The Vaccine Race
Page 31
Ferlauto didn’t know that on that score he was already too late. Throughout 1968 Koprowski had been actively talking to London-based Burroughs Wellcome and the family-owned French firm Institut Mérieux in Lyon, where the Wistar’s chief was good friends with the owner, Charles Mérieux. The three companies would spend 1969 sparring over who would be licensed the rights to sell Plotkin’s RA 27/3 vaccine in what portions of the world.
• • •
Plotkin may have garnered important industry support, but an event in the autumn of 1968 made clear just how far out in the political cold Plotkin’s vaccine still stood—along with the fetal cells it was grown in.
That October the NIH held an unusual press conference to announce the results of the first trial of rubella vaccine in the midst of a natural outbreak of the disease. In the spring of 1968 an islandwide rubella epidemic had taken hold in Taiwan. The disease had been completely absent there since the previous epidemic ten years earlier. As a result, children under ten years old had never been exposed to the virus and lacked immunity.
Researchers from the University of Washington, from the U.S. Naval Medical Research Unit 2 in Taipei, and from the Municipal Health Bureau in Kaohsiung, a seaport city in southern Taiwan, seized the opportunity to test Merck’s newly tweaked, duck-based vaccine—and, alongside it, Plotkin’s RA 27/3 vaccine. In late April and early May the scientists vaccinated hundreds of first to fourth graders at four schools in Kaohsiung. In the subsequent months less than 1 percent of the children who received injections contracted rubella. Among unvaccinated children the attack rate varied from 13 percent to 28 percent, depending upon the school.20
Daniel Mullally, the chief of the Vaccine Development Branch at the NIH’s National Institute of Allergy and Infectious Diseases, delivered the good news to the press conference that October. (It was Mullally who one year earlier had sung the praises of Parkman and Meyer’s HPV-77 vaccine in a letter to Koprowski explaining why his branch was refusing to fund Plotkin’s work on RA 27/3.) Both the New York Times and the NIH’s in-house newspaper, the NIH Record, covered the story on their front pages.21,22 The HPV-77 vaccine, invented on the NIH campus by Parkman and Meyer and tweaked slightly by industry, had shown itself to be remarkably effective in the Taiwanese epidemic, the articles reported.
A reader of either of these articles would have had no way of knowing that Plotkin’s vaccine too had been injected in the Taiwanese children, and that it had performed slightly better than Merck’s. One child out of 187 injected with the Merck vaccine had contracted rubella. One child of 198 injected with Plotkin’s RA 27/3 had gotten the disease.23
Either Mullally did not mention Plotkin’s vaccine at the NIH press conference or he gave it very short shrift. Either way, the result was the same. Neither the New York Times nor the NIH Record mentioned Plotkin’s RA 27/3 vaccine. It was as if it didn’t exist.
• • •
On a chilly evening in mid-February 1969, Plotkin attended an evening reception at Governor’s House, a hotel in Bethesda, Maryland, that catered to visitors and scientists from the nearby NIH. The hosts were Lewis Thomas and Saul Krugman, two leading lights of U.S. medicine and the dean and chair, respectively, of pediatrics at New York University Medical School. Their reception opened the International Conference on Rubella Immunization. Held in the largest venue on the NIH campus—the auditorium in the imposing Clinical Center, the NIH’s research hospital—the three-day meeting was attended by everyone who was anyone in the world of rubella vaccinology. More than four hundred people from all over the world turned up.
The meeting was charged with energy and expectation: virtually everyone present knew that the DBS was preparing within several months to license the one or more rubella vaccines it judged to be fit for the U.S. market. There was equally a sense that licensure could come none too soon, with the new epidemic that everyone feared expected as soon as 1970.
Murray himself had invited Plotkin to the conference in a letter months earlier. “Great strides are being taken in research directed to the control of rubella,” the DBS director had written in what passed for enthusiasm in his buttoned-down parlance. “Your participation will do much to contribute to the value of the conference.”24
Onstage at the huge meeting were the accumulated data for four vaccines. There was Plotkin’s RA 27/3, grown in WI-38 cells. There was Parkman and Meyer’s HPV-77, in its adaptations by Merck in duck embryo cells and by Missouri-based Philips Roxane, which had grown it in dog kidney cells. And there was Smith, Kline & French’s Cendehill vaccine, developed several years earlier in Belgium by virologists at RIT, the subsidiary of the Philadelphia drugmaker. They had captured their rubella virus from the urine of a ten-year-old girl.25
Plotkin’s vaccine was the only one that had not been in intimate contact with African green monkey kidney cells. It was also by far the underdog when it came to institutional support. More than fifty thousand people had received one of the four experimental rubella vaccines; of these, just five hundred people had received Plotkin’s injected vaccine.26,27
There were several surprises in store for the conferees.
First, when Hilleman stood to speak, he explained that while both Merck’s Benoit vaccine, the original vaccine that the company had developed, and its HPV-77 duck vaccine were “acceptable” for use in children, Merck had dropped the former in favor of the latter. Even though the HPV-77–based vaccine generated levels of antibodies in vaccinees several times lower than Merck’s Benoit vaccine, it was in the “best national interest” to concentrate on a single virus when it came to getting a vaccine licensed as quickly as possible, Hilleman explained cryptically.28 He did not address why that single vaccine should not be the Merck Benoit vaccine that generated superior antibody levels. And he did not mention a powerful philanthropist named Mary Lasker.
Then there was unsettling news from new studies of the HPV-77 vaccine candidates in adult women. Women who received the Merck and Philips Roxane vaccines were getting joint pain and inflammation—arthralgia and arthritis in medical parlance. Not just a few women. Lots of them.29 Hilleman’s group reported that in a trial of Merck’s HPV-77 duck vaccine, twenty of thirty-five women (57 percent) developed a rash, joint pain, joint swelling, or a combination of these. The pain and swelling afflicted their fingers, their big toes, their ankles, their wrists, and their knees. Two women were in enough pain to need steroids. The fluid sucked out of one woman’s swollen knee was found to contain live rubella virus.30
The dog vaccine made by Philips Roxane was just as bad: fourteen of twenty-five women (56 percent) developed joint pain, swelling, or both. In half of them it was distressing enough that they sought out their doctors.31
The Merck paper on the women’s joint problems presented at the conference would be published several months later and would conclude by noting that tests of Merck’s HPV-77 vaccine, further weakened by more passages through duck embryos, were in progress. It would be “desirable to eliminate” the joint pain and swelling, the authors conceded. Nonetheless, they put it on the record that “the vaccinated women accepted their vaccine-related illness and were reassured by their [new] immunity against rubella.”32
Ostensibly the adult women’s problems should not have been a deal breaker. The experts at the CDC who made vaccine recommendations were expected to target the vaccine at young children, on the theory that if they did not contract the disease, they would not pass it on to their pregnant mothers. In all the clinical trials so far, vaccinated children had rarely been bothered by joint pain or swelling. And, in fact, universal childhood vaccination is what the CDC did end up recommending, just two months later.33
At the time, experts were divided on whether it made the most sense to vaccinate children or women of childbearing age—after first ensuring that they weren’t pregnant, because it wasn’t clear if a weakened vaccine virus could damage the fetus.*34,35,36
The Un
ited Kingdom would opt to vaccinate schoolgirls just before puberty. (After serious rubella epidemics followed in the UK in 1978, 1979, and 1983, the country in 1988 began immunizing preschoolers of both sexes.)37
In the winter of 1969, with licensure of one or more rubella vaccines imminent, every physician in the packed auditorium at the NIH knew one thing with certainty. Even if the United States chose to routinely vaccinate small children rather than their mothers, their women patients with pregnancy plans would be at their doors demanding the vaccine the moment it was licensed. And they, as these women’s doctors, were going to be hard-pressed to refuse them. So the physicians may have taken note when, during his turn at the podium, Plotkin touched on his findings with his own vaccine in adult women.
Plotkin had decided to test the RA 27/3 vaccine’s effects in grown women the previous year, as soon as he heard by the grapevine about the arthritis problems with the Merck and Philips Roxane vaccines. By the time of the NIH conference, he had vaccinated sixty-one student nurses in Philadelphia hospitals; not one had developed joint pain or swelling, he told his audience.38 What was more, in preparation for the conference, he had gathered data on an additional eighty-six adult women vaccinated with RA 27/3 by his foreign collaborators. Again, none had developed joint symptoms.
Plotkin concluded his talk by touching on what he saw as his vaccine’s other advantages: it was as good at generating protective antibodies as his rivals’, but, unlike theirs, it was made in human cells, without the risk of lurking animal viruses. And it could, unlike its competitors, generate antibodies when given as a squirt in the nose.
Plotkin didn’t spell out his question as he wound up his talk, but to him it seemed to hang in the air. Why, with the disadvantages of an HPV-77–based vaccine—its joint pain, its arthritis, its rashes, its long lab-dish exposure to African green monkey kidney cells—would the DBS choose to license it, as it was almost certainly going to do in the coming months?
When Roderick Murray, the DBS chief, stood up to speak on the last day of the conference, it was clear that Plotkin’s unspoken question wasn’t bothering him. His talk did not mention Plotkin’s vaccine or Hayflick’s human cells. He did point out that the other candidate vaccines had had intimate contact with monkey kidney cells. As to the safety concerns this provoked, producing a rubella vaccine indisputably free of silent monkey viruses was simply unaffordable, he announced.
“The production of a [animal virus] free vaccine suitable for general use appears at this time to be infeasible from the economic standpoint,” Murray told the audience. The best he could suggest was careful, long-term follow-up of the vaccinees from the field trials for any untoward effects.39
Plotkin’s RA 27/3 vaccine, made using Hayflick’s virus-free human diploid cells, seemed once again simply not to exist.
• • •
The single session from the conference that participants remember vividly fifty years later came on its last afternoon, during a discussion that began with a question about the origins of the WI-38 cells used to grow Plotkin’s vaccine. The questioner, Dr. Kevin McCarthy from the University of Liverpool, in England, worried aloud that bits of the WI-38 cells’ DNA might be present in the vaccine and then become incorporated in the DNA of vaccinated people. McCarthy asked for information about the siblings of the WI-38 fetus. Were they normal? And what was the reason for the abortion? His implication was that there would be more reason to worry if the fetus had been aborted because it was diseased or abnormal, or if its parents had other diseased children.40
Plotkin offered the following confident response.
“This fetus was chosen by Professor Sven Gard, specifically for this purpose,” he told the audience. “Both parents are known and, unfortunately for the story, they are married to each other, still alive and well, and living in Stockholm, presumably. The abortion was done because they felt they had too many children. There were no familial diseases in the history of either parent, and no history of cancer specifically in the families; that is, the maternal or paternal sides.”41
(In fact, Mr. and Mrs. X were no longer married at this point and did not live in Stockholm. But this is beside the point, scientifically.)
Plotkin’s reassuring comments immediately prompted a response from the man who was arguably the most powerful person in the room. There were few people as respected—and feared—in U.S. virology as Albert Sabin, who had been known for his piercing intellect and first-rate science even before his live polio vaccine was licensed in the United States in 1961. Since then he had taken on near-godlike proportions in many eyes.
At age sixty-two Sabin was old enough to be Plotkin’s father. His receding hair was snowy white. He had thin lips, a thin mustache, and an intimidating gaze. He spoke with a self-assurance born from defeating innumerable lesser men. (He had been on the New York University debating team as an undergraduate, and, it was said, he had never lost a debate.) Hilleman recalled Sabin later as a “mean goddamn bastard” who “went from one field to another, always sneaking in.”42 “He always thought he was more important than anybody” was the DBS scientist Bernice Eddy’s recollection.43 In the 1960s Sabin’s influence on the Division of Biologics Standards was enormous.
Sabin took the floor to make two points. First, he challenged the repeated claim by WI-38 defenders that the cells were “fully characterized,” with its implication that they did not, and thus never would, show any nasty tendency to become cancerous; that they did not, and never would, be found to harbor hidden “passenger” viruses.
“There is no full characterization for any cell line, because for everything we do, there is always some hypothetical something for which we cannot test,” Sabin argued. Sure, Hayflick and Plotkin and other WI-38 backers had scrutinized WI-38 cultures with their electron microscopes for years and never found an unwanted virus. That didn’t mean such a virus mightn’t be there. They could keep looking until doomsday and never be sure.44
Sabin also objected to critics who had labeled him as reacting from emotion rather than reason. His audience need only consider that viruses had been found that caused leukemia in mice. And of course everyone was aware of the now-famous virus named after Peyton Rous that caused sarcomas—nasty tumors of connective tissue—in chickens. There was an urgent hunt on, Sabin continued—one that the NIH’s National Cancer Institute and Sabin himself were part of—to discover if a comparable human leukemia virus existed. If it did, there was every possibility that it was hidden in WI-38 cells. What was more, it was known from studying cells from these species in culture that leukemia-causing viruses didn’t always reveal themselves in early passages in the lab. They were there, nonetheless, invisible, waiting. So, Sabin concluded, “reasonable people can disagree” about whether WI-38 critics were an emotional bunch reacting from their hearts and not their heads.45
As Sabin held forth, Plotkin had begun making notes in his crabbed handwriting on a sheet of lined paper. “Pure theology,” he wrote. “No factual basis.” Plotkin was not a religious man, but at that particular moment a phrase from the first book of Samuel in the Hebrew Scriptures came, unbidden, into his mind: “The Lord hath delivered him into my hands.
When Sabin surrendered the floor, Plotkin stood and walked toward the microphone at the front of the room. On the dais Murray tried to shut Plotkin down, pleading limited time for debate.
“Let him talk!” someone shouted from the audience.
Murray acquiesced.
“As I recall from polio days,” Plotkin began, “debating with Dr. Sabin is very much like getting into a bear pit. One does not come out in exactly the same shape as one went in.”
But it was Plotkin who then bared tooth and claw.
Sabin had made the point that leukemia viruses sometimes did not show up in early passages of infected animal cells. Well, he should be aware that, using electron microscopy, viruses had not been found in young, middle-aged, or old WI-
38 cells—up through and including the point of cell death after fifty or so divisions. Nor had tests using antiviral antibodies to home in on viruses hidden in WI-38 cells ever been positive—not even tests using the blood serum of leukemia patients, whose antibodies presumably would have sought out any lurking “leukemia virus.” Nor had exhaustive chromosomal studies raised concerns. Nor had the cells ever turned cancerous.
“It has always been curious to me,” Plotkin continued, “that the same people who worry about WI-38 do not worry about the unknowns in other tissues.” How many lots of monkey kidneys that were used in vaccine production were studied to ensure normal chromosome numbers, he asked? How many were studied to see if the cells became cancerous with time?
“Dr. Parkman,” Plotkin went on, “indicated that the monkey kidney cells used in the first seventy-six passages of the HPV-77 strain were not subjected to detailed tests for silent monkey viruses. But this apparently does not disturb anyone.
“What we are dealing with here is theology,” Plotkin concluded. “And, you see, in theology it is very hard to disprove the existence of things. One cannot disprove the existence of ghosts. But that is not, to my mind, a basis for making intellectual decisions.”46
As Plotkin left the microphone, the auditorium filled with what he would recall decades later as “a thunderous ovation.”47
There was one person who wasn’t there clapping. Hayflick had left the conference early, upset, according to Plotkin, by the sidelining of his cells.
• • •
Four months later Murray’s DBS published the official manufacturing standards that first allowed the licensing of a rubella vaccine in the United States. The guidelines specified that the vaccine must be propagated on duck embryo or dog kidney cells, effectively anointing Merck and Philips Roxane as the only two companies that could seek a license.48 Merck’s vaccine was licensed by the DBS the same month. The decision was no surprise to the company, which had a flock of Pekin ducks, complete with pond, waiting at its West Point campus, and 600,000 vaccine doses ready for release on the June day that it won FDA approval.49 The Philips Roxane vaccine followed it to market in December 1969. A few months later the DBS expanded its guidelines to allow rubella vaccine to be made using rabbit kidney cells, allowing Smith, Kline & French’s injected Cendehill vaccine to be licensed early in 1970. Because it did not produce joint symptoms as often as its competitors, it became the vaccine of choice for doctors confronted with adult women asking to be vaccinated.50