HIV trial's halt reverberates
Since Merck stopped its testing, five other trials for vaccines, based on similar methods, are now delayed.
Merck & Co. Inc. stopped its much-anticipated HIV-vaccine trial nearly two months ago, but its effects keep reverberating.
A much-anticipated HIV-vaccine trial by the National Institutes of Health that would have taken place in Philadelphia, among other sites, is undergoing changes and has been postponed for at least six months, investigators said, citing the Merck case.
That is one of about five trials, including one involving the Ebola virus, that have been slowed because the vaccines have a similar structure to the Merck product.
Volunteers now have to be warned about the new potential dangers if they participate in vaccine tests that use a cold-virus carrier similar to the Merck effort, said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.
"The burden of proof is to at least say it's something that's a possibility," Fauci said.
The Merck results are stirring concern not only because the vaccine failed to work. The volunteers who took it appeared to contract HIV, the virus that causes AIDS, at a higher rate than those in the control group.
That unprecedented result was especially pronounced among volunteers exposed to cold viruses. They developed more cases of HIV than the control group. While the findings are small in number and could be due to chance, researchers have said they may be significant because the Merck vaccine and many others use a disabled cold virus to carry snippets of HIV genes into people.
To build the vaccine, researchers remove a gene from the cold virus so it cannot replicate. They then insert one of three synthetically made HIV genes.
After injection, the altered virus invades a human cell, expressing an HIV protein and triggering an immune response, especially from so-called killer CD8 cells. "They're like the infantry soldiers: They seek out infected cells and kill them," said Michael N. Robertson, Merck's cochairman of the study.
The vaccine was not expected to prevent infection, he said. But it was expected to rouse the immune system to minimize an HIV invasion.
Robertson gave three possible reasons for the vaccine's failure: The results could be due to chance. They could be caused by the participants' characteristics, including co-infections such as herpes. And the cold-virus carrier or the HIV genes could be at fault.
This week, Merck said that it would "unblind" this study, allowing participants to know if they got the vaccine or not. Patients do not typically know in a double-blind study whether they are getting the vaccine, in part so they will not alter their behavior.
The decision could lessen the long-term value of the study, but Robertson said that researchers could account for those changes and that it was imperative for patients to know. The vaccine was tested among nearly 3,000 people, including 125 women at the University of Pennsylvania. Other sites included Newark, N.J.; New York; Rio de Janeiro; and Sydney, Australia.
The Merck trial was the most advanced of any HIV-vaccine effort, and its unexpected stoppage Sept. 21 sent shivers through the HIV community. "I'm still depressed over it," said Hildegund C.J. Ertl, an immunologist at the Wistar Institute in Philadelphia, who is preparing to test another HIV vaccine based on a chimpanzee cold virus.
She hopes that a chimp-based cold virus will not create the problems that human cold viruses might be causing.
Even so, she said, the Merck effort will likely alter her study, due to start in a year. "I'm gearing up," she said. "The bar will be raised."
Gary J. Nabel, director of the Vaccine Research Center of the National Institutes of Health, is also feeling the effects. His group's PAVE 100 HIV-vaccine trial was ready to start early next year.
Now, it has been postponed at least until mid-2008.
The PAVE vaccine uses three shots of DNA followed by a cold-virus booster, albeit one with different components from the Merck product. The PAVE vaccine also gives volunteers less exposure to the cold virus, Nabel said.
Still, he is taking no chances. Among the changes he is making: The study will now be carried out on patients with low exposure to colds. And it will add more monitoring.
The concern is warranted, said Jane Shull, executive director of Philadelphia Fight, an AIDS medical and advocacy group.
"If there is a risk of acquiring HIV from a vaccine in Philadelphia, then people ought to know it," Shull said.
"It does sound like [Merck] and the government are moving to protect people in vaccine trials. . . . I'm glad to see that that is happening."