On February 27, 1950, an eight year-old boy from Letchworth Village, New York, received a prototype of the oral polio vaccine Hilary Koprowski had developed using the live, weakened (attenuated) virus. The boy suffered no side effects and Koprowski enlarged his experiment to include 19 other children.
At the time Koprowski was a scientist at Lederle Laboratories, a fast-growing pharmaceutical company. Since 1948 he had been working on a viral attenuation process:
A spinal cord suspension infected with Brockman's virus was adapted through successive passages on the brains of Swiss albino mice (...). By the seventh passage, the vaccine was safe; it could be injected without harm to the monkey brains. The virus made for mice then underwent passages on rats. After one to three passages, the vaccine was ready.(1)
Later Koprowski realized that this strain, which he believed to be type 1, the most common type, was actually type 2. He renamed it TN. As he would write 45 years later, "We had taken the path that would lead us to polio eradication."
His results were excellent. The virus was found in the stools of everyone who received the vaccine, which indicated it had reproduced in their digestive systems and triggered the production of antibodies. When the immunized children received the vaccine a second time, they were not re-infected, evidence that they were protected. The findings were so spectacular that when Koprowski presented them to a meeting of the NFIP's Immunization Committee, the committee members greeted them with skepticism.
All of these events took place four years before the Francis Field Trial of the Salk vaccine, but the oral polio vaccine would not be ready for use until five years after the injectable vaccine reached the market. Strong teams were competing to make an oral polio vaccine, including one led by Albert Sabin of the Children's Hospital Research Foundation in Cincinnati and another led by Hilary Koprowski of the Wistar Institute in Philadelphia, which he joined in 1957. Obtaining attenuated viral strains was an arduous task, which Koprowski likened to Hercules cleaning the Augean stables. Koprowski wrote that while his chore was less difficult, it was much more time-consuming because the same process had to be repeated again and again.
In 1951, Koprowski tested a prototype of the vaccine containing attenuated strains of types 1 and 2 on a group of 61 children in Sonoma State Home, an institute for mentally retarded children. The type 1 strains had been attenuated by 27 passages inoculated intraspinally in mice. Later, cell cultures would be used for virus attenuation.(2)
Herald Cox, who first hired Koprowski at Lederle, had a falling-out with him in 1952 and became one of his rivals. According to Roger Vaughan, Lederle invested an estimated 13 million dollars on the development of a live attenuated polio vaccine.
Albert Sabin, who was also working on live attenuated strains, paid a visit to Koprowski's lab at Lederle. In the words of Koprowski, the purpose of Sabin's visit was "to bury the hatchet and exchange samples of viruses. So I sent him some of my samples. But I never received any of his samples from him."
Maurice Hilleman, a major figure in vaccine research in America and director of the Merck Institute for Therapeutic Research, explains tersely that Sabin, "a self-pronounced genius, went in and took over Cox's and Koprowski's ideas."(3) According to John Paul, Koprowski would later complain that the polio vaccine he had discovered became known as the Sabin vaccine.
Sabin wasted no time. In 1954 he wrote his first article about research on attenuated viruses. In 1956 he administered his vaccine to roughly 9,000 monkeys, 150 chimpanzees and 133 young adults in an Ohio prison. He enjoyed the support of Merck, Sharp and Dohme, which gave him some 25 million doses of each selected strain, something for which, according to Vaughan, the company never received credit.
During a meeting in Stockholm to discuss polio vaccines in November 1955, Sabin presented results obtained on a group of 80 volunteers, while Koprowski read a paper detailing the findings of a trial enrolling 150 people. Koprowski explained that in a group of children who had been immunized previously, "antibodies remained for three years following administration of a single dose."(4) He was farther along than Cox or Sabin.
The various live, attenuated vaccines encountered two obstacles, however. First, after Salk's injectable vaccine had been proven effective, many people wondered if efforts to develop another type of vaccine were justified. Sabin would later tell the story of how his friend Tom Rivers, scientific advisor to the National Foundation for Infantile Paralysis (NFIP), which had financed his research, advised him to dump his strains in the sewer and abandon the project. Secondly, many scientists and public health officials feared the attenuated virus would revert to neurovirulence and cause cases of polio. Their fears were not unfounded.
In 1956, George Dick, a microbiologist from Queens University in Belfast, who had worked on the attenuated yellow fever virus, suggested to Koprowski that they organize a field trial in Northern Ireland. The individuals who received the vaccine suffered no undesirable side effects, but virus in their stools produced paralysis in monkeys. Dick voiced a warning about the risk that "by avoiding ten cases of paralytic polio, we could later cause hundreds of cases of paralysis," and recommended that Koprowski's vaccine not be used on a large scale.(5) His recommendations made the headlines.
In July 1957, the World Health Organization called a meeting of its Expert Committee on Polio, attended by Sabin and other researchers, to take stock of research on a live attenuated vaccine. The committee noted that trials to date had not caused undesirable side effects and recommended organizing large-scale trials, but under "extremely well-controlled conditions." It defined six criteria attenuated viral strains had to meet to guarantee they would be safe. The criteria had to be verified by several independent laboratories.
Cox and Koprowski were so excited about the recommendation to organize large-scale field trials that they neglected the recommendation about the six criteria on attenuation, which would have prompted them to re-examine their strains. The work they had begun was already far along, so they continued it. Later some would note, with irony or bitterness, that Sabin did not run into any problems because his strains were in perfect compliance with the WHO criteria, which he had helped define.
From 1958 to 1960, Koprowski immunized 40,000 children in Germany and more than seven million in Poland with attenuated type 1 or type 3 strains, or both (or, to be precise: 7.239 million with type 1 and 6.818 with type 3).
During the same period of time, Cox conducted trials in Florida and Berlin, Germany, that led to a high rate of paralysis due to vaccine-derived strains reverting to virulence, which prompted Lederle Labs to abandon all research with the strains Cox had used. In Germany, the father of a vaccinated child became infected with the vaccine-derived virus and died of polio.
In 1957, Sabin obtained a trivalent vaccine, that is, one containing attenuated strains of all three types of poliovirus. Over the next three years, he provided strains that were used to make vaccines against a single viral type (type 2 was administered to 200,000 children in Singapore in 1958) or against all three types. In the Soviet Union, a vaccine produced using strains provided by Sabin was administered to 15.2 million people in 1959 and 77.5 million in 1960, while 23 million people were vaccinated in several Eastern European countries. This marked a decisive step.
The speed and scope of the USSR's vaccine production were not unrelated to the cold war. In the mid-1950s, Anastas Mikoyan, a member of the Communist Party's Politburo had thrown all his weight into organizing the fight against polio. The workers' and peasants' state could not appear do be doing less about the problem than the American capitalists.
Thomas Rivers tells the story of listening to a presentation by Professor Konstantine Vinokouroff of the Institute of Neurology of the Academy of Medical Sciences during the Second International Congress on Poliomyelitis, held in 1952 in Copenhagen:
I will never forget him. He was a queer little fellow with a beard down to his upper chest. His talk was just as queer because he kept insisting that all the pioneer work in polio had first been done in Russia. That didn't bother anybody, but what was annoying was that he gave no indication that he was ever going to stop talking.(6)
Participants at the Congress were hardly convinced by Vinokouroff's claims that the Soviet Union had seen nothing like the dramatic epidemics that had struck in Western countries.
Sabin complained when his vaccine was at times referred to in the West as the "communist vaccine," but under the circumstances the vaccine was a guaranteed success, as if one of Stalin's Five-Year Plans were to exceed all expectations. The results of mass immunizations were published after being approved by the Presidium of the Academy of Medical Sciences. The Soviet researchers were pleased to announce them:
In the Soviet Union there were no poliomyelitis cases on record which could be attributed to the immunization with live vaccine from the Sabin strains. (...) Specialists hold that under conditions of mass immunization there may be instances when vaccinations coincide with all kinds of symptoms produced by other affections. (...) The question of reactogenicity of the live vaccine appears to require some further detailed study, but it is not now of any great practical importance.(7)
More than 90 million people had been immunized; everyone was aware by then that the oral vaccine at times reverted to neurovirulence and caused cases of polio. In 1961, an exchange of letters between Sabin and Mikhail Chumakov, the leading scientist in charge of the Soviet program, bears witness to Sabin's irritation.
In 1968, Sabin once again had an opportunity to question his Soviet colleagues, when Boris Petrovsky, Minister of Health and member of the Russian Academy of Sciences and Academy of Medical Sciences, wrote in a history of public health in the URSS that two Soviet scientists, Mikhail Chumakov and Anatoli Smorodintsev, had developed the live attenuated polio vaccine. Sabin was furious; the President of the Academy of Medical Sciences explained to him that this was due to a mistake in the English translation of the book, which had been written in Russian.
Charles Mérieux, a leading French figure in the vaccine industry who followed developments concerning the polio vaccine very closely, was not entirely convinced. With his usual sense of wry observation, he wrote:
When we asked the Soviet scientists to provide details and data, their only reply was that they had vaccinated 100 million people, and there were fewer and fewer cases of polio. They thought this was all we needed to know.(8)
When Albert Sabin asked Charles Mérieux to manufacture his vaccine on an industrial scale, Mérieux declined because he considered the results of the Russian experiment to be inadequate (although the Mérieux Institute would later produce the oral vaccine). But the massive utilization of the Sabin vaccine in communist countries established the vaccine internationally.
In 1958, the National Institutes of Health created a special committee on live polio vaccines, in charge of testing the strains authorized for the oral vaccine. The Koprowski and Cox strains were eliminated, as were those of Yale University, while the Sabin strains were selected for the three viral types. They rapidly became the only strains to be used worldwide.
Sabin had multiplied the number of passages in monkey and in cell lines in order to improve the attenuation and stability of the viruses. The attenuated type 1 virus strain, for example, was derived from the Mahoney strain isolated in 1941. Salk made 16 monkey kidney and monkey testicular passages, and other researchers had made 15 or so more by 1953. Then in 1954 Sabin had the virus undergo another ten more passages followed by two further passes in 1956. Scientists at Merck, Sharp & Dohme performed one additional passage on rhesus monkey kidney tissue culture before producing the vaccine.
Research to develop more stable strains continued, in particular for the type 3 attenuated virus, which reverted to neurovirulence more often than the other two. In 1973-1974, a team of British scientists conducting research on monkeys observed that the type 3 strain used by Pfizer Laboratories, developed by virologist Robert Stones, presented less risk of reverting to a virulent strain than did the Sabin strain. In 1975, the Mérieux Institute, today Aventis Pasteur, acquired all of Pfizer's biological material, including this type 3 attenuated strain, and distributed it to all other vaccine manufacturers.
(1) Koprowski, Hilary. "Histoire alternative du vaccine oral," L'aventure de la vaccination, under the direction of Anne Marie Moulin. Paris, Fayard, 1996.
(2) Vaughan, Roger. Listen to the Music: The Life of Hilary Koprowski, Springer, New York, 2000. Page 51.
(3) Vaughan, pp. 51 -56.
(4) Mentioned by John Paul in A History of Poliomyelitis. NY and London: Yale University Press, 1971, p. 15.
(5) Mentioned by John Paul.
(6) Benison, Saul . Tom Rivers: Reflections on a Life in Medicine and Science. Cambridge: MIT Press, 1968. p. 152.
(7) Chumakov, M.P. et al. Some Results of the Work on Mass Immunization in the Soviet Union with Live Poliovirus Vaccine prepared from Sabin Strains. World Health Organization. 1961.
(8) Charles Mérieux, Virus Passion, Editions Robert Laffont, Paris, 1997.