months after they were last administered. Some experts believe that immunity would wane dramatically over time.

Dr. Desrosiers believes that to ward off the AIDS virus, the immune system must maintain a high state of activation. The traditional way of doing that is to give booster shots. He is in the early phases of trying to create a built-in booster by hooking HIV genes onto the herpes virus, which persists in humans for life. The herpes virus, weakened so that it would be unlikely to cause disease, would constantly expose the immune system to HIV genes.

Finally, there is the possibility that HIV evolution may help make the virus resistant to vaccination. To protect the species, human immune systems differ, especially in the epitopes they recognize. If the virus escapes the killer T-cells of one patient and moves on to another with a different immune system, Dr. Watkins says, "the virus has to escape all over again."

But, he says, "what if it goes through five patients?" Such a virus might develop the mutations necessary to escape the killer T-cells in all five of them, making it a kind of supervirus able to overcome many immune systems, even those bolstered by a vaccine.

Dr. Berkley thinks that hopes for an AIDS vaccine may need to be tempered. Instead of one knockout immunization that eliminates the epidemic once and for all, he says, "I think it's going to be a continuous improvement process for a long period of time."

Write to Mark Schoofs at [email protected]

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Updated January 17, 2002 12:36 p.m. EST

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