The Vaccine Race

by Meredith Wadman

  The answer came back within a week. “The dividing line between this kind of activity and actual development of a [vaccine] product is not clear,” wrote Murray. Many labs that were early in the vaccine-making process did file their proposed trial procedures, called protocols, with the DBS, since at any time their work could “take on aspects of the development of a vaccine,” he added. But no, formally, Plotkin did not need to jump through those hoops. Whatever he did, “you would, of course, be guided by ethical considerations.”12 “You should protect yourself,” Murray suggested, by making sure that the proposed project was reviewed ahead of time by an “objective group of advisers.” Finally, Plotkin should follow the recommendations of the NIH expert committee that had pronounced on the human diploid cells in the pages of Science the previous year.13

  That committee was the one that Murray had put together within a month of the publication of Hayflick and Moorhead’s 1961 paper describing the new, normal lab-dish fetal cells and their potential for vaccine making.

  The committee had been exceedingly cautious in its report published in Science in January 1963, warning that the human diploid cells might harbor hidden viruses that could cause cancer or otherwise harm vaccinees. It had urged that new vaccines made in them should first be put into one or two adult volunteers, who should then be watched carefully for at least six months in case the vaccine was infected with hepatitis or another virus with a long incubation period. Murray added that Plotkin needn’t worry about these recommendations if “you already have data from other studies with diploid cells to meet these [committee] suggestions.”14

  Plotkin considered that he did have that data. It was just one year earlier that the quiet, determined Yugoslavian vaccinologist, Drago Ikić, had immunized five thousand Croatian preschoolers against polio with a vaccine made using WI-38 cells—to no apparent ill effect.

  As for summoning an “objective group of advisers” to preapprove the study, Plotkin didn’t do that. But it is probable, he wrote in 2016, that he consulted with Hilleman, Merck’s vaccine chief, and with Robert Weibel, a pediatrician at the University of Pennsylvania who worked closely with Merck running vaccine trials.15

  When Plotkin wrote to the DBS, he stated that he was using “non-vaccine material.” This was because he didn’t want Murray and his staff defining the RA 27/3 virus as a vaccine, giving them license to interfere with his trial, require lab and animal testing, and generally slow him down.16 In truth, he deeply hoped that RA 27/3 was a vaccine in the making. But he also knew that the virus was only very mildly weakened at this point. He had grown it through just four passages on WI-38 cells, hardly enough generations adapting to lab life for it to lose its punch for human beings. Rather, it would likely give the toddlers full-fledged rubella. This would prove beyond a doubt that the agent that he had captured from the kidneys of fetus 27 was indeed the rubella virus. Not that he doubted this. But others might.

  The trial would also allow him to study the spread of rubella infection from child to child and the immunity produced in the toddlers by the experimental infection, Plotkin wrote that spring to his colleague, Theodore Ingalls.17 Ingalls was a well-known epidemiologist at the Henry Phipps Institute (part of the University of Pennsylvania) who was supporting Plotkin’s work by funding the salary of a lab technician.

  Plotkin was not the first scientist to set out to cause rubella in human beings. In 1938 a pair of Japanese researchers, Sadataka Tasaka and Y. Hiro, produced rubella by injecting children with nasal washings from people with the active disease, demonstrating that rubella was almost certainly caused by a virus.18 In 1953 Saul Krugman, a pediatrician at New York University, gave one- to six-year-old children rubella by injecting them with blood drawn from infected children.19 And in 1962 John Sever, the director of virology at the NIH’s National Institute of Neurological Diseases and Blindness, produced rubella in male prisoners by injecting virus captured from a sick patient into their noses, using swabs and medicine droppers.20

  As with other similar studies in this era, these rubella-inducing studies did not elicit protests. And by the time Plotkin set about infecting children, the country was in the midst of an unprecedented rubella epidemic. Just as the clarion call of endangered soldiers on the front lines had made medical researchers willing to use people in unimaginable ways during World War II, in 1964 the urgency of the quest for a rubella vaccine in the face of a devastating epidemic consumed Plotkin and his contemporaries, causing them to lay aside any queasiness about testing their vaccines on powerless, institutionalized children. They also worked with this fact easing their minds: German measles—unlike polio and unlike the hepatitis with which the DBS’s Murray had purposely infected prisoners—is generally a mild disease if one is not a fetus. Its one documented, fatal complication—the brain inflammation called encephalitis—was rare in adults and extremely rare in children. So, Plotkin says, he did not worry as he launched the first human trial of RA 27/3.21

  • • •

  St. Vincent’s Home for Children had an ideal layout for Plotkin’s purposes. The two self-contained wings meant that the children in this first study—one-year-olds who lived on East 2 and two-year-olds who inhabited West 2—could be kept isolated, both from the children on the other wing of their floor and from the older children downstairs. But within East 2 and West 2 the toddlers would continue to eat, sleep, and play together.

  “They slept in one of two common sleeping areas each measuring approximately 256 [square feet] and containing eight cribs,” Plotkin reported.22 If the RA 27/3 virus was infectious enough to spread from vaccinated toddlers to the unvaccinated controls within each group, the close and self-contained quarters of East 2 and West 2 were the perfect place to observe it.

  Such spread of the virus was a top-of-mind concern, since small children were potential targets for a rubella vaccine, and if vaccinated kids spread the vaccine virus to their pregnant mothers, the results could be disastrous. Before the trial began, Plotkin tested the blood of all the female caregivers on East 2 and West 2—nuns and laywomen alike—for antirubella antibodies. All were already immune to rubella, he wrote in the paper that resulted from this first study at St. Vincent’s Home.23

  Plotkin planned to test two methods of vaccine administration: injection under the skin and intranasal administration, which meant squirting liquid vaccine into one nostril with a dropper “while the child was forcibly restrained.” Since in naturally occurring infection the virus colonizes the nose and throat before invading the blood, it stood to reason that intranasal vaccination might be feasible. What’s more, it might be cheaper, since it would take less skill to administer. And it would almost certainly cause less crying.

  Plotkin ran safety tests before he took RA 27/3 to St. Vincent’s Home. He tested the vaccine for the presence of bacteria, fungi, and the ubiquitous Mycoplasma and found it clean.24 He also injected it into animals, in the abdomen and in the brain: twenty baby mice, twenty adult mice, and six guinea pigs. He injected ten rabbits subcutaneously. All the animals stayed healthy for six weeks.25

  By the autumn of 1964, Plotkin felt ready to put his vaccine in the toddlers at St. Vincent’s Home. He ran the trial there in two parts, each six weeks long, separated by an interval of ten weeks, which included a break for Christmas. Children received an injection in the shoulder or a squirt in the nose. Some received a higher dose of the virus and some a lower dose. Other children received nothing, serving as controls.

  During each trial all the children, vaccinees and controls alike, were examined every day for fever, rashes, swollen lymph nodes, and other signs of illness and had throat swabs taken every three or four days. Their blood was drawn at the beginning and the end of the trial.

  Every few days Plotkin drove the three miles down Woodland Avenue to the Home for Children, where he examined the toddlers and collected throat swabs. On the days that he wasn’t there, others took temperatures and checked for rashe
s. They may have included Sister Mary Joseph, who was a trained nurse, and the archdiocese’s staff doctor, Horst Agerty.

  Virtually all of the small inhabitants of East 2 and West 2 participated in the trial. Almost none of them had antirubella antibodies before the study began.26

  Plotkin learned several important things from the trial. From the toddlers who had no rubella antibodies before the trial began he learned that his virus, given as an injection, caused rubella. Nine of the eleven antibody-lacking children who received injections developed a rubella rash. Most had swollen glands and half ran a fever of up to 103 degrees. All of them showed rubella living in their throats for about a week before and a week after the rash appeared. And their rubella spread. Four unvaccinated children were infected by the kids who had received the shots in the shoulder. Children who got the higher-dose injection got sicker, and they were the only ones who spread the virus to unvaccinated children.27

  RA 27/3 seemed to have an immunizing effect. All eleven of the children who lacked antibodies before the trial began and who received injections developed antibodies. And these antibodies were apparently protective: three of the toddlers who got jabs in the shoulder during the first trial were injected again on day one of the second trial. This time they didn’t get rubella. The antibodies generated by the first injection had shut down the virus when it was injected a second time.

  The intranasal vaccine, by contrast, didn’t cause illness or spread it—but neither did it generate antibodies in nine of the eleven toddlers who received it.

  Plotkin submitted his paper to the American Journal of Diseases of Children in early June 1965, and it was published that October. His coauthors—included largely as a courtesy, as Plotkin himself had done most of the work—were Ingalls, the University of Pennsylvania physician who had funded his lab technician’s salary, and David Cornfeld, a well-liked senior pediatrician at the Children’s Hospital of Philadelphia, who, Plotkin says, smoothed his entrée to St. Vincent’s.

  There are tables in the 1965 paper and diagrams that lay out how the RA 27/3 virus was developed. And there is one full-page photo. It is a close-up of a child who received a lower-dose injection. It shows his or her naked back and the back of a chubby left arm. There is a head of soft brown curls just visible at the top of the photo. In the middle of the child’s back there is a heart-shaped patch of white skin. The rest of the skin is covered by a bright red rash.

  The experiment had succeeded but also failed, Plotkin wrote. RA 27/3, when injected, generated protective antibodies but caused disease, and spread it too. And while the disease it produced was “a mild illness” with no complications and no severe symptoms, “only an agent unable to spread to contacts and, therefore, unable to endanger pregnant women” would make an acceptable vaccine, he concluded.

  Plotkin made clear his intention to keep moving forward. The results, he wrote, were a baseline. From here he would further weaken the rubella virus, with the goal of inventing a workable vaccine.

  In Plotkin’s view the work couldn’t happen quickly enough. The threat of the next epidemic hovered five or six years off, if history was a guide. In the meantime the heartbreaking results of the one that had just ended seemed to be everywhere.

  • • •

  Steve and Mary Wenzler were all about family. The newlyweds joked that they would have nine children. They had the energy. And they had the time, back in the early 1960s. Both were schoolteachers in their early twenties, settling into life in Toms River, New Jersey, an Atlantic shore town fifty-six miles due east of Philadelphia.28

  The jobs were what had drawn the Wenzlers to Toms River from the busy suburbs of Trenton, where they had grown up. Thanks to Toms River Chemical, a huge Ciba-Geigy plant that opened in 1952, the town of seventeen thousand was growing so quickly that school construction could hardly keep up. So Steve—officially Stephen Joseph Wenzler III—had taken a job as band director at Toms River High School, and Mary was teaching music at Central Regional Junior High School in nearby Bayville.

  During their first year of teaching, the Wenzlers also began working on the family project. In the autumn of 1963 Mary had a miscarriage. That was common. She wasn’t worried.

  Then, one morning in March 1964, Mary found a bulletin from the school nurse in her mailbox in the junior high school office. It announced that an epidemic of German measles was hitting the school. She recalls the bulletin warning that a big uptick in student absences could be expected, if teachers hadn’t noticed it already. Any student who was feverish or had a rash should be sent home. Any teacher with symptoms should not come to work.

  This was the first that Mary had heard of an epidemic. It wouldn’t have mattered, except that her period was slightly late and she had a gut feeling that she was pregnant. She knew what that felt like, after the miscarriage. She also knew, she does not remember how, that German measles during pregnancy was not a good thing. Some 125 seventh- and eighth-graders trooped through her music classes every day. It seemed highly likely that she had been exposed.

  That evening Mary and Steve discussed what to do. She hadn’t yet connected with a doctor in Toms River. They decided that she should see Vincent Pica, her trusted family doctor from her former life in Hamilton Square, a Trenton suburb.

  A day or two before her appointment with Pica, Mary developed a mild fever and a light red rash on her face and called in for a substitute. Worry gnawed at her as she drove the thirty-six miles to Pica’s office in Hamilton Square.

  As Pica heard her story and examined her, Mary saw worry in his eyes too. He gave her a shot in her rump. It was gamma globulin, an injection of pooled antibodies from blood donors. The aim was to confer the same kind of ready-made immune protection that the horse antibodies conferred when given immediately to people bitten by rabid animals—in this case to protect the fetus from infection by killing off the rubella virus in a woman’s bloodstream before it penetrated to her womb. But with rabies there was a vaccine that was also given, to kick the victim’s own immune system into high gear, producing its own antibodies. With rubella there was no vaccine to give along with the gamma globulin.

  Whether gamma globulin alone was actually effective against rubella was painfully uncertain. And there was no way to answer the question. Researchers couldn’t run a prospective, controlled clinical trial that would deny the gamma globulin treatment to some pregnant women and give it to others. Pregnant women would not put up with that. They were not orphans or prisoners who could be easily manipulated. So the scientists had to draw what conclusions they could from case histories.29

  The British physician J. C. McDonald examined the medical records from nearly thirteen thousand pregnant women given the injection between 1954 and 1961 after being exposed to rubella. The evidence suggested that gamma globulin effectively prevented rubella in these women, he wrote. But it was not conclusive. What was more, it was well known that the virus frequently invaded the blood without causing visible sickness. Therefore, preventing manifest illness in the mother might not be synonymous with protecting the fetus.30

  So when Mary Wenzler visited her longtime family doctor in the spring of 1964, the state of the art was this: physicians gave gamma globulin because it couldn’t hurt and it might help. And patients hoped.

  • • •

  After she missed a second period, Mary made an appointment with Alfred Pietrangelo, a local family doctor who delivered babies. He confirmed her pregnancy. She told him she had had rubella and the gamma globulin injection. Unprompted, he said that he didn’t do abortions and that if she was interested in ending her pregnancy, she would have to find a different doctor. She told him that she didn’t believe in abortions either. She said she wanted him to see her through this pregnancy and deliver the baby.

  On Tuesday, November 24, 1964, at 3:33 p.m., after an uneventful labor, Stephen Joseph Wenzler IV was born at Toms River Community Hospital. Baby Stephen weighed fiv
e pounds, thirteen ounces and was nineteen inches long. (This was less than the 10th percentile for weight and about the 17th percentile for length.) The delivery-room staff soon noticed something that they did not tell Stephen’s parents: there were milky white opacities where the black pupils of the baby’s eyes should have been. They didn’t give Mary the baby to hold.

  Mary still hadn’t seen baby Stephen when, that evening, as she lay flat in a shared hospital room, a thin, young ophthalmologist came to see her. He stood by the bed looking down at her and told her that her baby had cataracts blinding both eyes.

  Mary’s exhaustion didn’t blunt the shock. “What do we do?” she finally managed to say.

  “If I were you, I would get pregnant again, and then it won’t bother you so much,” he said.

  Fifty years later Mary doesn’t remember the rest of the conversation. She does remember the feeling of hopelessness that overwhelmed her and the kind nurse with a European accent who, after the ophthalmologist had gone, comforted her while she cried.31

  • • •

  Mary spent Thanksgiving Day 1964 in the hospital. She and Steve took baby Stephen home that weekend and set him up in a bassinet beside their bed. He nursed and slept and cried when he was hungry. When his eyes were open, they gazed emptily into space.

  Mary tried to do normal mother things. She dressed Stephen in a blue velvet vest with his name embroidered on it and matching blue short pants—a gift from her sister-in-law. She wrote in Stephen’s baby book: “I smiled when I was one week old.” “I grasped at a toy at three months.” “I cut my first tooth at ten months.” Then she stopped writing entries.

  Mary did something else soon after Stephen was born. She called her family doctor, Pica, the one who had given her the gamma-globulin injection. He had decided to leave general practice and happened to be completing specialty training in ophthalmology at the Newark Eye and Ear Hospital. He wanted Stephen’s eyesight to be assessed by his boss, Richard Stern, just as soon as possible.