From Culture to Vaccine — Salk and Sabin
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《新英格兰医药杂志》
The Nobel Prize–winning demonstration by John Enders, Frederick Robbins, and Thomas Weller that polioviruses could be propagated successfully in nonneural cell cultures paved the way for two brilliant, ambitious scientists to reorient and accelerate their development of poliovirus vaccines. The backgrounds of Jonas Salk (Figure) and Albert Sabin (Figure) were similar in many ways. Salk was born in New York City, the eldest son of an Orthodox Jewish designer of blouses in Manhattan's garment district. He was a superb student who made his way through a special high school for honors students, on to City College where he excelled in laboratory science, and from there, on scholarship, to New York University (NYU) Medical School, where he won further attention for his intellectual prowess. Sabin was born to a Jewish family that left Bialystok (part of Russia or Poland, depending on the year) and immigrated to Paterson, New Jersey, when Albert was 15 years old. In a six-week cram course, he mastered English sufficiently to proceed through high school and thence to NYU and its medical school. His education had initially been financed by a dentist uncle, who withdrew his support when Albert decided to pursue medicine rather than dentistry. He financed the rest of his schooling through a combination of scholarships and jobs, graduating with an M.D. in 1931.
Jonas Salk with His Inactivated Poliovirus Vaccine, 1953.
Photograph courtesy of Getty Images.
Albert Sabin Administering Oral Polio Vaccine, 1967.
Photograph courtesy of Bettmann/Corbis.
Both men were recognized by their professors as gifted students, so both were able to pursue an academic career. Salk's mentor was Thomas Francis, a professor of bacteriology from NYU, whom he later followed to the University of Michigan. There, he became deeply involved with the development of inactivated influenzavirus vaccines, providing the experience that later led him to a similar strategy for polio vaccine.
Sabin spent most of his career at the University of Cincinnati and its Children's Hospital Research Foundation. During World War II, he distinguished himself with research on sandfly fever, dengue, and Japanese encephalitis viruses, three agents that threatened U.S. troops in Africa and the South Pacific. After the war, he returned to Cincinnati to pursue studies of poliovirus that he had begun in 1936.
During the several years after the successful cultivation of poliovirus, the state of the science advanced rapidly. A major study demonstrated that there were three distinct serotypes of poliovirus; viremia was identified in early poliovirus infection (establishing the pathogenesis, which had previously been thought not to involve bloodstream invasion); and experiments showed that specific serum antibodies to poliovirus were protective in monkeys. Armed with these findings, Salk and Sabin raced ahead along divergent pathways to develop vaccines that would be safe and effective in humans. Salk chose to pursue an approach similar to the one he had taken with influenzavirus. Sabin, in contrast, was convinced by the efficacy of vaccinia and yellow fever vaccines that attenuated live viruses were more likely to prove immunogenic and protective; he therefore began a quest for attenuated variants of the three poliovirus serotypes. Each man adhered to his approach of using either killed or live vaccine throughout the remainder of a long and distinguished career.
The race might have gone differently if it had not been for a third figure, Daniel Basil O'Connor, friend and former law partner of the nation's best-known poliomyelitis victim, President Franklin D. Roosevelt. In 1938, at Roosevelt's favorite rehabilitation retreat at Warm Springs, Georgia, the two men had founded the National Foundation for Infantile Paralysis with O'Connor as its director. Both Salk and Sabin received generous research funding from the foundation, but O'Connor decided that Salk's vaccine was likely to be available sooner and became a catalyst to accelerate its development. When Salk's vaccine was ready for a major field trial, having been studied extensively in small groups of children, O'Connor recruited Thomas Francis to organize and direct it. The results of this remarkable trial, in which more than 1.8 million schoolchildren participated, were announced with great fanfare on April 12, 1955 (the 10th anniversary of the death of Franklin D. Roosevelt), in a press conference that became a media spectacle.
Overnight, Salk's name was spread across newspapers and heard in radio and television announcements throughout the country — and indeed throughout the world. Salk became an instant hero, since the results of the trial demonstrated rates of protection of approximately 80 percent with three doses of vaccine. Licensure followed immediately, and soon (despite the "Cutter Incident," in which incompletely inactivated vaccine caused approximately 260 cases of paralytic disease) more than 4 million children had received inactivated poliovirus vaccine (IPV, or Salk vaccine).
The widespread acceptance of the Salk vaccine made it very difficult for Sabin to conduct large trials of his own vaccine in the United States. He therefore chose the unusual strategy of collaborating with Soviet investigators to immunize millions of children in Eastern Europe with his live attenuated oral poliovirus vaccine (OPV). After several years, Yale University's Dorothy Horstmann was sent with a group from the World Health Organization (WHO) to review the results of these studies, and she returned with a favorable report. By then, the use of IPV had markedly reduced the rate of poliomyelitis in the United States — by more than 90 percent in the five years of its increasingly widespread use. Nevertheless, some evidence that the type 3 component of the vaccine was less than optimal, coupled with the attractiveness of oral administration and other attributes of OPV (lower cost, intestinal mucosal immunity, "free" spread to unimmunized contacts, ability to be administered by nonmedical personnel) attracted the support of many medical groups, and in 1961, OPV was licensed in the United States. During the next several years, it displaced IPV, becoming the primary polio vaccine in the United States.
With increasing use, surveillance revealed that rarely (perhaps once per 790,000 first doses), vaccine-induced paralytic disease (vaccine-associated paralytic poliomyelitis) developed in recipients of OPV. After 1979, the only cases of paralytic poliomyelitis in the United States (six to eight cases annually) were of the vaccine-induced type. To his dying day, Sabin would not concede that these cases were caused by "his" vaccine, even after the genetic characterization of the poliovirus isolated from such patients proved that neurovirulent revertants of Sabin-vaccine strains were responsible for their illness.
Salk, for his part, never relinquished his contention that inactivated vaccine was sufficiently immunogenic and enduring in its effect to provide lifelong protection after initial vaccination. Indeed, in 1999, after the United States had been free of "wild" poliovirus for 20 years while vaccine-associated poliomyelitis persisted, U.S. policy was redirected to an all-IPV strategy. Many Western European nations had adhered to the use of IPV since it first became available in the late 1950s. The WHO, however, has continued to use OPV since the beginning of its global eradication program in 1988.
Despite their similarities, the two scientists were treated quite differently by their scientific colleagues and by the public at large. Salk, a warm, confident, quiet man, was a public hero, acclaimed throughout the world and honored with a Congressional Gold Medal, a special citation from President Dwight D. Eisenhower, the French Legion of Honor, and a Presidential Medal of Freedom from President Jimmy Carter. Salk remained a household name; one commentator spoke of the three best-known doctors of the baby-boomer era: Drs. Salk, Spock, and Seuss. Surveys of the U.S. public revealed his to be among the top three or four names best known to Americans. The Salk Institute in La Jolla, California (a science palace designed by Louis Kahn), was constructed and dedicated in his honor.
Salk's colleagues in the world of science, however, never afforded him the recognition and awards that accrued to Sabin, who was lauded by fellow scientists, elected to the National Academy of Sciences, and embraced by virologists and vaccinologists worldwide — though he was known to be bombastic, sometimes caustic, and intolerant of those who did not share his views. Many attributed the professional discrimination against Salk to the flamboyant backing of O'Connor and the resultant media frenzies, which were offensive to "pure scientists." But in the end, both men should be remembered — by scientists and the public alike — for their valued contributions to the elimination of poliomyelitis, whose global eradication may possibly be imminent.
Source Information
From the Duke University Medical Center, Durham, N.C.(Samuel L. Katz, M.D.)
Jonas Salk with His Inactivated Poliovirus Vaccine, 1953.
Photograph courtesy of Getty Images.
Albert Sabin Administering Oral Polio Vaccine, 1967.
Photograph courtesy of Bettmann/Corbis.
Both men were recognized by their professors as gifted students, so both were able to pursue an academic career. Salk's mentor was Thomas Francis, a professor of bacteriology from NYU, whom he later followed to the University of Michigan. There, he became deeply involved with the development of inactivated influenzavirus vaccines, providing the experience that later led him to a similar strategy for polio vaccine.
Sabin spent most of his career at the University of Cincinnati and its Children's Hospital Research Foundation. During World War II, he distinguished himself with research on sandfly fever, dengue, and Japanese encephalitis viruses, three agents that threatened U.S. troops in Africa and the South Pacific. After the war, he returned to Cincinnati to pursue studies of poliovirus that he had begun in 1936.
During the several years after the successful cultivation of poliovirus, the state of the science advanced rapidly. A major study demonstrated that there were three distinct serotypes of poliovirus; viremia was identified in early poliovirus infection (establishing the pathogenesis, which had previously been thought not to involve bloodstream invasion); and experiments showed that specific serum antibodies to poliovirus were protective in monkeys. Armed with these findings, Salk and Sabin raced ahead along divergent pathways to develop vaccines that would be safe and effective in humans. Salk chose to pursue an approach similar to the one he had taken with influenzavirus. Sabin, in contrast, was convinced by the efficacy of vaccinia and yellow fever vaccines that attenuated live viruses were more likely to prove immunogenic and protective; he therefore began a quest for attenuated variants of the three poliovirus serotypes. Each man adhered to his approach of using either killed or live vaccine throughout the remainder of a long and distinguished career.
The race might have gone differently if it had not been for a third figure, Daniel Basil O'Connor, friend and former law partner of the nation's best-known poliomyelitis victim, President Franklin D. Roosevelt. In 1938, at Roosevelt's favorite rehabilitation retreat at Warm Springs, Georgia, the two men had founded the National Foundation for Infantile Paralysis with O'Connor as its director. Both Salk and Sabin received generous research funding from the foundation, but O'Connor decided that Salk's vaccine was likely to be available sooner and became a catalyst to accelerate its development. When Salk's vaccine was ready for a major field trial, having been studied extensively in small groups of children, O'Connor recruited Thomas Francis to organize and direct it. The results of this remarkable trial, in which more than 1.8 million schoolchildren participated, were announced with great fanfare on April 12, 1955 (the 10th anniversary of the death of Franklin D. Roosevelt), in a press conference that became a media spectacle.
Overnight, Salk's name was spread across newspapers and heard in radio and television announcements throughout the country — and indeed throughout the world. Salk became an instant hero, since the results of the trial demonstrated rates of protection of approximately 80 percent with three doses of vaccine. Licensure followed immediately, and soon (despite the "Cutter Incident," in which incompletely inactivated vaccine caused approximately 260 cases of paralytic disease) more than 4 million children had received inactivated poliovirus vaccine (IPV, or Salk vaccine).
The widespread acceptance of the Salk vaccine made it very difficult for Sabin to conduct large trials of his own vaccine in the United States. He therefore chose the unusual strategy of collaborating with Soviet investigators to immunize millions of children in Eastern Europe with his live attenuated oral poliovirus vaccine (OPV). After several years, Yale University's Dorothy Horstmann was sent with a group from the World Health Organization (WHO) to review the results of these studies, and she returned with a favorable report. By then, the use of IPV had markedly reduced the rate of poliomyelitis in the United States — by more than 90 percent in the five years of its increasingly widespread use. Nevertheless, some evidence that the type 3 component of the vaccine was less than optimal, coupled with the attractiveness of oral administration and other attributes of OPV (lower cost, intestinal mucosal immunity, "free" spread to unimmunized contacts, ability to be administered by nonmedical personnel) attracted the support of many medical groups, and in 1961, OPV was licensed in the United States. During the next several years, it displaced IPV, becoming the primary polio vaccine in the United States.
With increasing use, surveillance revealed that rarely (perhaps once per 790,000 first doses), vaccine-induced paralytic disease (vaccine-associated paralytic poliomyelitis) developed in recipients of OPV. After 1979, the only cases of paralytic poliomyelitis in the United States (six to eight cases annually) were of the vaccine-induced type. To his dying day, Sabin would not concede that these cases were caused by "his" vaccine, even after the genetic characterization of the poliovirus isolated from such patients proved that neurovirulent revertants of Sabin-vaccine strains were responsible for their illness.
Salk, for his part, never relinquished his contention that inactivated vaccine was sufficiently immunogenic and enduring in its effect to provide lifelong protection after initial vaccination. Indeed, in 1999, after the United States had been free of "wild" poliovirus for 20 years while vaccine-associated poliomyelitis persisted, U.S. policy was redirected to an all-IPV strategy. Many Western European nations had adhered to the use of IPV since it first became available in the late 1950s. The WHO, however, has continued to use OPV since the beginning of its global eradication program in 1988.
Despite their similarities, the two scientists were treated quite differently by their scientific colleagues and by the public at large. Salk, a warm, confident, quiet man, was a public hero, acclaimed throughout the world and honored with a Congressional Gold Medal, a special citation from President Dwight D. Eisenhower, the French Legion of Honor, and a Presidential Medal of Freedom from President Jimmy Carter. Salk remained a household name; one commentator spoke of the three best-known doctors of the baby-boomer era: Drs. Salk, Spock, and Seuss. Surveys of the U.S. public revealed his to be among the top three or four names best known to Americans. The Salk Institute in La Jolla, California (a science palace designed by Louis Kahn), was constructed and dedicated in his honor.
Salk's colleagues in the world of science, however, never afforded him the recognition and awards that accrued to Sabin, who was lauded by fellow scientists, elected to the National Academy of Sciences, and embraced by virologists and vaccinologists worldwide — though he was known to be bombastic, sometimes caustic, and intolerant of those who did not share his views. Many attributed the professional discrimination against Salk to the flamboyant backing of O'Connor and the resultant media frenzies, which were offensive to "pure scientists." But in the end, both men should be remembered — by scientists and the public alike — for their valued contributions to the elimination of poliomyelitis, whose global eradication may possibly be imminent.
Source Information
From the Duke University Medical Center, Durham, N.C.(Samuel L. Katz, M.D.)