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.
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.”