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Data Be Damned

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tagline 1999

AIDSVax Field Trial Makes a Splash While Humble Canarypox Phase II Plods Along Uncelebrated


AIDS 'end game'

While precious little has changed on the HIV vaccine front since last summer, when California-based VaxGen received the go-ahead to proceed with a Phase III "field" trial of its gp120-based AIDSVax (B/B') product in North America, the recent deluge of vaccine headlines would seem to have it otherwise. Early last month, a wave of press releases heralded the commencement of a large, 4-yearlong Phase III vaccine study in Bangkok, also with the VaxGen (B/E) product. Similar fanfare was paid to the announcement, later the same month, of a tiny yearlong study in Uganda -- using a vaccine based on the Euro-American clade B strain! To put all these feel-good vaccine pronouncements into perspective TAGline called upon Christopher Barillas, a plugged-in "new media" huckster whose daily take on the news can be found at Mediapolis' datalounge.com web site. Barillas is currently taking part in a multicentered Phase II study of the "prime boost" ALVAC canarypox+gp120 vaccine products of Pasteur Mérieux Connaught, and Chiron.

The most highly publicized HIV vaccine candidate -- and the furthest along through the clinical trials labyrinth -- is the recombinant gp120 product of Genentech, reborn in 1995 as AIDSVax after Genentech's HIV vaccine unit was spun off as VaxGen. When this rgp120 product came up before an NIH review panel in 1994, the group of experts voted against the vaccine's proceeding to Phase III trials, and a small storm of protest ensued.

CDC veteran Donald Francis, then employed by Genentech, made it his personal mission to see that the decision was overturned. And after tinkering with the product back in his California laboratory (adding a second epitope to the immunogen thereby rendering it "bivalent" and more likely to be effective against the major HIV strains common in the U.S. and Europe), Francis got his wish. Detractors of the vaccine crusader and his multi-year campaign to promote AIDSVax as a viable HIV vaccine weren't quite able to silence the triumphant press blast that greeted the official commencement of Phase III trials in the U.S. late last December.

In a December 21 story, The New York Times accompanied Troy Masters, publisher of the biweekly newspaper LGNY (Lesbian and Gay New York), as he signed his name to consent forms, stripped down to a hospital robe and joined those lining up to volunteer for the "world's first full-scale test of a vaccine to prevent AIDS."

"The virus needs a vaccine," Masters earnestly told Times reporter Lynda Richardson. "If there is a front of activism that needs to be developed that's it. To that end, I'm giving my behavior over to science. This is like signing for permission to end the AIDS crisis."

In his own January 14 cover story for LGNY, entitled "AIDS End Game," Masters declared his participation in the Phase III AIDSVax trial the beginning of the end of the epidemic and threw himself into the ring as a soldier in the fight. "The end of AIDS comes in stages," Mr. Masters wrote. "A vaccine is the end game." But how close are Francis -- and willing media savvy volunteers like Mr. Masters (he was also featured on UPN 9 News at Ten) -- to developing a viable vaccine?

There is a well-grounded belief among leading AIDS immunologists that an HIV vaccine that does not induce a strong cellular immune ("CTL") response -- and Francis' does not -- are a waste of time and money. "Seriously wanting" is how Dr. John Moore of the Aaron Diamond AIDS Research Center rates the AIDSVax vaccine in a July 1998 interview with POZ magazine. "I'm absolutely certain that the vaccine's efficacy will be immeasurably low," he said. "There is also a moral issue," he adds, arguing, "It's simply not appropriate to immunize human volunteers with a protein that has no chance of protecting them from HIV."

That's right: "no chance." Not that the prime boost trial I'm in stands a significantly greater chance of wiping out the epidemic. But it's only a Phase II, and the ALVAC+gp120 prime boost approach has shown at least some ability to stimulate both the humoral and cellular arms of the immune system -- even if, for some reason, about one third of the vaccinees don't seem to develop any CTL response (see table below). Besides, the organizers of the ALVAC prime boost trials are hardly declaring it the AIDS "end game."

The world was a darker and scarier place in October 1994. I was at the tail end of 29. I'd lived in New York for four years and had been more sexually active living than would have been possible where I grew up. I'd been careful but not perfect, and I hadn't been tested in six years. I had a raised purple welt on my hip. I was living one paycheck to the next and had no health insurance.

A friend told me about a group called Project ACHIEVE which gave gay men free HIV tests. "The hardest thing they'll ask you is how many men you've slept with in the last six months," he said. I thought he was kidding. Two weeks later I got the negative result and a pitch to join a study monitoring the sexual habits of high risk HIV negative men. In a rush of relief and gratitude I agreed.

Project ACHIEVE is a clumsily constructed acronym which stands for AIDS Community Health Initiative Enroute to a Vaccine Effort. My consent enrolled me in the Vaccine Preparedness Study (VPS) of the HIV Network for Prevention Trials (HIVNET). VPS was created to gather baseline data for future vaccine trials. The organization has offices in Manhattan and Brooklyn with major outreach programs directed at gay men, female and male IV drug users, and the girlfriends of male IV drug users.

The most frequently cited motivations for participating in the VPS are "helping to find a vaccine that works" (93%), followed closely by "helping to stop the epidemic" (91%). I'm not sure what the difference is between the two. Still, it's nice to see that there are good-hearted people out there sufficiently committed to the cause. Then again, good intentions pave the road to hell. Something like that. Maybe our hopes, as some have suggested, are ahead of the science. But maybe that's alright. So are our needs.

According to the New York Blood Center, the principal social concern listed as very or somewhat important in influencing the decision to participate was vaccine induced seropositivity (70%) and the impact a positive HIV-1 antibody result from a conventional serologic test could have on the study participant. Of these concerns, the most frequent was the fear the false-positive could affect health or life insurance decisions (56%) or lead to problems traveling to foreign countries (41%). An obvious concern, conspicuous by its absence, is that participation in an HIV vaccine trial in 1999 will likely disqualify a person for later participation in a trial of a, perhaps, more promising candidate. Once you give up your immunologic virginity, you never get it back.

Over the next two years, I came back every three months and went through the same routine I went through my first day in the office: How many sexual contacts have you had since your last visit? How many of those contacts were with men who were positive or whose HIV status you didn't know? Have you consumed any of the following controlled substances? Et cetera.

Through it all, changes were taking place at the group's Union Square headquarters. The offices moved from four cramped rooms to nearly 10 on a higher floor. Staff rippled in and out with funding tides. Most of the motivational posters trumpeting the joys of "hot" safe sex that reached a daring vogue in the early nineties were eventually moved out of sight. Once in a while though, a naked butt on a motorcycle seat with something roaring above it in Dutch will appear in a private office. It seems almost quaint.

The staff, almost all gay men when I joined, is almost all women now, professional competent women hailing from a variety of health and social science backgrounds. Joy Behar could broadcast a brilliant View segment from here. "Excuse me, I just reached into the candy jar for a butterscotch and came out with a packet of lube, a ribbed condom and a phone number for Eduardo. Where do I sign?"

According to Dr. Beryl Koblin, who co-authored a participant study for the Laboratory of Epidemiology at The New York Blood Center, a solid majority of VPS participants (77%) indicated they would definitely (27%) or probably (50%) be willing to participate in a randomized vaccine trial. I was among the 27% who were called back.

On the morning of October 7, 1997, I was greeted at the door by a crowd of smiling, slightly nervous people welcoming me as the first person in the program to receive injections testing the effectiveness of the two experimental vaccines, vCP205 (ALVAC) and gp120 (AIDSVax). A photographer took several pictures at awkward moments (hugging someone I'd never met, taking my shirt off, having my blood taken). I remember accidentally breaking the clinic's scale, twisting the retractable arm off the height meter. Someone dashed in and whisked it out of sight. Another picture flashed.

In earlier trials, the two vaccines were given sequentially, but the trial I'm in delivers the ALVAC primer vaccine (vCP205) simultaneously with the gp120 booster -- even though previous studies have shown that sequential immunization (that is, immunizing with the canarypox vectors and then later with the gp120 boost) appears to generate slightly higher levels of CTLs. Last month I received the last of my injections. Now I wait. The trial is double blind, so I have no idea whether I am getting two placebos, the ALVAC primer and a placebo, or the ALVAC primer and the Chiron gp120 boost. For all I know, I could be receiving two placebos, but that's the way clinical science works. In order to tell if the vaccine is doing anything (good or bad), you've got to have a group against which to compare it. I find out what I've been given in October.

According to materials published by the National Institute of Allergy and Infectious Diseases, this prime boost vaccine approach currently appears to show the most strategic promise (which, admittedly, isn't saying a whole lot) among current HIV vaccine candidates for eliciting cytotoxic T lymphocyte (CTL) responses against HIV and inducing neutralizing antibodies.

Trouble is, there's no telling how protective these antibodies will be against a strain of HIV I might encounter in real life. As for the CTL response, most studies show it to be short-lived. In two studies of ALVAC vCP205 presented last summer in Geneva, only 30-40% of vaccinees had detectable CTLs at each point of measurement. 65-75% had CTLs at at least one time point. After four immunizations, the number of vaccinees with newly detectable CTLs appears to level off. Animal data are sketchy at best. So-called "challenge" experiments, where an immunized chimpanzee is intravenously infected with HIV after completing the required series of vaccinations, almost without exception evaluate the vaccine's efficacy at a time when antibody and CTL responses are at their peak -- and often with the exact same strain of HIV from which the vaccine was manufactured. Hardly a real world scenario.

ALVAC vCP205, developed by the French biotech company Pasteur Mérieux Connaught, uses an attenuated canarypox virus to carry copies of parts of several HIV genes coded for the following proteins: the envelope protein rgp120 (MN strain); the protein that anchors gp120 in the envelope, gp41 (LAI strain); gag, a gene that codes for p55, the core protein (LAI strain); and pol, a gene that codes for the HIV enzymes (LAI strain). The gp120 booster in this study, for better or worse, is the Chiron product. Whereas earlier prime boost studies also used the gp120 immunogen of Chiron Corp., future studies -- including VPS -- will be using VaxGen's AIDSVax. According to Pasteur Mérieux's Michel Klein, the reason for the switch is that the VaxGen bivalent gp120 is derived from a primary HIV-1 isolate, whereas the Chiron gp120 is not. The ability of the canarypox vector to induce immune responses to the HIV core protein, gag, is thought to be of critical importance. Early data suggests that approximately half of vaccinees have measurable CTLs against HIV gag and env one year after the last immunization.

People that have experienced what I have experienced ask what motivates me to volunteer for an HIV vaccine study. I've been surprised by that. I learn more about them from their question than I could tell them about myself with an answer, but there's no need to rub it in, so I don't. Genuine humility is a hot commodity these days -- like Jesus Christ headlining in Las Vegas -- so I'm not going to try to sound humble and meek and self-sacrificing. Let's just say that it's not difficult to be altruistic in a selfish world when well-meaning people make it easy for you and draw up the papers for you to sign. I'm not so rare a bird as you might think. If you can't buy that, you can always go with the free publicity angle.  

Status of Current HIV-1 Vaccine Strategies:

 Safety
Concerns
Potency of Elicited Immune ResponsesOther Undefined Protective
Mechanisms
  Neutralizing antibodyCTL 
Live attenuated virusYesPoorEmerging EvidenceSome evidence
Killed virusLimitedPoorNegligibleNo evidence
Envelope subunitsNonePoorNegligibleNo evidence
Vaccinia or avipox prime/boostNonePoorWeakNo evidence
DNA prime/boostLimitedPoorWeakNo evidence
Source: Nature Medicine (vaccine supplement), May 1998