The Vaccine Race

by Meredith Wadman

  • • •

  Plotkin read the Parkman and Weller papers reporting on the lab isolation of rubella virus with great attention. The implications were impossible to miss. If rubella could be captured in a lab bottle, it could perhaps be weakened in a lab bottle to produce a vaccine. Koprowski’s gut-wrenching loss in the race to license a live polio vaccine had been painful for Plotkin too. But the isolation of rubella opened a whole new opportunity to create a lifesaving preventive. And as the months passed in London, Plotkin saw firsthand what the absence of a vaccine meant in human pain and suffering.

  Beginning in late 1962—nine months after cases of rubella began to surge in March of that year—babies with congenital rubella could be found on the wards of GOSH on practically any day. There was a two-month-old with cataracts and the heart anomaly called patent ductus arteriosus (PDA). A common heart defect in congenital rubella, it can cause a baby’s heart to fail without a surgical repair. There was a five-month-old with microcephaly. There was an eleven-month-old who was deaf and blinded by cataracts, and whose heart was hobbled by a hole in the wall separating the ventricles, the two chambers that pump blood out to the lungs and the rest of the body.

  There were also slightly older children, victims of the rubella that had circulated at lower levels prior to the epidemic, like the deaf and blind four-year-old who also suffered with a condition called tetralogy of Fallot. This four-part heart defect starves the blood of oxygen, sometimes turning sufferers blue.30

  When he wasn’t seeing patients, Plotkin worked in Dudgeon’s lab, using Paul Parkman’s new technique to grow the virus from throat swabs of patients with active rubella. He often got positive results from swabs taken during the first week of the rash and especially during the first few days. The problem was, while this test could confirm a rubella infection, a negative test could not rule out infection.

  The new technique for isolating the virus also allowed Plotkin to measure the change in rubella antibody levels in blood taken from patients with active disease and blood drawn from the same patients two or three weeks later, when, he found, their antibody levels had risen significantly. There was one kind of patient who desperately wanted laboratory confirmation of whether she had had the disease: the worried pregnant mother.

  “The fact that it is now possible to diagnose rubella infection by virus isolation from throat swabs and by [blood tests] is of practical importance in relation to rubella in pregnancy,” Plotkin, his British boss Dudgeon, and another colleague, A. Melvin Ramsay, wrote with what can only be called understatement in the resulting paper, published in the British Medical Journal.31

  Plotkin, Dudgeon, Ramsay, and another colleague, N. R. Butler, also studied what was happening in the immune systems of babies, toddlers, and children with congenital rubella syndrome—patients on the wards at GOSH or sent to them from elsewhere by other doctors. Some scientists had wondered if babies infected in the womb failed to “see” the virus as foreign and make antibodies against it—a phenomenon called immunological tolerance.

  But twenty-two out of twenty-five children with congenital defects who were older than six months of age—and therefore didn’t have maternal antibodies lingering to confuse the test—had rubella antibodies in their blood, meaning that they had responded normally to the presence of the virus, “seeing” it as foreign and making antibodies against it.32

  There was so much that still wasn’t known. Was the blood test not sensitive enough to pick up low levels of antibody that might nonetheless have been present in the other three children? Had the youngsters with antibodies generated these only after birth, when the damage was already done? If they had in fact produced their own antibodies while in the womb, when exactly during pregnancy had their immune responses kicked in? Clearly they couldn’t have been effective in those first vulnerable weeks of embryonic life.

  Plotkin and his colleagues were mapping uncharted terrain. Today it’s known that rubella is a spherical virus made of a single strand of the genetic material RNA wrapped in a protein coat that is in turn surrounded by a fatty envelope. This envelope is studded with protein spikes of two types, labeled E1 and E2. When the body’s immune defenses react to rubella, it’s mainly these protein spikes, especially E1, that they are reacting to.

  Rubella is, as viruses go, quite small. At fifty to eighty-five nanometers in diameter, it’s about half the size of the HIV virus.33 And it’s some one thousand times smaller in diameter than the human cells it invades. Of course, size isn’t what matters. What matters is what a virus does in the body.

  Rubella begins by colonizing the nose and throat, where it lives and multiplies in surface cells and local lymph nodes for several days before invading the blood. From there, and before a nonimmune pregnant woman has mounted her immune response, it travels to multiple tissues, including the placenta.

  Hunkered down in the placenta, the virus evades the maternal antibodies that soon obliterate it from the mother’s blood. It can persist and replicate in the placenta for months.34

  Probably due to damage that the virus causes to the blood vessels of the placenta, the virus is frequently able to infect the embryo, likely traveling in toxic clumps of cells that slough off from the inside of placental blood vessels and enter the embryo’s circulation. And the embryo, during at least the first twelve weeks of pregnancy, doesn’t have the tools to mount its own immune response. Instead it must rely on the mother’s own antibodies for protection.35

  But movement of maternal antibodies across the placenta isn’t very efficient early in a rubella-infected pregnancy. Even by the middle of pregnancy, fetal levels of the mother’s rubella antibody are only 5 percent to 10 percent of what they are in the mother’s blood. So the growing embryo, in the crucial, earliest stages of its life, is left mostly defenseless against the virus, which circulates widely in its blood and can take up residence in virtually any organ.36 Molecular tools and imaging methods available today have identified rubella virus in the livers, kidneys, lungs, hearts, spleens, lymph nodes, brains, and eyes of fetuses aborted due to maternal rubella.

  Rubella is different from other agents that cause birth defects, in that it doesn’t usually affect the carving out and shaping of organs and other structures. In rubella-affected infants, you won’t find the shortened, deformed limbs that marked thalidomide babies. You won’t find cleft palates or club feet or the exposed spinal cord that marks the failure of an embryonic structure called the neural tube to close. Instead the virus homes in on newly formed structures: the long, thin fibers of the lens of the eye; the delicate inner ear, the seat of hearing; the lining of the heart; the small blood vessels that feed what should be a growing brain with oxygen and nutrients.37

  Virologists have found that rubella doesn’t immediately kill the cells that it invades. Rather, it slows them down. They don’t replicate as quickly as uninfected cells; in fact, the virus prompts them to make a protein that inhibits mitosis.38 Eventually they die, sooner than they should, prompted by the virus. So it makes sense that organs of rubella-infected fetuses and infants have been found to have fewer cells than normal and that affected babies weigh on average 65 percent of normal. Why do any cells survive? Because the virus doesn’t by any means infect all the cells in an organ. As few as 1 in 100,000 cells may be invaded. These infected cells occur in patches that are scattered in affected organs.39

  There are very few embryos that escape rubella once it strikes in early pregnancy. There’s a 90 percent risk of fetal damage with a rubella infection during the first two months of pregnancy and a 50 percent risk of such damage during the third month.40 And during particular windows the growing embryo is exquisitely vulnerable: one prospective study found that ten out of ten embryos became infected when pregnant mothers had a rubella rash between three and six weeks after their last menstrual period.*41

  Once a pregnancy is into its fourth month, the odds of rubella infection doing damage to the
fetus diminish significantly. The reason: the increasingly active fetal immune response combines with antibodies from the mother to keep the virus in check.

  After a baby with congenital rubella is born, the virus can remain living in certain tissues and continue to do damage. Long-term problems can include the persistence of virus in the cerebrospinal fluid that bathes the brain and spinal cord, leading to bouts of brain inflammation called encephalitis.42 And whether because of direct viral damage to the pancreas or because the virus triggers an autoimmune reaction, causing the body’s own antibodies to attack the pancreas’s insulin-producing cells, babies with congenital rubella grow up to get type 1 diabetes at many times the rate of the general population.43 Congenital rubella sufferers also endure eye problems that go well beyond cataracts and include glaucoma—elevated pressure in the eyeball that damages whatever limited vision a person may have—and chronic inflammation of the iris and its appendages.44 It’s not known how often the virus itself continues to live in the confined chamber of the eye, doing damage. It certainly does in some cases: in 2006 living rubella virus was captured from the eyes of a twenty-eight-year-old man who was born blind and deaf from congenital rubella after a British rubella epidemic in 1978.45

  Papers documenting the long-term problems of rubella-affected children wouldn’t begin to appear until the late 1960s, when Australian virologists published a twenty-five-year follow-up on the damaged infants who were born in 1941.46 But Plotkin had plenty of other rubella-related problems occupying him as he finished his residency in London in June of 1963.

  It was clear to him that rubella was going to plague generations of newborns if a vaccine was not developed. Rubella epidemics recurred cyclically, predictably, every three to five years in the United Kingdom and every six to nine years in the United States.47 The next one was only several years down the road. Those were years, he was convinced, in which a vaccine could and should be made.

  That summer Plotkin and his wife, the former Helen Ehrlich, whom he had married as he graduated from medical school, set off on a three-month tour of Europe—along with their newest family member, one-year-old Michael. They drove a blue Ford two-door and otherwise lived, as Plotkin would write a few months later, “like gypsies.”48 They traversed France, Switzerland, and Italy and ended up on the Croatian Riviera. Finally, in September, they boarded a Great Holland Line steamer for home.

  Several months behind them, another traveler would cross the Atlantic, arriving in time for spring on the U.S. East Coast. It was the rubella virus.

  CHAPTER TEN

  Plague of the Pregnant

  Philadelphia, 1963–64

  . . . rubella does not seem to invoke the fascination of thalidomide despite the fact that in a single epidemic in the United States it caused more birth defects in one year than thalidomide did during its entire time on the world market.

  —William S. Webster, University of Sydney Medical School, Australia, 19981

  The Wistar Institute was still a bustling biological crossroads, when Plotkin reoccupied his third-floor lab there in October 1963. Koprowski had expanded his core scientific staff to thirty-nine. Eighteen graduate students were working in the labs, and Koprowski was playing his usual charming host to a near-constant stream of international visitors from Helsinki and Zurich, Paris and Milan, Tehran and as far away as Sendai, Japan. Some stayed perched in Wistar labs for weeks or months. Plotkin and Helen and baby Michael put down roots too, moving into a townhouse not far west of the university at 11 University Mews.

  Koprowski was busy nurturing the freewheeling science that set the Wistar apart. Plotkin’s mentor may have been an autocrat, but he was an autocrat who didn’t micromanage his hires, who left them to do their creative best, protecting them from administrative hassles and money worries while he presided over the whole impressive dance alternating benignity and charm with storms of temper and deviousness.

  What was more, Koprowski understood—a fact that still dazzled Plotkin—that life was more than science, that art and history and poetry and music and the enjoyment of beautiful women and excellent food and fine wine were as important as breathing. That Christmas parties in the atrium with him playing Chopin on a grand piano imported for the occasion were de rigueur.

  “According to the notice which I received on my desk yesterday, a Christmas party is scheduled shortly,” Plotkin wrote in a memo to Koprowski that December. “As I have been asked in the past to take care of some of the casualties, I would like to personally suggest that a tank of oxygen be in readiness for use in those who have embibed [sic] not wisely, but too well.”2

  Hayflick, by contrast, seemed to occupy a world apart, all seriousness and focus in his second-floor lab. A recollection from this era from Hayflick’s late colleague Vincent Cristofalo is telling. It was 1962, and Cristofalo had just completed his PhD in physiology and biochemistry. He was being recruited by the Wistar and was being shown around. The young Cristofalo knew of Hayflick from the increasingly famous 1961 paper declaring that normal cells aged in the lab, so he was a little awed when his tour guide stopped in Hayflick’s lab.

  Cristofalo wrote forty years later: “Here I was looking upon this man, sitting at a desk in the center of his laboratory, with people bustling to and fro on all sides of him, going to the incubators or to the sterile rooms. Seemingly unperturbed by this frantic activity, Leonard was dictating letters to a tape recorder. My host, David Kritchevsky, interrupted him to introduce me. Len looked, for all the world, annoyed at the interruption. His demeanor signaled that he wished I would go away and not return. Nevertheless, he was minimally cordial; he gave me a reprint of his 1961 paper with Paul Moorhead and returned to his dictation.”3

  • • •

  For Plotkin, freshly returned from London, the availability of Hayflick’s WI-38 cells meant the opportunity to study the rubella virus in the lab—and, with luck, the chance to create a rubella vaccine. He was already a convert to the use of the fetal cells for vaccine making; it was he who had worked alongside Hayflick developing and testing the polio vaccine that Hayflick first made with them in 1961. It was he who, with Koprowski, had written to the World Health Organization, urging the use of the human fetal cells instead of monkey kidney cells for making live polio vaccines. Now he would see if the fetal fibroblasts could be co-opted to generate a rubella vaccine.

  Plotkin knew that he wanted to make a live, weakened rubella vaccine—as opposed to a killed vaccine like Salk’s polio vaccine. There were several reasons why.

  First, he was more familiar with making live vaccines because of his work with Koprowski’s live polio vaccine. Second, scientists were learning that it was extraordinarily difficult to kill the rubella virus and have it nonetheless maintain the ability to induce an effective antibody response. Third, live vaccines tended to generate longer-lasting immunity. And if rubella was going to be a childhood vaccine, the immunity it generated would need to last for decades: from girlhood through a woman’s childbearing years. The decision worked out well for Plotkin. Merck experimented early with a killed vaccine and failed strikingly.4

  It was a fortuitous time for a young U.S. medical researcher. Government coffers were benefiting from the booming postwar economy, and there was a new enthusiasm for medical research in Congress, spurred by World War II–era advances.5 So the National Institutes of Health, the country’s prime medical research–funding agency, was flush with cash and able to make more and more research grants to scientists all over the country as its budget grew from $36 million in 1955 to $436 million in 1965. The happy beneficiaries nicknamed the agency the National Institutes of Wealth, and a running joke among biomedical scientists went, “While you’re up, get me a grant.”

  Koprowski had received a generous multiyear grant in the late 1950s from the NIH’s National Institute of Allergy and Infectious Diseases to support work on his polio vaccine. When he renewed the grant for five years in the early 1960s
, he redirected the money to cover Plotkin’s rubella vaccine research. On his return from London, Plotkin began receiving $130,000 annually from the NIH for studying rubella and trying to develop a vaccine—more than $1 million in 2016 dollars.6 Plotkin also sought out a foundation with a keen interest in projects related to disability: the Joseph P. Kennedy, Jr. Foundation, established in 1946 to memorialize the late President John F. Kennedy’s older brother, who was killed over Suffolk, England, during a secret bombing mission in 1944. Between 1964 and 1967 the foundation would steer $180,000 to Plotkin for his rubella work.7

  First Plotkin needed rubella virus—and he needed to see if it would grow in WI-38 cells. More than that, he wanted to know if several rubella strains—viruses collected from different, geographically dispersed people and thus possibly differing subtly from one another—would all find WI-38 cells hospitable to their growth. To collect them, he turned to colleagues.

  Maurice Hilleman, the vaccine czar at Merck, sent Plotkin the West Point strain, named after Merck’s big campus just outside Philadelphia. Paul Parkman, the good-natured young virologist who had first captured the virus in the lab, sent Plotkin M-33, the virus he had isolated from the throat of one of the young military recruits at Fort Dix, New Jersey. And Plotkin got still another strain of the virus, called Marshall, from Dudgeon, his former mentor at the Great Ormond Street Hospital, who sent it, ensconced in dry ice, on Pan Am flight 107, which flew direct from London to Philadelphia on Tuesdays and Thursdays.