The Vaccine Race

by Meredith Wadman

  It seems probable, especially in light of the events that followed, that the March 14 letter from Koprowski to Burroughs Wellcome is the one that so shocked Hayflick as he sat closeted in a sterile room with Plotkin.

  The following month, April 1968, a patent application describing Plotkin’s new method of making a rubella vaccine using WI-38 cells arrived at the U.S. Patent and Trademark Office. It listed one inventor, Stanley Plotkin, and assigned Plotkin’s ownership rights to the Wistar Institute, meaning that if the patent was granted, the Wistar would be the owner, and if the institute then licensed the vaccine to companies, the royalty money would flow to the Wistar.

  As was the case with Koprowski and Wiktor’s rabies vaccine, Plotkin’s rubella vaccine work had been funded by the NIH, meaning that, under the law in that era, the U.S. government owned Plotkin’s invention. But as it had done with the rabies vaccine, the United States would grant a waiver that allowed the Wistar to claim title to Plotkin’s process for making a rubella vaccine, patent it, and license it to companies.23

  The 1968 correspondence between the Wistar and Burroughs Wellcome culminated in Koprowski’s traveling to the company’s headquarters in London that October. There, on the assumption that Plotkin’s rubella vaccine would indeed be patented, he and senior company officials began negotiating the terms under which the Wistar would grant Burroughs Wellcome a license.24 (Koprowski also at that meeting prodded the firm to think about licensing the rabies vaccine, also made in WI-38 cells, for which the Wistar had won a patent just two months earlier. The company did not end up doing so, although others did.) A few years later, after a patent for Plotkin’s rubella vaccine was granted, Burroughs Wellcome negotiated a license with the Wistar Institute and began manufacturing the RA 27/3 rubella vaccine.

  • • •

  Hayflick was profoundly upset after the conversation with Plotkin in his tiny sterile room. He had spent the previous decade deriving the normal human diploid cells, noting that they aged in their lab dishes, and in doing so opening up a new, important field: the study of cellular aging. He had derived enough WI-38 cells to serve vaccine makers into the distant future, and he had worked as hard as was humanly possible to win their acceptance for vaccine making. In the process of all this, he had sometimes been ridiculed, and he had struggled for respect and validation.

  Then, as he prepared to leave the Wistar, the letter from Koprowski to Burroughs Wellcome signaled that he was being entirely sidelined by Koprowski in major decision making—and likely profit making—around WI-38. For Hayflick, at this juncture, “to have the vultures descend on what I had struggled so hard to give value to and try to take it for their benefit—I think that an average person would understand why I was, to put it mildly, concerned.”25

  The pill was especially bitter, Hayflick says, because he knew—it was no secret among Wistar scientists—that Koprowski was under tremendous financial pressure. He needed, among other things, to keep paying the salaries of the scientists who were full institute members when they were between, or without, grants.

  “I was not a full member of the institute, so that did not apply to me. And here I’m being asked to leave [the WI-38 cells] behind to benefit the full members of the institute, very few of whom could argue that they gave value to those cells.”

  On or around March 1, when, under the January agreement, the ampules were to have been moved from the Wistar to the ATCC, a specially outfitted station wagon arrived from Maryland, carrying the NIH project officer, Charles Boone, and John Shannon, the ATCC’s curator of cell lines. Hayflick turned them away, saying that he wasn’t ready to hand over the cells because he hadn’t prepared an inventory of them.26

  Sometime not long after this, when no one was looking, Hayflick visited the Wistar basement. There he packed every single one of the remaining original WI-38 ampules—some 375 frozen vials that composed the largest stock of young WI-38 cells on earth—into one or more portable liquid-nitrogen refrigerators and departed the premises. He left behind not even the ten ampules that Koprowski’s institute had been promised in the January agreement. He left behind, in fact, not a single original, low-passage ampule of WI-38.27

  Hayflick stored the frozen cells temporarily with a friend and colleague, Eugene Rosanoff, a vaccinologist at nearby Wyeth Laboratories who obligingly, from time to time in the next few months, topped off the liquid nitrogen that kept the cells frozen.

  Hayflick says that he took the ampules with the intention of keeping them only until title to the cells could be properly sorted out. In his mind, he says, their ownership was in question. He believed that there were several potential stakeholders who might reasonably claim ownership: him and Paul Moorhead; the “estate” of the WI-38 fetus, by which he meant the WI-38 fetus’s parents; the Wistar Institute; and, just possibly, the NIH. But he was not going to be so naive as to leave the cells in the NIH’s possession while ownership was sorted out. Do that and he was sure he would never see them again.

  • • •

  Moving a family of seven 2,900 miles was no small undertaking. The Hayflicks split the travel. Ruth flew out to the Bay Area with five-year-old Rachel and two-year-old Annie. Hayflick drove the three older children cross-country in their dark green Buick LeSabre—the latest in a series of sedans that Hayflick’s father had passed on to the family.

  Joel, age eleven, sat up front with his father most of the time, with ten-year-old Deborah and nine-year-old Susan in the backseat. They drove west through Pittsburgh, stopped to see drag races in Joplin, Missouri, and then drove on to Arizona, where they gazed at the world’s best-preserved meteor crater and marveled at the immensity of the Grand Canyon. All along the way, Hayflick says, some extra cargo traveled with them. Carefully strapped on the backseat beside his daughters was a liquid-nitrogen refrigerator stuffed with ampules of WI-38.

  CHAPTER SIXTEEN

  In the Bear Pit

  Philadelphia and Bethesda, 1968–70

  Science appears calm and triumphant when it is completed; but science in the process of being done is only contradiction and torment, hope and disappointment.

  —Pierre Paul Émile Roux, French bacteriologist and developer of the first effective treatment for diphtheria1

  As 1968 began, the race to develop a successful rubella vaccine intensified. Maurice Hilleman’s Merck team, now committed, thanks to pressure from Mary Lasker, to the HPV-77 duck vaccine, was conducting human trials in the United States and abroad. With all of the huge drug company’s resources behind the effort, eighteen thousand children were injected in field trials of the vaccine by early 1969.2

  The Missouri company Philips Roxane, which had tweaked Parkman and Meyer’s HPV-77 virus by growing it in puppy kidney cells, had sent it for human testing to physicians at Georgetown University in Washington, DC; at an inner-city clinic in Nassau, Bahamas, run by the Catholic Church; and at Parke-Davis, a drug firm in Detroit.3 The Detroit company, which had in-house expertise in running clinical trials, would inject nearly twelve thousand children.4

  In Genval, Belgium, the company Recherche et Industrie Thérapeutiques, known as RIT, was racing forward with a rubella vaccine made from a virus that its scientists had captured from the urine of a ten-year-old girl with rubella and grown in African green monkey kidney cells and then in kidney cells from three-week-old rabbits.5 By the end of 1968, the company had injected its experimental vaccine, called Cendehill, in 25,000 people.6

  All three companies, as they armed themselves with the extensive volume of vaccine, and the attendant monkey tests and other safety data that Plotkin was ill-equipped to provide, were keenly aware that the DBS was under pressure to get a vaccine licensed soon. And all were hoping that their vaccine would cross the finish line first. Whichever company persuaded the U.S. regulator to issue the first license would be poised to capitalize on the vast U.S. market of worried women and their small children.

  Plotkin was no
w the only independent scientist trying to push forward a vaccine. Despite Smith, Kline & French’s $10,000 grant late in 1967, the way forward was anything but clear. Roderick Murray’s January 1968 letter forbade him to send his RA 27/3 vaccine to out-of-state colleagues, unless and until he made and safety-tested what for him were daunting amounts of the RA 27/3 vaccine, including injecting the vaccine in the brains of monkeys and observing the animals for weeks on end.

  Plotkin could, and did, supply the vaccine to foreign collaborators in countries including Israel, Iran, Japan, and Taiwan. (Murray was using an arcane law to prevent Plotkin from shipping the vaccine between states but could not block him from sending it out of the country.) But even with their help, he couldn’t hope to muster the tens of thousands of vaccinees—and the corresponding invaluable data—that the three companies were accruing. Plotkin and his collaborators were looking at vaccinating hundreds of subjects at most in the coming year.

  In Philadelphia Plotkin wound up his trials at St. Vincent’s Home for Children. The turnover among the one- to five-year-olds at the home wasn’t large, and he had by now vaccinated most of the sixty-one children living there in the spring of 1968. That April he wrote a letter of thanks to Sister Agape, the administrator, and Sister Mary Joseph, the trained nurse at St. Vincent’s, and offered to vaccinate the handful of remaining children who had not received his vaccine.7 He also wrote to Archbishop Krol, who had recently been elevated to cardinal.

  Dear Cardinal Krol:

  During the last 3 years, we have been testing a vaccine against German measles at the St. Vincent’s Home for Children. This fact will, of course, be known to you, since permission was obtained before the studies began. What may not be known to you is that the results have been excellent and the development of this vaccine has been immeasurably advanced by these studies done at St. Vincent’s. This vaccine will ultimately protect women from the risk of having deformed children as a result of German measles during pregnancy.

  I want to express my appreciation to Sister Agape and Sister Mary Joseph of the St. Vincent’s Home for their unstinting cooperation and kindness during these studies.

  Very sincerely yours,

  Stanley A. Plotkin, M.D.8

  Within days he received a reply from the cardinal, pronouncing himself “delighted” with the news.”9

  In the spring of 1968 Plotkin also launched what he considered a crucial test of his vaccine in which he enlisted fourteen Philadelphia families, mostly from among friends and neighbors in the complex of town houses where he lived. Many of them had connections to the university and were likely well versed in the risks of contracting rubella during pregnancy. They included his own family.10 By this time the new government rules required him to get his subjects’ formal, written consent.

  Plotkin wanted to see how his RA 27/3 vaccine functioned in the real world. The children he had vaccinated in institutions certainly lived in close contact with one another, but their situations did not exactly mimic conditions in the outside world. If the vaccine virus was transmissible, the intimacy of family life would surely be a cauldron for its spread. In each of the fourteen families a child lacking rubella antibodies was injected. One of the child’s siblings, and the child’s mother, both also lacking antibodies, were followed as intimate contacts who would be at risk of contracting the disease if the vaccine virus was capable of spreading. If the nonimmune mothers and siblings had not developed antibodies by the end of the trial seven to nine weeks later, it was a sure thing that the vaccine virus had not spread.

  In Plotkin’s case his six-year-old son, Michael, was vaccinated. His wife, Helen, had given birth to a second son, Alec, in 1966. Alec was approaching two years old at the time of the trial early in 1968. Neither Helen nor Alec had antirubella antibodies. Asked in a 2015 interview if he had concerns about giving the vaccine to his son, Plotkin responded: “No, no, not at that point. If I had concerns, of course I wouldn’t have done it. I felt it was in some sense obligatory that I give it to my own family.”11

  By September 1968 the family study was finished and Plotkin had pulled together the results, along with the data from all of the trials he had conducted at Hamburg since he had published the first trial there one year earlier, in the midst of the Marburg outbreak. His paper on the new Hamburg studies, and on the family study, was published in February 1969 in the American Journal of Epidemiology. On the first page he and his coauthors—Farquhar, the genial director of pediatrics at Philadelphia’s Presbyterian Hospital; Katz, Plotkin’s Wistar colleague and former medical school roommate, who had escaped the Nazis; and another University of Pennsylvania pediatrician, a jokester named Charlie Hertz—thanked several people for their “invaluable help.” Among them was Hayflick.12

  Plotkin had a lot to be thankful for: Nearly all of the children he and his colleagues vaccinated had developed significant levels of antibodies—levels comparable to those of his competitors’ vaccines. And none of the children’s contacts, either at Hamburg or in the Philadelphia families, including his own, had become infected with rubella. Nor had any of the vaccinees developed signs of clinical rubella, save for a few swollen lymph nodes.

  He concluded that all of his latest RA 27/3 virus formulations—the formulations that in practice would be used in manufacturing by companies—generated robust levels of antibodies, were safe for vaccinees, and were noncontagious for their contacts. But the studies had been tiny: at Hamburg they had been conducted on seven, or four, or six children and, in some cases, a similar number of unvaccinated, antibody-lacking children living in the same ward and sharing the same playroom with them. And his collaborators who had tested the RA 27/3 vaccine abroad, while they had produced excellent results—antibodies in 100 percent of vaccinees—had injected a sum total of 163 people.

  “Larger studies will have to be done, of course,” Plotkin concluded, “to define completely the safety of RA 27/3 or other rubella vaccines.”13

  • • •

  And how to execute those larger studies, hobbled as he was by the constraints imposed by the DBS’s Murray? Fortunately for Plotkin, Bob Ferlauto, the feisty Sicilian who was the director of microbiology research at Smith, Kline & French, had become keenly interested in Plotkin’s RA 27/3 vaccine since he first funded Plotkin with $10,000 at the end of 1967.

  This might seem mystifying for two reasons. First, Murray’s implacable opposition to using WI-38 cells to make vaccines was well known among drugmakers. Smith, Kline & French had no reason to be optimistic that he would change his mind and allow such a vaccine to come to market in the United States. But the Philadelphia company had its eye on a route of administration of RA 27/3 that it hoped might overcome Murray’s resistance.

  After that first trial in 1965 at St. Vincent’s Home, Plotkin hadn’t abandoned the idea of giving the vaccine as nose drops. He had continued to include the nasal formulation in his human trials. And it had begun to work. His was the only vaccine that induced immunity when given intranasally, and Smith, Kline & French, in the person of Ferlauto, was hopeful that the DBS would be less averse to a WI-38 cell–manufactured vaccine that wasn’t injected and therefore didn’t come into such deep and intimate contact with the vaccinee. What was more, children clearly would love to avoid needles, and that could conceivably give the company a market edge. It would later emerge that large amounts of the vaccine needed to be squirted into the nose in order to ensure its effectiveness. Because the big volumes would offset any market edge that it might give companies, the nasal vaccine became a financial nonstarter. But as Ferlauto considered Plotkin’s vaccine, this drawback wasn’t yet evident.

  There is another reason that Smith, Kline & French was interested in Plotkin’s vaccine. Early in 1968 the company acquired RIT, the Belgian firm that was pushing hard to bring to market its own injectable rubella vaccine, the Cendehill vaccine. With the purchase of RIT, Smith, Kline & French became the owner of the Cendehill vac
cine at the same time as the company was investing in Plotkin’s RA 27/3 vaccine. At a time of fast movement in the rubella vaccine race, and with uncertainty about how well any single vaccine would perform once on the market, the company was hedging its bets.

  “They are riding two horses as a hedge against an accident which could remove Cendehill from contention,” Plotkin wrote in a memo that fall.14 If the Cendehill vaccine failed to perform, then RA 27/3 could take its place.

  Early in 1968 Smith, Kline & French’s Ferlauto brought all the resources he could muster to Plotkin’s RA 27/3 vaccine. In April he saw to it that the monkey-brain injection tests required by the DBS were contracted out to scientists at RIT in Belgium.

  “For Ferlauto. Stop. Monkey safety and neutralized virus controls will be started on Plotkin’s vaccine as soon as possible. Stop. Results will be available within six weeks. Stop,” read a telegram that arrived at Smith, Kline & French on April 9, 1968, from Constant Huygelen, the head of vaccine development at RIT.15

  And beginning in January 1968, a smart young Smith, Kline & French patent agent—Alan D. Lourie, who would go on to become one of the country’s top intellectual property lawyers and a senior federal judge—was enlisted to get Plotkin’s vaccine patented, pronto.16 The patent had to be applied for quickly, because Plotkin’s American Journal of Epidemiology publication of September 1967—the one that had announced to the world that he had created an effective vaccine—had set the patent application clock ticking.17 A patent had to be applied for within a year after an invention was divulged publicly.

  On April 1 the company, with government permission, filed for a patent on Plotkin’s behalf.

  By August Ferlauto was proposing that his company make ramped-up quantities of the vaccine and hurrying to apply to the DBS for what was by then called, as it is today, an Investigational New Drug permit, or IND, which would allow the company to launch human studies.18 In the meantime Ferlauto wrote to Koprowski, “I would like to strongly recommend” that the Wistar not seek financial support or commercial interest from other companies.19 He wanted to protect his company’s market, in the event that the Plotkin vaccine was licensed.