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 rabies.)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 next day, nineteen hours after the attack, Billy was back at the hospital as instructed. He was injected with another dose of duck-embryo vaccine. Doctors also injected Billy’s wounds, and his buttocks, with antirabies antibodies from horses. This is called “passive immunization” and gives victims ready-made immunity to protect them until their own immune responses, prodded by vaccination, kick into full gear. Passive antibody injections are a crucial part of postbite rabies treatment to this day. (In rich countries human antirabies antibodies have replaced those from horses, which frequently provoke allergic reactions.)
Two days after the attack the dog’s brain was examined at the Institut Pasteur in Casablanca. Looking at the canine brain cells under the microscope, pathologists found them scattered with deeply purple-staining, circular densities. They were called Negri bodies. They were full of virus, and they are the microscopic hallmark of rabies.
For twelve more consecutive days, Billy returned to the hospital and was injected with duck-embryo vaccine. Ten and twenty days after these injections were completed, he received booster shots. Then, in mid-June, he resumed the life of an eight-year-old boy.
RABIES THREAT WORSENS ran a headline in the Kingsport Times-News, published in a town in the mountains of northeastern Tennessee, on May 9, 1964, one day after Billy was bitten in Morocco. “Rabies among the grey fox population of Hawkins County is getting worse, with nine confirmed cases being found among the critters during the past month,” the article began.
“The situation is getting so bad here that a health department official is advising persons walking in hilly or wooded areas to carry clubs to defend themselves with.”28
One man reported that a gray fox had come out of hiding underneath his front porch and tried to attack him. The animal escaped after a fight with the man’s three dogs. They were unvaccinated and had to be put down.29
In Greene County, directly south of Kingsport, some 1,100 unleashed dogs would be shot and more than one hundred people bitten by rabid foxes in the coming months. Farmers carried shotguns. When the days shortened later that year, schools began to open late, so that children would not have to wait for buses before daybreak.30
In 1964 cases of animal rabies in the United States jumped by 20 percent to nearly 4,800. The increase was driven by wild animals. While rabies in domestic dogs and cats was falling steadily as more people vaccinated their pets, that decline was more than offset by rabid skunks and foxes in particular, along with other wild animals. Wild creatures accounted for 4,155, or 86 percent, of the animal cases that year.31 Some scientists speculated that a decline in the hunting of animals for pelts had caused their populations to boom and provided a large reservoir for rabies.32
In Mississippi, where no animal rabies had been reported in the prior two years, fifty-seven residents were bitten by rabid bats—which were also identified in forty-three other states. In southern Georgia, where no cases had been reported for seventeen of the previous eighteen years, 107 rabid raccoons were identified. Northeastern states including Maine, New Hampshire, and Connecticut saw their first significant increases in animal rabies in two decades.33 “Frankly, we’re faced with a problem for which we see no solution,” James H. Steele, the chief of the veterinary section at the CDC, told the Wall Street Journal.34
In the same article Koprowski was quoted saying that he was developing an improved vaccine made in human cells and was tentatively preparing to test it in seventy “volunteer” inmates at the state prison in Vacaville, California. It appears that this trial never came to fruition, for there is no report of it in the medical literature.
On August 3, 1964, three months after his dog attacked him in Rabat, Billy became irritable. He complained of a sore throat and ran a low-grade fever. A doctor looked at his throat, saw that it was red, took a swab to see what bacteria might grow from it, and prescribed penicillin.
Over the next three days Billy became more testy. He withdrew. He lost his appetite. He reacted to changes of temperature with cries or muscle spasms. He became afraid of water and swallowed the penicillin pills without it. He complained that it hurt when he swallowed.
On the third day of these symptoms, his parents took him back to the hospital at the Naval Air Station, where he was admitted. He was alert, but he didn’t want to be touched. When a doctor tried to examine him, he withdrew forcefully.
Over the next two days Billy deteriorated. He refused to drink anything. He began salivating excessively. He wouldn’t swallow the extra saliva, so he drooled. Forty hours after he arrived at the hospital, he got on his hands and knees on his hospital bed. He told the nurses that this relieved the irritating feeling of the sheets on his skin. He began trying to bite his attendants and kept trying, even after being sedated. He bled into his digestive tract. He battled severe muscle spasms and struggled to breathe. Finally he had several uncontrollable seizures and died, forty-seven hours after arriving at the hospital and ninety days after his dog attacked him.
An autopsy was performed. The experts at the Institut Pasteur in Casablanca found no Negri bodies in Billy’s brain. (They are missing in at least 20 percent of rabies cases, and their absence doesn’t rule out the disease.) So they took his fresh brain tissue and injected the brain of a rabbit with it. Sixteen days later they sacrificed the rabbit and looked at its brain cells. There they found Negri bodies.
The doctors who later described Billy’s case in the Annals of Internal Medicine did not declare it an open-and-shut case of vaccine failure. Perhaps the vaccine had been potent when it was shipped from the United States to the Naval Air Station in Morocco but was damaged in transit. Perhaps nineteen hours had been too long to wait to inject the horse antibodies at the site of the wounds, and the virus was already making the relatively short journey from Billy’s facial nerves to his brain by then; some experts believed that, once in the nerves, the virus became inaccessible to attacking antibodies. Perhaps the horse antibodies had destroyed enough of the rabies virus in the duck embryo vaccine that Billy did not generate a powerful immune response of his own. Such interference with the vaccine by the horse antibodies had been shown to occur in humans, which is why at least fourteen injections of the vaccine and two booster doses were required. Perhaps Billy should have had more than fourteen injections, or his booster doses should have been spaced out further in time after the initial injections, keeping his immune system gunning. They would never know.35
While Billy was dying in Morocco, a ten-year-old boy named Gary Sprick was camping in a tent on his family’s farm in Wabasha County, Minnesota, with his sister and four-year-old nephew. On August 5, as he slept, a skunk came into the tent and bit him on his right wrist and on the pointer and pinkie fingers of his left hand. The skunk would not let go until Gary’s sister shone a flashlight at it. It escaped. The resulting bites, doctors would later note, “were not clean puncture wounds but appeared to be chewed.”36
Gary was injected with duck-embryo vaccine on the day that he was bitten and for thirteen more days running. It is not recorded whether he also received an injection of equine antirabies antibodies. On August 25, twenty days after the attack, Gary noticed that his right forearm was numb. He developed a fever and his muscles ached. He complained that his neck was stiff. Three days after his symptoms began, he was admitted to a hospital in Rochester with paralysis that was climbing up his body from his limbs. He was hallucinating, uncoordinated, and running a fever of 40 degrees Celsius. He died on September 1.
One year later the CDC published an assessment of Gary Sprick’s death. It noted that the incubation period of his disease, the time from the bites to the first symptoms, had been, in the context of rabies, very brief—twenty days. “As experience has shown that rabies vaccine is usually effective in preventing rabies only when … the incubation period exceeds thirty days,” they concluded, “this is not considered to be a case of vaccine failure.”37 The circularity of that reasoning apparently didn’t faze the authors.
The agency’s opinion had changed by 1966, when it published a similar report involving another ten-year-old boy; another backyard tent, this one in South Dakota; another rabid skunk; another timely series of twenty-one duck-embryo vaccine injections; and another agonizing, protracted death.
The South Dakota boy’s demise, the CDC authors wrote, showed the current therapies’ stark limitations. “In spite of nearly ideal management including thorough cleansing of the wounds, [injection of the wound with anti-rabies antibodies from horses], and a full course of vaccine, the patient developed rabies in less than 30 days from the time of the bite.”38
In 1964, the year that rabies in wild animals surged to the highest level in at least a generation, roughly thirty thousand people in the United States were vaccinated after encounters with potentially rabid animals; the CDC would later estimate that only one hundred to two hundred of the animals were actually rabid.39 Among the bite victims Gary Sprick was the only person to die. In 1965 just one American died after being bitten by a rabid dog: a sixty-year-old West Virginia woodsman who had also received a prompt fourteen-dose course of vaccine.40 The boy in South Dakota, who also promptly received the duck-embryo vaccine, was the only person to die of rabies in the United States in 1966. Clearly the duck-embryo vaccine worked in many cases. But for several heartbroken families, it didn’t work often enough.
In September 1964, the month that Gary Sprick died, Koprowski, Wiktor, and Fernandes published for wider circulation, in the Journal of Immunology, the exciting findings that Koprowski had presented one year earlier at the symposium in Opatija, Croatia, showing that they had developed a rabies vaccine using WI-38 cells, and that it successfully immunized mice.41 By that time they had tested the new vaccine in a species much closer to humans: fifty rhesus monkeys at the National Center for Primate Biology at the University of California at Davis.42 The results were encouraging. All of the animals promptly developed antirabies antibodies, and the levels of those antibodies peaked at fourteen days after vaccination. After this they declined just slightly, then remained consistently high compared to control animals for the three months that Koprowski’s team followed them before publishing the paper.43 Of course, the vaccine hadn’t yet passed the only test that mattered: protecting the animals when they were injected with real-world, disease-causing rabies virus.
That September Koprowski also filed with the U.S. Patent and Trademark Office an application for a patent on a “method of producing rabies vaccine.”44 It named him, Wiktor, and Fernandes as the inventors of a new vaccine that was both more effective and safer, by virtue of being grown on the human fetal cells that Hayflick had provided.
Because a grant from the NIH’s National Institute of Allergy and Infectious Diseases had supported the trio’s work to develop the improved rabies vaccine, the Wistar Institute would normally have been prevented from applying for a patent: in this era the U.S. government claimed ownership of all inventions discovered using its funding. However, the government did grant waivers on a case-by-case basis, if U.S. officials could be convinced that allowing an institution like the Wistar to patent an invention and then license it to a company was the only way to speed it to market for the public good. In the case of the potentially much-improved rabies vaccine, the United States granted a waiver, allowing the Wistar to become the owner if its application was successful.45
A patent would give the Wistar the exclusive right to make and sell the new vaccine for seventeen years going forward. Of course, the Wistar wasn’t a vaccine company. But a patent would also give the institute the right to negotiate licenses with companies to make and sell the new vaccine—in exchange, they would have to pay royalties to the institute. And as director Koprowski would have the power to steer a portion of those royalties to the personal pockets of the inventors: himself, Wiktor, and Fernandes.
Hayflick was not named on the rabies vaccine patent application. In fact, he was completely unaware of it.