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Sitting in the bayside corner suite of the Brisbane office tower from which he steers his new venture capital start-up, VaxGen Inc., Don Francis is quick to display the qualities that have made him perhaps the most polarizing figure in the fight against AIDS.
Within minutes of greeting a disinterested, naive-to-AIDS visitor, he dives into a discourse so impassioned, so engaging, so effortlessly compelling, that it would seem better directed toward a panel at the National Institutes of Health. And within the same breaths, he also manages to indirectly attack his AIDS-research colleagues, AIDS patients, government health officials, and the citizens of the United States of America.
His gentle, helpful, gregarious, yet mildly self-effacing style is just the sort that, in another medical context, might be described as a skillful bedside manner. But just as a gentle physician might speak venomously of an illness that had felled a favorite patient, Francis' phrases are laced with scorn.
"Why is there so little interest in a vaccine, when that's the only way the disease would be stopped? And why is there so much interest in anti-virals? Once you are HIV-infected, you know you have something to gain from treatment. In this day and age, why do you hear nothing about vaccines, even though they are the cheapest form of treatment? To me, it's an interesting social question. For me, it's easier to discuss vaccines in Thailand than in the United States," he says, ramping up with every passing word. "Diphtheria, polio, whooping cough -- with these awful, awful diseases, there was a common social value seen in vaccines. But there's an exception with AIDS, this incredible, incredible disease with 100 percent mortality."
It is with this almost irresistible force of verbiage and will that Don Francis has single-handedly managed to push his 14-year-old idea for a novel type of AIDS vaccine through a harrowing gauntlet of opposition.
He has moved past the protests of gay activists, who have said that money spent on trials for this vaccine might take away from AIDS treatments; past government health care officials, who declined to fund efficacy trials for the drug; and past rival scientists, who say his vaccine is doomed to fail.
Now, Don Francis' vaccine is being injected into thousands of volunteers in the U.S. and Thailand as part of a trial to see whether it will vanquish the greatest epidemic in the world.
On March 18, 1999, at 25 Van Ness Ave., an S.F. Department of Public Health worker pushed a needle into the arm of a healthy, sexually active gay man, emptied a cylinder full of colorless, watery liquid, covered the pinprick with a band-aid, and brought Don Francis' struggle full circle back to San Francisco. This city's two test sites were among the last of 59 around the country to begin hosting Phase III vaccine trials, the first FDA-approved trials in history to test whether an AIDS vaccine will actually work.
Don Francis began fighting AIDS in 1981. He was among the first to warn that the disease could become an epidemic of global proportions. He was among the first to recommend massive government funding to stanch the disease. He campaigned to close San Francisco bathhouses, and to pressure blood banks to take precautions against spreading AIDS. He was also the central figure in Randy Shilts' book And the Band Played On, the seminal chronicle of the AIDS epidemic. And for the past 11 years he has battled every sort of foe to champion gp120, a type of vaccine he described in a 1985 scientific paper.
If Don Francis fails -- and much of the scientific community seems to have rallied around the notion that he will -- his efforts will be remembered as a footnote in the history of AIDS.
If Don Francis wins -- if the clear, watery liquid injected into vaccine trial volunteers spawns effective HIV antibodies in the flesh of the first San Francisco volunteer and thousands like him -- this former Marin County kid will become a pivotal figure in world history. He will have brought within sight the end to one of the greatest of all epidemics. He will have given full lives to children of Zimbabwe, Zambia, and Swaziland who now, in the shadow of AIDS, have a life expectancy of less than 40 years.
He will have vanquished what scientists call history's cleverest disease, and he will have done it with warm words, a well-stocked medicine bag, and venom for everything and everyone standing in his way.
Most in the world AIDS establishment believe Francis' vaccine will not work. The entire scientific infrastructure of the United States of America has been unable to come up with an effective vaccine for AIDS, and does not think a scurrilous firebrand from the Bay Area has succeeded where the establishment failed.
Five years ago, the federal government refused to fund so-called Phase III trials for gp120 -- that is, experiments that would show whether the vaccine actually works -- citing weak evidence of the vaccine's potential efficacy. A paper last year in the Journal of Virology suggested this vaccine may have no immunological effect at all. And even Francis' admirers say that his AIDS vaccine may not be the most promising among the dozens that companies are now attempting to devise.
But if Francis has faced no small amount of scientific opposition over the last decade, his most formidable opponent by far has been the AIDS virus itself. AIDS is a retrovirus, which means it insinuates itself into the genetic makeup of a cell, wrapping its own genetic code into a host cell's DNA. And as scientists know from battling diseases such as leukemia, it is extremely difficult to get rid of a virus or bacteria when it is inside a cell.
The human immunodeficiency virus is astonishingly elusive. It is able to mutate more rapidly than other disease-causing organisms, morphing itself like Arnold Schwarzenegger's foe in Terminator 2 to slough off any weapon thrown at it. HIV mutates and transforms itself 100 times faster than common influenza viruses, so there are dozens of strains and subgroups and recombinant types of the retrovirus. This makes it a particularly slippery target for vaccines and remedies. Just as a remedy targets one strain of HIV, a different strain takes its place. In the case of vaccines, as the body's immune system is fortified to attack one sort of HIV, mutant cousins the body isn't prepared to defend against manage to insinuate themselves into cells.
In a traditional vaccine, such as the ones devised to wipe out polio and smallpox, a weakened or killed virus is injected into a person's body as a sort of feint, provoking a large immune response that combats the real disease. But science hasn't yet figured out a way to inject weakened HIV into people without making them sick.
For these and other reasons, vaccines have so far been elusive, despite increased money spent on research. The National Institute of Allergy and Infectious Diseases recently announced that vaccines will become its primary focus in combating AIDS, and the federal government has pledged $200 million to the cause. Some 30 private companies are now investigating the possibility of creating a vaccine, so far with no conclusive results.
If Don Francis is an arrogant firebrand -- and he is -- he's not your ordinary variety. Francis is an arrogant firebrand with one of the most exquisite epidemic-fighting pedigrees in the world.
At 33, not long out of medical school, the former Marin County kid was one of a small group of Centers for Disease Control doctors sent to the Sudan, India, and Bangladesh to wipe out smallpox. He was also on the front line of the cholera epidemic in Nigeria in the early 1970s. After a stint studying feline leukemia, he returned to Africa, this time to deal with the ghoulish virus that was turning the insides of people along the Ebola river in Zaire to mush. There, he forced local residents to abandon age-old funerary rites in which they handled the flesh of the fallen. Many of those affected by these edicts were outraged. But they no longer died of Ebola.
Next, he completed a doctorate that focused on the study of retroviruses, a type of virus that, unlike others, reproduces itself by reprogramming, in its own image, the genetic instructions inside a cell. After completing his Ph.D., Francis went to Phoenix, where he worked as director of a hepatitis B study that involved working closely with the city's gay community.
In 1981, Francis' hepatitis work led him to stumble across an as-yet-unnamed epidemic: A hodgepodge of bizarre, ordinarily non-lethal infections had begun killing homosexual men in New York and San Francisco. He witnessed the first outbreaks of Kaposi's sarcoma among AIDS patients, and he was one of the first scientists to suggest that AIDS was caused by an infectious agent. Later, as director of the CDC's AIDS Laboratory Activities, Francis worked closely with the Institut Pasteur to prove that HIV was the cause of AIDS. And he was one of the earliest scientists to predict that AIDS was not a passing affliction among homosexuals, but rather an emerging global scourge. His work made him the hero of Randy Shilts' book And the Band Played On, a chronicle of how folly among government officials in the Reagan administration and activists in the gay community, when combined with indifference and prejudice in society at large, made AIDS vastly more deadly than it might have been.
Francis' central role in combating the disease has brought him prestige -- he served as the CDC AIDS adviser to the state of California, special consultant on AIDS to Mayor Art Agnos in San Francisco, and chairman of the Mayor's HIV Task Force -- but it has also brought him plenty of frustration. This is true in part because epidemics thrive on just the sorts of personal liberties human beings hold dear.
It is instructive that Cuba has become one of the most successful countries in the world in stemming the spread of AIDS, despite that country's status as a global sex-tourism destination, because it has carefully educated prostitutes, and taken steps unlikely to be sanctioned in a democracy -- among them, the quarantining of AIDS patients.
Epidemiologists such as Francis have also been stymied by the utterly human desire to look away from the horrifying.
Early on, Francis and other health professionals wished to warn gay men, politicians, federal health agencies, and the public of the seriousness of the AIDS epidemic. These harbingers were met with charges that they were stirring up prejudice against homosexuals. Francis campaigned to have San Francisco's gay bathhouses shut down, after it became evident that they were the sumps where the virus lurked and spread. Outraged patrons and owners countered that bathhouses were a cornerstone of gay liberation. Francis campaigned to get blood-banking firms to take steps to prevent the spread of AIDS through blood compounds given to hemophiliacs and serum used in blood transfusions. Blood banks were slow to comply, and more people died.
But these encounters were mere skirmishes compared to Francis' 11-year, all-out battle for his own approach to creating an AIDS vaccine.
As any good epidemiologist knows, a vaccine is the only way to really wipe out a disease. You can teach sanitation -- or safe sex -- until your lips turn blue. You can distribute remedies to everybody and their uncles and wives, but without a global NORAD of reinforced immune systems, diseases will generally survive.
In this light, Francis wrote a paper in 1985 describing a technique he thought might allow a vaccine to combat HIV without infecting people with the disease. Using the emerging alchemy of biotechnology, Francis imagined a way technicians might devise synthetic proteins identical to ones present on the outer covering of the HIV virus. Appearing, as they would, to contain a complete, deadly virus, these blank shells might startle the immune system into developing defenses against the virus just as a weakened real virus might, Francis postulated. A similar technique had been used in developing a vaccine for hepatitis B.
Researchers at Genentech, the South San Francisco biotechnology company, set out to synthesize such a protein -- in scientific terms a glycoprotein with a molecular weight of 120, gp120 for short -- and figured out how to replicate it in cells taken from a hamster.
The first version of the protein, created in 1986, failed to provoke the sort of response Francis had predicted. But after further tinkering by Genentech scientists, a modified version of the protein produced in 1989 appeared to protect chimpanzees -- the animal whose body reacts most similarly to humans in response to HIV -- from becoming infected.
This, Francis says, was the first evidence that an AIDS vaccine might work.
"Chimps are expensive, around $60,000 each. They're endangered, and you can't get that many, but chimps are the only susceptible animal. If we could use monkeys, pigs, rabbits, it would be great, but we have to use protected chimps, and they had a 100 percent immune response," Francis says.
In 1992, Francis retired from the Centers for Disease Control to run trials of Genentech's new vaccine. That year, a vaccine made with the new protein was injected into volunteers to prove that it was safe. This Phase I trial went off without a hitch, and the company began Phase II trials, designed to determine whether the vaccine caused recipients' immune systems to produce HIV-specific antibodies, and to further test for safety.
By December of that year, it appeared as if Phase II volunteers were producing healthy batches of HIV antibodies. But there was a catch. The antibodies produced in Francis' volunteers reacted specifically to a virus cultured in a Genentech lab. Given HIV's chameleonlike talent for genetically refashioning itself, the results indicating the vaccine provided protection against an artificially crafted strain had little real-world meaning, critics said. Worse, when these artificially provoked HIV antibodies were mixed in a test tube with real-world HIV, the antibodies had no effect at all.
The results of these Phase II tests were enough to convince Anthony Fauci, director of the National Institute for Allergy and Infectious Disease (NIAID), that government money shouldn't be used to fund Phase III trials that would prove whether the vaccine did or did not provide some level of immunity to HIV infection.
Without government money to fund the trials, Genentech decided not to continue developing the vaccine, and it was shelved. Fauci's decision was savaged in a March 1995 New York Times Magazine cover story, which suggested that his agency had succumbed to pressure from gay activists who felt the money would be better spent on education and other AIDS prevention programs.
After 10 years and $50 million in research, gp120 was dead. Or so it seemed.
Francis found a way to rise again. Somewhat in the manner of his chameleonlike viral foe, Francis has mutated from research scientist to political crusader to his current manifestation, that of a Silicon Valley entrepreneur.
In 1995, he convinced Genentech to spin off its gp120 division into a separate company that Francis would run, with Genentech keeping a 25 percent interest. With the help of a Seattle financier, Francis raised $20 million in venture capital, and rented a suite of offices near the San Francisco airport. Just last month the company, VaxGen, opened a production facility for vaccines to be used in the trials. Funding in hand, Francis convinced the government of Thailand -- a popular destination for "sex tourists," and a country ravaged by AIDS -- to cooperate in the first gp120 trials. And earlier this year, following an additional round of safety trials, the FDA gave its approval for large-scale Phase III testing in the United States.
For the past few months, Francis has been flying around the country doing road shows for an initial public offering of VaxGen stock. He has found it much easier to convince Wall Street financiers of his vaccine's promise than to convince rival scientists. The offering has proven wildly successful, raising $40 million. Last week, shares had increased in value from their $13 offering price to $17.06.
The market's bet would seem an odd one, given the slim chance scientists give VaxGen's vaccine of working. But when you consider the potential reward, VaxGen shares begin to resemble gold-mining stocks traded in Toronto, rather than your ordinary shares from the NYSE. If the gp120 vaccine is successful, or even if it is only partially successful and becomes a mere component of a future vaccine, VaxGen patent medicine will eventually be injected into virtually every arm in the world.
For Francis, entrepreneurship was the only logical step following his failure to coax funding from the government in 1994.
"We got into the conflict of, one, 'Will it work?' and the decision got turned over to a political committee that saw money being taken away from treatment research. The activist community represented HIV-infected people, and it wasn't going to go anywhere," Francis says. "We said, 'Is there enough interest in the financial community to try to go this alone?' We signed up with a brilliant entrepreneur in Seattle, went out and hit the road, begging people, and raised $27.5 million, and so we rented this space, and with the money we spend, 80-some percent goes to the clinics carrying out the trials, and we pay Genentech to make the vaccine that we design."
Of course, the situation is not that simple. With the crusades of Don Francis, things are never simple. The scientific cloud that formed over his vaccine in 1994 has since darkened, at least in the minds of many researchers.
A widely discussed report in the February 1998 issue of the Journal of Virology cast further doubt on whether VaxGen's vaccine actually protects against HIV. The study looked at 18 volunteers who participated in an early gp120 trial and were later infected with HIV, and found that the vaccine did not seem to reduce viral infection in the supposedly protected volunteers.
"Basically, the data that we had, and the data we published, were not encouraging with respect to efficacy," says Steven Wolinsky, a Northwestern University AIDS researcher who was the principal investigator for the group that conducted the journal study. "We just were not able to find any benefit from the vaccine that was given in the context of a Phase I or Phase II trial."
Northwestern University was asked to act as a test site for the VaxGen trials and declined, Wolinsky says. "We decided to see what other candidates for a vaccine became available," he says.
For Fauci, the director of the NIAID, the journal article served as proof that his decision in 1994 not to fund a gp120 study was based on scientific, rather than po-litical, grounds. The study "fortifies the decision I made 3 years ago," Fauci was quoted as saying in Science magazine. (Fauci didn't respond to an SF Weekly request for comment.)
Francis argues that the previous trials with gp120 vaccines, which researchers used as a point of departure for the Journal of Virology article, were safety trials, and weren't designed to test the actual efficacy in preventing HIV infection. The only true efficacy trial conducted so far has been in a group of chimpanzees, Francis says, and VaxGen's gp120 vaccine has a proven ability to protect chimpanzees against HIV, and to produce strong immune responses in humans.
"The fact that none of our chimps came down with an infection was a very good sign," Francis says. "What you have to do is take five chimps, and put millions of dollars on those results. Everyone who receives the vaccine has an antibody against it, and the antibody looks the same as the one that protected the chimpanzees."
Nobody could have predicted that it would take 20 years and millions of deaths worldwide before this moment would come. But it has arrived. A version of the vaccine gp120, the first attempt to prove an inoculation can wipe out AIDS, is being tested in the city that has been seen as the disease's ground zero.
But in San Francisco -- a city that musters tens of thousands for AIDS rides and walks, for gay pride parades, and for gay Halloween bashes -- this historic moment has gone largely unnoticed, despite a fairly aggressive gay-community advertising campaign. After two decades of successfully enlisting gay men to help wage battle against AIDS symptoms, by way of AIDS-treatment research and AIDS-remedy drug trials, San Francisco health care workers are having a harder-than-expected time recruiting volunteers to help fight against the epidemic itself.
According to Healthline magazine, this is true all over the country: A national study to test the effectiveness of the vaccine, dubbed AIDSVax, has been slowed by would-be volunteers' reluctance to participate. In Irvine, Orange County, and Cleveland, reports have come back to VaxGen that recruiters are meeting people who "don't want to hear about" the vaccine, according to a Cleveland AIDS counselor quoted in Healthline.
VaxGen's public relations department insists that enrollment is going well around the country, claiming that two-thirds of the needed volunteers have been signed up nationwide. But the company refuses to provide specific numbers.
"Those were my instructions," says VaxGen's Amy Shuba.
The dearth of volunteer vaccine subjects is especially troubling in San Francisco, a city presumably at the front lines of the battle to defeat AIDS. At a trials site run by UCSF -- which is co-administering San Francisco's portion of the study along with the city Department of Public Health -- workers have so far only been able to recruit 31 of their 75-volunteer target group.
"The community is not coming forward with great gusto," says James O. Kahn, associate director of San Francisco General Hospital's AIDS program. Kahn, a man careful with his words, blames his site's lack of ability to recruit volunteers on the traditional reluctance of San Franciscans to settle down. Volunteers have to return to his clinic for regular checkups for at least three years. "A lot of people have less-than-consistent living situations or financial situations, and we don't want them," Kahn says.
Even so, the lack of response is puzzling.
"There's quite a bit of altruism among San Franciscans," he says, "but this is not as easy as we thought."
Perhaps the low turnout can be blamed on the unusual place vaccines occupy in the turn-of-the-millennium universe of AIDS. For many gay men, the AIDS crisis is over. Protease inhibitors and other drugs have considerably extended the lifetimes of HIV-infected people. Many Castro denizens haven't lost a close friend for years following a period during the '80s and early '90s when they seemed to lose one every couple of weeks. Anecdotal reports and some small studies indicate that S.F. gay men are returning to the old, unsafe-sex ways, as if the disease had ceased.
The criticism VaxGen's vaccine has received in the scientific press can be troubling to potential volunteers, too. VaxGen is only one of 30 companies engaged in research to produce an HIV vaccine. U.S. Rep. Nancy Pelosi is pushing to give such firms a 30 percent tax break, and the U.S. government is putting up $200 million to back Bill Clinton's 1997 pledge to have an AIDS vaccine by the year 2007. These facts present a unique quandary to potential vaccine-trial volunteers, who stand to be disqualified from future, perhaps-more-promising vaccine trials by signing up to be injected with gp120.
Given the nature of the way these trials measure a body's response to vaccines, one can be a vaccine virgin only once. If one is going to fill three years of one's life with repeated blood tests and AIDS talk, it may as well be for an inoculation that's likely to work, this line of thinking goes.
It's still too early to say whether the low volunteer turnout will hurt the trials. The AIDS clinics, hospitals, health agencies, and gay health groups around the country that are carrying out the trials have until the end of the year to finish recruiting the 5,000 necessary volunteers. A VaxGen spokesman insists plenty of volunteers will be signed up by then.
"Certain sites often have problems, but there are lots of sites," the spokesman says.
Recruitment efforts are sure to benefit from the proselytic verve of some study participants.
Marcus Loy, a 38-year-old gay man who works in the Financial District, says the reasons for volunteering were clear. Among them is the moment, while he's sitting around with friends, when he learns that AIDS has been eliminated from Earth.
"I'd like to have a magical day like that," he says. "It's been a long, dark, dreadful time. It's been going on since I lost my best friend from college in 1985, and things haven't gotten much better. Recently, guys are letting up on safe-sex practices, and people are still becoming infected, still people are dying, so a vaccine seems to be the logical solution.
"So I'm doing this for my friends who have died."
Given the irresistible drama of Don Francis' struggle so far, it's easy to believe volunteers will eventually sign up in droves to test his vaccine. It's easy to envision the gp120 vaccine swimming through 7,500 bloodstreams, startling thousands of immune systems to attention. It's not even much of a leap to conceive of a final step, in which millions, then billions of vials of colorless, watery liquid are shipped all over the globe and injected into the arms of African children, San Francisco gay men, Burlingame soccer moms, Mexico City taxicab drivers, Slovakian engineers. It's easy to imagine an afternoon happy hour in the Castro, during which guests overhear on the radio that the last of the AIDS virus has been eliminated; that scientists are putting one vial of the scourge into cold storage, for its historic and scientific value.
It's not a likely scenario, most AIDS researchers say, but it's possible. If it happens, it will have been in large part due to the efforts of a mild-featured man in a Brisbane office suite, the good-natured raconteur, the one with the venomous words for everything that stands in his way. The man with the effective bedside manner.
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