March 2002

Merck's Mission: An AIDS Vaccine

Continued from page 1

By Jon Cohen

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.)