Plotkin needed the Hamburg children for experiments he considered crucial. In order to generate production-level volumes of vaccine, companies would need to expand his virus through still more passages in WI-38 cells. He had already taken on the task himself, generating new twenty-sixth-, twenty-seventh-, and thirtieth-passage versions of the RA 27/3 vaccine. He needed to test them in human beings.
In July 1967 Plotkin wrote to Director of Nursing Colley at Hamburg with a promise to bring along a technician next time to handle the throat swabs and the blood draws, “since you apparently feel that the nursing time needed to assist us is a significant drain.” He assured her that attendants who worked in the area of the trial (one wing of the second floor of building 1), once they were shown to have antibodies to rubella, could circulate freely both in the trial area and in the rest of the institution with no problem—he wouldn’t, in other words, commandeer them and keep them away from their workaday duties. If necessary, he would probably allow older women—he meant women too old to get pregnant— to work in the vaccine trial area too, without having their antibody levels tested.11
Colley acquiesced, and the trials continued, with promising results.
Plotkin was, and is, a stubborn man, an attribute that worked to his advantage when, on January 5, 1968, he received an ominous letter. Roderick Murray wrote to forbid Plotkin from sending his vaccine to out-of-state collaborators for human trials until he had conducted safety tests in monkeys, and until he had run a much larger volume of vaccine—the amount required of commercial manufacturers—through the full gamut of required safety tests in the lab and in animals.12 Murray in fact was asking for safety tests on more vaccine than Plotkin had ever made, and far more than he now had on hand.
“For the Wistar Institute to prepare a lot [of vaccine] which would be large enough to satisfy Dr. Murray’s criteria would be prohibitively expensive,” Plotkin soon wrote to his longtime collaborator, Theodore Ingalls, who had since moved from the University of Pennsylvania to the Epidemiologic Study Center in Framingham, Massachusetts, and to whom Plotkin had hoped to send his RA 27/3 vaccine so that Ingalls could run trials there. The months of delay while he prepared it, Plotkin wrote, would in effect eliminate his human cell–based vaccine from the race for U.S. licensure.13
“You will understand, I am sure, how neatly this puts us in a box,” Plotkin wrote in another letter, to Wistar lawyer and board of managers member Robert Dechert. “The Vaccine Development Board has stated that they would test our material if DBS would approve it. If DBS will not approve it, the Vaccine Development Board need not act.”14
The upshot, he explained to Dechert, was that Murray was shutting down vaccine development as an option for anyone but big pharmaceutical companies.
• • •
In the meantime Plotkin’s DBS rivals, Parkman and Meyer, had landed in the vaccine race with a splash, with a pair of articles in the New England Journal of Medicine in September 1966 reporting on their success vaccinating the intellectually disabled children at the Arkansas Children’s Colony with HPV-77, the rubella vaccine produced in African green monkey kidney cells.15 Two other DBS scientists, Ruth Kirschstein and Hope Hopps, were also authors on the first of these papers; Hopps would remain heavily involved in rubella vaccine work.
Meyer and Parkman had since hurriedly expanded their HPV-77 trials, sending the virus out to several collaborating teams that promptly ran more human studies in more intellectually disabled institutionalized children. The DBS duo’s summary report on these new trials, submitted to the American Journal of Diseases of Children in October 1967, as the crisis in Marburg unfolded, and published the following June, reported that their vaccine had successfully generated antibodies in 152 of 159 injected subjects, or 96 percent. What was more, the virus had not spread to any of the 145 contacts living in close quarters with the vaccinees.16
Before the Marburg outbreak the plaudits had already begun to pour in for Parkman and Meyer’s HPV-77 vaccine, which its backers promptly labeled “the first effective” one.17 The events in Germany did not dampen the enthusiasm. Parkman was also praised, rightly, for his all-important isolation of the rubella virus with his colleagues at the Walter Reed Army Institute for Research back in 1961. And the Parkman-Meyer duo, with four other NIH colleagues, were justly credited for developing, in 1967, an important blood test that allowed worried women with rashes to learn in hours, rather than days or weeks, whether they had rubella. The new test also sped vaccine research by allowing researchers to test hundreds of blood samples quickly for the presence of antirubella antibodies.18
For developing the blood test and the HPV-77 vaccine, Parkman and Meyer collected a $3,000 cash award from the American Academy of Pediatrics. The U.S. Junior Chamber of Commerce named Parkman one of America’s Ten Outstanding Young Men of the year 1967.19 At the award ceremony a letter to Parkman from President Lyndon Johnson was read aloud. “Few men can number themselves among those who directly and measurably advance human welfare, save precious lives and offer new hope to the world,” the president wrote. “On behalf of all people who look forward to a healthier world, I offer you my congratulations and best wishes.”20
• • •
As Parkman and Meyer basked in praise, executives at Philips Roxane, the St. Joseph, Missouri–based subsidiary of Philips Electronics and Pharmaceutical Industries Corporation, took note of all the attention to the duo’s HPV-77 vaccine. It seemed clear that the vaccine developed within the DBS’s own redbrick walls, by the two young scientists with the starlike buzz around them, was bound to be looked on favorably by the man who mattered: Roderick Murray.
So, soon after the first results from the Arkansas Children’s Colony study were published in 1966, scientists from Philips Roxane asked Parkman and Meyer to send them the HPV-77 virus. They grew it through eleven more passages in kidney cells from three- to six-month-old puppies. The Missouri company dubbed its rubella vaccine HPV-77/DK-11, denoting the additional eleven passages through dog kidney cells.21 Then its scientists too began testing their vaccine, working against the epidemic clock that was ticking toward 1970.
At the Merck campus at West Point, the hard-charging Maurice Hilleman had labored through 1965 and 1966 developing several formulations of the company’s Benoit strain of rubella virus—the virus captured from the throat of that eight-year-old Philadelphia-area boy with the surname Benoit back in 1962. Hilleman and his team experimented by growing the Benoit virus for varying numbers of passages in African green monkey kidney cells, followed by varying numbers of passages in duck-embryo cells. Like Plotkin, Hilleman was trying to find the sweet spot: a live virus that was weakened but not too weak, a virus that prompted the body to make plentiful antirubella antibodies but didn’t cause full-blown disease.
By the summer of 1966, Hilleman’s team had created several variations of the Benoit vaccine, which differed from one another by the number of passages they had gone through in African green monkey kidney and then duck-embryo cells. The Merck researchers had safety-tested the varying formulations in lab cultures, in mice, and in monkeys and injected them into intellectually disabled children in and near Philadelphia. One of their Benoit vaccine formulations, version B, looked particularly promising. It generated hefty levels of antibodies without giving the vaccinees rubella. Hilleman felt that he was closing in on his mark.
Hilleman was the last man to shrink from an all-out race to a vaccine. In fact, being a drug-company scientist, it was his job to produce his own vaccine candidate and then to make sure it crossed the finish line first. In his career Hilleman would develop more commercially successful vaccines than any other human being before or since. But in the case of rubella vaccine, he backed down from a fight—not once but twice. In both cases it was women who stared him down.
The first of these women, Mary Lasker, was the widow of advertising magnate Albert Lasker. She was sixty-five years old in early 1966 and a veter
an of three decades of political activism. She had jumped into public life in the late 1930s as secretary of the Birth Control Federation of America, which would later become Planned Parenthood. But her consuming focus soon became medical research. She and her husband established the Albert and Mary Lasker Foundation in 1942, a decade before he died of cancer. Its medical research awards quickly became the most prestigious in the country. To this day, their recipients often go on to win Nobel Prizes.
An art historian by training, Lasker had never lifted a test tube or cultured a cell in her life. But she was a philanthropist with an outsized influence on U.S. medical research—a woman used to bending ears and twisting arms at the highest levels of U.S. government and industry. And she was convinced that Parkman and Meyer’s HPV-77 was on a glide path to victory in the rubella race, if only because its inventors worked just up the stairs from Roderick Murray in the DBS’s building 29. One day in 1966, Hilleman and his boss, Max Tishler, the president of Merck Research Laboratories, met with Lasker, at her bidding, in her elegant apartment on Central Park West.22
As Hilleman explained to the writer Paul Offit in 2004, Lasker had summoned the two men to put to them her considered view: that competition from a Merck vaccine candidate would do nothing but slow down DBS approval of any rubella vaccine. And in any event, whose vaccine did they think would win approval, theirs or the one developed in-house at the DBS? Lasker had seen the consequences of the recent epidemic, she said pointedly, and she was deeply disturbed. The goal was to get a vaccine licensed fast, before the next outbreak wreaked more devastation. Hilleman was dubious. He told Lasker he didn’t think the HPV-77 vaccine would get approved, “because [Parkman and Meyer] didn’t make it into a vaccine. It’s just a goddamned experiment.”23
Lasker wasn’t convinced. She told Hilleman to go away and think about it. He didn’t need to think for long. Lasker was politically powerful. She could make life very unhappy for him if she chose. Grudgingly, Hilleman told Lasker that he would get some HPV-77 vaccine from Parkman and Meyer and put it in kids himself and see what he thought. He vaccinated about twenty children and was appalled by the side effects. “Jesus Christ it was awful. Toxic, toxic, toxic,” he recalled.24 The results of this trial were apparently not published.
So late in 1966 or early in 1967, Hilleman further weakened HPV-77. Instead of growing the virus through more passages in African green monkey kidney cells, he put it through five sequential cultures of duck-embryo cells. Hilleman liked ducks as experimental hosts. Unlike most animals, they were, he would soon write, “remarkably free of infectious diseases and [cancer].”25 Hilleman named the tweaked vaccine HPV-77/DE 5 to reflect the fact that it had now been grown through seventy-seven passages in African green monkey kidney cells followed by five passages in duck embryos.
In June 1967 Hilleman tested the new Lasker-prompted vaccine in eight intellectually disabled, institutionalized children. It generated only one fifth of the antibody levels that Merck’s best Benoit formulation, version B, did.26 But the number of subjects was so small that the difference could have been due to chance. He needed much bigger numbers if he was going to make a decision—and he needed those numbers from a real-life situation: a situation full of mothers and children and pregnant women; a situation in which, if the vaccine virus was going to spread, that would quickly become evident.
In September and October 1967 Hilleman tested the new duck vaccine in a heavily Irish Philadelphia suburb called Havertown-Springfield. “I tell you something, that was a gutsy day for me because I was extremely worried about transmissibility,” Hilleman recalled in 2004.27 He resigned himself to losing his job if a pregnant woman in the trial gave birth to a baby with any kind of abnormality whatsoever. Because of the background rate of non-rubella-related birth defects, he put the odds of that happening at about one in three hundred, even if the vaccine didn’t spread and cause rubella in a single pregnant woman.
He and his team injected 269 youngsters, from babies to five-year-olds. Virtually all developed antirubella antibodies. The researchers also tracked the nonimmune, unvaccinated siblings of the children who were vaccinated. None of those 262 siblings became infected. Nor, crucially, did any of the thirty-four nonimmune mothers whose children were vaccinated, three of whom were pregnant. But the new HPV-77 duck vaccine still underperformed in the children: it generated antibody levels just one third of those produced by Merck’s best Benoit vaccine, version B.28
Hilleman had a decision to make. It wasn’t a pretty choice. The Merck vaccine was better, but the adapted Parkman-Meyer vaccine still delivered “substantial” levels of antibodies, didn’t spread to contacts, and didn’t give vaccinees rubella, he wrote in the paper that resulted.29 The difference between the vaccines wasn’t, perhaps, big enough to go to the mat for. Yet it would be no small enterprise to switch tracks now. It would involve, among other expensive hassles, building duck houses so as to raise colonies of ducks on the Merck campus.30 Hilleman was caught between the rock of data showing clearly that Merck’s Benoit vaccine, version B, was better and the hard place of Mary Lasker’s political clout and adamantine will. Her words came back to Hilleman: “Which vaccine do you think DBS is going to approve?”31
Hilleman dropped Merck’s Benoit vaccine. Lasker had triumphed. The big drug company would pour its resources into Parkman and Meyer’s HPV-77 vaccine, developed in African green monkey kidney cells within the walls of the DBS, grown by Merck a handful more times through cultures of duck embryos, and bound for injection, if Hilleman could make it happen, in millions of Americans just as soon as was humanly possible.
• • •
It had been six years since Hayflick began proselytizing for lab-grown human fetal cells as clean, safe, normal, noncancerous microfactories for making viral vaccines. European virologists and vaccine makers had been embracing them for nearly as long. It had been more than five years since Mrs. X’s abortion and since Hayflick, with NIH funding, had produced from her fetus’s lungs eight hundred ampules of what had become the gold-standard human diploid cell strain: the WI-38 cells. It had been three years since the 1964–65 rubella epidemic devastated tens of thousands of American lives and since Plotkin had wrested something good from that tragedy: a rubella vaccine made using the WI-38 cells. And still there appeared to be not the slightest indication that his vaccine, or any vaccine made using the WI-38 cells, would see the light of day in the United States. Not if it required Roderick Murray’s approval.
CHAPTER FIFTEEN
The Great Escape
Philadelphia, 1967–June 1968
When Dr. Leonard Hayflick left Philadelphia for California in 1968 he had something with him few travelers carry in their luggage—frozen human cells.
—Philadelphia Evening Bulletin, April 4, 19761
If the WI-38 cells were ignored in the United States, abroad they were increasingly in use. In 1967 the Yugoslavian republics of Croatia and Slovenia began the first large-scale, routine use anywhere of a WI-38 cell–produced vaccine—the oral polio vaccine that the tall, soft-spoken Drago Ikić, the vaccine chief at the Institute of Immunology in Zagreb, had championed from practically the moment that the WI-38 cells were launched, in 1962. Yugoslavian authorities licensed that polio vaccine for the whole of the country in 1968, when they also licensed a measles vaccine made using WI-38 cells “for massive use.”2
Scientists at Britain’s Burroughs Wellcome had asked Plotkin to send them his RA 27/3 rubella virus in 1966 and were working on developing a vaccine using the WI-38 cells. France’s Institut Mérieux obtained the RA 27/3 virus from Plotkin and began making an experimental rubella vaccine in 1967—the same year that it began commercial development of Koprowski and Wiktor’s rabies vaccine, also made using WI-38 cells. And at a research and development center near the tiny town of Sandwich, on England’s southeastern coast, vaccine makers at Pfizer were laying plans for a polio vaccine made using WI-38 cells.
The WI-38 cells were also being put to work in labs on the front lines of public health. Britain’s Medical Research Council, the rough equivalent of the U.S. National Institutes of Health, had already been supplying WI-38 cells for diagnostic purposes to public health labs in England and Wales for several years. In February 1967 the World Health Organization began paying the MRC to expand the cells’ reach by providing them to disease detectives on four continents. Every two weeks, on Wednesday mornings, bottles of WI-38 cells, bathed in medium, were airlifted from London to Dakar and Montevideo, Hong Kong and Cairo and Port of Spain. They traveled well, seemingly not bothered by the changes in ambient temperature.
At their destinations scientists used the WI-38 cells to identify viruses that were landing children in hospitals with serious, sometimes deadly, respiratory infections. Then they constructed a map of what viruses were at work where. The far-flung users reported back that the WI-38 cells detected a broad range of viruses—a bigger spectrum than the monkey kidney cells that were supplied by the same program. They reported the WI-38s were particularly useful for picking up cold-causing rhinoviruses and two more-dangerous viruses: respiratory syncytial virus (RSV) and herpes simplex.3
(Independent of the MRC’s effort, Hayflick acted as a roving supplier and ambassador for the cells, training dozens of scientists in how to grow them. Whenever he boarded an airplane, he would carry, wrapped in both arms, a liquid nitrogen refrigerator that looked like nothing so much as a one-hundred-pound bomb, minus the fins. It was eighteen inches high and packed with ampules of WI-38. Sitting in his economy-class seat, he kept it on the floor between his legs. It had to be kept upright or the gaseous nitrogen inside it might leak out, sending up a dense white cloud of vapor that would doubtless have terrified his fellow passengers.)
It was a sign of the esteem in which Hayflick’s WI-38 cells were held that the British vaccine authorities—namely, the silver-haired Frank Perkins, the UK’s top vaccine regulator, and three of his colleagues at the Medical Research Council in London—decided, perhaps as a matter of national pride, to derive their own analogous normal, noncancerous human diploid cells. They wanted to produce a cell strain that was, if not the UK’s rival to WI-38, then its complement to it.
The Vaccine Race Page 28