“The viruses . . . arrived Thursday. Many, many thanks,” Plotkin wrote to Dudgeon in early November 1963. He added: “There is a fair amount of rubella [vaccine] activity going on in the States, though this statement is mainly based on rumors rather than . . . publications. Merck is said to be experimenting with the vaccine, but they are very secretive about it.”8
Merck, under the ever-ambitious Hilleman, was indeed working on a rubella vaccine. Hilleman had been happy to share his company’s West Point strain with Plotkin because Hilleman had his team using a different strain, called Benoit, to develop a vaccine. It had been isolated in 1962 from the throat of an eight-year-old Philadelphia-area boy with that last name. (The French pronunciation of Benoit is “ben-WAH”; the American scientists called it “ben-OYT.”) The Merck scientists grew the Benoit virus through multiple generations on African green monkey kidney cells and then in duck-embryo cells, aiming—as with any live virus vaccine—to weaken it to the point where it provoked an immune response without causing illness.
Plotkin had another competitor, in the Division of Biologics Standards, the vaccine-regulating arm of the U.S. government, where the taciturn Roderick Murray had now been the director for nearly a decade. Paul Parkman, at thirty-one years old, was exactly the same age as Plotkin. He had just moved from the Walter Reed Army Institute for Research to a job in the DBS. From there he was working full tilt on his own live vaccine under the mentorship of his boss, Harry “Hank” Meyer. Meyer, only a couple of years older, was a tall, ambitious, take-charge virologist with close-cropped, prematurely gray hair who had been at the DBS since 1959. He had recently been working in West Africa, helping to administer an experimental vaccine to millions of children in the face of an epidemic of classical measles.9
Parkman and Meyer were using African green monkey kidney cells to try to weaken the virus that Parkman had isolated from the Fort Dix soldier. They would end up naming the resulting vaccine HPV-77, for “high-passage virus,” and because they had inoculated it sequentially into seventy-seven cultures of African green monkey cells, injecting first one culture of kidney cells, then, once the virus had multiplied in those, taking fluid from that first culture and inoculating a second culture, and so on until they reached what was commonly called the seventy-seventh “passage”—since fluid had been “passed” from one culture on to another seventy-seven times.10
Importantly, Parkman’s new job had placed him at the power center of U.S. vaccine regulation: the DBS approved vaccines for the U.S. market. And Parkman’s boss and partner, Meyer, had just been named chief of the DBS lab charged with viral vaccine work.
Plotkin soon realized that he was fighting an uphill battle against Parkman, with his inside track at the Division of Biologics Standards, and Hilleman, with his years of vaccine-making expertise and all the resources of a huge drug company behind him. But Plotkin was stubborn, and young, and confident. And he thought he could make a superior vaccine with Hayflick’s better, cleaner cells. What he needed to do, and quickly, was to establish whether those cells would become infected by rubella; if not, they would be useless for making a vaccine. He also wanted to study how exactly rubella wreaked its damage in infected cells.
So, working with André and Joëlle Boué, a Parisian husband-and-wife team who then were guest scientists at the Wistar, Plotkin injected bottles of Hayflick’s WI-38 cells with the three strains of rubella virus that he had collected from the other scientists. He also grew uninfected control cultures of WI-38. As he had hoped, all three rubella strains readily infected the WI-38 cells.
However, once infected, the cells didn’t act like the uninfected cells in the control bottles. In the control bottles the WI-38 cells, as expected, began to vigorously multiply. They reached confluence and needed to be split into new bottles every three or four days. They kept dividing for months. In the bottles that were full of infected cells, the cells stopped dividing after being split into new bottles just one, two, or three times. They ground to a complete halt within a few weeks.
When he looked at the uninfected control cultures under the microscope, Plotkin saw a field densely packed with the elongated, compass needle–shaped WI-38 cells. When he examined similar cultures of infected cells—and virtually all the cells were infected after a few days—they had the same tapered shape and appearance as healthy WI-38 cells. The virus wasn’t exploding them, filling them with holes, or otherwise leaving distinct footprints.
But what was striking was the amount of white space. The infected cells were few and far between. The virus was somehow shutting down their ability to replicate. Plotkin wondered immediately if this damper on division in a lab dish translated to the fetus—and to the damage he had seen in babies. Two years later he and a Finnish collaborator, Antti Vaheri, would use WI-38–infected cells to identify, and publish in Science, their discovery of a protein responsible for inhibiting cell division in the rubella-infected cells. They dubbed it RVIMI, for “rubella virus-induced mitotic inhibitor.”11
The good news for Plotkin was that, in the process of dividing just two or three times, the WI-38 cells had produced reams of new rubella virus particles: one million or more times the number of viruses he had initially inoculated into the bottles. For vaccine-making purposes, the fact that the WI-38 cells stopped multiplying after a few divisions didn’t matter. In the vaccine-making context the cells’ job was to produce virus, not to reproduce themselves.
In August 1964 Plotkin and the Boués submitted a paper to the American Journal of Epidemiology, reporting their finding that rubella somehow suppressed the division of WI-38 cells—but that those cells nonetheless produced huge quantities of the virus during their short lives in lab bottles. The WI-38 cell, the authors concluded, “might be used as a [cellular factory] for rubella vaccine.” They ended the paper by citing the by-now-familiar list of the advantages of Hayflick’s human diploid cells for vaccine making: their cleanliness; their normal chromosomes; their reassuring, noncancerous behavior; the fact that they could be frozen and later pulled out of the freezer and expanded into huge quantities.
Even before submitting the paper, Plotkin had reported his good news to Koprowski. The institute’s chief couldn’t make it to the June 1964 meeting of the Wistar’s board of managers. But Art Stern, the Wistar’s research administrator, brought the board into the loop at that meeting. “We have been successful in getting rubella virus to grow in diploid cells and are now attempting to [weaken] it,” he told them. “A vaccine could be the possible end product of this work.”12
• • •
On March 27, 1964, the CDC devoted the first half of its Morbidity and Mortality Weekly Report—the influential publication alerting doctors to circulating infectious diseases—to one subject.
“A nationwide epidemic of rubella (German measles) appears to be in progress,” the article began. “A rise in reported cases was first noted late last fall in the northeast, with peak incidence being observed only during the past few weeks. The outbreak appears to have spread rapidly to the south and west.”
The eight-page report laid out the local damage.
“Cases are about five times greater than for the comparable period in 1963, one of Massachusetts’ high years for this disease.”
In New York City, with nearly 8,700 cases already in 1964, “rubella cases are reported at about 17 times the number for the comparable period a year ago.”
In Kentucky cases exceeded by 60 percent the comparable period in 1963; in Illinois the figure was 86 percent.
In Allegheny County, home to the city of Pittsburgh, the number of cases through March 13 already exceeded the number in the whole of 1963. The same was true in the state of Colorado and in Maryland.
The city of New Orleans had noted a “sharp increase” in rubella cases, starting, apparently, in the week of February 17.
Only the non-Colorado mountain states and the Pacific states appeared to have b
een spared. This wasn’t altogether surprising. The MMWR noted that in the past the Pacific states had experienced rubella epidemics one year later than the rest of the country. (In 1965 the epidemic would indeed visit the Pacific and mountain states.)13
The epidemic would become the worst one since authorities in some U.S. states had begun keeping records nearly forty years earlier.14
Plotkin, primed for an epidemic onslaught by his experience in London, began tracking the babies born with congenital rubella at the University of Pennsylvania Hospital, Philadelphia General Hospital, and other area hospitals. He made an index card for each affected baby. “R-1,” he labeled the first. With time, he would label card R-60, then R-105, and then R-132.
The cards had notations, including:
Baby M. Cyanotic.
Baby F. Congenital heart.
Baby T. Cataracts.
Baby-HUP-Autopsy. Died of congenital heart disease.15
Ultimately Plotkin compiled a list of rubella patients—the babies and their mothers—that ran to 1,700 entries.16 He and colleagues also tallied all of the babies born with congenital rubella at Philadelphia General Hospital. From this they estimated that between April 1964 and March 1965 at least 1 percent of black newborns in Philadelphia were affected by congenital rubella—more than triple the number in the preceding twelve months.*17
Soon after Plotkin’s return from London, it had become known among Philadelphia-area physicians that the young virologist at the Wistar was adept at running the diagnostic blood test that would tell a pregnant woman if she had had rubella. His lab was soon deluged with requests for help.18 He began meeting with pregnant women and couples in an office adjoining his lab.
Most often prospective parents were sent to Plotkin via their doctors. Sometimes they contacted him directly. The following letter, in cursive handwriting on a plain half sheet of white paper, arrived from a woman in nearby Pennsauken Township, New Jersey.
April 2
University of Penn.
Wister [sic] Lab
Dear Sir:
Could you let me know is it dangerous or fatal. I have a daughter pregnant 3 months and had the measles. Is the danger over of injury to baby. It is no [sic] 4 month. Please let me know?
Thank You.19
The testing that Plotkin could offer was far from perfect and could rarely provide the kind of definitive answers that women were seeking. He could confirm the disease by isolating rubella from a nose or throat swab. But swabs were reliably positive only if taken during the first day or two that a woman had had a rubella rash, and women seldom found him that quickly. Even if they did, isolating the virus from a throat swab with the cumbersome interference test using the ECHO-11 virus took ten days. Growing the virus for longer, to be certain his result was right, consumed another two or three weeks.
Blood tests, which he used more frequently, were no speedier. Plotkin first tested a blood sample taken during the acute phase of a pregnant woman’s illness—or as soon as possible thereafter, and ideally within two weeks of the rash. If she had waited longer to see a doctor, the odds of getting a definitive diagnosis diminished markedly.
But that first blood test alone wasn’t enough. Next Plotkin needed to wait two or three weeks, take blood again, and measure the woman’s antibody level again. A rise in antibodies from the first test to the second confirmed recent rubella.
Start to finish, Plotkin’s blood testing could easily stretch to four weeks. The wait was excruciating. Some women, and some doctors too, couldn’t bear it.
“Many physicians do not feel such a delay is tolerable,” Plotkin wrote in a paper published in the Journal of the American Medical Association that October. He pointed readers to patient number 13 in table 3. The twenty-eight-year-old mother of two was eight weeks pregnant when she developed a rash not typical of rubella: it was only on her abdomen, and her lymph nodes weren’t swollen. Her blood was taken quickly, on the second day of the rash, and then again three weeks later. When Plotkin got back to her doctor with the clearly negative results, it was too late. The woman had already had an abortion.20
At the other end of the spectrum, some patients with unambiguous positive test results continued with their pregnancies. Patient number 19, aged twenty, had developed a rash, a fever, and swollen lymph nodes when she was nine weeks pregnant with her first child. Plotkin’s blood tests showed that her antibody levels had soared eightfold over two weeks. She opted not to have an abortion because of “religious objections,” the paper said in a footnote.21
Plotkin himself was a reserved man who, when he sat down with parents, was loath to push them either way in their decision making. But in his own heart he had no objection when they opted to abort a potentially damaged fetus. And it rankled him when antiabortion critics lambasted abortion as a means of avoiding possible congenital rubella, as did the authors of two letters to the editor of the British Medical Journal in the autumn of 1964.22
One critic, a pathologist at a regional hospital in Ipswich, England, wrote that logical consistency demanded that, if one were to abort fetuses likely to be blind, deaf, or intellectually disabled, the same should be done with those likely to suffer asthma, diabetes, high blood pressure, myopia, or personality disorders. This, he concluded, would allow the country to “finish up with a one-party State and no prisons.”23
Plotkin was furious. The critics’ “sense of ethics is apparently so fine that it enjoins others to suffer,” he shot back in a letter that the journal did not publish. “What justification is there for increasing the burden of a family by a child with heart disease or deafness? . . . We have no right, because of personal moral or religious imperatives, to demand acceptance of an unnecessarily high risk of congenital abnormality.”24
This isn’t to say that Plotkin thought any parent’s decision easy or obvious. “What I remember is the anguish, of course, of the parents, trying to make a decision about whether to continue with the pregnancy,” he said in a 2012 interview. “Some were already decided when they came to see me. . . . Whatever the risk was, they didn’t want to take it. Others, of course—particularly those with religious beliefs—were conflicted about what to do.”25
In many cases women who wanted to abort weren’t given the option. Saul Krugman, who headed the Department of Pediatrics at New York University, reported to an American Academy of Pediatrics meeting in May 1965 that the therapeutic abortion committee at NYU had “many situations where a woman had had rubella which she has ignored for a week or more until she realizes she has missed a period.” The NYU committee, he noted, “does not approve abortions in such cases,” despite the likelihood that the woman would give birth to a damaged infant.26
Robert Hall, an obstetrician at Columbia University in New York City, wrote that at first only “the wives of insistent physicians” received therapeutic abortions for rubella, “under psychiatric guise.”27 As the epidemic escalated, more women succeeded in obtaining hospital abortions. These were almost always well-positioned women. In 1965 Hall estimated that for every nine privately paying patients—that is, wealthier women—who obtained rubella-related abortions, one poorer, publicly supported patient was able to terminate her pregnancy.28
For every woman who managed to obtain an abortion, there were scores of pregnant women worrying, in the absence of any episode of fever or any telltale rash, that their own fetus might nonetheless be infected. They scanned their memories, hoping that an ill-recalled childhood episode of German measles might mean that they were immune.29 Public health officials told newly pregnant women—often mothers with several children already at home—to stay away from children, who were the most likely carriers of the disease.30 How exactly a mother of young children might manage to do this was unclear.
“In epidemic years, the specter of tragedy hung over virtually all pregnant women,” writes the rubella historian Leslie J. Reagan. “No one could rest easily
knowing that the epidemic had spared her; perhaps she had failed to recognize the disease.”31
Plotkin’s regular conferences with anguished parents continued for most of 1964. The follow-up letters to their doctors were, occasionally, a joy to write.
“Many thanks for your letter regarding Mrs. [F.],” he wrote to an Allentown, Pennsylvania, doctor in February 1965. “It’s a great pleasure to hear that her baby was entirely normal and I am glad that I had some part in giving her the confidence to continue the pregnancy.”32
But far more often the testing left a painful uncertainty. One pregnant patient’s antibody levels rose between September 11 and 25, but only somewhat. Plotkin wrote to her doctor in mid-October that the levels “are not diagnostic and could reflect either infection in the recent past or the distant past. I suspect the problem is that we did not see the patient until 18 days after the onset of the rash.33
In the end, the rubella epidemic that swept the United States in 1964 and 1965 infected an estimated 12.5 million people, or 1 in 15 Americans. More than 159,000 of these infections included joint pain or arthritis, typically in women. Roughly 2,100 people developed encephalitis, a brain inflammation with a 20 percent mortality rate.34
Some 6,250 pregnancies ended in miscarriages or stillbirths. An estimated 5,000 women chose to get abortions. Still another 2,100 babies died soon after birth.
Roughly 20,000 babies were born, and survived, with congenital rubella syndrome. Of these, more than 8,000 were deaf; nearly 4,000 were both deaf and blind; and 1,800 were intellectually disabled. About 6,600 babies had other manifestations of congenital rubella, most typically heart defects. Often babies were born with several of these disabilities.35
The Vaccine Race Page 21