The Vaccine Race

by Meredith Wadman

  In the late 1950s there had been a bump in polio cases in babies aged six to twelve months old—a vulnerable period when protective antibodies inherited from a baby’s mother have waned away but the baby’s immune system is still immature and can’t mount a full-fledged attack on foreign invaders. Koprowski and Plotkin argued in a 1959 paper that this meant that babies should be vaccinated as early in life as possible. The paper reported their success in a trial of Koprowski’s live polio vaccine, which was then still a contender for licensure; it had boosted antibody levels in babies as young as one day old.29

  Importantly, babies also provided a source of unvaccinated trial subjects in which to test Hayflick’s new, live vaccine. Such subjects were otherwise tough to find: by 1961 an estimated 90 percent of the nation’s children and adolescents had received the Salk vaccine, as had 60 percent of adults younger than forty years old.30 Many among the other 40 percent likely had antipolio antibodies already, having been exposed to polio during decades of living. The presence of preexisting antibodies would make the results of a live vaccine test difficult to interpret.

  Thanks to Koprowski’s connections, the Wistar researchers had a ready-made source of newborns to vaccinate, at an unusual women’s prison headed by an equally unusual woman.

  Clinton State Farms was located in rural New Jersey, sixty miles northeast of Philadelphia. The campuslike institution, which housed women serving prison sentences of more than one year, was run by Warden Edna Mahan. She had been in charge of the prison for thirty-three years.

  Mahan, then sixty, was a 1922 graduate of the University of California at Berkeley. She had a warm smile, an aquiline nose, and large, light, penetrating eyes. She was a 1960s-style liberal well before that decade arrived. An ardent advocate of rehabilitation, she banished handcuffs and allowed the several hundred inmates to earn trust by steps. They wore color-coded uniforms reflecting their degree of freedom, and the best-behaved were allowed to work in the surrounding community by day, at jobs as farmhands and domestics.

  “The atmosphere at Clinton Farms is not that of a prison. No girl is locked in,” former First Lady Eleanor Roosevelt wrote after attending an eighth-grade graduation ceremony for inmates in 1956.31 Roosevelt remarked that the prisoners actually cheered when Mahan’s name was mentioned and noted that up to four hundred girls were allowed to picnic on a hillside with a single attendant accompanying them.

  That same freedom made an impression on Koprowski, who reported in interviews late in his life that the Clinton inmates, being red-blooded women, took advantage of their freedom by hailing eighteen-wheelers on nearby Route 78 and enjoying moonlit trysts in the truck cabs—a claim that makes for a good story about how babies came to be born at the prison but for which there is no evidence but Koprowski’s word.32 What isn’t in dispute is that about sixty infants were born to inmates every year, either in the prison’s own Stevens Hospital or at nearby Hunterdon County Medical Center. In 1960 there were fifty-four births at the prison.33

  At the time that Hayflick produced his polio vaccine, Koprowski had already been vaccinating newborns at Clinton Farms with experimental monkey cell–produced polio vaccines for five years. The door to the prison opened for him because a colleague, a University of Pennsylvania doctor named Joseph Stokes, socialized with a member of the Clinton Farms Board, and because Stokes’s brother, Emelen, also a physician at Penn, sat on New Jersey’s Board of Control of Institutions and Agencies. It didn’t hurt that the strong-willed Mahan herself was a big believer in medical research. In the first experiment she approved, in 1946, inmates were infected with body lice daily to gauge the effect of their nutritional status on the pace at which lice bred on their bodies.34

  Plotkin, who did much of the actual vaccinating for Koprowski in the late 1950s, recalls making the drive to the prison as often as twice a week in that era. The prison babies had the great advantage that they didn’t disappear into the surrounding community within a week, as newborns did from city obstetrical wards. It was not unusual for babies to remain in the nursery at Clinton Farms for four to six months, allowing for follow-up testing to measure antibody levels in response to experimental vaccination.

  Whether the inmates who were new mothers felt able to refuse to participate is an open question. “Dr. Agnes Flack, Medical Director, and Miss Edna Mahan, Superintendent, of Clinton State Farms, were extremely helpful in obtaining permission for vaccination of the infants,” Koprowski and Plotkin wrote in the acknowledgments of one 1959 paper.35

  There may have been a strong incentive for the prisoners to volunteer their infants for the studies: the chance to spend more time with their babies. In his 1999 book The River, writer Edward Hooper examined Clinton Farms birth records from the mid-1950s and determined that babies enrolled in Koprowski’s polio vaccine trials stayed an average of four to six months at the prison, a figure also reported by Koprowski and his colleagues in the 1959 paper.36 Hooper found that those not in trials were placed with a social welfare agency or with relatives after about four to six weeks.37

  Before taking the new live polio vaccine made in fetal cells to Clinton Farms, Plotkin and Hayflick ran what they would describe in the resulting paper as “exhaustive” safety tests on it. First they needed to ensure that the vaccine wasn’t contaminated with some virus or bacterium besides polio—a virus or bacterium that could theoretically be lurking in the WI-1 cells. So they injected the vaccine into dozens of mice, rabbits, guinea pigs, and hamsters, then watched them for symptoms of illnesses caused by microbes known to infect these species, like herpes simplex and the Bacillus that causes tuberculosis. None got ill. This test, they would later write, “presumably” ruled out the presence in the vaccine of such microbes.38

  Next they neutralized the vaccine virus with antipolio antibodies and injected the resulting fluid into plates of monkey cells. If a hidden nonpolio virus was lurking in the vaccine, it would damage the kidney cells. Hayflick and Plotkin were thinking of SV40, and also of a lethal herpes virus known as B virus that occasionally killed researchers and animal handlers who were bitten by monkeys. But the plates of monkey cells remained healthy. (To be sure that SV40’s effects would be noticed, they used kidney cells from African green monkeys.)

  Then they ran several tests to make sure that the genome of the vaccine virus hadn’t mutated to a different, dangerous form when it was grown in WI-1 cells. Their tests indicated that it hadn’t. This was decades before the advent of gene-sequencing techniques, so they had to infer the results from indirect laboratory tests. One test involved injecting the vaccine virus into the brains of five monkeys, then observing them for twenty-one days before euthanizing them and looking at slices of their brains and spinal cords under the microscope. The monkeys didn’t get polio, and their brains appeared normal.39

  After weeks of testing the vaccine, Plotkin and Hayflick felt that they had done all that they could do. Hayflick recalled in a 2014 interview being so confident of the new vaccine’s safety that he at one point fed it to his own children, Joel, Deborah, and Susan, then aged four, three, and two years old respectively. He did not recall whether this occurred before or after the first trial of the vaccine at Clinton Farms.40

  The first baby at Clinton Farms swallowed the human cell–based polio vaccine in the late spring or early summer of 1961. The vaccine was administered either by Plotkin or by Suzanne Richardson, a nurse assistant who often helped him.

  The timing was apt. Bernice Eddy’s paper about the lethal hamster tumors caused by a “substance” in rhesus monkey kidney cells had finally been published in May, after being held up for months by her boss, Smadel. Then, in late June, Koprowski used the high-profile annual meeting of the American Medical Association in New York City to put the SV40 issue on the radar of practicing physicians for the first time. He warned them that the “obsolete” method of making polio vaccine with monkey kidney cells risked more “virus surprises.” He called Hayflick and M
oorhead’s human cells “the obvious choice” for making polio vaccine going forward.41

  Not long after, the lay press picked up on SV40. Late in July, the Associated Press, in a story that appeared on page thirty-three of the New York Times, reported that both Merck and Parke-Davis had stopped making the Salk vaccine because it had been found to contain a monkey virus “believed harmless” by the NIH. The story did not mention cancer.42 Nor did it report that Hilleman, at Merck, had insisted that the company drop its production of the Salk vaccine when the company’s tests found live SV40 in its vaccine.43

  The National Enquirer wasn’t as sanguine. Despite its reputation for hyperbole, the tabloid that August ran an accurate, thorough story under the headline THE GREAT POLIO VACCINE COVER-UP. “The polio shots you have taken may KILL you,” it began, beside a subheadline that screamed 70% OF HAMSTERS DEVELOPED CANCER IN LAB TESTS. The paper reported clearly on Eddy’s findings and quoted Koprowski, again promoting Hayflick’s cells and suggesting that companies were clinging to monkey cells only due to fear of change.44

  Days before the Enquirer story appeared, the Division of Biologics Standards at the NIH began for the first time to require vaccine makers to sample their Salk polio vaccine lots to ensure that they were free of live SV40 before sending them out. The change was made eighteen months after the letter to the editor in the Lancet first reported that live SV40 could survive in the Salk vaccine. The DBS did not recall any of the Salk vaccine that was already on the market. Nor did it at this point require companies to make the expensive switch to using African green monkey kidneys for making polio vaccine. These monkeys don’t naturally harbor SV40, so using kidneys from this species would have obviated the contamination problem.

  By the end of the summer of 1961, six full-term Clinton Farms infants, aged between nine and fifty-seven days, had been vaccinated with Hayflick’s human-cell-propagated vaccine.45 That October Hayflick sent the resulting paper, with himself as first author—the others were Plotkin, Koprowski, and Koprowski’s administrative deputy and lab manager, Tom Norton—to the American Journal of Hygiene, the premier academic journal of the day for public-health research.

  Their findings were encouraging, the authors reported in the paper, which was published in March 1962.46 The polio vaccine that was made using human fetal cells was free of extraneous, nonpolio viruses that critics might contend could have been living in the WI-1 cells in which it was produced. Five out of the six vaccinated babies excreted the virus in their feces for more than one week, a sign that the virus had established an active infection in their intestines. Such an infection was needed to provoke an antibody response. What was more, the vaccine appeared genetically stable—tests of virus from the feces of the five babies showed that it hadn’t morphed into something more toxic during its trip through the infants’ bowels.

  An earlier draft of the paper, written before most of the babies had been vaccinated, conceded that all of the testing in the lab and in animals wasn’t proof positive of the vaccine’s safety. “It is possible,” the draft read, “that the growth of a [weakened] poliovirus in human cells may increase its [ability to cause illness in humans] or change other of its characteristics. Only a large scale field trial, which we are presently organizing, can determine whether or not pathogenicity for man is increased.”47

  By the time the paper was published, however, the wording had been changed. “Our results with a [weakened] poliovirus vaccine grown in human cells indicates [sic] that the virus does not increase its pathogenicity for the human, or change any other of its characteristics,” the paper stated. “We are presently organizing a large-scale field trial to further demonstrate the safety and efficacy of this material.”48

  The authors ended the published paper by singing the virtues of all of Hayflick’s human diploid cell strains for making antiviral vaccines. These were superior, they wrote, in a dozen ways to the monkey kidney cells still being used to make both the Salk and the Sabin vaccines, and there was theoretically no end to the vaccines that could be made with them, against diseases as diverse as rabies, measles, chicken pox, and even the common cold.

  And what became of SV40, and Eddy? Her dressing-down from her boss, Smadel, in the summer of 1960 didn’t cow her. In fact, within weeks she used the occasion of a meeting of the New York Cancer Society to present her findings that a “substance” in rhesus monkey kidneys caused hamster-killing tumors. She hadn’t cleared the content of her presentation with Smadel.

  “I knew when I was doing it I’d be in trouble,” Eddy recalled late in life. “And I didn’t care much.”49

  Soon thereafter, Roderick Murray, the chief of the NIH’s Division of Biologics Standards, where Eddy worked, told her in a memo that she was being freed of her “irksome” responsibilities trying to ensure vaccine safety.50 Instead she would begin conducting her own independent research. In a separate memo Smadel let her know that she wouldn’t speak at any more meetings without his reviewing and approving her remarks first.51

  In the summer of 1961, shortly after her paper documenting the hamster tumors appeared, Eddy was downsized to two assistants and assigned to room 207 in building 29 at the NIH, which had until then been a supply room.52 It measured about sixteen by fourteen feet. Ruth Kirschstein, who was a young DBS scientist during Eddy’s demotion and who later rose to become the NIH’s deputy director, would, late in her own life, describe the DBS’s failure—including her own—to take Eddy’s findings seriously as “not a terribly pretty story.”53

  Hilleman, whose Merck lab identified SV40 and who ended the company’s production of the Salk vaccine, recalled years later that Eddy’s NIH bosses “tore the hell out of her” for her findings because her studies failed to use rigorous controls. “But,” he added, “she was right.”54

  Eddy’s next paper, on which she labored for a year despite the punishing atmosphere, would demonstrate that SV40 and the monkey kidney “substance” that caused tumors in her hamsters were one and the same thing. It was published in May 1962 after Smadel again held it up for several months before allowing Eddy to submit it.55

  The following month Koprowski rushed into print a paper by Wistar researchers and the surgeon Robert Ravdin showing for the first time that the silent monkey virus affected human cells—cells scraped from people’s skin and the insides of their cheeks. The cells became abnormally shaped, divided faster, piled up on top of one another, and outlived their uninfected counterparts. The paper featured photos of the cells’ disrupted, abnormal chromosomes at 2,500 magnifications.56 A short time later the Nobelist John Enders and his colleagues Harvey Shein and Jeana Levinthal published similar findings in the Proceedings of the National Academy of Sciences. The trio had found that SV40 caused malignant changes in kidney cells from human fetuses, newborns, and three-month-olds.57

  Nine months later, in March 1963, the NIH’s Division of Biologics Standards began requiring that all polio vaccine be free of SV40 before its inactivation by formaldehyde, rather than allowing companies to sample vaccine once it was inactivated and ready for market. This in effect forced manufacturers to switch to using the kidneys of African green monkeys, which don’t naturally harbor SV40, rather than continuing to use kidneys from SV40’s natural hosts: rhesus and cynomolgus monkeys.

  By this time 98 million Americans had received the Salk vaccine since its launch in 1955. Another 10,000 had potentially been exposed to SV40 when they participated in trials of live polio vaccines between 1959 and 1961. In addition 100,000 members of the military were potentially exposed to the silent monkey virus when they were injected with adenovirus vaccine between 1955 and 1961 to protect them from the respiratory infection, which travels easily in the close confines of military barracks.58

  CHAPTER EIGHT

  Trials

  Philadelphia and Environs, Spring 1962

  Bethesda, Maryland, 1955–63

  Europe, 1962–63

  My min
d is not entirely free from the prejudice that our research teams want these infants because they are always available in quantity and under conditions which permit [a] wide variety of controls.

  —John Cardinal O’Hara, archbishop of Philadelphia, June 26, 19591

  In March 1962, as Hayflick and his colleagues’ new paper reported the launch of a polio vaccine made using human fetal cells, the Wistar Institute made a new hire.

  Jimmy Poupard was the son of a paper box factory worker and a housewife. He was a devout Catholic and onetime altar boy in the rough center city Philadelphia neighborhood where he grew up. By the time he graduated from Roman Catholic High School for Boys in 1960, Poupard, a slight, dark-haired loner, knew he was finished with formal education. He loved maps and science and National Geographic, but he hated school and knew no one who had gone to college. His hard-drinking contemporaries were hanging out on street corners playing cards and were bound for either the army or jail. But Poupard’s fussy young parish priest, Father Arthur Nugent, urged the graduating Poupard to take an intense one-year program in medical technology at the Franklin School of Science and the Arts in downtown Philadelphia. It was his idea of heaven: there were ten female students for every young man who attended the med tech course.2

  As he learned to draw blood and process patient specimens, Poupard also became smitten with virology. He began reading everything about viruses and vaccines that he could get his hands on. The field was blossoming. He wanted to be part of it. He landed a job at the drugmaker Wyeth but grew restless when he realized it would take him years to move to the virology department. After a few months he wangled an interview at the Wistar Institute. When he was hired, he couldn’t believe his luck; Hilary Koprowski inhabited the most exalted realms of virology.