Gloom in scientific community as two promising AIDS vaccine trials are halted. The drugs might have put volunteers at increased risk, it is feared.
The results of the trials conducted across four continents, have spurred unprecedented soul-searching as researchers try to make sense of what happened and assess whether they should have seen it coming.
"This is on the same level of catastrophe as the Challenger disaster" that destroyed a NASA space shuttle, said Robert Gallo, co-discoverer of the human immunodeficiency virus (HIV), which causes AIDS, and head of the Institute for Human Virology in Baltimore.
Both field tests were halted last September, and seven other trials of similarly designed AIDS vaccines have been either stopped or put off indefinitely. Some may be modified and others canceled outright. Numerous experts are questioning both the scientific premises and the overall strategy of the nearly $500 million in AIDS vaccine research financed annually by the U.S. government, Washington Post reports.
The recently closed studies, STEP and Phambili, used a vaccine made from a common respiratory virus called adenovirus type 5 that had been crippled and then loaded with fragments of HIV. Both studies were halted when it became clear the STEP study was futile and possibly harmful.
The results of the Phambili vaccine trial, which was conducted in South Africa, were revealed last month and only worsened the gloom. Although the number of new HIV infections in that study was far smaller than in STEP — and too few from which to draw firm conclusions — those results, too, hinted at a trend toward harm among vaccine recipients.
Many researchers are questioning the scientific premises on which all those studies were based, and wondering, along with AIDS activists, what effect this near-worst-case scenario might have on tests of future vaccines.
The working hypothesis for what went wrong is that the vaccine somehow primed the immune system to be more susceptible to HIV infection: a scenario neither foreseen nor suggested by previous studies.
The National Institutes of Health, which funded the STEP and Phambili trials, is convening a meeting next week to reassess its AIDS vaccine program. But some respected scientists have already reached a verdict.
"None of the products currently in the pipeline has any reasonable chance of being effective in field trials," Ronald Desrosiers, a molecular geneticist at Harvard University, declared last month at an AIDS conference in Boston. "We simply do not know at the present time how to design a vaccine that will be effective against HIV."
He told a rapt audience that he has reluctantly concluded that the NIH has "lost its way in the vaccine arena" and that he believes it should redirect its AIDS vaccine funds to basic research and away from human trials.
In this fiscal year, the NIH's budget for AIDS vaccine research is $497 million. The STEP and Phambili trials were each expected to cost about $32 million. Pharmaceutical giant Merck & Co. has spent an undisclosed amount developing the vaccine and helping to manage the studies.
"We can't afford to have any more trials like this," said Mark Harrington, head of the activist Treatment Action Group and a longtime observer of AIDS research. "We have to stop and reassess and recommit to basic science, or people will begin to lose faith."
At the moment, only two things are certain.
The first is that the vaccine, developed by Merck, could not have caused HIV infection because it contains only three proteins from HIV, not the entire virus. The second is there are no obvious villains.
"I do not think that what happened in this trial is an example of scientists blindly rushing into dangerous things," said John Moore, an AIDS virologist at Weill Cornell Medical College, who has criticized vaccine trials he considered futile. "In the general HIV-research community, I didn't know anyone who said this was going to happen."
Both trials recruited people who were at high risk of HIV infection through sexual activity. The STEP subjects included many male homosexuals; the Phambili volunteers were male and female heterosexuals. Half the people in each trial were randomly assigned to get three shots of vaccine, and half to get three shots of a harmless liquid containing no adenovirus or HIV proteins.
Each trial was to have 3,000 participants. STEP had finished enrolling subjects in North and South America, the Caribbean and Australia. Phambili (which means "moving forward" in the Xhosa language of South Africa) had signed up 801 by the time it was shut down.
Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition in New York,says, "I have two reactions. One is frustrated in that there is no news in that story that's new. This information's been out for months now. But secondly and I think more importantly, my feeling is one of also frustration about both how challenging the search for a vaccine is and how that frustration plays out in really difficult ways. And certainly the results of the recent vaccine trials are a tremendous setback to the field, but I think people kind of go so much further in exaggerating it. And I think it shows really a misunderstanding of the product development process.
Developing an AIDS vaccine or developing any biomedical intervention is an incredible challenging exercise. And the product development process is more often filled with setbacks than advances."
Professor Alan Whiteside of the University of KwaZulu-Natal in South Africa, said,"I think it's extremely depressing that there isn't a vaccine yet; and I think one also has to be aware that there isn't one available in the short term. But then there aren't quick, biomedical fixes for this disease."
However, solutions need to be tailored to different regions. "First of all, what we have to recognize is that the epidemic is greatly differentiated across the world. In the part of the world that I live in, southern Africa, we have what we call hyper-epidemics, where up to 20 percent of the population is infected. In much of the rest of the world the epidemic isn't as serious, although its impact may be considerable. So, the question is what's driving the epidemic.... And the answer would seem to lie in inequality, particularly gender inequality, which leads to people putting themselves at risk," he says.
Whiteside says empowering women and behavior change are key. "It's about women not having the power to say with whom they will have sex, when they will have sex and how they will have sex in the sense of being protected. It's about men believing there are certain expectations of them in relationships as well. So, it is an enormously complicated issue. And I think for us in southern Africa, the one thing, which we also look at with concern, is concurrency of partners, where people have partners fairly close together," he says.
Whiteside does see the news of the latest trials changing AIDS policy much. "Perhaps what we will start doing is looking for the social vaccine that we need. It's ironic because there are certain things that one could do, which would stop the epidemics in their tracks. For example, one idea that I've been toying with is if you could get an entire nation to either use condoms for either every sexual act or to abstain from sex. Let's just say everybody does it (abstain) for eight weeks. Then that would actually have a huge impact on the transmission dynamics of this epidemic. It's simple, effective. Could it happen? I don't know," he says.
The University of KwaZulu-Natal professor warns he's beginning to see a gap between resources and needs; and is concerned whether too much hope is being pinned on science to end the HIV/AIDS and not enough on the social aspects.