The Vaccine Race

by Meredith Wadman

  It seems highly unlikely that Hayflick ever got that written statement, given Koprowski’s active efforts in 1969 to negotiate license agreements for Plotkin’s RA 27/3 rubella vaccine, made using the cells, with the Institut Mérieux in France, with Smith, Kline & French in Philadelphia, and with Burroughs Wellcome in the UK. What is clear is that, as the spring of 1969 turned into summer and Hayflick entered his second year at Stanford, he was taking definite satisfaction in holding out on Koprowski.

  At one point Plotkin wrote to inform Hayflick of moves by the Philadelphia drugmaker Wyeth to pressure the DBS to accept the WI-38 cells. Wyeth had used the cells to manufacture a new adenovirus vaccine for the U.S. military. Now it wanted to bring that vaccine to the civilian market. The company was getting fed up with Murray’s resistance. Wyeth officials were preparing to take their case to Richard Schweiker, a Republican U.S. senator from Pennsylvania.19 Hayflick responded by complaining about being left in the dark and threatening to tell the senator that the Wistar couldn’t either provide or control the precious young ampules.20

  At some point Koprowski seems to have given up on any serious effort to recover more of the hundreds of remaining ampules of WI-38 cells that Hayflick had at Stanford. Perhaps this was because Hayflick was now so geographically out of reach. Perhaps it was because Koprowski disliked direct conflict, much as he was prone to it. Perhaps it was because several companies already appeared to have adequate supplies of the youngest WI-38 ampules. Or maybe it was because by now Koprowski understood just how obdurate Hayflick could be.

  CHAPTER EIGHTEEN

  DBS Defeated

  Washington, DC, Spring 1972

  The DBS has acted in many major areas by simply not acting at all.

  —Leonard Hayflick, in testimony to the United States Senate, April 20, 19721

  In March 1972 Hayflick saw a decade of relentless proselytizing finally pay off. The Division of Biologics Standards approved for the U.S. market a vaccine made in WI-38 cells, for polio.

  Pfizer was the company that had at last wrung a license from Roderick Murray. The huge drug firm was headquartered in midtown Manhattan, but—thanks to the United Kingdom’s friendliness to WI-38—it had a facility in Sandwich, England, that was already online to make the new polio vaccine. Initially it would be shipped to the United States from Britain.2 It was called “Diplovax,” named with a nod to Hayflick’s “diploid” cells, which Pfizer had put to use pumping out Sabin’s polio vaccine virus, now the dominant polio vaccine in most of the world, including the United States.

  It was a deeply satisfying moment for Hayflick. The very box in which the new vaccine was packaged proclaimed his accomplishment for the world to see, in bold blue letters on a bright white background: “Propagated in a Human Diploid Cell Strain (WI-38 Hayflick).”

  Characteristically, Hayflick promoted the new vaccine in the pages of the New York Times, where on March 8, 1972, an article appeared under the headline VACCINE PRODUCED IN HUMAN CELLS.3 Once again Hayflick was the only person quoted in the article, and once again he reminded readers that “the monkey kidney is a notorious reservoir of unwanted viruses.” He went on to forecast that rabies, rubella, and measles vaccines made with WI-38 cells would soon be on the U.S. market.

  Why the inscrutable Murray had at last seen fit to approve a human cell–based vaccine is difficult to know. To a reporter from Science magazine he claimed that the approval—ten years after WI-38 cells became available—happened quite simply because Pfizer’s was the first application the DBS received for a vaccine using the cells.4 His comment is hard to take at face value, given Murray’s power, his resistance to Wyeth’s efforts to license the adenovirus vaccine it had made for the U.S. military using WI-38 cells, and his undoubted awareness that no drugmaker aiming at the civilian market would invest the time and resources required to develop a vaccine without at least an informal indication that the DBS would be open to such an application.

  In any event, Murray had much more preoccupying him in March 1972 than explaining the reasons for his decade of resistance to WI-38. The previous autumn a seasoned, outspoken U.S. senator had taken a keen interest in Murray’s DBS and how it was—or wasn’t—performing.

  Sixty-two-year-old Abraham Ribicoff, a liberal Democrat from Connecticut, had briefly been secretary of the Department of Health, Education and Welfare, the huge department that housed the NIH, during the administration of his longtime friend President John F. Kennedy. A lawyer from humble origins and a former governor of Connecticut, Ribicoff was a tough political street fighter and someone whose scrutiny must have made for severe indigestion at the DBS. He was in a perfect perch from which to train a laserlike eye on Murray’s division, because of his chairmanship of a Senate subcommittee overseeing “executive reorganization and government research” as part of the larger Committee on Government Operations.

  Ribicoff had been contacted in the summer of 1971 by a whistle-blower, J. Anthony Morris, a veteran DBS scientist who had been a firsthand witness to, among other things, Bernice Eddy’s silencing and demotion a decade earlier for finding and pursuing the “substance” in the rhesus and cynomolgus monkey kidney cells used to make polio vaccine that caused cancer in hamsters—the “substance” that turned out to be the silent monkey virus, SV40.

  The whistle-blower Morris wasn’t always easy to work with, but he was an accomplished scientist who among other things had discovered an important respiratory virus, respiratory syncytial virus, and had demonstrated, after its discovery in polio vaccine, that SV40 could directly infect human beings when squirted into their noses. His complaints about the DBS were lent gravitas by Morris’s scientific record. What was more, his lawyer, James S. Turner, was a serious and capable DBS opponent, having recently written The Chemical Feast, a critical study of the FDA, for Ralph Nader’s Center for Study of Responsive Law.

  In October 1971 Ribicoff took the Senate floor to detail Morris and Turner’s long and extremely damaging catalog of the DBS’s alleged incompetence, paralyzing conservatism, and inherently conflicted position acting as both regulator and developer of some products, notably rubella vaccine.5 Most disturbing, Morris claimed that the DBS had repeatedly shut down or ignored scientists’ research when their findings pointed to safety or effectiveness issues with vaccines already on the market or soon to be approved.

  Morris alleged that the DBS knowingly approved watered-down influenza vaccine—a charge confirmed six months later by the nonpartisan Government Accounting Office (now called the Government Accountability Office, the investigative arm of Congress).6 He highlighted the DBS’s slowness to insist that companies stop using potentially SV40-infected cells from rhesus and cynomolgus monkeys to make polio and adenovirus vaccines in the early 1960s. He charged that the suppression of Eddy’s findings on SV40 was part of a pattern in which the division regularly shut down or ignored scientific research that challenged DBS decisions or views on the safety of vaccines—including the Merck rubella vaccine.

  At one point in 1969, Morris alleged, a DBS scientist found foreign viruslike particles in lab cultures of duck embryo tissue—precisely the kind of tissue that Merck used to make its rubella vaccine. The scientist was told to abandon the research because the particles were “biologically inactive.” Murray was heard to comment: “We must be very careful because if we were to reveal viral contamination this would cause a severe financial loss to the producer.”7

  Morris himself was removed from a position heading influenza vaccine regulation in 1966, when he concluded from a clinical study he had just conducted that the vaccine protected only about 20 percent of vaccinees and told his bosses he wanted to explore the reasons why.

  Ribicoff’s highly public release of the charges from Morris and Turner made it immediately clear that the DBS was in deep political trouble.

  To Hayflick the scrutiny was beyond overdue. And when Ribicoff invited him to be one of the witnesses during four
full days of subcommittee hearings the following spring on Capitol Hill, he accepted. Hayflick was the third among the seventeen witnesses who appeared before the Ribicoff panel over four days in April and May 1972. He testified on the first day.

  Hayflick held nothing back. He lauded the “clear superiority” of his “absolutely clean” WI-38 cells over monkey kidney cells, telling the senators: “Each monkey is a universe unto itself and may carry harmful viruses in its cells, unlike WI-38. . . . The scope of this problem can be appreciated if one realizes that each lot of [polio] vaccine may require the sacrifice of several hundred monkeys whose kidneys are a veritable storehouse for the most dangerous kinds of contaminating viruses. In fact, monkey kidney is in this sense the ‘dirtiest’ organ known.”

  Hayflick lamented that the DBS staff had “dug in their heels” after SV40 was found contaminating polio vaccine, by refusing to offer companies even the slightest indication that the agency would license a vaccine that used WI-38 cells. He assailed the division for its “slothful,” “ultraconservative” positions, which had led to the Sabin polio vaccine being fed to fifteen million Russians before it touched American lips. He deplored the situation in which Murray sat as judge and jury on a rubella vaccine developed by his own scientists. He called for panels of expert but external advisers to weigh in on licensing decisions. He bemoaned the finality of Murray’s decisions, for which there was no mechanism of appeal. He noted that there was no limit to Murray’s now-seventeen-year tenure. And he called for Murray’s replacement with someone from outside the DBS.8 (It was already public knowledge that the NIH had convened a search committee to look for an immediate replacement for Murray.)9

  Nowhere in his comments was Hayflick sarcastic or glib. He was, on the contrary, deeply sincere. But nowhere was he the least bit politic, either. In this he was classically Hayflick: unable to resist a podium and, once on it, unable or unwilling to pull any punches.

  “I think you have made a devastating case against DBS and its present policies and practices,” the chairman of the full Senate committee, Senator Fred R. Harris, told Hayflick the moment he concluded his remarks.10

  It seems certain that the attendant humiliation was deeply felt at the DBS. In one memo written six days after Hayflick’s testimony—a memo that became part of polio-vaccine litigation and was unearthed in the book The Virus and the Vaccine—a member of the public relations department at Lederle Laboratories, then the dominant U.S. maker of polio vaccine, wrote: “Received a call from DBS Information Office informing us that they have finally decided to take strong action in opposing Dr. Hayflick’s allegations concerning monkey tissue vaccines. Apparently the CDC is involved in this counter move.”11

  Hayflick likely aggravated feelings at the NIH further with a hard-hitting attack on DBS scientists that he published the next month in Science under the headline HUMAN VIRUS VACCINES: WHY MONKEY CELLS?12

  The contrast of Hayflick’s in-your-face testimony with Plotkin’s response to the Senate hearings is striking and aptly crystallizes the difference between the two men. It also reflects the fact that the stubborn Plotkin still hoped that his rubella vaccine would one day win approval from U.S. regulators. So he had no wish to offend them. When Ribicoff asked him to testify, Plotkin kept his head down, replying to the senator with a succinct letter that explained: “I have decided against testifying in person because this whole history has been rather unpleasant for me and I do not wish to become actively involved in the problem again.” Instead, he wrote, because he felt compelled to do so as a citizen, he would summarize in writing “the facts as I know them.”

  Plotkin then related, in pale, measured language, the chronology of his attempts to develop a rubella vaccine in the face of DBS resistance and of his being driven as a result to look for manufacturing interest from English and French companies. He concluded with the most passive, inoffensive sentence he could construct: “I believe that the events unfolded above could have been avoided under different administrative circumstances.”13

  Plotkin, who as a boy had survived pneumococcal pneumonia, influenza, and asthma, continued, decades later, to be a survivor.

  The man who didn’t survive was Murray. By the time of the Ribicoff hearings, Murray was “requesting [to] be reassigned” within the NIH, where he became “special assistant” to the director of the National Institute of Allergy and Infectious Diseases, until his mandatory retirement sixteen months later. The man of few words left his position with only a cloaked regret about his “request”: “I do this even though I have strong feelings of loyalty to my staff.”14

  With Murray out, it was the NIH deputy director for science, a kidney physiologist named Robert Berliner, who was left trying to explain the DBS’s failings to the senators. He was one of a bevy of officials who accompanied Elliot Richardson, then the Secretary of Health, Education and Welfare, to the hearing.

  By the time it happened, the outcome of the Senate subcommittee’s investigation surprised no one. In July 1972 the DBS’s 258 employees were transferred to the Food and Drug Administration, and the division—which would nonetheless remain physically on the NIH campus until 2014—was renamed the Bureau of Biologics. Later it became today’s Center for Biologics Evaluation and Research at the FDA. In 1972, its new director was familiar to both Plotkin and Hayflick. He was Harry Meyer, of the Meyer-Parkman duo in the now-defunct DBS, who had developed the HPV-77 rubella vaccine that Merck had later made its own.

  • • •

  The Pfizer polio vaccine that the DBS approved in March of 1972 ended up surviving not a great deal longer on the U.S. market than human diploid cells in a lab bottle. As documented in the book The Virus and the Vaccine, the company struggled with chronic supply shortfalls, making pediatricians reluctant to rely on it.15 At the same time a hostile campaign against Pfizer’s WI-38–propagated newcomer was launched by Lederle Laboratories, which in 1972 dominated the U.S. live polio vaccine market. (By the early 1970s Sabin’s live vaccine had supplanted Salk’s killed one in much of the world, including the United States, where companies had stopped making, and pediatricians had stopped giving, the Salk vaccine.) Only one other company, Wyeth, made a live polio vaccine for sale in the United States, and the company withdrew that vaccine in the early 1970s.16

  Lederle did all it could to sink Diplovax, the new vaccine made in WI-38 cells with Hayflick’s name on the box. Among other things, the company targeted an important committee of the American Academy of Pediatrics, the main membership organization for the pediatricians who dispensed polio vaccine. Lederle urged the committee not to recommend, in its annually updated Red Book desk reference for children’s doctors, that they switch from the Lederle vaccine to Diplovax. In this effort the company sought to enlist help from the DBS.

  Ruth Kirschstein oversaw polio-vaccine safety testing for the division and was as close as any employee could be to Murray. The Virus and the Vaccine recounts how, as Lederle geared up to lobby the association of pediatricians, the company wrote to the DBS: “In preparation for such a confrontation [with the American Academy of Pediatrics committee] it would be valuable to have the support of the DBS. Could we count on Dr. Kirschstein?”17

  Whether the late Kirschstein went to bat for Lederle with the pediatricians’ group—and, if she did so, how heartily—is unknown. But it seems unlikely that she would have been given pause by any warm feelings toward Hayflick, who for most of the decade that Kirschstein had been charged with overseeing polio-vaccine safety at the DBS had been publicly assailing the monkey kidneys used to make the vaccine.

  Pfizer stopped selling Diplovax in the United States in 1976. From 1977 until 2000 Lederle’s African green monkey cell–propagated vaccine was the only live polio vaccine available in the United States, in an era when live oral vaccine was used almost exclusively. In 2000 the Centers for Disease Control recommended that pediatricians move back to using a more potent version of Salk’s killed polio
vaccine, and Lederle’s live vaccine was withdrawn from the market.

  The killed, injected vaccine was substituted for Sabin’s live vaccine because rarely—about once for every million doses administered—the live vaccine virus can mutate into a more toxic form and cause paralysis, especially in babies with compromised immune systems.18 When polio was a scourge, paralyzing and killing hundreds of thousands of people around the world every year, that was a risk worth taking. But because over the last sixty years vaccines have obliterated most polio on the planet, that risk-benefit ratio has changed. As a result, in 2015 the World Health Organization asked countries around the world to begin phasing out Sabin’s live vaccine, beginning in April 2016. The phase-out won’t be completed until naturally occurring polio is completely eradicated. In 2015 it was reported in two countries: Afghanistan and Pakistan.19 In the summer of 2016, several more cases were documented in Nigeria.20

  CHAPTER NINETEEN

  Breakthrough

  Philadelphia, Pennsylvania, and New Haven, Connecticut

  September 1970–October 1973

  Vaccinology, I would say that it’s not rocket science. It’s a lot harder than rocket science.

  —Alan Schmaljohn, virologist at the University of Maryland, 20141

  Given all that went before, one could be forgiven for assuming that nobody in the United States much noticed, or cared, when Smith, Kline & French dropped its development of Stanley Plotkin’s rubella vaccine in the autumn of 1970, after the company won approval for its Cendehill vaccine—and after Plotkin’s patron, Ferlauto, left the company. Nobody, that is, besides Hilary Koprowski, Plotkin, and the small circle of colleagues who had worked with him to test it.