Vaccinated (7 page)

Hilleman promised to make hundreds of thousands of doses of JEV vaccine for the military. But Squibb didn't share his patriotic enthusiasm, certain that Hilleman couldn't possibly make that much vaccine that quickly. “We had nothing on the plant site other than an old horse barn,” recalled Hilleman. “And we had to start production in thirty days. They gave me an engineer. He said to me, ‘How in the hell are we going to start production in thirty days?' So we sat down and tried to figure out how to make a laboratory. We bulldozed all of the horse manure out of the barn and painted a concrete floor. We cleaned out the loft upstairs, where all the hay had been stored and put in a stairway. Then we put in heating and electricity.”

To make the vaccine, Hilleman's technicians injected JEV into mouse brains. Then they waited a few days until the virus reproduced. Hilleman remembered what happened next: “The girls would take the mice and [kill] them with ether. Then they would dip the mice in Lysol, strip the skin from the skull, and scoop out the brains with scissors.” Before treating the virus with formaldehyde, Hilleman put hundreds of tiny mouse brains into a Waring blender (named for the popular bandleader Fred Waring, who marketed it). Sometimes, when homogenized brains leaked out of the blender, Hilleman worried that technicians would catch the disease. “We put the brains into Fred Waring's cocktail blender. And those damned blenders would leak out of the base, and sometimes brains would squirt out of the tops of the blenders. Waring didn't give a damn about cocktail loss, but when mouse brains started to leak onto the floor, it scared the hell out of me.” (For whatever reason, television commercials for the Waring blender in the 1950s never featured its capacity to homogenize mouse brains.) Thirty women, working eight-hour shifts and processing two mice per minute, harvested about thirty thousand mouse brains a day. Because the JEV vaccine was given as a series of three doses, it took about three months to make enough of it to immunize six hundred thousand American troops. Military epidemiologists never performed studies to determine whether Hilleman's JEV vaccine worked during the latter stages of the Second World War. But it is likely that the vaccine prevented disease in thousands of soldiers. JEV vaccine is still made in mouse brains today.

 

A
LTHOUGH
H
ILLEMAN HAD A REMARKABLE RECORD OF SUCCESS IN
making vaccines, he failed to make one to prevent the world's most widespread and most annoying infection: the common cold. But he tried.

The common cold has plagued humankind since the beginning of recorded history.

Countless efforts to cure it have generally failed. In the fifth century
B.C
., Hippocrates noted that despite many attempts, therapeutic bleeding didn't work. In the first century
A.D
., Pliny the Elder recommended “kissing the hairy muzzle of a mouse” (which also didn't work). In the eighteenth century, Benjamin Franklin said that colds were spread from one person to another (which was true) and that people would be less likely to catch colds if they avoided damp, cold conditions (which wasn't true). Today, people treat colds with echinacea, St. John's wort, vitamin C, vitamin E, and zinc. But perhaps the best advice came in the nineteenth century from the renowned physician William Osler. “There is just one way to treat a cold,” he said, “and that is with contempt.”

Colds account for half of all acute medical conditions. But despite tremendous technological advances in isolating, identifying, sequencing, and cloning cold viruses, as well as advances in understanding how the immune system responds to these viruses, scientists and researchers have done nothing to prevent the common cold.

Most of our understanding of the common cold has been an indirect consequence of the Second World War. When the U. S. Army evacuated Britain at the end of the war, it left behind an army hospital in Salisbury, England, that had been staffed by doctors from Harvard Medical School. Christopher Andrewes, a British researcher who was the first to isolate influenza virus from people, set up the Common Cold Research Unit in the abandoned buildings. During the next four years, Andrewes persuaded two thousand adults to take “ten-day holidays” at his research unit. He wanted to see what would happen if he inoculated volunteers with nose and throat washings taken from people suffering from colds. (On its face, this doesn't sound like much of a holiday.) Andrewes found a few things that surprised him. About half of those inoculated with cold viruses came down with colds; women were more likely to catch colds than men; antihistamines, which had just been developed, were worthless; and people who were cold were not more likely to catch colds—they were actually less likely. Andrewes figured out the last point by asking people who had been inoculated with cold viruses to stand in a draft for thirty minutes in a wet bathing suit. He also found that people inoculated with a cold virus from one person weren't protected months later when challenged with a virus from someone else.

The first apparent breakthrough in preventing the common cold came in the fall of 1953, when Winston Price, a thirty-four-year-old biochemist working at Johns Hopkins Hospital, isolated a virus from the nose of a student nurse. He called it JH virus, for Johns Hopkins. Then he took the virus, grew it in monkey kidney cells, killed it with formaldehyde, and injected it into the arms of a hundred boys in a local training school. The results were dramatic. During the next two years, children who had received Price's vaccine were eight times less likely to get a cold than those who hadn't. Price was cautious. “It's absolutely misleading if anyone thinks we are going to have an all-inclusive cure for colds,” he said. “This is just the opening wedge, the first piece out of the pie, and an opening we have not had before. What we hope is that by using similar methods we may help isolate one or more viruses which make up the other part of the cold pie.”

Scientists and physicians hailed Price's findings as groundbreaking. George Hirst, director of the Public Health Research Institute in New York City, said that “the work by Dr. Price on the new JH virus is a promising lead in the attack on the common cold.” By the end of the year, one vaccine maker said that it would soon have a vaccine to prevent colds. But to make a vaccine, researchers needed to find out how many different viruses caused the common cold. In the early 1960s, Maurice Hilleman answered the question. Hilleman swabbed the throats of Merck employees, students at the University of Pennsylvania, and children admitted to The Children's Hospital of Philadelphia. He also collected samples of cold viruses from other researchers. Then he grew the viruses in laboratory cells, obtained blood from people who had just been infected, and tested the serum to see whether the viruses were immunologically similar or distinct. Hilleman identified fifty-four different types of cold viruses; forty-one of these were first isolated in his laboratory. Further, Hilleman found that natural infection with one type of cold virus protected against disease caused by that same virus for at least four years, but it didn't protect against disease caused by other types. The common cold was common, not because immunity was short-lived but because there were so many different cold viruses. “If there was just one type, then a vaccine could protect against colds for the rest of your life: just like the measles and mumps vaccines,” said Hilleman.

Hilleman tried to make a common cold vaccine by putting different types of cold viruses into a capsule. On May 26, 1965, in concert with the ethic of the time, he fed his vaccine to nineteen mentally retarded children in the Vineland State School in New Jersey. Hilleman obtained frequent X-ray films of their stomachs to determine when the capsules opened. Although swallowing live cold viruses didn't cause any symptoms, no one developed antibodies; Hilleman's attempt to make a common cold vaccine had failed. Then Hilleman tried to find some degree of similarity among the different cold viruses that he could exploit to make a vaccine. But he never found it. “There was just no crossing at all between these strains,” he said. Today, more than a hundred different types of cold viruses have been found, and no one has been able to make a vaccine to prevent them.

So why did the vaccine trial conducted in Baltimore by Winston Price work? If there are at least a hundred different types of cold viruses, why did a vaccine that contained only one strain of virus cause such a dramatic decrease in the incidence of colds for two years? The truth is that it didn't. “His study was a complete fraud,” said Hilleman. “He made up his data. I found out about it when I was working at Walter Reed.” No one has ever duplicated the success found by Winston Price in the mid–1950s, and given the un-likelihood of using one type of virus to protect against a disease caused by more than a hundred different strains, no one probably ever will.

Although he failed to make a vaccine to prevent the common cold, Hilleman had shown why it was so common. Next he set his sights on a virus that most doctors ignored, unless it infected pregnant women.

I
n the spring of 1941 two mothers struck up a conversation in the waiting room of a doctor's office in Sydney, Australia. Both were holding babies on their laps. The mothers soon discovered that they were there for the same reason—their babies were blind. Looking for a clue to their misfortune, they compared pregnancies. Neither had traveled outside of Sydney, neither had relatives with eye problems, both had eaten well, and both had taken their vitamins faithfully. They had one more thing in common: both had been infected with German measles early in their pregnancies. Sorting through papers at the nurse's desk, the ophthalmologist, Norman McAlister Gregg, overheard the conversation. Gregg thought of German measles as a trivial infection of childhood. He couldn't believe that it caused blindness.

 

F
IRST DESCRIBED BY GERMAN DOCTORS AS A DISEASE SIMILAR TO MEASLES
, German measles was later named
rubella
by a British physician during an outbreak in an all-boys boarding school in India. The doctor reported that students first experienced an uncomfortable swelling of the lymph glands behind their ears and on the backs of their necks. In a few days they were weary with fever and pinkeye. Later, a rash—red and slightly raised from the skin—appeared at the hairline and spread to the rest of the face. (In Latin,
rubella
means “little red.”) The rash was barely noticeable, the fever was slight, and the fatigue was so mild that only a few boys missed school. Compared with measles, chickenpox, and scarlet fever—other diseases that caused rash and fever—rubella seemed to be the mildest of all childhood infections.

 

F
OR THE NEXT FEW WEEKS
G
REGG EXAMINED THE MEDICAL RECORDS
of every woman in his care who had a baby with birth defects. He knew that two years earlier, in 1939, a rubella epidemic had swept across the continent. As he sorted through the records, Gregg had the uncomfortable sense that beginning nine months after the epidemic, he was caring for more and more babies who were blind. Was it possible that rubella had damaged babies in their mothers' wombs? Gregg found seventy-eight mothers whose babies were blind; sixty-eight had had symptoms of rubella early in their pregnancies.

In 1941, in a now landmark paper titled “Congenital Cataracts Following German Measles in the Mother,” Norman McAlister Gregg published his findings in a little-known, little-read medical journal,
Transactions of the Ophthalmological Society of Australia
. He was fifty years old. Gregg had never published a scientific paper, was unknown to medical researchers, and lived on a continent far away from influential medical centers in the United States and Europe. His anonymity, coupled with the fact that he was proposing something that had never been proposed before—that a virus could cause birth defects—cast doubt on Gregg's observations. Few believed him.

 

A
LTHOUGH MANY RESEARCHERS WERE SKEPTICAL, SOME WERE
intrigued by Gregg's hypothesis. In the twenty years following his observation, researchers in Australia, Sweden, England, and the United States confirmed and extended his findings. They found that not only did rubella infection during pregnancy cause blindness but it also caused heart defects and deafness. (Viruses or drugs that damage babies in the womb are called
teratogens
—literally “monster makers.”)

Although epidemics had occurred throughout the twentieth century, Americans didn't experience the full horror of rubella until the early 1960s. Between 1963 and 1964, in one of the worst epidemics ever recorded, rubella infected twelve million Americans. Among those infected were thousands of pregnant women. Rubella virus killed six thousand fetuses soon after conception and two thousand more at birth. The virus permanently harmed another twenty thousand unborn babies by infecting the liver, causing hepatitis; the pancreas, causing diabetes; the lungs, causing pneumonia; and the brain, causing mental retardation, deafness, blindness, epilepsy, and autism. Knowing that eight of every ten pregnant women infected with rubella early in pregnancy would give birth to babies who were severely harmed by the virus, mothers were left with a Sophie's choice: deciding whether their unborn babies should live or die. Unwilling to take odds that were so heavily stacked against them, five thousand women chose to abort their pregnancies. Many would never conceive again.

While rubella virus was sweeping across the world in the early 1960s, the war in Vietnam had just begun. When it was over, ten years later, fifty-eight thousand Americans had lost their lives. At home, rubella virus killed or wounded thirty thousand children in one year. But unlike the Vietnam War, the war waged by rubella against American children was unaccompanied by news bulletins, demonstrations, or lively debates in Congress. And not a single shot was fired.

Although rubella virus was the first infection found to cause birth defects, it wasn't the last. Bacteria such as
Treponema pallidum,
which causes syphilis; parasites such as
Toxoplasma;
and other viruses such as the chickenpox virus all cause birth defects. But no organism is more common, more thorough, or more consistent in its destruction of unborn children than rubella virus.

 

I
N THE EARLY
1960
S, A FEW YEARS BEFORE THE WORST RUBELLA
epidemic in history, Maurice Hilleman began to work on a rubella vaccine. Hilleman knew that massive outbreaks of rubella had occurred in the United States in 1935, 1943, 1952, and 1958—about one every seven years. While working on his vaccine he witnessed the rubella epidemic of 1963–1964. He anticipated that the next one would arrive between 1970 and 1973. To have any hope of saving the lives of unborn children, he would have to make a rubella vaccine quickly.

Hilleman started by capturing rubella virus from the throat of an eight-year-old Philadelphia boy whose last name was Benoit. The vaccine would be known as the Benoit strain. He weakened the virus by growing it in monkey kidneys and duck embryos. On January 26, 1965, Hilleman injected his rubella vaccine into the arms of mentally retarded children in group homes in and around Philadelphia. All developed rubella antibodies, and none had symptoms of infection. Months later, when a small epidemic of rubella swept through Pennsylvania, Hilleman found that 88 percent of unimmunized children got rubella, but all who had received his vaccine were protected. Confident, he couldn't wait to test it in more children. But Hilleman's efforts would soon be thwarted by someone he had heard of but never met—someone who, although not a researcher, doctor, politician, pharmaceutical company executive, or public health official, was more powerful than any one else in science or medicine.

 

H
ER NAME WAS
M
ARY
L
ASKER, THE WIFE OF ADVERTISING EXECUTIVE
Albert Lasker. Albert “had a new gimmick to make money, and that was to work for nothing,” recalled Hilleman. Immediately after graduating from high school, Albert joined the advertising agency of Lord and Thomas in New York City. Figuring that no one would be impressed by his youth, he offered to work for free, asking only to be paid in his clients' stock. When some clients became Fortune 500 companies, Albert Lasker became a multimillionaire. At twenty-eight, he owned Lord and Thomas; two years later, he retired. In 1940, when he was sixty years old and she was forty, Albert married Mary Woodard. When they met, Mary was working at the Reinhardt Galleries in New York City, setting up private loan exhibitions of French master painters. A native of Watertown, Wisconsin, Mary had graduated from Radcliffe in 1923 and studied briefly at Oxford before returning to the United States. In 1942, Mary convinced Albert to create the Mary and Albert Lasker Foundation.

Although the twentieth century witnessed many philanthropists interested in social change, few had the indomitable will, courage, or resources of Mary Lasker. Her generous gifts to Planned Parenthood in the 1930s and 1940s made her the principal source of funding for the birth control movement in the United States. But her real passion was medical research. Lasker was responsible for a federal bill in 1971 that made the conquest of cancer a national goal. And she was a dominant force behind the creation of the National Cancer Institute, the first institute within the National Institutes of Health. Scientists and the media adored Mary Lasker. Jonas Salk said, “When I think of Mary Lasker, I think of a matchmaker between science and society.” Michael DeBakey, the inventor of artificial hearts and pioneer in heart transplants and Mobile Army Surgical Hospitals (MASH units), said, “The National Institutes of Health has flowered because in many ways [Mary Lasker] gave birth to it and nursed it. It was in existence, but it was she who got the funding for it.”
BusinessWeek
called her “the fairy godmother of medical research.” Lasker won the French Legion of Honor, the Presidential Medal of Freedom, and the Congressional Gold Medal. She also established the Lasker Award, the most prestigious prize for biomedical research in the United States. (Its winners often later win the Nobel Prize.) But despite all her good works, Maurice Hilleman feared Mary Lasker. “You have to credit Mary Lasker for doing all of that,” he said. “But she could kill you.”

Mary Lasker stands between President John F. Kennedy and Vice President Lyndon B. Johnson at the White House, April 11, 1961, during a meeting of the Committee on Equal Employment Opportunity (courtesy of the Bettmann Archives).

Lasker called Merck and asked Max Tishler, Hilleman's boss and the president of Merck Research Laboratories, to come to New York for a meeting. Lasker wanted Tishler and Merck to stop working on their rubella vaccine. She knew that Harry Meyer and Paul Parkman, both of whom worked at the Division of Biologics Standards (the agency responsible for licensing new vaccines in the United States) were making their own vaccine by taking rubella virus from an army recruit and passing it seventy-seven times through monkey kidney cells. Lasker reasoned that because Meyer and Parkman worked for the licensing agency, their vaccine would be licensed more quickly than Hilleman's, and she didn't want competition to slow the process. Initially, Lasker wanted to meet with Tishler alone, but Tishler refused, saying that he would meet Lasker only if Hilleman were there too. “I got a call from Max Tishler one day,” said Hilleman, “and he said, ‘Do you know this guy Harry Meyer?' Mary Lasker says that he has developed a rubella vaccine. Mary has talked to some people, and she thinks it could be a pretty good vaccine. [She] wants us to come up to her apartment in New York City and tell us what she thinks needs to be done.” In Tishler, Hilleman now had a powerful ally.

 

L
IKE
M
ARY
L
ASKER,
M
AX
T
ISHLER WAS USED TO GETTING WHAT HE
wanted. Born in 1906 to European Jewish immigrants, the fifth of six children, Tishler survived a difficult childhood. His father, a cobbler, abandoned the family when Max was only five years old. To supplement the family's income, Max went to work by selling newspapers, working as a pharmacist's assistant, and delivering doughnuts for a local bakery. He was an outstanding student. Winning several awards and scholarships, Tishler later graduated from Tufts College and Harvard University, where he got a doctorate in chemistry. But positions in academia were scarce. So in 1937 Tishler landed a job at a growing pharmaceutical company in Rahway, New Jersey: Merck. He was attracted to Merck because of its solid revenues from chemicals such as iodine, silver nitrate, ether, and chloroform; because it was one of the few chemical companies in America that would hire a Jew; and because its president, George Merck, was interested in innovation.

Tishler's genius, combined with Merck's resources, led to an unparalleled series of successes. Tishler figured out how to mass-produce riboflavin (vitamin B
₂
) and pyridoxine (vitamin B
₆
), allowing food makers to add vitamins to enrich white bread. In 1942, after doctors found that penicillin treated deadly infections, Max Tishler was one of the first Americans to make it. In 1948, when a young researcher at the Mayo Clinic found a hormone, cortisone, that treated painful, achy joints, Tishler found a way to synthesize large quantities. In addition to penicillin, Tishler made other antibiotics. One, sulfaquinoxaline, treated a bacterial infection of chickens; when the drug was added to their feed, more chickens made it to market and sold for less.

Short, with red curly hair, horn-rimmed glasses, and a raspy voice, Max Tishler was a difficult man. “Max was driven to do things well,” recalled a co-worker, “and he couldn't tolerate problems not being solved. He was utterly fearless in the face of trouble and actually impatient to hear all the bad news—all of the failure of good ideas, or setbacks from whatever source. Unlike most of us, who seem to need a little time to face up to reversals, he never even blinked.” Roy Vagelos, former chief executive officer at Merck and an early pioneer of cholesterol-lowering drugs, also remembered Max Tishler. “So the story goes, and it's a true one; Max had the group geared up to isolate vitamin B
₁₂
, which is ruby red. It was isolated from tons of livers, and it was a breakthrough at Merck. People were working around the clock to get it done. Max had the habit of wandering around the laboratory at any time and would just burst in to ask you questions. So, one time in the middle of the night, these guys, having purified the substance, were putting it through a pressure filtration, and they were squeezing it through this tube. The tube broke and it started to leak. The door opened and Max walked in, and he looked at the red stuff on the floor and looked at them. They were sweating profusely. ‘I hope that's someone's blood,' he said.”