955: The Making Of The Polio Vaccine
On April 12, 1955, Dr. Jonas Salk, a slightly built, forty-year-old research professor from the University of Pittsburgh, became a hero. On that morning, before one hundred and fifty news reporters and five hundred scientists and physicians crammed into an auditorium at the University of Michigan, “amid fanfare and drama far more typical of a Hollywood premiere than a medical meeting,” according to an account in The New York Times , it was announced that Dr. Salk had developed a vaccine that had been found effective in preventing poliomyelitis. The setting embarrassed many scientists and offended others, but Dr. Salk’s vaccine had become something much greater than the small, final step that crowns most scientific endeavors. This was the culmination of one of the most concentrated and eagerly watched research campaigns ever organized in the United States. Hundreds of doctors and scientists had spent several decades developing a substance that might eradicate the nation’s most feared infectious disease. Like any complex invention, the process had involved identifying many aspects of an intricate problem, finding workable solutions to each, and combining the results into a novel and successful whole.
The ensuing celebration—including a presidential citation, the awarding of the first Congressional Medal for Distinguished Civilian Service, and a picture story in Life magazine with the headline “A Hero’s Great Discovery Is Put to Work” —did not endear Dr. Salk to his scientific colleagues. It not only obscured the fact that the vaccine was the end result of a long, cumulative effort; it also obscured the intense disagreement that existed over the potential effectiveness and safety of the new vaccine. Dr. Salk’s vaccine used a “killed” virus, a virus that could no longer infect but that could still, theoretically, produce immunity by arousing an antibody response. This was not a new technique, but the orthodox belief was that only a “live” virus —modified and weakened but not inactivated—could provide a powerful enough vaccine. Dr. Albert Sabin, who was developing a live vaccine even as Dr. Salk’s killed one was being licensed, attacked Dr. Salk’s work and his killed-virus theory at every opportunity. Dr. Salk would later say, “The worst tragedy that could have befallen me was my success.”
People had been praying for a victory over polio since the early 190Os. In the summer of 1916 a frightening epidemic of poliomyelitis, then known as infantile paralysis, had ravaged the United States. There were 27,363 reported cases, including 7,179 deaths, in the twenty states that kept such statistics. Hardest hit was New York City: 9,023 cases, 2,448 of them fatal. The New York Times published a daily list of victims under the heading “New Cases and Deaths.” Public health officials thrashed about for answers but found little to ease their sense of helplessness. We now know that the disease is caused by a viral agent that enters the victim by way of the mouth, multiplies in the intestines, and travels from there to the central nervous system, where it attacks the motor neurons of the spinal cord and part of the brain. We also now know that polio epidemics arose in this century partly because of improved hygiene: children were now avoiding infection until a later age—past infancy—when serious illness is more likely to result.
In 1909, in Vienna, Dr. Karl Landsteiner made a first breakthrough toward understanding the disease, suggesting that it was caused by a virus, but it would be many years before the virus would be understood. A second key discovery was made twenty-two years later in Australia, where Dr. Frank M. Burnet and Dame Jean Macnamara found that there were fundamental immunologie differences between at least two strains of polio virus. In other words, a successful vaccine would have to provide immunity against more than one type of virus. This discovery had little impact in the United States, even though, at the time, a concerted effort was being started to raise money and find a cure, beginning in 1934 with President Franklin D. Roosevelt’s “Birthday Balls”—“to dance so that others may walk.” The money so raised was spread around to researchers by the Birthday Ball Commission, and in 1935 two vaccines were tried, one developed by Dr. Maurice Brodie, of New York City, and the other by Dr. John Kolmer, of Philadelphia.
As if a precursor of future disputes, Dr. Brodie’s vaccine, given to some nine thousand people, used a killed virus; Dr. Kolmer’s vaccine, given to about twelve thousand, used a live virus. By December Dr. James P. Leake of the U. S. Public Health Service reported twelve cases of poliomyelitis, six of them fatal, following the use of one or the other of the vaccines. The live vaccine, using a virus cultured in monkey spinal cords and treated with glycerol, sodium ricinoleate, and phenyl mercury nitrate, was considered dangerous. Dr. Leake publicly begged Dr. Kolmer to stop using it. As for Dr. Brodie’s vaccine, “killed” with a formaldehyde solution, it was never described as hazardous but was deemed useless when other scientists proved unable to duplicate Brodie’s experiments. Use of both vaccines was halted.
At this point the consensus of virologists was that vaccines could not work against polio. Due to incomplete and sometimes misleading research, most tended to agree that the disease was caused by only one type of virus (despite Burnet’s discovery); that it grew only in living nerve cells; that it entered the body through the nose; and that it traveled from the nose to the brain and spinal cord by way of nervous tissue. All of these assumptions were wrong.
In 1938 the Birthday Ball Commission was replaced by the National Foundation for Infantile Paralysis (NFIP). A presidential radio address kicked off the new campaign, the March of Dimes, and millions of dimes were sent to the White House. As important as all the small contributions, however, was a simple move made by the foundation’s president, Basil O’Connor. A Wall Street lawyer, O’Connor was the driving force behind the NFIP’s research effort. He asked Dr. Thomas Rivers, head of the hospital at the Rockefeller Institute for Medical Research and dean of American virologists, for a list of research priorities. The two men in effect organized the attack on the disease, calling for a concerted basic investigation to replace the helter-skelter hunt for a cure. The research would address specific questions about the disease in man: How did the virus affect human tissues? How did it enter the human body? Where did it establish itself in the body and how did it travel to the central nervous system? How did it depart and spread? Last on the list was the production of a good vaccine. The activity that resulted did not lead to immediate discoveries, but it pushed along the flurry of postwar developments that would make a vaccine possible. O’Connor remained the guiding spirit throughout the effort—as Rivers put it, he “often needled us doctors and scientists into taking some courageous action that we otherwise would not have taken.”
Perhaps the most important development—one that would not only speed the creation of a vaccine but greatly facilitate its manufacture once devised —was made by Dr. John F. Enders and his associates, Dr. Thomas H. Weller and Dr. Frederick C. Robbins, at Harvard. In 1949 they succeeded in growing a strain of polio virus in test tubes containing cultures of nonnervous tissue. It had been assumed since the mid-1930s, on the basis of experiments performed by Dr. Peter Olitsky and Dr. Albert Sabin, that polio virus would grow only in nerve cells. Dr. Sabin would later find that this conclusion was true only of the particular strain of virus he had tested. With their new finding, Dr. Enders and his associates eliminated two major barriers to polio immunization: They made possible the laboratory cultivation of unlimited quantities of polio virus for experimental use, and they found a way around culturing the virus in foreign nervous tissue (a monkey’s spinal cord, for example), which could be dangerous to humans. As a result of this work, Drs. Enders, Weller, and Robbins were awarded the Nobel Prize in 1954.
There were two other crucial developments in the late 1940s and early 1950s. First, it was found that the polio virus broke down into three distinct immunologie types, one more than Burnet had found in 1931. Second, polio virus was discovered in human blood. The virus in the bloodstream could probably be overcome by relatively small amounts of circulating antibody before spreading to the nervous system.
Dr. Salk was in a position to take advantage of these developments. He had been recruited in 1947 to play a major role in the tissue-typing program, classifying the more than one hundred strains of polio virus into the three immunologie types. Before taking over his own laboratory at the University of Pittsburgh, he had worked with Dr. Thomas Francis at the University of Michigan on the development of an inactivated— killed—vaccine for influenza. And he was uniquely prepared temperamentally, eager to move quickly where others hesitated and to work day and night on the project.
Salk rapidly mastered Dr. Enders’s tissue-culture techniques and, after disposing of hundreds of variations, largely by trial and error, settled on a vaccinemaking process using formaldehyde to kill the infectivity of the polio virus while leaving it able to provoke the formation of antibodies. The method was similar in theory to Dr. Brodie’s, but with two major differences: it worked for all the types of virus, and it involved much better control of the inactivation process. Dr. Brodie’s methods have been described as “crude” and “nonquantitative”; Dr. Salk’s process was based on his experimental finding that, as the virus was killed, its infectivity declined at a specific rate. The vaccine could, therefore, be monitored to ensure that the inactivation proceeded properly.
In the summer of 1952 Dr. Salk performed his first human experiments, at the D. T. Watson Home for Crippled Children, about fifteen miles up the Ohio River from Pittsburgh. At the time, many scientists remained unconvinced that a killed-virus vaccine could work, Dr. Sabin being among the most vocal in his disagreement. Others felt that Dr. Salk had chosen the wrong method of inactivation and the wrong strain of polio for the vaccine. Nevertheless, O’Connor and the NFIP pushed for a field trial in 1954.
That trial, larger and better-controlled than any before, became a model for tests used in future vaccine development. Each batch of vaccine was first examined in test tubes and tried on mice, rabbits, and monkeys. Then some 650,000 children received injections— 440,000 got the vaccine; the rest got dummy solutions. Another 1,080,000 children were monitored as uninjected controls. The results, announced at the tumultuous April meeting in 1955, were a spectacular success showing 80 to 90 percent effectiveness, with a promise of improved performance in future vaccines. The vaccine was licensed by the Public Health Service the same day and immediately went into production. Just as quickly there were problems. Several lots produced by one company slipped out with live virus, resulting in 260 cases of polio. Critics said the vaccine had been irresponsibly rushed into use. An investigation by the Public Health Service placed the blame on inadequate virus inactivation and failed safety tests; the other firms manufacturing the vaccine had no such problems. Disaster never again occurred, and in seven years the Salk vaccine reduced the incidence of polio in the United States by more than 96 percent, from 38,476 reported cases in 1954 to 1,312 in 1961.
Dr. Sabin’s live oral vaccine was licensed for use in the United States in 1961 after being successfully introduced in other countries, including the Soviet Union. It was easy to use—swallowed instead of injected—and therefore could be expected to be more widely administered; it also had a reputation for providing longer-lasting immunity. It quickly became the vaccine of choice in the United States. It was not, however, without flaws. Soon, cases of polio were being reported that were “associated” with the vaccine—the vaccine had evidently caused the disease, something not possible with a killed-virus vaccine. The total number of such cases was infinitesimal when compared with the number of doses, but they were and are still there, irritants in the drive to eradicate polio.
The Salk and Sabin vaccines have eliminated polio as a public health problem in the United States. Yet the disagreement between two scientists is still fundamental and unresolved: Dr. Salk believes it is unneccessary to reproduce the infection to provide immunity; Dr. Sabin feels that doing so produces a more natural immunity. Dr. Salk has never been invited to join the National Academy of Sciences, perhaps the most telling example of how his “victory” estranged him from his colleagues. Dr. Sabin, a brilliant scientist, has seen his vaccine adopted around the world, but he hasn’t forgotten Dr. Salk. In a recent interview Sabin pointed to his citation for the 1970 National Medal of Science and declared himself pleased because it said, “contrary to what’s been written in some newspapers, that I developed the vaccine, not a vaccine.”
Regardless of Salk’s and Sabin’s fundamental differences, their mutual success against polio has led to a much better understanding of how both live and killed vaccines work. A killed vaccine, like Salk’s, which is injected, produces an antibody in the bloodstream but not in the intestine, where the virus enters the system, so it protects against the disease but not against the initial infection. The live vaccine goes to work in the intestine and thus protects at an earlier stage. According to Dr. Alfred S. Evans of the Yale Medical School, the clarification of these “two contrasted approaches” is, along with the experience gained in the field tests, a “major contribution” of the polio battle to the subsequent development of other vaccines.
Meanwhile, a more nearly perfect polio vaccine is still being sought in the laboratory, and two pharmaceutical companies have recently developed more powerful Salk-type killed-virus versions —“new, improved, higher-potency,” in the words of Dr. Roger Bernier, of the federal Centers for Disease Control. The new formulas are currently undergoing testing in Baltimore, and one of them may replace the live vaccine in the United States within the next several years. If it does, federal officials say, it just might eliminate the last traces of polio in this country.