At last the monkeys landed at the Frankfurt airport, and from there they were sent to three destinations: the Torlak Institute in Belgrade, then the capital of Yugoslavia, which produced and safety-tested polio vaccines; the Paul Ehrlich Institute in Frankfurt, which safety-tested polio vaccines; and the Behringwerke facility in Marburg. The monkeys at Marburg and Frankfurt were soon dispatched and their kidneys harvested. They weren’t killed at Belgrade until about six weeks later. By then they didn’t seem so healthy. The Torlak Institute reported a mortality rate 33 percent above what would normally be expected in the monkeys.40
In early and mid-August in Marburg, several Behringwerke employees suddenly began feeling ill. So did a handful of workers at the Paul Ehrlich Institute in Frankfurt. They had headaches behind their foreheads and in their temples. They had muscle aches. They spiked fevers—some over 102 degrees Fahrenheit. They felt generally awful. Still, for the first three or four days, the illness didn’t seem too unusual, and those affected simply stayed at home.41
By the end of one week, though, they were beginning to vomit and to have severe, even explosive, diarrhea. Most developed a generalized skin rash, and many had conjunctivitis—an inflammation of the membrane lining the eyeball and the inner surface of the eyelid. More worrisome still, some of the sick people just weren’t themselves. They weren’t thinking or acting normally. Something was going on in their brains, it seemed.
Over the course of several weeks, some two dozen patients were admitted to university hospitals in Marburg and Frankfurt. Many of the afflicted were gravely ill. Some patients’ faces grew swollen and unexpressive. One patient became psychotic; others were sullen and negative. Some patients’ spleens and livers grew far bigger than they should have been.
The signs from their blood tests were frightening: their disease-fighting white blood cells were sinking dangerously low, as were their blood-clotting platelets. The levels of certain enzymes that rise during liver damage had soared.42
The sickest patients began bleeding from every orifice: noses and eyes, mouths and rectums, the puncture wounds where hospital workers drew their blood. Under the patients’ skin, pinprick spots of bleeding appeared. So did bigger bruises. Their scrotums and vulvas turned a dark reddish blue. More than one patient collapsed from massive bleeding on the day after being admitted to the hospital. Others bled more slowly. Bleeding was an ominous sign. The people who ended up dying—seven would perish before the episode ended—were those who had bled.43
In all, twenty-one Behringwerke workers grew ill. In Frankfurt four employees at the Paul Ehrlich Institute became sick. About one month later at the Belgrade center, a veterinarian fell ill after conducting autopsies on five of the monkeys that had mysteriously died in Belgrade.44
It emerged that every sick employee had been in direct contact with blood, organs, or cell cultures from the monkeys. They had killed the monkeys, or dissected their kidneys, or bored holes in their skulls. They had handled monkey kidney cells in culture or washed the glassware afterward.45 The published proceedings of a conference that was held two years later described some of the cases:
The monkey-keeper Heinrich P. came back from his holiday on August 13th 1967 and did his job of killing monkeys from the 14th–23rd. The first symptoms appeared on August 21st.
The laboratory assistant Renate L. broke a test-tube that was to be sterilized, which had contained infected material, on August 28th, and fell ill on September 4th, 1967.46
Soon several of the hospitalized patients’ caretakers got sick too.
The nurse Anneliese K. began to work in the ward on August 23rd and became ill on August 30th.
The doctor Inga H., who was infected by the stitch of a needle on August 22nd, showed the first symptoms of the disease 5 days later on August 27th.47
Before the outbreak ended, two doctors, a nurse, and a medical student were infected. A morgue assistant helping to conduct an autopsy on one of the dead became infected when he cut his forearm.
The autopsies of the victims showed the internal devastation that had transpired while they were deteriorating and, finally, bleeding to death. Whatever had infected them was an equal-opportunity pathogen, attacking brain and spleen, pancreas and thyroid and liver, kidney and testes and ovaries and skin, leaving these organs strewn with bloody lesions. Their stomachs and intestines were full of blood.48
For the survivors recovery was long and painful. Their hair fell out in clumps, as if they had had radiation therapy for cancer.49 The agent had a predilection for testicles, and the scrotums of some patients—three quarters of the victims were men—grew inflamed and ballooned up with a raging testicular infection. Later, doctors following the patients discovered that the culprit pathogen could linger for months not only in their testicles but also in their eyes and their semen. The wife of one survivor in Marburg became infected three months after the outbreak; his semen tested positive for the disease agent.50
From late August labs inside and outside Germany raced to identify the unknown pathogen in blood and serum samples from the patients and in the liver, spleen, kidney, and brain from one autopsy.51
In the United States the production of vaccines in green monkey kidneys all but halted, and the release of existing vaccines was suspended.52
On November 20, 1967, three months after the death of the first victim, a scientist named Günter Müller at the Bernhard Nocht Institute in Hamburg, Germany, looked through an electron microscope at blood serum from guinea pigs that had become ill after being injected with blood from the sick human patients. He saw a virus unlike anything anyone had seen. Viruses were often spherical; this one was a long, stringy thing, like a thread. It would eventually be assigned to the same taxonomic family as Ebola virus: filoviruses (from the Latin filum, meaning “thread”). While it acted a lot like Ebola when it infected a person, it was not Ebola; it preceded Ebola, at least in human awareness. Following scientific practice, the discoverers named it for the place where it first appeared: Marburg virus.
Years later a writer named Richard Preston dug into the question of where and when the monkeys that caused the Marburg outbreak became sick. He found an English veterinarian who had been responsible in 1967 for clearing the animals as healthy before they were exported from Entebbe Airport in Uganda. In Preston’s 1994 book, The Hot Zone, the airport veterinarian explained that the animals were exported by an unscrupulous monkey trader. When monkeys that appeared sick were pulled off outgoing flights by the veterinarian, the trader was supposed to euthanize them. Instead he had them crated and taken to a small island in Lake Victoria, where they were released. Later, when he was short of animals for a shipment, the trader would visit the island and select the healthiest-looking animals that could be found to fill out the shipment. It is not certain that the Marburg-infected monkeys came from that island, but the veterinarian thought it was certainly possible.53
During this first-recorded Marburg virus outbreak, 7 people died of the 32 who were infected, a case fatality rate of about 22 percent. That rate has been much higher in outbreaks in Africa that have happened since. During the deadliest of these, in Angola in 2004 and 2005, 227 out of 252 infected people died, a case fatality rate of 90 percent.54
In 1967 the German outbreak came up repeatedly when, early in November, the DBS convened a big conference on the NIH campus. This was several weeks before the Marburg virus was identified by Müller, the scientist in Hamburg. The conferees were gathered to tackle the increasingly contentious question of which cells were best for making viral vaccines. There could hardly have been a more dramatic backdrop than the unsolved outbreak in Germany and Belgrade.
Five years after the publication of the influential Science paper that sowed doubts about Hayflick’s human cells, the DBS—in effect, Roderick Murray—remained opposed to their use in vaccine making. And it became clear during the three-day conference that the events in Marburg were not going to
change the regulator’s position one whit.
Plotkin wasn’t at the conference, but Hayflick was there, and by the last day he was brimming with frustration. He accused the DBS and its backers—of whom there were a significant number, some illustrious, in the crowd—of a head-in-the-sand position that amounted to preferring the devil they knew to the one that they didn’t.
“The better we know our devil, the happier we are with him,” Hayflick held forth. “Consequently, this year when seven people tragically died in situations where monkey kidney was used, we presume that we now know our devil a little better. Next year when, perhaps, other tragedies occur and the following year when tragedies of greater magnitude result, I presume that this will reinforce the contention that the devil we know is being known better and better and is consequently more desirable.”55
Murray had sat in typical, imperturbable silence throughout the conference. Hayflick’s angry comments, however, succeeded in rousing him to a rare, brief speech.
“About this monkey situation,” he began. Conference participants had said several times, incorrectly, that the DBS had shut down all vaccines made using monkey kidney cells. This was not true—only African green monkey–based vaccines were undergoing “a temporary halt in release,” and this would last only until the DBS sorted out whether the unidentified agent causing havoc in Marburg could be a danger “to the vaccine itself.” All signs, he added, suggested that DBS screening requirements for imported monkeys “would probably have picked up this agent” if the infected monkeys had arrived on U.S. shores.56 There would have been, he implied, no danger of distributing Marburg virus–laden vaccines.
Once the current situation was clarified, Murray concluded, the DBS would decide what to do about the use of African green monkeys going forward. Several months later, Murray’s office cleared African green monkey kidney cells for use once more in vaccine production.
The Marburg virus had not invaded the polio vaccine supply as SV40 virus had invaded it a decade earlier, which is to say pervasively and silently, being injected into tens of millions of vaccinees without doing apparent, immediate harm. Rather, Marburg’s devastation had been wreaked only on those working directly with infected animals or with their remains—and those in intimate contact with such people. And the results of Marburg infection had been immediately and highly visible. For Murray and those who shared his views, the Marburg events were therefore a blip, if an unfortunate one, and no kind of long-term threat to the vaccine supply. They were not a reason to jettison the use of African green monkey kidneys.
But for Hayflick and Plotkin the Marburg tragedy was yet another piece of evidence in the growing case for making the switch away from dubious monkey kidneys to using human fetal cells to make viral vaccines.
CHAPTER FOURTEEN
Politics and Persuasion
Philadelphia, 1967–68
The silent pressure for conformity exists whenever grants and contracts for research are under the direct control of governments; . . . then . . . no science is immune to the infection of politics and the corruption of power.
—Jacob Bronowski, Polish-British mathematician and science writer, 19711
In November 1967, as the conferees debated at the NIH, Plotkin found himself in need of two things: time and money. The first he could control only by sleeping less—and he was already down to six hours a night. The second was becoming a problem that was just as hard to solve. The grant from the NIH’s National Institute of Allergy and Infectious Diseases that had so generously funded Plotkin for the last several years was set to expire on November 30, 1967. The steady support from the private Joseph P. Kennedy, Jr. Foundation was also at an end. Only the last $6,100 of the $180,000 from that Washington-based foundation flowed to Plotkin in 1967.2 “We are operating on a tight budget, unsupported by a pharmaceutical firm,” Plotkin wrote in a letter to Benjamin Clark, the superintendent at Hamburg, as he watched the money running out.3
Plotkin’s competitors—drug companies with deep pockets, like Merck, and the Parkman-Meyer duo at the DBS, with the resources of the NIH behind them—were far better funded, he was sure. The disparity now threatened to sink him.
Looking for a fresh source of support in the early autumn of 1967, Plotkin applied for a piece of a new pot of NIH money specifically earmarked for developing a rubella vaccine. The funds had been authorized by Congress in 1965, as the damaging reality of the huge rubella epidemic sank in with politicians. The $1 million that Congress allotted (equal to $7.2 million in 2016) was enough to fund work on several vaccine candidates, it seemed to Plotkin.
The purse strings of the new rubella-vaccine fund—and the job of getting a rubella vaccine developed quickly—were held by the Vaccine Development Branch in the NIH’s National Institute of Allergy and Infectious Diseases.
In the summer of 1967 Plotkin did all he could to put together a first-rate application, gathering data from collaborators in Paris and Leningrad who had injected children with his RA 27/3 vaccine, tabulating the results of his own human experiments at St. Vincent’s Home and at Hamburg, and even traveling to the NIH to run his draft application past John Sever, a senior rubella scientist and an influential member of the Vaccine Development Board, which advised the decision makers in the Vaccine Development Branch as to what projects were worth funding. Plotkin was asking for $60,000, which would see him through one more year of work.
Plotkin took time to write a separate letter to the Vaccine Development Branch, suggesting that it use some of its rubella money to run a head-to-head trial of his vaccine against Parkman and Meyer’s HPV-77 vaccine, the one that the DBS duo had grown through scores of passages on African green monkey kidney cells. Such a comparison would show clearly which vaccine generated a better antibody response and which one was less likely to result in the vaccine virus colonizing the nose and throat, with the attendant risk of spread from vaccinees to the unvaccinated.
On November 21, 1967—incidentally, the day after Marburg virus was finally isolated in Germany—scientist Earl Beck, an administrator at the Vaccine Development Branch, wrote to Plotkin. The branch and its board of advisers had considered his application carefully. The answer was no.4
“As you know,” Beck wrote, “there are already a number of rubella vaccine strains available to the program.” That was all Plotkin got by way of explanation. A follow-up letter from Koprowski elicited a lengthier reply from Daniel Mullally, the chief of the Vaccine Development Branch, who waxed enthusiastic about Parkman and Meyer’s HPV-77 vaccine, while explaining that the branch didn’t have the funds to support every vaccine candidate.5
Still, Beck had written to Plotkin that his proposed head-to-head trial of his own RA 27/3 vaccine versus HPV-77 was an “excellent” idea. All that Plotkin needed to do to make it happen was to provide the branch with a complete manufacturing protocol for his vaccine, including records of all the safety tests he had run in the lab and in live animals. The latter tests needed to include injecting the brains of live monkeys and watching them for weeks to see if the vaccine caused neurological symptoms, then sacrificing them and studying their brains under the microscope. And, of course, he would need an Investigational Exemption for a New Drug—the permission that the Division of Biologics Standards alone was poised to bestow. Presumably, he had already filed for one.
Plotkin had not done monkey tests. Nor had he applied to the chubby, cigar-smoking Joe O’Malley in the DBS for an Investigational Exemption for a New Drug.
Plotkin would end up being rescued by industry: specifically, by the Philadelphia-based drug company Smith, Kline & French, with whom he had been corresponding that autumn. He had even driven out the Schuylkill Expressway to the company’s labs in Upper Merion Township, where he met with Bob Ferlauto, a sometimes-hot-tempered Sicilian who ran the company’s microbiology research and had seen the potential in Plotkin’s vaccine.*
On December 1, the day after his NIH
funding ran out, Plotkin received a grant of $10,000 from the company.6 The funding—more than $72,000 in 2016 dollars—amounted to a godsend, if a temporary one. Plotkin hoped that there would be more where it came from.
• • •
As Plotkin scrambled for funding in 1967, he was also struggling to push ahead with more trials at the Hamburg State School and Hospital. After running the first trial there in the summer and fall of 1966, he had written to Benjamin Clark, the physician who was the institution’s superintendent, thanking him for his “magnificent cooperation” and asking if he could begin another trial at the hospital early in the new year.7
“I am very sorry to have to inform you that the Nursing Service at this hospital has adamantly opposed any continuance of the rubella vaccine trials,” Clark wrote back, without offering further explanation.8
Nonetheless, by January 1967 the nurses had somehow softened—or been required to soften—and Plotkin soon launched another trial.
There was another nurses’ revolt in the summer of 1967, when Plotkin proposed still more trials at Hamburg, to begin in the autumn.
In a sharply worded memo the director of nursing, Miss Lois Colley—a tall, smart, take-charge woman—pointed out that the hospital was in the middle of training personnel, converting a hospital wing, and opening two new areas. “It will be impossible to provide staff for another Wistar program,” she wrote to Clark. What was more, Plotkin’s written contention that the new trial “would involve no more work for nursing personnel other than transfer of residents shows little insight into the nursing care and time involved.”9
“She might be less resistant to the program by September,” Clark wrote to Plotkin. “But I think we should not plan too much on being able to continue.”10
The Vaccine Race Page 27