These numbers are, at the very best, approximations. They come from a 1969 CDC report whose authors stressed that it was not until 1966 that physicians were required to report rubella cases to authorities. Before then data were gathered by many, but not all, states and were voluntarily passed on to the CDC. The authors noted their data’s incompleteness, called it “preliminary,” warned that it was intended primarily for disease-control experts, and wrote that it should be “interpreted with caution.”36 Nonetheless, these have become the “official” numbers and are reported on the CDC Web site and elsewhere to this day. One top rubella expert who was deeply involved with patients in the 1960s and for decades afterward says that the numbers are “SWAG”—a scientific wild-ass guess.
• • •
As he undertook his first steps toward making a rubella vaccine late in 1963, Plotkin decided that his vaccine virus was not going to be captured, as Parkman had done at Fort Dix, from the nearest convenient patient who had the virus colonizing his or her throat. That approach, he reasoned, risked contamination with other “passenger” viruses also resident in the patient’s throat. Instead, like Hayflick did when he first sought to grow normal, clean cells in culture, Plotkin turned to the likeliest source at hand for isolating rubella virus and only rubella virus: infected fetuses.
On January 23, 1964, Plotkin wrote to Franklin Payne, the head of obstetrics and gynecology at the Hospital of the University of Pennsylvania.
“Dear Dr. Payne, as you know, we have been collecting aborted fetuses from your service for some time now and using them for tissue culture. We have now entered a new phase of the project in which we are trying to isolate viruses from the fetuses which may be associated with abortion. . . . We hope that you will be able to help us in this project.”37
Plotkin did indeed receive Payne’s help, and that of the obstetrics and gynecology departments at other area hospitals. The most help, though, came from the rubella epidemic that was then bearing down on the eastern United States.
As the epidemic unfolded, Plotkin began to receive a steady stream of aborted fetuses. Some were delivered in plastic bags from area hospitals. Some he fetched himself, carrying them across the street from the university hospital in glass lab bottles. He would dissect and mince their organs, plant minuscule bits of tissue in culture bottles, put them in the incubator, grow them, and then test them for the presence of rubella virus. It worked to his advantage that rubella infected virtually every fetal organ.
When a fetus came from a patient whom Plotkin hadn’t personally encountered, it’s not clear whether the doctors involved asked the woman’s consent for its use. When a fetus came from a woman whom Plotkin had seen and who had decided to abort based on his laboratory findings from her throat swab or blood, he did ask her permission for its use. In at least one case that led to knowledge that must, for the woman involved, have been wrenching.
“Dear Dr. Eisenberg,” Plotkin wrote to a Cherry Hill, New Jersey, physician two days before Thanksgiving in 1964. “In answer to your letter regarding our studies on the conceptus of Mrs. [F.], please be informed that as of the moment, we have not yet recovered rubella virus from the foetus. . . . In Mrs. [F.]’s case the virus had probably not penetrated to the foetus.”38
By the time he wrote that letter, Plotkin had received and tested thirty-one fetuses for rubella. He found that seventeen were infected with the virus.39
Of the thirty-one fetuses, it is fetus 27 that made its way into scientific history. It came from a twenty-five-year-old woman who was exposed to rubella eight weeks after she missed her period. Sixteen days later her lymph nodes were swollen and she developed a blotchy rash. A swab taken from her nose on the second day of the rash tested positive for rubella. Two weeks later the mother of fetus 27 had an abortion.
The fetus was dissected immediately, Plotkin would write in the paper that put the scientific world on notice that he was a contender in the vaccine race. “[Tiny pieces from] several organs were cultured and successful cell growth was achieved from lung, skin and kidney. All . . . were found to be carrying rubella virus.”40
The kidney tissue from fetus 27 produced virus that grew particularly well—there was a lot of it present in the fluid bathing the cells. He named this virus RA 27/3. The “RA” signified “rubella abortus.” The “27” denoted that its source was the twenty-seventh fetus he received during the 1964 epidemic. And he chose the “3” because the kidney was the third organ that he harvested from fetus 27. It was this virus that Plotkin chose to develop into a vaccine.
Like Hayflick before him, Plotkin grew the kidney cells from fetus 27 in glass bottles, bathing them in medium, placing them in the incubator at 95 degrees Fahrenheit, and splitting the cells into two new bottles when they covered the floor of the first one. When he had split the kidney cells into new bottles four times, he took the virus-filled fluid that bathed them and inoculated it onto fresh cultures of WI-38 cells that Hayflick provided.*
He repeated this inoculation of fresh WI-38 cultures three more times, every ten days or so. From the final set of WI-38 cells he harvested all of the yellow, virus-laden fluid and divided it into aliquots, distributing one-teaspoon amounts into screw-top test tubes and freezing these at –76 degrees Fahrenheit. It wouldn’t be many months until he removed the vaccine, thawed it, and prepared to put RA 27/3 in human beings for the first time.
CHAPTER ELEVEN
Rabies
Philadelphia, 1962–64
Morocco, 1964
Wabasha County, Minnesota, 1964
The currently available rabies vaccines are indisputably the crudest biological products injected under the human skin.
—Hilary Koprowski, speaking to the First International Conference on Vaccines Against Viral and Rickettsial Diseases of Man, Washington, DC, November, 19661
Rubella was one among many. The chase for new virus vaccines in the 1960s was as hot as today’s quest to unravel the profound mysteries of the human genome. Virology and vaccinology attracted the best and most ambitious scientists. And if they succeeded, vaccine inventors could expect to see the fruits of their labors saving lives not merely in their lifetimes but, in the best cases, within several years.
Its chief, Hilary Koprowski, was the most ambitious of the many ambitious virologists at the Grand Central Terminal of virology that was the Wistar Institute in the 1960s. And he was a man in a hurry when it came to one vaccine, for a disease that had preoccupied and fascinated him since he observed a rabid vampire bat—its brain was later dissected to look for the microscopic hallmarks of rabies—when he was working for the Rockefeller Foundation in Rio de Janeiro in the early 1940s. His visit with the eminent rabies scientist J. L. Pawan in Trinidad in 1944 only stoked that interest.2 Koprowski was lured by rabies even in the midst of his race to beat Sabin to an oral polio vaccine in the 1950s. He published 21 papers on the terrifying disease in that decade alone—and 187 in the course of his lifetime, nearly four times as many as he wrote on polio.
Rabies is the most lethal infectious disease to afflict humans. Once a person develops symptoms, death virtually always follows.3 Globally it is a serious burden. In 2013 the World Health Organization estimated that the virus kills one person every nine to twenty minutes, conceding simultaneously that this is likely an underestimate, due to underreporting and misdiagnosis.4 A great number of the deaths are of children, most of them poor, and almost all of them are in rural areas of the developing world. In India, for instance, rabies kills somewhere between thirteen thousand and thirty thousand people every year.5
Rabies is a bullet-shaped virus carried in animal saliva. It is almost always contracted through a penetrating wound from a rabid animal.6 (Very occasionally transmission by inhalation has been documented—for instance, in explorers of bat-infested caves.7 And rarely people have contracted rabies by receiving corneal transplants from people dying of unknown causes that turned out to be r
abies.)8
Unlike rubella, rabies virus does not invade the blood. Rather, it has a strong predilection for nerve cells. After a person is bitten, the virus migrates to the nerve cells at the site of the bite and travels up them, toward the brain. When it arrives there days, weeks, months, or even years later, it causes a uniquely horrifying set of symptoms. They begin mildly, with symptoms that can include a fever, a sore throat, muscle aches, and a loss of appetite. Then, as the virus disseminates rapidly within the brain, victims go downhill. Commonly they become hypersensitive to bright lights, loud noises, and touch. They become agitated, confused, and combative. They may experience hallucinations and convulsions. While lucid spells are typical, these grow briefer over time.
From the brain the virus also travels down nerve cells, away from the brain to the kidneys, lungs, liver, skin, and heart—and to the glands that produce tears, sweat, and saliva, which it puts into overdrive. At the same time, the virus can make swallowing hard and painful, which, in combination with the extra salivation, causes foaming at the mouth. In about half of affected people, the sight, sound, thought, or swallowing of water causes painful, jerky spasms of the diaphragm, throat, and respiratory muscles. Thus the terror of water that is seen in rabies and rabies alone has given the disease its nickname, “hydrophobia.”
In some people the limbs become paralyzed and then the paralysis climbs until it reaches the respiratory muscles and suffocates the victim. The others lapse into a coma and die. The whole process, from the onset of symptoms, takes from five days to three weeks.
At the midpoint of the twentieth century, rabies started to appear with markedly increased frequency in wild animals in some U.S. states, alarming public health authorities and terrifying people in affected communities. In Indiana laboratory-verified cases of animal rabies jumped from 156 in 1952 to 374 in 1954. In New York State over the same two-year period, the number of confirmed cases of animal rabies grew from 340 to 511. In Minnesota, which had reported 5 cases of animal rabies in 1948, there were 264 cases of animal rabies in 1952. That was the year of a huge polio epidemic, but in the Land of 10,000 Lakes people were more afraid of rabies. Cases were verified in cattle, cats, gophers, groundhogs, muskrats, foxes, horses, and raccoons, in addition to the better-known carriers: skunks and dogs. And they weren’t confined to rural areas. In Minneapolis a rabid skunk was captured at 55th and Colfax and a rabid cat at 42nd and Pillsbury. There were reports of children being chased by rabid skunks.
“We seem to be sitting on a powder keg here,” remarked Dean Fleming, the state’s director of disease prevention and control.9
In 1952 twenty-four people in the United States died of rabies.10 Remarkably, none of them died in Minnesota.11
The rabies vaccine that was then available in the United States differed little from the crude formulation that the French microbiologist Louis Pasteur had famously invented in 1885.12
It was made from the pulverized, dried brains or spinal cords of rabies-infected rabbits, in which the virus had been killed with a chemical or with ultraviolet light. The vaccine was administered after a bite in a series of daily injections of increasing potency, in the abdomen, for fourteen to twenty-one days.
The injections were painful and risky. While the rabies virus in them was supposed to have been killed, it wasn’t always. In Fortaleza, Brazil, in 1960, sixty-six people were injected with rabbit brain–produced vaccine in which the virus had supposedly been inactivated with the chemical phenol but in fact was still alive. Eighteen of them—all thirty years old or younger—developed rabies and died.13
Other people who received the brain tissue–generated rabies vaccine were weakened, paralyzed, rendered comatose, or killed by a debilitating allergic reaction to the nerve tissue in the vaccine.14 Called allergic encephalomyelitis, it affected one in every five or six hundred vaccinees and resulted when the body’s immune system, activated by exposure to the animal brain protein in the vaccine, attacked that same protein, called myelin basic protein, in the vaccinee’s own brain.15
People bitten by animals that were only questionably rabid were therefore confronted with an agonizing choice: submit to the vaccine and risk a possibly fatal allergic reaction, or refuse and gamble with their life that the animal had not been rabid.
In the mid-1950s scientists working at the Eli Lilly company in Indianapolis took what seemed to be a step forward, developing a rabies vaccine in which the virus was grown in fertilized duck eggs—duck embryos—before being killed with a clear, colorless liquid chemical called ß-propiolactone.16 “The use of [duck embryos] in place of rabbit brain for propagating the virus eliminates the myelin,” the authors wrote, referring to the substance that causes the severe allergic reaction. In making the vaccine, the virus-ridden embryos were harvested a few days before they hatched—and their heads were cut off. The result was a diminished risk of reactions and a vaccine offering “distinct advantages.”17
Like its predecessor, the duck-embryo vaccine had to be injected into a bite victim beginning as soon as possible, for fourteen to twenty-one days running, depending on the severity of the bite. The initial course of injections was followed by booster shots at intervals. And while it only rarely provoked allergic reactions after it was brought to market by Eli Lilly in 1958, it would emerge that the duck-embryo vaccine too had a serious problem: it was not as effective at generating antirabies antibodies as vaccines made in rabbit brains.18
In the meantime the wild animal problem wasn’t going away. In the United States in 1961, there were nearly 2,700 confirmed cases of rabies in animals, not counting pet cats and dogs—nearly triple the number that there had been twenty years earlier.19 The associated human deaths—121 between 1950 and 1961—didn’t come anywhere near the fatalities due to, for instance, measles or meningitis.20 But they were invariably horrifying in their particulars, and, as is the case in the developing world today, the virus disproportionately killed children: half of the U.S. victims between 1946 and 1965 were fifteen years old or younger.21
From practically the moment that Hayflick derived the WI-38 cells in June 1962, his boss, Hilary Koprowski, planned to use them to try to invent a safe, effective rabies vaccine—a vaccine that would make for a badly needed improvement on the vaccines then available. A recent, important advance told him that using the WI-38 cells should be eminently possible: in 1958 a virologist named R. E. Kissling working in a CDC lab in Montgomery, Alabama, had shown that rabies virus didn’t have to be propagated in ground-up animal brains and spinal cords, or even in whole duck embryos that were then guillotined: it could be grown in cell culture, and even in nonnerve cells.22 By November 1962 Koprowski had seen to it that rabies virus was being grown in WI-38 cells at the Wistar Institute.23
The heavy lifting of developing the vaccine—the long, workaday hours in the lab—he delegated to an amiable émigré and Polish cavalry veteran named Tadeusz “Tad” Wiktor. Wiktor had earned a PhD in veterinary medicine at the renowned National Veterinary School in Alfort, France. In 1955 he and Koprowski met at a course on rabies in Muguga, Kenya. At the time, Wiktor was working for the government Veterinary Service in what was then the Belgian Congo. There, it’s said, he himself had been bitten by a wild dog and submitted to the long course of brain tissue–manufactured rabies vaccine injections.24 Koprowski began a campaign to lure Wiktor to the Wistar, where he landed in 1961, as he turned forty years old.
Koprowski was normally a hands-off manager. But when it came to rabies, his keen interest led him to closely supervise Wiktor and another Wistar scientist, a stout, often-smiling doctor of veterinary medicine with slicked-back hair named Mario Fernandes, who had recently moved to the Wistar from the National Institute of Veterinary Investigation in Lisbon, Portugal.
At first the men struggled to get the virus to grow in the WI-38 cells. When they bathed fresh, uninfected cultures of the cells with the fluid medium from a previously infected culture, it was tough
to infect the new cells. In 1963 they got past this problem by using trypsin, the “jackhammer” enzyme, to break up the cell sheet in an infected bottle before moving the cells, not just the fluid bathing them, into fresh bottles of uninfected WI-38 cells. It emerged that the virus was passed by cell-to-cell transmission and not via the fluid medium.25
Their success was such that by September 1963, scarcely one year after Hayflick launched the WI-38 cells, Koprowski was in a position to deliver an upbeat report to a group that could readily appreciate what a new rabies vaccine would mean: scores of virologists from eighteen countries who had converged at the Croatian resort town of Opatija for a symposium on the new human diploid cells and their potential for viral vaccine making.
Koprowski reported to the assembled scientists that he and his colleagues had succeeded in adapting rabies virus to grow vigorously in WI-38 cells. After the WI-38–grown virus was killed with the colorless liquid chemical ß-propiolactone and the resulting vaccine was tested in mice, it protected the animals when they were later injected with live rabies virus. In fact, its protective effect far exceeded the minimum level that regulators required in this mouse test.26
Mice are not men, but the signs were all good. “The production of effective and safe antirabies vaccine for man now seems feasible,” Koprowski declared.
• • •
On May 8, 1964, an eight-year-old boy named Billy (a pseudonym), the son of a member of the U.S. Air Force stationed in Rabat, Morocco, was bitten on the face by his own dog, a stray German shepherd that the family had adopted off the street one year earlier. They had not immunized the dog against rabies and had let it roam at will. The boy’s father shot the dog and took his son to the hospital at the U.S. Naval Air Station at Kenitra, thirty-three miles from Rabat. They were at the hospital within three hours of the attack. Doctors there counted eight muscle-deep puncture wounds in Billy’s left cheek and chin. They cleaned the wounds and injected a dose of U.S.-manufactured duck-embryo rabies vaccine into the sixty-pound boy’s abdomen.27
The Vaccine Race Page 22