Title: Eulogy for a Doomed Vaccine
Author: Kennedy, Sean
Source: Advocate, 1.29.2008; Issue 1001, p39-42
It was bad enough when a promising HIV vaccine's global trial was halted last September because the drug under study failed to prevent infection. But it got even worse when scientists discovered in November that in some of its recipients the vaccine might actually have promoted HIV infection. The twist was like a sick joke: A product designed to protect people from HIV could instead help them get it?
LABRAT ARTICLE 1 QUESTION 1: WHAT IS THE NAME OF THIS DRUG AND, RESEARCH ABOUT IT SINCE 2008?
The vaccine under study--only the second ever to garner a critical Phase II clinical trial--was expected to be a major breakthrough in the fight against HIV. Developed over the course of a decade by drug company heavyweight Merck & Co. and being tested in nearly 3,000 people from North and South America, the Caribbean, and Australia, the vaccine was designed to stimulate the body's T cells in order to better ward off the insatiable virus. The previous vaccine to reach the Phase II stage had targeted antibodies, the immune system's other set of defenders, but it had proved a bust in 2003. Hopes were high that the T-cell approach would succeed.
LABRAT ARTICLE 1 QUESTION 2: WHAT HAPPENED WITH THIS DRUG IN 2003?
LABRAT ARTICLE 1 QUESTION 3: WHAT TYPE OF T-CELLS ARE THEY TALKING ABOUT HERE AND WITH HIV?
Instead, a midpoint analysis made public on September 21 showed statistically comparable rates of infection for volunteers (all HIV-negative at the start of the trial) who had received the vaccine and those in the placebo group. What's more, in those vaccine recipients who became infected with HIV, the vaccine also failed to lower their virus levels--another area of inquiry for investigators. The vaccine was a loser, and there was nothing to do but stop the three-year-old trial.
It was a devastating denouement for anyone aware of the stakes--experts widely believe that a vaccine, if not a cure, is the only thing that can turn around the runaway HIV/AIDS pandemic. But like a thriller, this trial held one last plot surprise in store: People who had received the vaccine were in fact becoming infected with HIV at a higher rate than those in the placebo group. According to the latest data available, 49 of the 914 men who received the vaccine became infected with the virus, while 33 of the 922 who received the placebo tested positive. (The remaining 839 volunteers were women, only one of whom became infected.)
Suddenly what had been a straightforward story of loss became a vexing mystery. Although the vaccine was made with three HIV genes, they were synthetic--like Xerox copies of original documents--so it was impossible to get infected from the vaccine itself. That left two possible explanations: Either vaccine recipients who contracted the virus guessed that they had been vaccinated--like any legitimate scientific study, the trial was double-blind, meaning neither subjects nor researchers knew who received what--and, assuming they were protected, consequently engaged in riskier behavior. Or, more probably, the vaccine facilitated infection in some way.
LABRAT ARTICLE 1 QUESTION 4: WHAT DOES THE AUTHOR MEAN BY “SYNTHETIC” GENES?
LABRAT ARTICLE 1 QUESTION 5: WHAT DO THEY MEAN BY THREE HIV GENES, HOW MANY TYPES OF HIV ARE THERE?
Indeed, the leading hypothesis among investigators is that the vaccine somehow made the immune system more susceptible to infection. However, the increased susceptibility appears to be limited only to those vaccine recipients who had a preexisting immunity to the cold virus used in the vaccine to transport the HIV genes into the body. For reasons that still need to be determined, that was the group that saw an increase in HIV infection. If you had been given the vaccine but had lower immunity to the cold virus, your risk was likely no greater than that of the placebo recipients.
Either way, as a study participant, this was the last thing I wanted to hear.
I have always felt guilty for being HIV-negative. As much as we know about safe sex, the importance of protecting ourselves, and the ravages of AIDS, accidents still happen--including the accident of birth. What if I had been born early enough to arrive in New York City as a young man in the early 1980s, when the virus was just beginning to circulate, incubating among a generation of men who had no idea what was about to befall them? Fresh-eyed and adventurous, I would surely have died. Instead, I came to the city after college in 2000, having never met anyone who was positive. That difference in fates weighed heavily on me, a kind of spiritual survivor's guilt.
So when I learned three years ago in the course of my work as a journalist that an international HIV vaccine trial was enrolling gay men and other people at "high risk" (such as heterosexual black women) for contracting the virus, I decided to participate. I knew it would make a good story, but I also hoped it would assuage my feelings of guilt. Instead of helping just one person, as the save-a-starving-child proselytizers constantly beseech us to do, a viable HIV vaccine could benefit an untold number of people. It could even end the global epidemic. Medical progress so often relies on human guinea pigs--it seemed like my duty to participate.
Still, it was not a decision I made lightly. During the initial consultation at the trial site in a nondescript office suite in New York City's Union Square, one of 25 cities where the HIV Vaccine Trials Network conducted the study, a staffer apprised me of what lay ahead. Although the gist was simple enough--three injections of the vaccine over the course of six months, then follow-up visits that would slowly dwindle before ending 4 1/2 years later--the details were harder to comprehend. For one thing, I would have to give a lot of blood, sometimes filling as many as 32 vials, which would be sent to a lab for analysis. For someone squeamish about needles, let alone seeing my own red liquid outside my body, the prospect made me want to throw up.
Then there were more practical considerations, like the fact that because of the HIV genes that would be injected into my body, I would turn up as positive in routine HIV screenings. Consequently, I could be tested only at the study site (and as part of the study, I was, on a regular basis). If I needed to prove that I was negative for any reason--say, to visit a country that currently bars HIV-positive visitors, such as China--I would have to disclose my participation in the trial and provide documentation. I doubted people would understand. (In fact, they didn't: When I would bring up the subject in casual conversation, I realized that many people assumed I was HIV-positive, even though by definition a vaccine is given to those who don't have the target of prevention.)
But my biggest concern, as attested to by the mounds of paperwork I signed, was that there was no telling what could happen to me in this unprecedented experiment. Though I was reassured that the vaccine was innocuous, no one had received it before, so there was no long-term knowledge of its effects. If it worked (and I had received it), then great--I would be biologically protected from a most nefarious scourge. But what if it didn't work--or worse, had some unforeseen negative consequences? The staffer had no answers for me. That's how it is on the leading edge of science: murky and uncertain.
Yet my hand was forced when a friend of mine, nearing 30, suddenly became infected with HIV. Thanks to a single unsafe sexual encounter, his life was changed forever. It was too late to save him from infection, but maybe I could save others--maybe even myself.
Until this fall, the whole experience was as smooth as could be. The injections were akin to getting a flu shot, and the various sums of money I collected at the end of each appointment, between $25 and $75, were welcome pocket change. I would leave the study site, get a Jamba Juice around the corner, and go on with my life. I rarely thought about the trial; it was a nonissue.
The only time it became a problem was when I told a boyfriend about it. Normally I didn't disclose my participation to sex partners, since the vaccine couldn't affect them, but he was different. We were in a relationship, and I felt like he should know. So one night, in the middle of a certain sex act, I blurted it out. "Now you're telling me?!" he practically yelled. I shrugged. It seemed like an opportune time.
Being in the trial, I even learned a valuable lesson: that my own safe-sex regimen works. I've been tested more than a dozen times since I enrolled in the study, and every time the result has been negative. It's embarrassing to admit now, but I didn't get my first HIV test until I was 25 because I was irrationally afraid that it would come back positive, even though I had never engaged in unsafe behaviors. To know that I was effectively shielding myself was tremendously reassuring.
And then, of course, I discovered that maybe I hadn't shielded myself at all--that maybe, instead, I had inadvertently thrown myself into the lion's den. When a trial staffer called in November to inform me that the vaccine might have promoted HIV infection and that all study volunteers would be "unblinded" so they would know what they got, I didn't quite understand her. "Isn't an HIV vaccine supposed to prevent infection?" I asked. The staffer nervously laughed.
It wasn't until the following day that the reality of what had happened started to sink in. There, on the front page of The Waft Street Journal's Marketplace section, was a story whose headline said it all: "Canceled Vaccine May Have Boosted HIV Risk." I started to feel anxious. All my initial concerns about participating in the study came roaring back to the forefront of my mind. Had I put my body on the line for science only to have harmed it?
I didn't know the answer to that yet, but the vaccine effort itself was clearly damaged. As Anthony Fauci, the well-known HIV researcher who directs the National Institute of Allergy and Infectious Diseases, which provided funding for the trial, told the Journal, the vaccine's failure will force the field to "relook at everything."
"It's just extraordinarily disappointing to be faced with another vaccine that is not effective," epidemiologist Beryl Koblin, the principal investigator for two of the study sites in New York City, told me recently. "Sometimes it's hard to find the words because of the urgency, and that desire to be able to find a vaccine as quickly as possible." Indeed, at an HIV Vaccine Trials Network conference in Seattle in November, where the troubling results were announced, one staffer told me she had never seen such grief.
As for the apparent increased risk of infection, Koblin said, "For me, personally, that is just really hard. You never want to put people at more risk than is already there." But she cautions that there's still a "huge amount of data that needs to be sorted through to see whether there's a true biological effect going on." A special committee has been charged with assessing the results; study participants will also be tracked. There are lots of factors to consider. Among the clues: People from outside the United States or Europe tend to have a higher prevalence of immunity to the cold virus used in the vaccine; non-Americans in the study were also less likely to be circumcised. What does it all mean? Only time will tell.
From a public relations standpoint, however, this has to be a disaster, right? Koblin said that so far, recruitment for the various Phase I trials she oversees--there are more than 30 currently under way worldwide--hasn't been affected, but she knows there may be problems down the road, when volunteers are needed for a Phase II trial of a new vaccine. One had been set to start last September, but it was scrubbed when the Merck vaccine failed. It's now being redesigned, and she thinks it could begin in another year.
LABRAT ARTICLE 1 QUESTION 6: WHAT ARE THE DIFFERENT PHASES OF VACCINATION AND MEDICATION TRIALS?
"We have to keep going," Koblin said. "But we need to be really careful about how we proceed."
In December, I went to the study site to find out whether or not I had received the vaccine. Volunteers who had been given the placebo would be eligible to participate in future vaccine trials, and before my appointment, I wondered if I would want to. I was hoping I had been given the placebo simply because I wouldn't be at higher risk of contracting HIV, which would be a relief. But it would also mean I would have to decide whether to put my life on the line again. It seemed like a game of Russian roulette; Spin the barrel of the gun and you could be fine--but maybe not.
"What do you think you got?" Leah Strock, a nurse practitioner and the resident clinician, asked me. Over the last three years I had grown quite fond of Strock, a doting big-sister type and former punk rocker who had dated the cartoonist R. Crumb in the 1980s. I told her I hadn't really thought about it. "You'd be the only one," she said with a laugh. (Jokes aside, all the study participants have been very understanding about the turn of events, Strock told me. One who learned he was at increased risk took the news in stride, pragmatically deciding to use condoms for every kind of sex act going forward.)
Strock was waiting for an answer to write down on the sheet in front of her, so I said "placebo," which is what I was praying for. She turned to a spreadsheet that listed all the participants at the site, coded by numbers. Next to my number it said "vaccine." My stomach turned over. "But you don't have the immunity to the cold virus, so you're fine!" Strock quickly added. My mood lurched again. I wanted to hug her.
As happy as I was, it also meant that, for better or worse, I could never again participate in an HIV vaccine study. The decision was made for me--and I can't say I'm unhappy about it.
LABRAT 303, 7/11/2012 1729