The leading polio vaccinologists who convened at the conference at Georgetown University that June were buzzing with optimism. The killed-virus Salk vaccine had already been on the market for five years, and the incidence of polio in the United States had fallen dramatically, from nearly 25 cases per 100,000 people in 1955 to fewer than 5 per 100,000 people in 1960.14 But pockets of polio stubbornly persisted, particularly in poor communities. Still more worrying was the fact that the worst cases—the ones that paralyzed people—had not declined at as steep a rate as cases that sickened people but from which they recovered fully. Alarmingly, cases of paralytic polio more than doubled between 1957 and 1959 to more than 6,000. It seemed clear that the Salk vaccine was going to curtail polio but not conquer it. And so the assembled virologists were eagerly awaiting the licensing of a second solution—the first live polio vaccine—a vaccine that, they anticipated, would be cheaper, easier to administer, and more effective than Salk’s. It would be swallowed rather than injected, and so would mimic the natural route of polio infection. It would generate robust levels of antibodies in the lining of the digestive tract, where the virus first encounters the human immune system, as well as in the blood—unlike Salk’s killed-virus vaccine, which was injected into muscle.
The scientists at the conference knew that they were witnessing the home stretch of an intense three-way race to win a U.S. license for a live vaccine. The high-powered, sharp-tongued Albert Sabin was clearly in the lead. But Herald Cox, Koprowski’s former boss at Lederle, had taken the vaccine that Koprowski developed while at the company and continued tweaking and testing it; he was fighting hard to stay in the race. And Koprowski himself had refused to give up on beating his archenemy, Sabin. Since leaving Lederle, the Wistar czar had adapted and renamed the vaccine he had brought with him from Lederle and continued to test it, vaccinating more than 300,000 people in central Africa, mainly in the Belgian Congo.
But what the audience heard from Hilleman at that June 1960 conference put a damper on the buzz about the hoped-for licensure of a live vaccine. Hilleman shocked them with the news of an unexpected finding by Ben Sweet, a scientist he supervised at Merck’s West Point, Pennsylvania, campus. Sweet had discovered a new, invisible simian virus contaminating Sabin’s live vaccine and almost certainly Cox’s and Koprowski’s live vaccines too. All three vaccines were made using monkey kidney cells. And unlike Salk’s killed vaccine, none of the live vaccines were treated with the formaldehyde that was presumed to kill simian viruses.
This new simian virus differed in an important way from the dozens of others that were now known to infect the monkey kidneys used by polio vaccine makers. The new virus didn’t declare itself by damaging cultures of the cells. It didn’t “go on a rampage,” as Koprowski put it. Instead it sat quietly, leaving the monkey cells looking and acting perfectly normally in their bottles. It was impossible to detect, making it impossible for vaccine makers to jettison infected cultures. But it was there nonetheless.
How, then, did Sweet stumble on the new virus? A detailed rendering of his discovery comes from The Virus and the Vaccine by Debbie Bookchin and Jim Schumacher.15 The authors recount that Sweet happened to be working with a different species of monkey from the species whose kidneys were normally used to make polio vaccine. When he exposed kidney cells from this different species, the African green (or grivet) monkey, to fluids from rhesus monkey kidney cells—the cells used to make polio vaccine—the African green kidney cells sickened and died. It emerged that the rhesus cells had passed to the African green cells a virus—a virus that lay silent and invisible in rhesus monkey cells but caused major damage in the kidney cells of African greens, bloating the cells and riddling them with holes.16 (The virus was also discovered to live silently in the kidney cells of another monkey species also used in polio vaccine preparation: cynomolgus monkeys.)
If there was any good news in the Merck scientists’ findings, it was this: Sweet had found that the silent simian virus was inactivated by the same formaldehyde that was used to kill the polio virus in the Salk vaccine. So while the virus may have been injected into the arms of some of the seventy million Americans who had received the Salk vaccine, it had also, it seemed safe to say, been dead on arrival.
The remaining days of the conference buzzed with talk of the new virus, which Hilleman dubbed the “vacuolating virus” because of the holes, or vacuoles, it made in the cells, leaving them looking like Swiss cheese. Formally the new, silent virus was named SV40. News of it soon reached Eddy at the nearby NIH.
Eddy didn’t know what it was in the rhesus monkey kidney cells that had caused her hamsters’ tumors. She hadn’t had the tools on hand to identify whatever it was, so she had simply called it a “substance.” But when she heard of Hilleman’s vacuolating virus, she immediately suspected strongly that her “substance” and the new, silent virus, SV40, were one and the same thing.
On July 6, 1960, one month after Hilleman’s much-noted talk at the Washington conference, Eddy sent a memo to her boss, Joseph Smadel, who was newly in charge of vaccine safety testing at the DBS. She titled the memo “The presence of a [cancer-causing] substance or virus in monkey kidney cell cultures.”
Eddy wrote to Smadel that she had heard about Hilleman’s SV40 virus—and that she herself had inoculated newborn hamsters with “specially prepared monkey kidney cells.” Tumors occurred at the injection sites, she wrote. “Eventually, the animals die.” She hoped, she added, to do some follow-on experiments as quickly as possible, to see if the “substance” causing her hamsters’ tumors was in fact SV40.17
Smadel was a man’s man, a foul-mouthed, no-nonsense, dictatorial virologist in his early fifties who had staffed an advanced World War II field laboratory in France after D-Day and later, working in Malaysia, discovered that an antibiotic, chloramphenicol, could effectively treat typhus and typhoid fever. Smadel had come to the NIH in 1956 on the heels of the disastrous Cutter incident. He had been a key advocate of the Salk vaccine, and he was acutely aware of the damage that another round of Cutter-like bad press could do to public adoption of any polio vaccine. So as Smadel read Eddy’s note, he got angry. He summoned her and tore a strip off her in language he later acknowledged was “not even diplomatic.” He dismissed the tumors in Eddy’s hamsters as “lumps,” called her data “inadequate,” and shut down her “entirely unwarranted” suggestion that they might be related to SV40 or have implications for human cancer.18
Eddy wasn’t fazed. She went back to her lab determined to identify the “substance” that had caused the cancers in her hamsters. It was completely conceivable that her “substance” had been injected, alive, into the millions of people in other countries and the roughly 10,000 in the United States who had participated in Cox’s, Koprowski’s, and Sabin’s trials of live polio vaccine. And it was also possible, she was convinced, that it had been injected—and was still being injected, in the Salk vaccine—into the arms of tens of millions of U.S. schoolchildren.19
• • •
Hayflick recalls learning about the discovery of the SV40 contamination by Sweet at Merck even before Hilleman’s bombshell speech at the Washington conference in June of 1960. Hayflick was a friend of Sweet’s, and the circle of virologists in the Philadelphia area was a close one in which news was freely exchanged and traveled quickly. Similarly, Eddy’s findings soon made their way to Hayflick through the scientific grapevine, as bad news always does.
Hayflick immediately grasped the headache that SV40 posed for polio vaccine makers and regulators. Admittedly, Hilleman and Sweet had argued that it wasn’t an insurmountable obstacle. They had tested the blood of people who had swallowed live polio vaccines in trials and found no antibodies to the simian virus, strongly suggesting that SV40 did not proliferate massively in the human intestinal tract and from there invade the body. Still, they conceded, the possibility could not definitively be ruled out. Nor could the long-term possibility that, having in
vaded the body, such a virus could eventually cause cancer, “especially when administered to babies” with their less-developed immune systems. Going forward, the pair wrote in the paper that summarized their SV40 findings, “the simple solution” would be to ensure that the live polio virus seed stocks—the stocks that were amplified by companies to make production-scale quantities of vaccine—were not contaminated with SV40, and to throw away vaccine lots that were already tainted.20
The problem, Hayflick was convinced, was not so simply solved. For one thing, the testing of the live vaccine to ensure that it was free of SV40—testing that would clearly be needed going forward—would be time-consuming and expensive. And even if no ill ever came to those already vaccinated, Hilleman and Sweet themselves had admitted that “other undetected [simian] viruses might also await demonstration.”21 Surely there was a better answer than passively waiting to stumble on the next unwelcome “passenger” virus in monkey kidney cells.
In the summer of 1960 Hayflick was still fully two years away from launching WI-38 from the lungs of Mrs. X’s fetus. As news of the discovery of SV40 landed, Hayflick was still working with the first twenty-five fetal cell lines, coming to realize that they aged and died in their dishes, with all that that portended. He was also finding them, to all appearances, free of lurking, unwanted viruses. At the same time, he was discovering that they could be infected with many other disease-causing viruses—including polio. And Moorhead, bent over his microscope, was reporting that their chromosomes were reassuringly normal. The obvious thing to do fairly shouted at Hayflick. He would make a polio vaccine using his normal human diploid cells. Then he would see if it worked.
• • •
Down the hall from Hayflick’s lab and across the atrium, in the other wing of the V-shaped Wistar Institute, another brain was buzzing with the vaccine-making implications of the new human cells. Koprowski had been front and center at the June conference in Washington, DC, where the sudden specter of SV40 took top billing. There he had given a speech downplaying SV40’s significance, and that of any other monkey virus that might be found contaminating live polio vaccine.
Koprowski pointed out that in the last several years of trials, millions of people around the world had already received various live poliovirus vaccines made using monkey kidney cells—his vaccine and Sabin’s and Cox’s—to no obvious detrimental effect. The discovery that SV40 had been lurking in those vaccines, he argued, “should hardly deter anybody from accepting the product.” Silent viruses inhabited all kinds of animals cells, he argued, and doubtless would be found, for example, in the calf lymph that had been successfully used to make smallpox vaccine for two hundred years. Should we therefore stop vaccinating against smallpox?
He conceded that it would be desirable, going forward, to try to rid monkey cells of extraneous viruses, and he mentioned several possible approaches, including using—he didn’t mention Hayflick or the Wistar by name—some newly available human cells.22
As he minimized the risks of SV40, Koprowski was still holding out the ambitious hope that the U.S. surgeon general—Leroy Burney, whom Koprowski had been sure to invite to the Wistar’s gala opening symposium the previous year—was going to pronounce his live polio vaccine the favorite child of the U.S. government; the vaccine that would be chosen to move through licensing, leaving its two competitors in the dust.
Burney was under pressure to make a choice, soon, among the three vaccine candidates, not least because the United States was still exclusively using Salk’s killed, injected vaccine while the country’s bitter cold war rival, the USSR, had already fed eighty million people Sabin’s purportedly superior, oral, live vaccine. Not only that, but there had been sporadic new outbreaks of polio in the United States in 1958 and 1959. These outbreaks had—fairly or unfairly, for most cases occurred in undervaccinated populations—undermined confidence in the Salk vaccine.
On August 24, 1960, Burney told a press conference that he had picked a winner: Sabin’s vaccine had bested its two competitors in safety tests in monkeys, and he had chosen it to proceed through licensing. Any live vaccine licensed in the future would have to be as good as Sabin’s, or better. Within hours, three major vaccine manufacturers announced that they would begin making the Sabin vaccine, and others appeared ready to follow suit. Koprowski’s vaccine was done, to all appearances.
But for the ever-enterprising Koprowski, Hayflick’s new human cells meant that the game was not necessarily over. In late October, Koprowski—joined by a twenty-eight-year-old Wistar physician/scientist, Stanley Plotkin, who had helped run trials of Koprowski’s monkey cell–based polio vaccine—sent off a long letter of advice to a World Health Organization committee. The group was soliciting input on the standards that live polio vaccines should be held to.
Koprowski had minimized the SV40 monkey virus problem only four months earlier, when his own monkey kidney–based polio vaccine was still in the running for U.S. approval. Now, with Sabin’s vaccine rolling quickly toward being licensed, he sounded more alarmed. The letter noted that monkey kidneys are riddled with simian viruses. Eliminating SV40 from the live vaccine, the writers observed, “may present insurmountable obstacles.”23 And yet hundreds of thousands of fresh monkey kidneys would continue to be needed to make live polio vaccine, increasing the chances of a potentially cancer-causing virus finding its way into some lots of vaccine and “making the case even weaker for the use of such a tissue.”
By contrast, Koprowski and Plotkin wrote, cells were now available from normal human fetuses—cells that had normal numbers of chromosomes. They could be frozen and used for vaccine production when needed. And each line of such cells could be “scrupulously investigated” for hidden viruses. Koprowski and Plotkin laid out the pros and cons of monkey-kidney versus human cells in an accompanying table. Its columns had titles like “Possibility of freeing poliovirus from simian viruses” (with the human cells it was “possible”; with the monkey kidney cells it was “impossible”) and “Procurement of tissue” (with the monkey kidney cells it was “difficult”; with the human cells it was “easy”).24
Koprowski sent the letter off to Geneva. Then he waited for Hayflick to show just how a polio vaccine could be made—using the human fetal cells and not Sabin’s but Koprowski’s polio vaccine.
• • •
Hayflick first grew a small amount of Koprowski’s polio vaccine virus in petri-dish cultures of his normal WI-1 cells.*
Then he inoculated fluid from these petri-dish cultures into bigger quantities of WI-1 cells in quart-sized bottles. Koprowski’s polio vaccine virus destroyed the cells within two days, first causing the long, tapering fibroblasts to become round and then causing them to burst, or “lysing” them. Each lysed cell ejected up to ten thousand new virus particles into the nutrient fluid that bathed it.
Next Hayflick inoculated that fluid into still more WI-1 cells, this time in still bigger, gallon-plus bottles. These he left to incubate at body temperature. Five days later he filtered the resulting soup of culture medium, cellular debris, and live viruses to strain out bacteria. He froze it at –94 degrees Fahrenheit. He had just produced the first vaccine grown on his human diploid cells.25 (It was not the first vaccine ever grown in human cells; Sven Gard’s group in Sweden had done that when they made that fleeting polio vaccine using fetal skin and muscle cells in the mid-1950s—the vaccine that was impracticable because they couldn’t make enough of it.)
As Hayflick prepared the vaccine, another stunning piece of news arrived about the silent simian virus, SV40. The previous summer, vaccine makers and regulators alike had taken heart from the finding by Sweet and Hilleman at Merck that SV40 was killed by the same formaldehyde used to kill the polio virus in the Salk vaccine.
But in March 1961 British researchers reported in the Lancet, a widely read medical journal, their discovery that, contrary to the Merck scientists’ report, SV40 was resistant to formaldehyde:
it was not inactivated by the chemical as quickly as poliovirus was. That meant that the simian virus could survive sometimes, alive, in Salk’s vaccine. They argued for “an accumulating body of evidence that killed poliomyelitis vaccine in the past has contained [SV40], probably in the living state.”26
A few months later researchers from the Medical Research Council Laboratories in London reported in the British Medical Journal that they had found antibodies against the SV40 virus in eleven of twelve schoolboys who had received the full slate of three Salk injections.27 The presence of antibodies did not mean that the virus was alive and replicating in the boys—the whole principle of injecting a killed vaccine is that the body forms antibodies even to a dead virus. The boys might well have received dead SV40 with their Salk injections. But the presence of SV40 antibodies in eleven of the twelve boys was an alarming indication of just how widely SV40 might have infiltrated the supply of Salk vaccine. And the more widespread it was, the more likely that some vaccinees had received injections in which the virus had survived alive.
The same month, March 1961, that the Lancet article appeared, a House of Representatives subcommittee held hearings on production of the live vaccine. Koprowski had a conflict and couldn’t testify, but he wrote to the lawmakers, making the same argument that he had made to the World Health Organization a few months earlier. Given the ubiquity of the silent SV40 virus in the monkey cells used to make the live vaccine, it would be impossible to produce it in a cost-effective manner. It would be both cheaper and sounder scientifically to switch to human cell strains. There was, he added, “not a shred of evidence” that they caused cancer.28
This was the backdrop against which Hayflick pushed ahead with his human fetal-cell–produced polio vaccine. He finished making the vaccine in or about January 1961. Now, as the SV40 problem emerged as more widespread than anyone had first understood, Hayflick and Plotkin set about ensuring that the new vaccine would be safe to inject into the most fragile of human beings: newborn babies.
The Vaccine Race Page 14