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Merck's Mission: An AIDS Vaccine

With a hugely ambitious new research program, the pharmaceutical giant has revived the hunt for a vaccine to prevent AIDS. Will others follow?

Emilio Emini, a bear of a man, spreads his arms wide and slaps one hand on either side of a 20-ton globe that rotates in a fountain in front of the Merck Research Laboratories in West Point, PA. Etched onto the globe are the seven continents, with stars marking the 10 satellite Merck research labs. “You can stop it,” says Emini, muscling the globe to a halt. He then rotates it himself, showing off the stars in the United States, Canada, Europe and Japan; Africa sinks into the water and then reemerges.

Emini, who headed the Merck R&D team that in 1996 brought to market what has become a bestselling “protease inhibitor” drug against HIV, now runs the company’s large AIDS vaccine research project. The effort’s unprecedented scope and analytical rigor have invigorated the world of research aimed at shackling HIV with a vaccine, which could ultimately provide a far more powerful weapon against AIDS than drugs. While cocktails of anti-HIV drugs have lengthened many lives, no one has been cured, and patients must take several different kinds of pills, on a strict schedule, several times each day. The drugs also are costly, toxic, tricky to prescribe and, if improperly used, can lead to drug-resistant strains of HIV. Compare that to a vaccine, which after a few shots could protect someone from AIDS for years or decades.

It’s far too early to know whether the Merck effort will have any success in stopping HIV and rescuing sub-Saharan Africa and other regions that are drowning in the disease unleashed by the virus, which now has infected 40 million people and killed 25 million more. But the effort signals that big pharmaceutical companies at long last are devoting serious resources to the search for a vaccine, the best hope the world has for ending this epidemic.

Since 1984, the year scientists proved that HIV causes AIDS, drug and biotech companies have tested 50 different anti-HIV vaccines in humans (see “The AIDS Vaccine Pipeline,” p. 65). Only two of those vaccines, however, have made it beyond the first phase in the three-stage human-testing process, and both have had mediocre performances. Indeed, many researchers expect them to fail when put to real-world tests. Part of the problem, critics say, is that the pharmaceutical industry’s investment in such human studies and the experiments leading up to them has been inadequate. Drug companies prefer to invest in treatments, which are much more profitable than vaccines. Only three big pharmaceutical companies other than Merck-Aventis Pasteur, American Home Products and GlaxoSmithKline-even make vaccines. Although each has an AIDS vaccine program, with Aventis Pasteur’s by far the most advanced, all have much smaller programs than Merck’s; and all, unlike Merck, rely heavily on government funding to stay afloat. As a result, cash-strapped biotech firms, many of which have no experience making vaccines, have dominated the field, often pushing forward dubious strategies and hyping small advances in desperate attempts to raise funds from private investors.

Emini’s AIDS vaccine project not only enjoys the full-fledged, deep-pocketed support of a major pharmaceutical company, it also has an unusually strong scientific foundation. Last year, Merck revealed details of an ambitious four-year monkey study more extensive and systematic than any researchers had seen before. In the study, Emini’s team used hundreds of monkeys to analyze and compare several different vaccine approaches, and used the results to choose a novel vaccine strategy, which Merck now is starting to test in humans and hopes to take into large-scale trials in conjunction with the National Institutes of Health.

These developments have injected a huge dose of hope into a field rife with disappointment. “Their program is world class,” says Caltech president David Baltimore, a Nobel laureate who heads NIH’s AIDS Vaccine Research Committee. Baltimore compares Merck to Aventis Pasteur, which now has a vaccine that’s poised to enter the final stage of human testing. “The difference between Merck and Aventis Pasteur is the depth of the basic research. Aventis’s commitment has been long and strong, but not deep. Merck got strong animal data before they moved into humans. I give Aventis tremendous credit for what they’ve done, but I think they’ve been potentially passed by Merck.”

But despite the optimism it has generated, Merck’s AIDS vaccine effort raises some troubling questions. Why did Merck take on AIDS with such ferocity now and not 10 years ago? Why has an AIDS vaccine remained a stepchild, without the intense scrutiny and sense of urgency that have surrounded anti-HIV drugs? Will Merck’s rigorous program prod others to ramp up their efforts? Is the search for an AIDS vaccine, even with Merck’s contribution, as ambitious as it should be?

Detours and Dead Ends

On April 23, 1984, secretary of health and human services Margaret Heckler held a press conference in which she announced that scientists from the National Institutes of Health had discovered that HIV was the probable cause of AIDS, and she made this infamous prediction: “We hope to havea vaccine ready for testing in approximately two years.”

Many have made a fool of Heckler for this statement, which now sounds so naively optimistic. But Heckler, like a member of the chorus in a Greek drama, unwittingly augured the future with tragic accuracy. The first AIDS vaccine tests did take place in 1986, yet the field has progressed in such a lumbering, haphazard fashion that 16 years later researchers still cannot draw firm conclusions about the worth or worthlessness of any approach.

Merck’s own program met its share of dead ends. With Emini at the helm, the company began working on AIDS vaccine R&D in 1986. That same year, the company brought to market a hepatitis B vaccine that exploited the wonders of genetic engineering, ushering in a new era for vaccinology. The stunning success with the hepatitis B vaccine led Merck and many others in the field to investigate a similar strategy for an HIV vaccine. But they soon realized that they had underestimated their foe. Like the Hydra, which sprouted two more heads in place of every one that Hercules clubbed off, HIV dodges immune attack by constantly sprouting mutations. “HIV is able to grow in the face of the best immune response the body can make,” emphasizes Caltech’s Baltimore.

Traditional vaccines exploit an irony of nature: the bug that causes a disease can, when given in a modified form, safely prevent the disease by teaching the immune system to identify and cripple it on sight. The genetically engineered hepatitis B vaccine went one better, priming the body to make antibodies by using nothing more than a protein that studs the surface of the virus, reducing side effects and leaving no room for infectious viruses to accidentally make it into the vaccine. But when researchers tried the same technique with AIDS, using a genetically engineered version of the surface protein that studs HIV, the result was as ineffective as cutting off one of Hydra’s heads. (One company, VaxGen of Brisbane, CA, has doggedly stuck with this approach, and its vaccine in 1998 became the first to enter full-scale efficacy trials in humans, which are still under way.)

By 1993, Merck had all but scuttled its AIDS vaccine project and shifted Emini to the head of a team developing a protease inhibitor against HIV. (Protease inhibitors don’t prevent infection but quell the ability of an infected person’s cells to make new viruses, slowing-and for a time even reversing-the disease.) In 1997, one year after Merck marketed the bestselling protease inhibitor Crixivan, Emini turned back to the AIDS vaccine project. In a remarkable flip-flop, Merck quietly began a new program that completely ignores HIV’s surface proteins and antibodies. “Now it seems like a reasonable thing to do,” Emini says. “Will it seem like a reasonable thing to do two years from now? I’ll let you know two years from now.”

And Merck’s reentry into the field with an intensive, methodical new program has buoyed spirits tremendously. Researchers are excited because Merck makes a habit of backing its scientists-and has ample cash with which to back them. In 2000, Merck grossed $40 billion and funneled nearly one-third of its $6.8 billion net back into R&D. In short, if Merck wants something, it does not need help from the government or philanthropies. It just takes out its checkbook.

Consider how Merck responded to Emini’s decision to build the new AIDS vaccine program around studies in monkeys, which are in short supply and notoriously expensive. Ordinarily a company that does such experiments relies on academic collaborators who have access to government-funded primate research centers, or it hires a private firm that raises the animals. Merck simply bought its own monkey-breeding colony in 1999 and since has supplemented it with hundreds of additional animals. Anthony Fauci, director of NIH’s largest AIDS branch, the National Institute of Allergy and Infectious Diseases, notes that Merck has a long history of converting basic research insights into products. “Merck’s record speaks for itself,” says Fauci.

Turning Point?

Emini and his right-hand man, John Shiver, first unveiled Merck’s monkey data to their scientific colleagues at a prestigious AIDS vaccine meeting in spring 2001 in the ski town of Keystone, CO. Merck came to the meeting in full force, sending 30 of its scientists, accounting for nearly 10 percent of the total participants. No other company even has 30 scientists devoted to AIDS vaccine R&D. When Shiver and Emini showed a slide at the end of their presentations that listed nearly 50 senior investigators with their own teams working on the project, there were audible gasps from the audience. Merck towered over the other companies with its mountain of new scientific data.

When it came time for Shiver to speak, he showed a head-to-head comparison of five different vaccines in 21 monkey experiments. Asian monkeys develop an AIDS-like disease when infected with simian immunodeficiency virus, a monkey cousin of HIV, or with a laboratory-made hybrid virus that combines the monkey virus and HIV. Researchers can vaccinate monkeys and then challenge their immune systems with an injection of either of the two viruses to test the worth of the vaccine. Merck created its test vaccines by stitching a gene that codes for a protein from the interior of the monkey AIDS virus into five different “vectors” that carry the gene into the body. Three of the vectors were simply circular pieces of bacterial DNA, or “naked DNA”; the other two were harmless viruses commonly used in vaccines.

Merck’s best results in these monkeys closely resembled those seen by some of the academic researchers at the meeting: vaccinated monkeys became infected when challenged with the hybrid virus. But unlike unvaccinated animals used as controls, the vaccinated monkeys remained healthy. The researchers linked their protection not to antibodies but to a less famous contingent of the immune system, killer cells. Antibodies and killer cells work in concert. Antibodies glom onto invaders and prevent them from infecting cells; killer cells clean up, targeting and eliminating cells the invader manages to infect. Merck’s research showed an edge over other groups’ work in such subtle parameters as killer-cell production and levels of the hybrid AIDS virus found in the protected animals. More importantly, Merck had moved quickly to begin testing the most promising vaccines in humans, a feat that none of the academics could match.

Everyone acknowledges that the monkey results may not translate into humans. Ronald Desrosiers, head of Harvard University’s primate center and a pioneering AIDS vaccine researcher, emphasizes that researchers still are guessing whether a vaccine needs to crank up production of killer cells, antibodies, a combination of these responses, or some other immunologic warriors. “Believe it or not, we have no frickin’ clue what one needs for an effective immune response,” Desrosiers says.

Another huge problem is that different labs often test their vaccines against different challenge viruses, each of which has a different potency. “You can get basically any result you want based on the challenge virus you use,” says Desrosiers, who believes that the hybrid AIDS virus used in Merck’s tests is relatively easy to thwart. “Nothing against Merck, but it’s going to be damn tough to protect against viruses in the field,” he says, where much more robust strains of HIV run rampant.

Despite the caveats, Merck is going forward with extensive human studies to evaluate a strategy combining two different vaccines-the combination that best stimulated killer-cell production in monkey studies. In all, a few hundred volunteers at 50 different university medical centers and private clinics will receive Merck’s naked-DNA vaccine followed by booster shots that use a common-cold virus as a vector. If the human tests prove that the vaccine strategy is both safe and consistent in stimulating strong killer-cell responses, the one-two punch may move into a full-scale efficacy trial in thousands of people to assess whether it truly is the biological better of HIV. Merck refuses to speculate when such trials might start, but Emini allows that even in the best of all possible worlds, his team will not have evidence that its strategy works for at least five more years.

MARKET FAILURE

Why has it taken so long to get to this exciting-if uncertain-moment? Part of the answer lies in the economics of vaccines. There’s a reason why the big pharmaceutical companies are reluctant to get into the vaccine business: it’s notoriously unprofitable. The most recently available figures estimate that in 1999, the worldwide sales for all licensed vaccines totaled between $4.3 billion (according to GlaxoSmithKline) and $6 billion (according to Theta Reports, which specializes in health-care market research). Merck’s bestselling product that year, a cholesterol-lowering drug, grossed $4.5 billion in sales. One bestselling drug, that is, grossed roughly the same amount of money as the entire worldwide vaccine market. Vaccines, which go into healthy people, including children with parents who aggressively sue if their offspring are injured, also have a much higher liability risk than drugs.

For these reasons, the mid-1990s saw a “market failure”: the big pharmaceutical firms simply were not spending a lot of money on pursuing an AIDS vaccine. To address the failure, academic and government researchers banded together and in 1996 formed the nonprofit International AIDS Vaccine Initiative. Billing itself as a “virtual industry,” the organization set up product development teams that match scientists from wealthy and poor countries with biotech firms in an effort to produce affordable vaccines. NIH revamped its program to work more closely with industry, building its own Vaccine Research Center, which can manufacture experimental products. European researchers established an AIDS vaccine consortium called EuroVac. And AIDS activists, who long have focused on treatment issues and all but ignored vaccines, started the AIDS Vaccine Advocacy Coalition, which has chastised the pharmaceutical industry for not doing more.

All of which has increased the pressure on companies like Merck to put their weight behind the push for a vaccine, but none of which has significantly altered the financial risks. Merck CEO Ray Gilmartin has a Field of Dreams attitude about this uncertainty, pshawing the idea that the dodgy marketplace for an AIDS vaccine has influenced his company’s efforts. “There’s a commitment to say that if the science is there and it’s possible to do, we’re going to do it,” he says. “We haven’t run any numbers on this, either. I think there’s the implicit belief that if you come up with a breakthrough drug and you’re serving a large unmet need, the commercial success takes care of itself.”

Gilmartin guarantees that if a Merck AIDS vaccine ever exists, the company will, from day one, sell it at a steep discount to poor countries. “Offering vaccines at far lower prices in the developing world is a way of generating volume that otherwise would not be there,” says Gilmartin. “So everyone really benefits.” Gilmartin’s cheery view of the marketplace makes sense-up to a point. Merck surely has moved forward because the science is more “there” than ever before. Not only has the field recognized the difficulty of making an antibody-based vaccine, the scientific tools have advanced. A few years ago, for example, hardly any primate researchers could precisely measure killer cells or levels of virus found in the blood of monkeys. Now, these tests are the cornerstone of Merck’s program.

Clearly, though, there are more forces at work than just scientific advances. “In an arena as complex as this, there’s never just one thing,” says NIH’s Fauci. “It’s not waking up and going, Ah, now we have enough science.’ It’s also an ever growing awareness of the monumental scope of this epidemic.” But as the urgency has mounted, researchers also have lowered their expectations about what an AIDS vaccine must do. Rather than aiming for complete protection from HIV infection-the original target-they would now be happy if their preparations mimicked the monkey experiments and prevented or delayed disease. A vaccine that fails to block infection-and might have been discarded 10 years ago-now would be widely heralded if it could just thwart AIDS.

Ed Scolnick, the head of Merck Research Labs and Emini’s boss, sees another potential market for AIDS vaccines: boosting the immune systems of people who are already infected. Merck already has started early trials of AIDS vaccines as treatments, combining this theoretically nontoxic immune-boosting strategy with the drugs that attack the virus directly. Although it will take a few years before researchers can determine whether this “postinfection” vaccine can help stymie HIV’s assault on the immune system, the mere fact that Merck is attempting this approach signals a huge shift in thinking-one that could pay off financially as well as medically. “Maybe we’ll make more economic return on that than the preventive side,” says Scolnick.

Two other large vaccine makers, GlaxoSmithKline and American Home Products (through its Wyeth Lederle Vaccines division), have taken notice of the changing landscape, moving several new vaccine candidates toward clinical trials since Merck’s human tests began. Aventis Pasteur, with help from the U.S. military, NIH and the French government, hopes to soon launch full-scale efficacy trials of its vaccine, which stitches HIV genes into a harmless bird virus called canarypox. And by the end of 2002, VaxGen should complete its full-scale efficacy trials-which involve nearly 8,000 people in North America, Europe and Thailand-determining once and for all whether a genetically engineered protein of HIV can bolster the immune system against the virus. Something of an AIDS vaccine renaissance, then, is under way. “It’s night and day between now and five years ago,” says David Baltimore.

Microsoft chairman Bill Gates, whose charitable foundation will give the International AIDS Vaccine Initiative more than $126 million over the next five years, feels it’s been a long time coming. “Come on, it’s 2001 and we don’t have an AIDS vaccine,” he said in an interview last year. Gates applauds Merck’s involvement, but he believes that even the company’s evaluation in monkeys of five different vaccine candidates falls short of what’s needed, and he is frustrated by the absence of a study that would carefully compare the performance of 50 or even 100 vaccines. “I’m not a biologist, I’m a computer scientist, and so the idea that you can be very systematic about things and measure things, in the world of computer science you almost take that for granted,” says Gates. “In biology, that’s the hard part.”

MERCK 002

Sean, a 33-year-old gay man, is one of the participants in Merck 002, the first human trial of the company’s AIDS vaccine. On a morning in April 2001, a nurse at Massachusetts General Hospital (Harvard Medical School’s largest teaching hospital) fills two test tubes with his blood, which she will then send to Merck for analysis. Like others in the study, Sean, who asked that his last name not be used, classifies himself as low risk for becoming infected and says he has joined the trial for altruistic reasons. Like all initial human trials of vaccines, this one is not designed to test the preparation’s effectiveness. But the 17 blood samples that Sean will give during Merck 002 will help establish whether the vaccine is safe and how it affects the immune system. “Maybe this isn’t the be-all and end-all of it, but hopefully it will lead to something they don’t know now, and it will give them a better starting point for the next one,” he says. “The epidemic didn’t just happen, and it’s not going to just go away.”

These words are music to Emini’s ears. Emini well understands that the excitement about Merck directly ties into the bleak reality that AIDS vaccine researchers have become accustomed to-a diet of confusion, dashed hopes and promising leads that go nowhere. But he knows, too, that every AIDS vaccine developer hoping to reach the marketplace likely will meet up with the scientific, social and ethical equivalent of Hydras, man-eating horses and birds that can use their feathers as arrows. “Understand, two years from now, we may be working on plan B,” says Emini. “I hope we have a plan B. I just don’t know.”

Emini shrugs his wide shoulders when asked whether he’s beginning to feel competition from the intensified efforts of other companies, NIH, the International AIDS Vaccine Initiative and EuroVac. “The competition isn’t anyone else in this field,” he says. “It’s that virus.” And Emini cringes at the congratulations he has been receiving from people who have learned the details of Merck’s program. “Even though they don’t overtly say it, you can hear that there’s hope there,” he says. “And you say, Well, yeah, thank you, but I don’t know if it’s going to work.’ I keep on saying, If all this works, God willing.’ I don’t say it because I’m superstitious. I mean it. I certainly don’t have the answers here.”

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