In the meantime, back in his lab at the Wistar Institute, Plotkin had set about weakening his rubella vaccine virus, RA 27/3, in two ways. He had already grown it through four passages on Hayflick’s WI-38 cells before the trial at St. Vincent’s. Now he grew it through twenty-one more, assuming that the more adapted it became to life in lab bottles, the less virulent it would be in the human body. In addition, he tried a technique that he knew had successfully weakened a different virus, polio: incubating the virus at slightly cooler temperatures than he had done initially.
Plotkin grew the virus at three different temperatures as he passaged it. One set of bottles he kept at 95 degrees Fahrenheit, the same temperature at which he had grown the virus before taking it to St. Vincent’s Home. With the other, as he passed the virus-laden solution from one bottle to the next, he dropped the temperature first to 91.4 degrees and then to a relatively chilly 86 degrees Fahrenheit.
Each time he harvested a batch of fluid from the WI-38 cells to pass into a new bottle of fresh WI-38 cells, Plotkin set aside some that could be used as experimental vaccine and put it through safety testing. By the end of many months of work, he had produced RA 27/3 virus grown at three different temperatures and at many passage levels. He had on hand, for instance, eighth-passage virus grown at 95 degrees; thirteenth-passage virus grown at 91.4 degrees; and twenty-first- and twenty-fifth-passage virus grown at 86 degrees.
One of these many recipes, he hoped, was going to strike the right balance, making the virus weaker but not too weak. He didn’t know where the sweet spot was. Plotkin went back to St. Vincent’s Home to find out.
In the autumn of 1965, in the spring of 1966, and again early in 1967, Plotkin ran three more trials involving forty one- to three-year-olds at St. Vincent’s Home.
He tried different vaccines in different groups of toddlers, injecting them in the shoulders. Then for six weeks he followed up, although not entirely on his own. Plotkin enlisted the help of two physician colleagues. John Farquhar was an amiable, bespectacled pediatrician with a keen interest in infectious diseases who was director of pediatrics at Philadelphia’s Presbyterian Hospital. Michael Katz had been Plotkin’s medical school roommate and was, like Plotkin, a scientist at the Wistar. He was an erudite man who as a fourteen-year-old in Nazi-occupied Poland escaped under cover of dark from the Janowska concentration camp in Lwów, in what is now Ukraine. He spent most of the rest of the war under an assumed name, working as a runner for the Polish resistance in Warsaw. He made it to the United States in 1946, at age eighteen. All the rest of his family was killed by the Nazis.
Plotkin, Katz, and Farquhar divided the trial work, getting in their cars and dodging the streetcars out Woodland Avenue to St. Vincent’s Home. There they checked the toddlers for rashes and fevers and swollen lymph nodes, swabbed their throats, and checked their noses for virus with cotton-tipped wires that the doctors stuck in the children’s nostrils. On the days in between these trips, another doctor, Horst Agerty, who was the archdiocese’s physician for St. Vincent’s Home, examined the children for signs of illness. Sister Agape, the home’s administrator, and Sister Mary Joseph, who had trained as a nurse and worked for years in a remote corner of South Africa, were also on hand—Sister Mary Joseph in a nurse’s office complete with examination table on West 2, where a goldfish tank was a particular attraction for the small visitors.15
As he worked his way through the roughly sixty-five occupants of St. Vincent’s Home, where there was little turnover, it became clear to Plotkin that he was running out of subjects. He would need to go farther afield. In August 1966 he drove ninety miles northwest of Philadelphia to the Hamburg State School and Hospital—a sprawling former TB sanatorium on a hilltop one mile outside the small town of Hamburg. The sanatorium, with its circular driveway and elegant Spanish mission–style main building, had emptied as tuberculosis faded with the advent of effective anti-TB drugs, better diagnostic tools, and improved prevention measures. In 1960 the state of Pennsylvania repurposed it, transferring nearly 1,000 intellectually disabled people there from another state institution—and from a swollen waiting list of 2,700 others whose families were seeking spots for them in state facilities.16
While the Pennsylvania legislature renamed the white-walled, three-hundred-acre facility a “school” and “hospital,” it was, at the time of Plotkin’s studies there, little of either. Few of its residents were taught anything, and while it had a surgical facility to deal with urgent problems, it was primarily a warehouse for people incapable of functioning on their own. The residents lived in wards of thirty or forty beds. They were nominally called “children,” but many would age into adulthood at Hamburg and remain there for decades.17
Many residents were profoundly disabled. They were bedridden or confined to wheelchairs, diapered, incapable of feeding themselves. Many couldn’t speak. One ten-year-old boy who died at Hamburg in 1967 succumbed to what an autopsy described as “convulsions due to mental retardation,” which in turn was due to being starved of oxygen by a prolapsed umbilical cord at the time he was born.18 Another, a quadriplegic ten-year-old, was affected by “severe inanition and dehydration”—meaning essentially that he was wasting away. His death was attributed to “cardiac arrest complicating congenital spastic paralysis.”19
Cleaning, cooking, nursing, and otherwise caring for the roughly 950 residents employed scores of people from the town. The work could be physically taxing and sometimes dangerous: caregivers were on occasion attacked. Six years later a nearby newspaper, the Observer-Reporter of Washington, Pennsylvania, reported that straitjackets, heavy drugging, and confinement in three-by-five-foot steel cribs were used to restrain unruly inmates.20 The staffing challenges complicated Plotkin’s efforts to launch a trial. “We will provide help in holding the children,” he wrote to Benjamin Clark, the short, stocky physician with a military bearing who was in charge at Hamburg.21
In late summer 1966, in the first of many trials he would run at Hamburg—again with help from Farquhar, the affable Presbyterian Hospital pediatrics chief, and Katz, the Wistar physician/scientist who had escaped the Nazis—Plotkin injected the RA 27/3 vaccine in the shoulders of seven children, aged four to thirteen, whom he described as “moderately to severely retarded.” Another seven such children served as unvaccinated contacts and shared close quarters—one floor of one building—with the vaccinees. “Contact between subjects was promoted by placing them together in a playroom for regular periods,” Plotkin wrote in the paper describing the trial.22
Plotkin began conducting trials at the Hamburg State School and Hospital at a critical juncture in the history of human experimentation in the United States.
In June 1966 Henry Beecher, a doctor who specialized in anesthesia at Harvard Medical School, published an article entitled “Ethics and Clinical Research” in the New England Journal of Medicine, a leading U.S. medical journal. It shook the medical establishment.
Beecher outlined, without naming names or institutions, twenty-two human experiments chosen from the medical literature from 1948 through 1965 that, he reported, had risked the health or life of their subjects. “Grave consequences have been suffered as a direct result of experiments described here,” the paper began—experiments for which, Beecher wrote, “it must be apparent that [subjects] would not have been available if they had been truly aware of the uses that would be made of them.”23
The experiments had been conducted by doctors at prestigious hospitals and universities, including the Clinical Center, the huge research hospital at the NIH. They had been published in top medical journals and funded by the NIH, the U.S. military, drug companies, and private foundations. What was more, Beecher had chosen the twenty-two from a far longer list of ethically suspect studies that had not been difficult to compile.24 The abuses were everywhere.
In one experiment doctors had withheld chloramphenicol, a treatment known to effectively fight typhoid fever, from char
ity patients with the disease, to see if they died at greater rates than patients who received the drug.25 (They did.) In another, they withheld penicillin, which was known to be effective against strep throat, from a control group of 109 U.S. airmen with the ailment, knowing that they could develop well-known, potentially life-threatening complications. Three men went on to do so after the bacteria in their throats spread.26 Children in an institution for the “mentally defective” were purposely infected with the hepatitis A virus. (This institution, it emerged, was New York’s Willowbrook State School for the Retarded, another horrible holding pen, and the pediatrician who infected the children was the prominent Saul Krugman, the same man who had earlier infected children with rubella.)27 Separately twenty-two elderly, senile hospitalized patients were injected with living liver cancer cells and told simply that they were receiving “some cells.” Leading this trial was the prominent cancer scientist Chester Southam of Memorial Sloan-Kettering Cancer Center, whose example Hayflick and Moorhead had followed in deciding to inject dying cancer patients with the new human diploid cells in 1960.28 The list went on.
With the article’s publication, the NIH was finally called to account for the lack of informed consent or observance of other ethical constraints in the human experiments that it funded. Beecher’s explosive findings had been circulating and had received press coverage since he gave a public talk on them in March 1965, and the NIH had already received at least one letter from a member of Congress, the Chicago Democrat Roman Pucinski, asking how the agency was going to react. So the government was ready.29
On July 1, 1966, two weeks after Beecher’s article appeared—and exactly one month before Plotkin began his first trial at Hamburg—the U.S. Public Health Service, the NIH’s parent agency, published new guidelines under which U.S.-funded researchers like Plotkin would henceforth have to operate in running human experiments.30 They would have to collect, and document, the informed consent of all participants in the research. They would also need to win ethical approval for their experiments ahead of time from new committees at their institutions—if these hospitals and universities wanted their scientists to continue to receive NIH funding.
Institutions, including the Wistar, got the message quickly. By July 22, three weeks after the government guidelines went into effect, Koprowski had constituted a “committee of associates” to pass ethical judgment on human trials run by Wistar researchers. It comprised four scientists, including Moorhead, Hayflick’s coauthor on the 1961 paper that announced the mortality of normal human cells in lab dishes, who was not a physician; and Werner Henle, the eminent virologist at the Children’s Hospital of Philadelphia, who himself had run wartime experiments testing an experimental influenza vaccine by infecting with influenza both vaccinated and unvaccinated juvenile offenders, and intellectually disabled residents at a state facility, Pennhurst.31
As word of the new rules spread, Plotkin scrambled to respond. On July 25, 1966, he wrote to Clark, the physician in charge at Hamburg:
National Institutes of Health has requested that in any trial using human subjects there be records of consent. Therefore, I wonder if you could write me a letter simply stating that you, as the person responsible for the children to be used in the first trial, assume the responsibility for them. The letter will be filed until such time as NIH requests it, if ever.
With regard to subsequent groups of children, from whose parents you have agreed to obtain consent, I think it would be desirable to include in the consent form, statements similar to the following: “German Measles in the mother may cause birth defects in the infant, including mental retardation. We are trying to find ways to vaccinate against the disease. In these trials we wish to inoculate your child with a living vaccine virus. We understand that the German Measles infection, if it takes in our child, may produce a rash and slight fever. We understand that this is normally a mild or nonserious illness but that very rarely ill effects have been attributed to German Measles.”32
Clark responded two days later with the letter that Plotkin requested, taking responsibility for the children injected in the first trial. They were inoculated at Hamburg on August 1, 1966.33
Plotkin could have put off the first trial and sought permission from the parents of the fourteen children involved. But he did not. He had already laboriously arranged the staffing and subjects for the first Hamburg trial. Getting consent from the subjects’ families would have meant more delay. And he was a man in a hurry.34
Two years later, after launching a tenth trial at Hamburg, Plotkin would obtain another for-the-record letter from Clark, attesting to the fact that written permission had been obtained from the parents of the participants in all ten of the trials at Hamburg—or from Clark, acting in the place of their parents.35
By the spring of 1967 Plotkin had conducted a total of four new studies—three at St. Vincent’s and one at Hamburg. Their results showed that thirty-seven of thirty-eight vaccinated children had developed antibodies—a 97 percent success rate. Admittedly, the numbers were small, but the percentage boded well.
As for side effects and spread to unvaccinated contacts, the message from the new studies was this: the higher the passage number and the cooler the incubation temperature, the less likely an experimental vaccine virus was to cause symptoms of the disease, like a rash, fever, and swollen lymph nodes; the less likely it was to colonize a child’s throat; and the less likely it was to spread to unvaccinated children living in close quarters with the vaccinees. In the very last of the new trials, five one-year-olds at St. Vincent’s Home received coolly incubated twenty-fifth-passage virus. Not one of them developed a rash or swollen lymph nodes. Not one of the toddlers’ throat or nose swabs tested positive for rubella virus. The kids weren’t contagious, and their blood tests showed that the vaccine had generated protective levels of antibodies.36
Plotkin had hit his target.
As he wrote up his new findings for the American Journal of Epidemiology, Plotkin also returned to his argument for WI-38 cells, which was by now well rehearsed: that the cells were cleaner and therefore safer than the animal cells his competitors were using to make their rubella vaccines. He had new ammunition, and it targeted African green monkeys, the very species that Parkman and Meyer had passaged their rubella vaccine in seventy-seven times and that Hilleman had initially used to grow the rubella vaccine that Merck was now developing. Hilleman had captured the Merck rubella virus, Benoit, from that eight-year-old Philadelphia boy with the same last name, grown it through nineteen passages on the African green monkey kidney cells, and then weakened it further in duck-embryo cell cultures.
African greens were perceived as relatively safe. They did not harbor SV40, the cancer-causing monkey virus that was discovered in 1960 in the rhesus and cynomolgus monkey kidneys then in use to make polio vaccines. That problem had forced the DBS to require polio vaccine makers to switch to using the kidneys of African greens, because they did not naturally harbor the SV40 virus. However, since that change in 1963, more disturbing information had emerged about African green monkeys.
In 1966 scientists at Lederle, a leading maker of the Sabin oral polio vaccine, published a paper in the Journal of Infectious Diseases. It concluded that the DBS-required safety tests now in place for African green monkey kidney cells were “thorough and effective” at ensuring the safety of the oral Sabin polio vaccine that had by then virtually replaced the killed, injectable Salk vaccine in the U.S. market.37
However, Plotkin saw the Lederle data as saying the opposite—that the green monkeys were a continuing source of concern. The Lederle scientists reported that they had studied 865 polio vaccines that they made using the kidneys of 865 individual green monkeys. They had been forced to reject 309 of the vaccines—36 percent—because of the presence of unwanted viruses.
“There is abundant evidence that primary African green monkey kidney is rife with latent viruses,” Plotkin wrote in the new
paper reporting on his recent studies at St. Vincent’s Home and the Hamburg School—and he pointed to the Lederle study.38
Plotkin sent his new paper reporting RA 27/3’s promising results to the American Journal of Epidemiology in mid-May 1967. Then he waited for the journal’s production gears to grind. Early in August, as the paper was in press for the September issue, events in the picturesque university town of Marburg, West Germany, made Plotkin’s case for his vaccine, produced in a human diploid cell strain, intensely, immediately relevant.
• • •
Marburg is a historic university town nestled on the river Lahn in central Germany and dominated by an eleventh-century hilltop castle. In 1967, it was home to Behringwerke, a vaccine and blood serum producer that was then part of the pharmaceutical company Hoechst. The company made live polio vaccine, and for this it harvested kidneys from African green monkeys.
That summer, probably in late July, Behringwerke received a shipment of African green monkeys from Uganda. The animals (Chlorocebus aethiops), also known as grivet monkeys, had black faces framed by striking white tufts of hair, bristly fur, and stomach skin with a tint of blue. They weighed anywhere from seven to seventeen pounds, and this lot of them looked healthy, despite their long journey: they had been sidetracked to London to avoid the Israeli-Arab Six-Day War. Then they were delayed in England due to an airport employees’ strike. (Two monkeys escaped an animal house in London where the monkeys were housed during the delay. They were later recaptured and sent on to Germany separately.)39
The Vaccine Race Page 26