A Shot in the Dark

The world's first large-scale AIDS vaccine trial will soon begin in Thailand.

By Jon Cohen|Saturday, June 01, 1996
One evening last September three dozen AIDS experts gathered in a meeting room of the Pang Suan Keaw Hotel in the town of Chiang Mai, northern Thailand. As a storm brewed outside, they began to lay the groundwork for one of the most significant medical undertakings of our time: a full-scale human trial of an AIDS vaccine. Although over the past ten years 36 AIDS vaccines have been injected into more than 2,000 people, none has yet received the kind of real-world test that can show whether it actually works. Now these researchers were preparing to launch such a trial by the beginning of 1997. And they would do it in Thailand, one of the nations hardest hit by the worldwide explosion of AIDS.

If the participants had been in an argumentative mood, or if they had been meeting elsewhere perhaps, they could have seized on any of a large number of contentious issues--the most obvious being that the two vaccines under consideration, made by the California-based companies Genentech and Biocine, had been rejected for human trials in the United States just 15 months earlier. The National Institutes of Health (NIH) had decided that these vaccines were too questionable to justify the government’s spending millions of dollars testing them on Americans. But no one here, in this room in Chiang Mai, saw fit to raise the point. They all understood that Thailand, struggling to deal with a raging epidemic of HIV infections, has an urgent need to try something--even something that has only an outside chance of working. As many as 1 million of Thailand’s 60 million residents are already infected with HIV, and anyone who travels through the country these days can see the deep scars AIDS is causing--not only because of the steadily mounting death toll but because of the lives utterly wrecked.

And so, as the rain fell and the wind rose in the dark outside the Chiang Mai hotel, a representative from Biocine faced no hostile questions as she addressed the group. Rather, the gathered officials--from the Thai government, the World Health Organization (WHO), and the U.S. military--all listened attentively as she went into the details of launching large-scale Thai trials of an AIDS vaccine. It was clear that everyone in the room thought this approach made sense. Then, suddenly, there was a clap of thunder and the room went black.

Just keep talking,’’ someone said in the darkness.

And they did--this assembled brain trust of AIDS vaccine experts just went on talking in the dark. By now it is a condition anyone involved in AIDS vaccines is used to.

As soon as researchers first offered convincing proof, in April 1984, that HIV causes AIDS, the search for a vaccine began. Genentech, a darling of the biotechnology industry, was one of the first companies to take up the challenge. Across San Francisco Bay, another zealous biotech firm, Chiron, also assigned a team of scientists to the problem. In 1987 Chiron hooked up with the Swiss pharmaceutical giant Ciba-Geigy to form Biocine, and the next year Biocine’s HIV vaccine was injected into a few dozen volunteers in Switzerland. In keeping with vaccine-development tradition, the first tests aimed only at determining whether the vaccine was safe and whether it triggered basic immune responses, such as the production of antibodies. Similar small-scale tests of a Genentech vaccine began in 1991.

Both companies exploited genetic engineering to get around the vexing problems posed by old-fashioned approaches to a viral vaccine. Most of these contain a harmless version of the whole virus: the polio vaccine designed by Jonas Salk, for example, contains killed, or inactivated, poliovirus, while the more commonly used vaccine devised by Albert Sabin contains weakened but still viable strains of the pathogen. Both approaches have their dangers. It’s possible while trying to prepare a vaccine made of inactivated viruses to let a few live ones slip through. Just such a mishap once occurred with an early batch of the Salk vaccine, and more than 100 children were inadvertently paralyzed by polio. A botched inactivated-HIV vaccine would almost certainly mean death for many.

A weakened-virus vaccine could be even more dangerous. Researchers might, for example, misjudge how weak to make the HIV virus. What if it could still cause AIDS, although perhaps in 20 years instead of the usual 10? Even a properly weakened virus might be risky. HIV belongs to a group of viruses that insert their own genetic code into a host’s DNA, and there is evidence that the insertion alone can cause cancer. And finally, there was always the possibility that once injected into people, the weakened virus would replicate and in some cases produce mutated, stronger strains.

The Biocine and Genentech vaccines employ the same basic strategy for evading these dangers. While many of the details of the two vaccines differ, each, instead of relying on whole HIV, is fashioned from just a part of the virus. HIV looks something like a ball studded with little gearshift knobs. It uses these knobs, made of a protein known as gp120, to make its way into white blood cells. Biocine and Genentech produced engineered versions of gp120 and used these alone in their vaccine. Since the rest of the virus is missing, the vaccine cannot possibly cause HIV infection, but it can, the companies hope, prime the immune system to make antibodies to gp120. Theoretically, if HIV infects a vaccinated person, his or her immune system will attack the gp120 knobs and disable them, leaving the virus disarmed. Theoretically.

In 1988, when the first Swiss volunteer received an injection of the Biocine vaccine, Thailand was just learning that it had an AIDS problem. For three years the country had been regularly testing visa applicants for HIV, in addition to testing members of high-risk groups, such as injecting drug users, male and female prostitutes, blood transfusion recipients, and men who visited sexually transmitted disease (STD) clinics. By 1987 fewer than 100 HIV-infected people had surfaced out of 200,000 tests. But in 1988 the numbers began to change. In one methadone clinic, for example, the HIV rate jumped from 1 percent at the beginning of the year to more than 32 percent by September. By 1990, 44 percent of injecting drug users surveyed in Bangkok were infected.

A second wave of infection began in 1989: rates among female prostitutes went from 1 percent to more than 40 percent in some places. And in the far larger population of heterosexual men who visited STD clinics, a third wave struck: the rate went from two-tenths of a percent in 1988 to 5 percent by 1991--a prevalence 50 times higher than that among heterosexual men in the United States.

Many researchers, though, saw something odd in the pattern of these numbers. Among drug users, the infection rate was fairly uniform throughout Thailand. But among female prostitutes and heterosexual men, the outbreak was far worse in the north, in cities like Chiang Mai, than in the south, in cities like Bangkok. Among 21-year-old men drafted into the Royal Thai Army, for example, 10 percent of the conscripts from the provinces around Chiang Mai were infected, compared with 1 to 3 percent elsewhere in the country.

AIDS experts around the world had by this time begun to pay attention to Thailand’s raging epidemic. Among them were researchers attached to the United States Army. The Army has a long tradition of vaccine research--its intent is chiefly to protect its far-flung soldiers from local diseases. But there is another motivation at work here: the Army believes it is possible that AIDS could kill so many people in developing countries that these nations could become destabilized and that the United States might ultimately be pulled into the wars that would follow.

In December 1990, Colonel Donald Burke, head of the U.S. military’s AIDS research program, attended an AIDS meeting on one of his visits to Thailand. There he heard reports of the peculiar, and perplexing, patterns of new Thai cases. It appeared to be a very hot heterosexual epidemic in the north,’’ says Burke. I had no reason at all to expect that. Why, of all places, Chiang Mai?’’ Was sexual activity different in the north? Did HIV get help in the north by cofactors, such as sexually transmitted diseases, that increased the infection rate? Or was the virus that was infecting heterosexuals in the north different from the one infecting drug users? It could have been any one of these,’’ Burke says.

Burke soon discovered, however, that STD rates were no higher in the north than in the south. Not only did this finding make the cofactors explanation unlikely, but it also cast doubt on the popular notion that Thai men in the north had sex with prostitutes more frequently than did men in the south. Thus Burke was left with an explanation that, while it made more sense to him, was more disturbing: what was different about northern Thailand was not the behavior of heterosexuals infected with the AIDS virus but the behavior of the virus itself.

The quickly mutating AIDS virus has evolved into several different subtypes distributed around the world. HIV is like the buffalo’’ is how Somboon Suprasert, a nurse who works with AIDS patients in Chiang Mai, puts it. The buffalo from Thailand, India, Bangladesh, and Burma-- their habits are not the same. But they’re all buffalo.’’ In 1990, when Burke was looking at the pattern of Thai infections, there were four HIV subtypes under scrutiny: A, B, C, and D. In the United States and Europe the overwhelming majority of AIDS victims carry subtype B.

To find out what was going on in Thailand, Burke collected 20 blood samples from HIV-infected soldiers at Kawila Hospital, which is located on a Thai army base in Chiang Mai, and had the blood analyzed. He quickly discovered that while the drug users in Thailand were carrying subtype B, the heterosexuals in the north were infected with a subtype that had never been seen before--now called subtype E. (The list has since gone up to I.)

Some hints have since emerged as to why E would be so potent in heterosexuals: in test-tube studies led by Max Essex at Harvard, subtype E viruses infected cells from the vaginal lining more easily than did subtype B viruses. But whatever the mechanism, this heterosexual epidemic of subtype E has given the AIDS epidemic in Thailand a different look from those in the United States and Europe, where HIV has hit gay men and drug users the hardest. Ninety percent of HIV-infected Thais are heterosexuals. At Kawila Hospital, long, dark wards are filled with hundreds of soldiers lying in clunky metal-frame beds, withering from AIDS. Here in Thailand, explains Colonel Sakol Eiumtrakul, who heads the hospital, HIV is a problem of the family. Every family can have HIV if a man has sex with a prostitute who is infected.’’

Recent surveys back up his point: 96.5 percent of HIV-infected Thai military recruits in the north said they had had sex with a prostitute, and 38 percent of prostitutes in the same area are infected.

Simple numbers alone, of course, do not show the true face of AIDS here.

Pratoom thajorn is a nurse and social worker in San Patong, a district 20 kilometers outside Chiang Mai that some AIDS researchers believe has the highest rates of HIV infection in all Thailand. As she travels from one village to another in the driving rain, it becomes clear that HIV assaults the Thai family from every angle.

Pratoom begins with a visit to the home of Deng Boonyarat, a 68- year-old water buffalo tender who died of AIDS two days before. He didn’t have any money for prostitutes or for any risky behavior,’’ Pratoom explains; this man was infected by a blood transfusion. Pratoom is sitting on a woven mat in his wood shack on stilts, a bare lightbulb hanging from the ceiling, and idyllic posters of mansions in bucolic settings tacked to the walls. As his disease progressed, she says, he had to sell his animals to pay for medical care. He died broke, and his family, with less than $7 to their name, could not afford to have him embalmed, let alone to put on a funeral with a traditional meal for all the mourners. But as his body sat packed in ice to keep it from rotting, the villagers donated nearly $800; his family would in the end be able to feed 300 people at his funeral. Today it is Pratoom’s turn to help: another social worker she has brought along hands the family an envelope stuffed with money.

Pratoom drives over rutted muddy roads through rice fields to reach another clutch of shacks on stilts. Again the client is a 68-year-old man, but this one is not infected with HIV. Rather he is taking care of his 30-year-old daughter and his 25-year-old son, both of whom are infected. They have the thin limbs and sunken faces of people who have progressed to full-blown AIDS. The father, who has pustules on his limbs from his own battle with tuberculosis, explains that both his children moved in with him because their spouses had died of AIDS. His son, who has a 5-year-old boy himself, appears to have dementia and wanders aimlessly about the little village. The daughter says that though her 10-year-old son is uninfected, AIDS is taking a heavy toll on him. He doesn’t want to get married, because he’s seen both his uncle and his father get sick from AIDS,’’ she explains.

On the other side of Chiang Mai, a Buddhist monk, or phra, named Phongthep Dhammagaruko offers another form of care for people with AIDS. Phra Phongthep runs the region’s only hospice for AIDS patients who are in the last stages of the disease, many of whom have been rejected by their families and have nowhere else to live. Although his traditional yellow robe and clean-shaven head give him the look of another time, Phra Phongthep is very much a monk of the late twentieth century. He is using every tool he can in his fight against the disease--including a supply of medicine for opportunistic infections associated with AIDS.

Phra Phongthep desperately wants people to understand just how grave the situation in Thailand is. To that end he has put together an elaborate slide show, with a written text, to illustrate the problem. One slide shows a former hospice resident being cremated. The man’s charred hand reaches out from the fire. It looks as though he’s beckoning people to join him if they persist in their unsafe behavior,’’ says Phra Phongthep. The man, he points out, is being burned on a log fire in an open field. Customarily Thais use a crematorium, but like many crematoriums around the country, the local one has been used so much in recent years that it is broken.

Thailand entered the AIDS vaccine race in 1991. That fall, the World Health Organization announced that it had selected Thailand, along with Rwanda, Brazil, Uganda, and Zaire, as a finalist for hosting a trial. The U.S. Army, with a project of its own, simultaneously revealed that Thailand was its first choice. Meanwhile the National Institute of Allergy and Infectious Diseases (NIAID), one of the institutes that make up the NIH and the world’s largest supplier of funds for AIDS vaccine research, had its eye on Zaire and the United States.

With any vaccine, a long road runs between the decision to prepare for efficacy trials and the actual launch of those trials. Countries must ready all the components that fall under the vague rubric infrastructure’’--everything from laboratories to paved roads to telephone lines. Staff must be hired and trained. Epidemiologists and behavioral scientists must identify the groups that will make the best volunteers. At the same time, the country’s political climate must remain relatively stable (unrest in Rwanda and Zaire knocked them out of contention). And even though researchers may already have put the vaccines through preliminary, small-scale trials in the United States or Europe, the potential large-trial hosts have to repeat some of the same tests to make sure that the vaccines are safe with their own people and produce a similar immune response.

By April 1994 the United States had moved further than any other country down the road to efficacy trials. That month, a group of leading AIDS vaccine researchers met at NIAID’s behest and decided the government should find out whether the Genentech and Biocine vaccines would work.

Staging trials in U.S. populations would, without question, be difficult. Among the problems was that the new infection rates in the people at greatest risk were relatively low compared with the rates in groups in places like Thailand. This meant that even a two- or three-year trial involving thousands of people might yield data that were too weak to prove conclusively whether a vaccine worked.

Moreover, to many researchers the data that already existed on gp120 vaccines were not inspiring. Although the vaccines had prevented HIV infections in chimpanzees, those experiments involved only a handful of animals, and the tests were done under highly artificial conditions. To make matters worse, chimpanzees are widely considered to be an iffy animal model. It is next to impossible for a chimpanzee to get AIDS after infection with HIV; in ten years of experiments, only one chimp has succumbed. Monkeys, on the other hand, do develop AIDS from a close relative of HIV called SIV. But researchers had little convincing evidence of success with vaccines based on the SIV surface protein.

If the animal data presented a murky picture, test-tube studies made the situation even more confusing. Researchers achieved encouraging results when they took antibodies produced in vaccinated humans and put them in a lab culture of HIV: the antibodies neutralized the virus. It appears, though, that HIV in the body is significantly different from HIV in a test tube. When researchers mixed these same antibodies with HIV freshly extracted from patients, the antibodies had virtually no effect.

Still, despite some reservations, the NIAID group was nearly unanimous in its recommendation that the vaccines move into efficacy trials to assess their true worth. But the recommendation was just that--the final decision rested with NIAID director Anthony Fauci.

A month later, in May, the vaccines’ prospects were damaged when the U.S. media made much ado about a handful of gp120 vaccine recipients who had subsequently become infected with HIV. It mattered little to critics that these cases involved people who had not received their complete number of doses, or that the trials had been too small to measure the efficacy of the vaccine. In the wake of the hubbub, at a NIAID meeting in June, Fauci reconsidered the question of staging efficacy trials. This time the debate attracted a horde of journalists.

With television cameras whirring, scientists from Genentech and Biocine made their cases for staging the trials. Representatives from prominent AIDS activist groups told the panel that their communities were wary of testing the vaccines, given their hazy effects. The NIAID group’s April recommendation was scrutinized in detail. At the end of the day, the panel voted to put efficacy trials on indefinite hold until more promising vaccine candidates moved through the pipeline. Fauci quickly announced that he concurred.

Why did Fauci reject the April recommendation? Critics charge that he was afraid of the political repercussions of spending millions on trials that had become high profile and that might well fail. Supporters contend that sound logic prevailed. Whatever the reasons, the decision incensed many longtime vaccine testers. I thought it was atrocious,’’ says epidemiologist Kenrad Nelson of Johns Hopkins. The only way to determine whether a vaccine works is to test it. It’s impossible from the data they had in hand to determine whether a vaccine would work.’’

Thai scientists were dismayed as well. Before Fauci’s June meeting, they had sent him a letter expressing their worry that if Fauci decided not to conduct the U.S. efficacy trials, Biocine and Genentech might substantially reduce their efforts in developing countries. And they wanted the NIAID panel to emphasize to the world one point: Given the explosive character of the epidemic in Thailand . . . we feel that the parameters for choosing whether or not to proceed with vaccine trials, including efficacy evaluation, are substantially different here.’’

In Thailand they like consensus--they don’t like to go against the current,’’ says Jose Esparza, who until recently headed AIDS vaccine development at WHO. Taking a different position from the United States is not easy for a small country like Thailand. They admire U.S. science and can’t just ignore it.’’

And as a result, the Thais were deeply stung by Fauci’s decision. You have the enemy around here and you give me the pistol,’’ says Prasert Thongcharoen, an AIDS expert at Mahidol University in Bangkok. One day you tell me, don’t fire that pistol! It will burst and it will harm you.’’ Prayura Kunasol, who at the time headed Thailand’s Department of Communicable Disease Control, was equally beside himself about the decision. I was not happy with that,’’ he says. It demonstrated selfishness.’’

But in the end, the Thais, who themselves have a long tradition of vaccine development, resolved to go it on their own. We Thai people have to do for our Thai people,’’ says Prayura. We have to be self- reliant.’’

In October 1994, WHO tried to bolster Thailand’s decision by convening a group of experts and asking whether vaccines such as the ones made by Genentech and Biocine merited trials in hard-hit developing countries. The answer was a qualified yes, although the experts warned that vaccine developers needed to take into consideration the subtypes at large in the trial population. The gp120 protein varies among subtypes, and no one knew for certain whether a vaccine for one subtype could help a person infected with another.

Thailand did not follow the prescription. When NIaid torpedoed the vaccine trials in the United States, Genentech found itself stuck with 300,000 doses in its refrigerators--300,000 vaccines tailored for subtype B, the one prevalent in the United States. Until that point, the company had been working with Thailand on setting up a subtype E vaccine trial among heterosexuals. After Fauci’s rejection, however, Genentech suddenly switched gears. The biotech firm decided instead to use its B vaccines among Thai drug users (who had been reported to be infected with subtype B). In February 1995, Genentech launched a trial on 31 recovering drug users in Bangkok. If the vaccine appears as safe and able to stimulate immune responses in this population as it did in 561 cases in the United States, the researchers hope to begin an efficacy trial in 2,500 Thai drug users by the end of this year.

But even as Genentech and the Thais prepared their trial, the nature of the epidemic was changing. Last September Thai and American researchers reported that while in 1989, 97 percent of Thai drug users were infected with subtype B, by 1993 only 56 percent were. The rest were carrying subtype E, which is now spreading like wildfire through the drug users just as it had in the heterosexual population.

Is there any chance a vaccine designed for one strain will work for a different one? John Moore, an investigator at New York’s Aaron Diamond AIDS Research Center, recently conducted some intriguing research on the subject. He and his co-workers tested samples of five HIV subtypes and of the antibodies that people exposed to each subtype had produced. They mixed each virus subtype with each group of antibodies, known as a serotype, and waited to see if the serotypes in the different combinations had a greater or lesser ability to neutralize the viruses. They found no clear pattern.

Such a result leaves researchers arguing whether the glass is half empty or half full. The backers of the vaccines look at Moore’s data and claim that exposure to a vaccine from one subtype can prime the immune system equally well against any other subtype. Moore, a notoriously gloomy critic of the Biocine and Genentech vaccines, thinks otherwise: If there were a single serotype that strongly neutralized several isolates, that argument might be valid, he argues. But however badly the serotypes from infected people do, serotypes from vaccinees do much worse, even against the serotypes from the same subtype. So if the vaccines do badly against the same subtype, why would they do better against a different subtype?

Biocine’s vaccine study, however, could ultimately render the subtype issue moot. While the company is starting small trials with a synthetic version of subtype B’s gp120 protein, it has recently developed a subtype E version that should be ready for tests this fall. Biocine hopes to mix the two in a single vaccine, and if all goes well, it will start efficacy trials on this cocktail at the end of 1997.

For critics like Moore, however, even Biocine’s preparation seems unlikely to work. Not only does a vaccine for one subtype not work well against another subtype, they argue, but the vaccines don’t work well, period. Moore points to a recent study of his in which he analyzed volunteers from the earlier American gp120 trials who had become infected with HIV. Twelve of them had received three or four doses of the vaccine, and all but one had high levels of gp120 antibodies. Everything I know about the performance of the current generation of gp120 subunit vaccines reinforces my belief that Tony Fauci made absolutely the right decision in not approving efficacy trials in the United States,’’ Moore declares.

Despite the naysayers, it looks as though in the end the Thais will stage real-world tests of at least one of these vaccines. The Thais are going to make decisions for efficacy trials by themselves, and they’re not going to be confused by a paper by John Moore,’’ says Esparza. But even if efficacy trials of the Biocine or Genentech vaccine do get the final go- ahead, the trials won’t be easy. For starters, finding the best people to participate will be a challenge, to say the least. Ethics demands that the volunteers be told how to avoid contracting HIV, but if they take the education to heart, their infection rates may become too low to prove whether the vaccine is effective. At the same time, the volunteers have to be reliable enough to show up for their full series of shots and then come for follow-up visits, which could easily take three years. Finding a few thousand people who fit such a bill won’t be easy.

And even if everything goes as planned--which would be a first-- there remains the question of who will pay for a trial, which could cost $10 million. Both companies say they’ll chip in, but they can’t afford to fund everything. WHO and the Thai government have verbally committed themselves to helping pay for trials, but no other countries or foundations have offered help, despite the reality that, for now, the Thai vaccine trials are the only real game in town. Since Fauci’s June 1994 decision, the development of new vaccines has slowed to a trickle, with a handful of new formulations currently only in their first trials in a few dozen people apiece.

The vaccine trials will need not only money but time, and that is something Thailand has little of. The nation is just beginning to see the impact of HIV on its society: only 6,000 people have died so far, but by the year 2000 some 100,000 people will be dying annually, and the rate will keep climbing. Even if the trials do start soon, it will take several years to see whether these AIDS vaccines work. As Colonel Sakol puts it, From the history of many infectious diseases that kill a lot of people, we know that scientists win. But it takes a lot of time. Now we’re taking the first step.
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