The Vaccine Race
Page 40
The traumatized villagers stayed at the institute in Tehran after receiving the first, “day zero” injection and were again injected on day three. Then they returned to Aghbulagh, where a member of the Pasteur Institute team would travel in order to administer four more injections on days seven, fourteen, thirty, and ninety—if the victims were still alive.
In the meantime a veterinarian at the institute dissected the wolf and tested its brain and saliva for the rabies virus. Both tested positive.
• • •
Koprowski and his fellow Polish expatriate Tad Wiktor had begun working to make a rabies vaccine with the WI-38 cells at the Wistar Institute in November of 1962, only a few months after Mrs. X’s abortion. They had traveled a long road to arrive at this moment of truth in the waning days of 1975.3
In the mid-1960s, after winning the initial struggle to get rabies virus to grow in WI-38 cells, they needed to choose a virus from among the various strains of rabies virus that had been used in making vaccines. They settled on a strain called Pittman Moore, which they obtained from the NIH and which was descended from the original vaccine virus that Louis Pasteur had developed in the 1880s.
In 1965 they developed a “seed” stock of this vaccine, growing it through fifty-two passages in WI-38 cells. They then began handing it out to companies: the Institut Mérieux in Lyon in 1966; the Behringwerke company in Marburg, West Germany, in 1969; and Wyeth in Philadelphia in April 1971. As the companies worked to develop the vaccine, Koprowski, Wiktor, and other scientists refined procedures for concentrating and purifying the vaccine, making it more potent at producing antibodies.4
As late as 1966 Koprowski argued for the merits of making the vaccine with a live, weakened virus, rather than a killed one. He believed that in postbite patients, where time was critical, a live virus might well cause a vaccinee to produce more antibodies more quickly with fewer injections.5 But the dire consequences if even a small amount of disease-causing virus somehow survived in a live vaccine made the approach unpalatable to the companies. They instead zeroed in on different ways of killing the purified vaccine virus. Wyeth used an odorless, colorless chemical called TBP (tri-n-butyl phosphate), which broke the virus into pieces. Company scientists then delivered an additional toxic blow with ß-propiolactone, the same liquid chemical that had been used to kill the virus in earlier vaccine incarnations.6 Mérieux and the German company Behringwerke, by contrast, used only ß-propiolactone, leaving the dead virus whole.7 The difference, it would emerge, may have been crucial.
For Koprowski’s purposes, something else essential also happened in the late 1960s. In August 1968, not quite four years after it was submitted, the U.S. Patent and Trademark Office granted Koprowski and his colleagues’ application for a patent on their new method of making rabies vaccine.8 Koprowski, Wiktor, Fernandes, and the Wistar were now looking at a reliable royalty stream, presuming that the companies involved could win marketing approval from the regulators in their respective countries.
Finally, on a foggy, drizzly November day in 1971, nine years after they first inoculated a bottle of WI-38 cells with rabies virus, a long-awaited event took place at the Wistar Institute.
Sixteen staffers including Koprowski, Wiktor, and Plotkin became the first human beings injected with the new rabies vaccine. Wyeth provided the vaccine; the Wistar provided the photographer. The volunteers, half of whom had never been vaccinated against rabies, were injected in the forearm or the shoulder. Within days, their antibody levels soared. After another injection more than a month later, the levels in the never-before-vaccinated Wistar staffers exceeded, with one exception, those in people who in other studies had received fourteen doses of the preexisting duck-embryo vaccine—the one that had failed to save the boys in South Dakota and Minnesota and Morocco a few years earlier. In the Wistar volunteers who had been vaccinated against rabies in the past and who thus had preexisting antirabies antibodies, the vaccine had a big booster effect, sending their antibody levels even higher than in those who had never been vaccinated. As for untoward reactions, apart from a few sore arms, there were no complaints.9
Koprowski and Wiktor had good cause for optimism as they prepared their results for publication in the Journal of the American Medical Association.10 But it would require four more years of human trials of all three companies’ vaccines, in the U.S. and six other countries, confirming the safety of the human-cell vaccine and the fact that it produced much higher antibody levels than existing vaccines—and working out how many doses to give, how many days apart, in order to maximize those levels—before the researchers felt ready to test the vaccine in people bitten by rabid animals, at the Pasteur Institute in Tehran.11
• • •
In late January 1976, as James Schriver put the finishing touches on his report on Hayflick’s activities with WI-38, staff from the institute in Tehran traveled for a final time to the village of Aghbulagh, where they administered the last rabies injections, three months after the wolf attack, to the bite victims. All seven were alive and well.12
The Aghbulagh villagers were among forty-five people bitten by rabid wolves and dogs in Iran who were vaccinated by the Pasteur Institute team in 1975 and early 1976, in the first real-world test of the new WI-38 rabies vaccine. All were from rural villages in northwestern Iran. Along with the Aghbulagh villagers, the victims included a ninety-year-old man and a three-year-old boy who didn’t receive a first dose of vaccine until six days after a rabid dog bit him deep in the hip and leg. They included seven dog-bitten people, mostly teenage boys, from villages so remote that it took seven and eight days before the first vaccines were administered. All of the animals involved—six dogs and two wolves—were captured, killed, and confirmed through laboratory testing to have been rabid.
Of the forty-five people who were vaccinated, forty-four were alive and well six to twelve months after being attacked, at the time that Koprowski and the Iranian scientists wrote up the results of the trial. Only the ninety-year-old man had died, to all appearances of a heart attack, two months after his last rabies injection and after working a full day and then developing acute chest pain that radiated to his arms. He had no symptoms of rabies.13
The trial’s spectacular results appeared in December 1976 in the Journal of the American Medical Association. “We are convinced that a major breakthrough has been achieved in the postexposure treatment of humans exposed to rabies infection,” the authors wrote. “Not only can the number of injections . . . be decreased from between 14 and 21 to 6 or less, but in contrast to the vaccines used in the past and others in current use, the [human diploid cell vaccine] causes virtually no side effects and is highly immunogenic,” by which they meant that it was a potent provoker of antibody production.14
The French government licensed Mérieux’s Institut vaccine, and the company—which has since, through a series of acquisitions, become part of the giant vaccine company Sanofi Pasteur—began selling its vaccine, Imovax, in France in 1978. The U.S. Food and Drug Administration licensed both Imovax and Wyeth’s competing vaccine, Wyvac, in 1980. The same year, the CDC pronounced the new human-cell vaccines superior to the existing duck-embryo product, noting that they generated on average ten times more antibodies than the duck vaccine, which soon disappeared from the market.15
• • •
The vaccine business is risky, and in the worst cases completely unforgiving. Early in 1985, fourteen years after it began developing its WI-38 rabies vaccine but only a few years after bringing it to market, Wyeth was forced to withdraw it. An article in the CDC’s Morbidity and Mortality Weekly Report explained that in routine studies of the Mérieux and Wyeth vaccines—so-called postlicensure studies, conducted once approved products are on the market—the Wyeth vaccine, Wyvac, had produced subpar levels of antibodies. These levels, which didn’t meet the CDC’s minimum standards for protection, had shown up in three out of seventeen people who had been vaccinated a
fter being bitten by potentially rabid animals. In fact, one of the three had developed no antibodies at all.16 By contrast, all twenty-two people who had been vaccinated with Mérieux’s competing vaccine, Imovax, had developed protective levels of antibodies.
The CDC authors couldn’t say why the Wyeth vaccine had failed in these three people—in the past it had consistently prompted protective immune responses. The failure couldn’t be attributed to one bad batch of vaccine; several different lots had been involved. Perhaps it was related to age, the authors suggested: people’s immune responses become less vigorous as they get older, and the poor responders had been some two decades older than the other subjects. Then again, the vaccine’s action might have been interfered with when, against CDC-recommended procedures, it was injected into the vast islands of fat in the buttocks of the obese thirty-two-year-old man who developed no antibodies at all. (The CDC called for injection into the shoulder.) Possibly the problem was due to intrinsic differences in the two vaccines—in other words, to something inherent to Wyeth’s production procedures, in which the virus was broken into pieces in the process of killing it. Or it might have been due to a combination of these factors.17
Whatever the reasons, the CDC urged anyone who had been bitten and received the Wyeth vaccine in the previous four months to be revaccinated immediately with the vaccine made by Wyeth’s competitor, Mérieux.
“We wouldn’t want anyone to receive our drug and get rabies,” said Wyeth spokesman James Pearce. “It hasn’t happened and we don’t anticipate it will happen but we want to take preventive measures.”18
Wyeth executives didn’t resurrect the vaccine. In the space of time that it took the company to announce that it was recalling Wyvac, the Mérieux vaccine became the only rabies vaccine for humans on the U.S. market.
• • •
New vaccines against many infectious diseases were still being hotly pursued in the mid-1970s. There was every reason for charging ahead. The approvals of measles and mumps vaccines, in 1963 and 1967 respectively, resulted in plummeting incidence of those diseases and in measles-associated deaths.19*
• • •
Merck, under Hilleman, pioneered both the measles and mumps vaccines. After the company won approval of its HPV-77 duck rubella vaccine in 1969, it quickly packaged the three vaccines together and in 1971 introduced the first “MMR” vaccine. (The duck vaccine would remain the “R” in Merck’s vaccine until Plotkin’s replaced it in 1979, at which point the company renamed the vaccine MMR II.)
In the mid-1970s, Merck was also racing to beat its competitors to vaccines against chicken pox and hepatitis A. Both viruses were being grown, on different sides of the world, in human diploid cell strains. In 1974 a Japanese physician and virologist, Michiaki Takahashi of the Research Institute for Microbial Diseases at Osaka University in Japan, published the news that he had successfully vaccinated hospitalized children against chicken pox, which is caused by the varicella zoster virus—VZV for short.20 The virus is wildly contagious and could and did regularly spread among children on hospital wards, thus the site of his clinical trial. While chicken pox is usually mild, if maddeningly itchy, in ordinary children, it can occasionally be devastating, and even lethal, both to healthy children and to sick kids with diseases like leukemia, whose immune systems are weakened. It can also endanger immunosuppressed adults such as those with HIV/AIDS or transplant recipients who must take immune system–suppressing drugs. When the chicken pox virus, VZV, takes over the body, it ravages the lungs, invades the brain, causes multiple organs to fail, or does all of these things. In the elderly, the same virus causes shingles, the excruciating, blistering skin ailment that also can be fatal.
To make his vaccine, Takahashi had weakened VZV that he captured from virus-filled vesicles on the skin of a sick three-year-old boy with the last name of Oka. This weakening was not easily achieved. The virus is famously finicky about what kinds of cells it will invade. But Takahashi managed it, by growing it first in fibroblasts from an unnamed human fetus, then in fibroblasts from guinea pig embryos—these are the only other kind of cell that VZV will invade—and then in WI-38 cells.21 In the mid-1970s, as Takahashi pushed ahead in Japan with more clinical trials of the promising “Oka” vaccine, Merck was struggling to develop its own chicken pox vaccine, using a different strain of VZV that it, too, had grown in WI-38 cells.22 The company was not meeting with much success.23 Children in its trials developed antibodies but these soon declined precipitously.24
At the same time, on the same Merck campus near Philadelphia, a mild-mannered vaccine scientist named Philip Provost was using WI-38 cells to weaken the hepatitis A virus. Then as now, hepatitis A was often a disease of poverty, spread when people ingested food or water contaminated with virus from the feces of an infected person and abounded where people lacked clean water and basic sanitation. An asymptomatic or mild disease of fever, nausea, and loss of appetite in children, it was much more serious, or fatal, in older adults. Globally hepatitis A was a bane; at home it was a particular problem among gay men. A vaccine could put a huge dent in the damage, and Provost was doing everything he could to make one before some competitor beat him to doing so.
It was into this environment that the news of the NIH’s investigation of Hayflick and his WI-38 cells landed like a bomb.
• • •
If vaccine makers weren’t alarmed by the arresting headline in Science in April 1976—HAYFLICK’S TRAGEDY: THE RISE AND FALL OF A HUMAN CELL LINE—they certainly were by the time they reached the second paragraph of Nicholas Wade’s long article.
The cells are increasingly being used for the manufacture of vaccines, as well as for research purposes. . . . Yet it now appears that there are sufficient stocks only for the next several years. Moreover, many of the surviving ampules which NIH authorities decided to remove from Hayflick’s laboratories last August are proving to be contaminated with bacteria, a fact which may make them unsuitable for vaccine use and render the supply situation even more acute.25
Whether or not the article was accurate in forecasting a supply crisis, its appearance had the effect of spooking vaccine makers. So they turned to the cells that the British had derived using Hayflick’s methods: MRC-5, developed at the Medical Research Council in London from the lungs of a fetus aborted in 1966.
At West Point Merck’s vaccine chief, Hilleman, ordered Provost to stop using WI-38 cells to develop Merck’s hepatitis A vaccine; he was to begin again, using MRC-5 cells.26 In France the Institut Mérieux stopped making its new rabies vaccine using WI-38 cells and began growing it in MRC-5. And a few years later, in 1981, when Merck gave up trying to make its own chicken pox vaccine and licensed Takahashi’s Oka vaccine from the Research Institute for Microbial Diseases at Osaka University, the American company didn’t grow its newly acquired vaccine in WI-38. Instead it turned to MRC-5.27 It would do the same a few years later, when it tweaked the dose of virus in the Oka vaccine to create a vaccine against shingles.
Wade’s concluding assessment in the 1976 Science article seemed to have become a self-fulfilling prophecy: “The real tragedy for Hayflick is not what the NIH inquiry or Stanford has done to him but what he has done to the future of WI-38s.”28
• • •
The story in the end was not quite so clear-cut. The WI-38 cells remained in use in the United States for three important vaccines. Wyeth had been using WI-38 cells since it obtained them from Hayflick in the early 1960s to make an adenovirus vaccine for the U.S. military, to replace the monkey virus–contaminated vaccine that the Pentagon had used from 1958 until 1963.29 By the late 1960s more than 250,000 U.S. recruits had received the new, WI-38–propagated adenovirus vaccine in clinical trials. It proved highly effective at fending off the respiratory infections that plagued soldiers in the close quarters of their barracks, and in 1971 the Pentagon began administering the vaccine as oral tablets to every incoming recruit—hundreds of tho
usands of them annually. When news of the WI-38 debacle broke in March 1976, Wyeth did not change course. Nor did the company stop using WI-38 cells to make its ill-fated rabies vaccine.
However, the markets for the adenovirus and rabies vaccines—about twenty thousand to thirty thousand people received postbite rabies vaccinations in the United States each year—were tiny compared with the customer base that Merck was facing as it pushed ahead with development of Plotkin’s rubella vaccine in the mid-1970s. In addition to catch-up vaccines for older children, tens of millions of whom were still being vaccinated, every American toddler received rubella vaccine and would do so open-endedly—more than three million children annually in the mid-1970s. (In 1990 the CDC would add a second dose of the rubella vaccine, just before school entry, to the childhood immunization schedule, instantly doubling Merck’s customer base.)30
But despite the alarm raised by Wade’s article in Science, it seems that Hilleman, who was a stickler for getting details and process right, was comfortable that he had enough ampules of young WI-38 cells to vaccinate generations of American children against rubella. If he didn’t, he was quickly able to secure them after the Schriver report became public.
In the burst of media that followed the articles in the New York Times and in Science, Merck officials said that the huge contract with Hayflick, securing the company’s right to purchase up to 250 ampules of young WI-38 cells for up to $1 million, was never executed. Rather, a company official said, the firm had purchased only “smaller quantities” of the cells from the Stanford scientist.31 So it seems likely that, soon after the Schriver investigators descended on Hayflick, Hilleman was able to turn to a different, much cheaper source.