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What is the history of Polio vaccine use in America?
Early vaccine development
The first use of a poliovirus vaccine in the United States occurred in 1934, prior to the discovery that there were three poliovirus types, type 1, 2, and 3. This unlicensed experimental vaccine contained a poliovirus obtained from the nerve tissue of an infected monkey which was then ground up and mixed with formalin, a formaldehyde agent, in an attempt to inactivate the poliovirus without impairing its ability to stimulate antibody production.
William Park and Maurice Brodie, the two researchers responsible for the experimental poliovirus vaccine, published their findings in the Journal of the American Medical Association (JAMA) in 1935 and after vaccinating a dozen children, reported that their vaccine appeared to be safe.
Following publication of their findings, health officials experiencing polio outbreaks requested that this vaccine be tested on a larger number of individuals. While some officials involved in the vaccine trials reported the experimental poliovirus vaccine to be effective at preventing polio, others blamed cases of polio on the vaccine itself. The vaccine trials were poorly run, and no accurate information could be gathered to determine the vaccine’s effectiveness.
At the same time as Park and Brodie were conducting clinical trials on their inactivated poliovirus vaccine, John A. Kolmer, a pathologist from Philadelphia began testing his live virus vaccine. This experimental vaccine was reportedly weakened with chemicals that included two highly toxic mercury containing compounds -mercurophen and merthiolate. After testing the live virus vaccine on a few monkeys, Kolmer vaccinated himself, his 2 sons, and 23 additional children before expanding its use to include over 10,000 individuals. Nine people who received his vaccine died and dozens were paralyzed.
In the late 1940s, research aimed at determining how many poliovirus types were circulating in the environment began. By 1949, a team led by Dr. David Bodian reported that at least 3 distinct poliovirus types existed but researchers continued to study polio strains by collecting samples of throat cultures, stool, and even nerve tissue, from persons who developed or died of polio. Between 1949 and 1951, more than $1.2 million dollars was spent on poliovirus typing, with most of the money used to purchase and transport monkeys for experimental purposes.
Poliovirus researchers used monkeys for polio research, and during the typing experiments, stool samples from persons who had developed polio were injected into the brains of monkeys. These monkeys were monitored for symptoms of polio and when these occurred, they were killed so that their poliovirus-infected spinal cords and brain tissues could be collected. Over 17,000 monkeys were killed between 1949 and 1951 but no additional poliovirus types were isolated.
Researchers had already concluded that the poliovirus could be grown in the nervous tissue of monkeys but were aware that they could not use this tissue to develop a vaccine because monkey nervous tissue was known to cause an inflammation of the spinal cord and brain (encephalomyelitis) in humans. In 1949, however, a team of researchers from the Children’s Hospital of Boston led by microbiologist Dr. John Enders, discovered that the poliovirus could also be grown in kidney, skin, and muscle tissue and in a test tube, instead of in the spinal cord or brain of a monkey.
Once it was determined that only three poliovirus types existed, and that cultures could be grown in a test tube in other tissues besides monkey nervous tissues, work on a killed virus vaccine began.
At this time, however, research on a live attenuated poliovirus vaccine was already underway, led by Dr. Hilary Koprowski, a scientist with Lederle pharmaceuticals. In 1950, Koprowski tested his vaccine on institutionalized children residing at New York’s Letchworth Village without permission from New York state officials. Koprowski reported that children involved in the secretive trial developed antibodies against type 2 poliovirus without experiencing paralysis. His experiment was, however, criticized by fellow researchers who questioned the ethics of experimenting on institutionalized children.
Salk’s Inactivated poliovirus vaccine
By 1950, University of Pittsburgh poliovirus researcher Dr. Jonas Salk had begun working on a killed poliovirus vaccine derived from monkey kidney cells seeded with live poliovirus. Researchers working with Salk had found monkey kidneys to be ideal for developing cell cultures and that one monkey kidney could produce several thousand poliovirus vaccine doses.
The killed poliovirus vaccine would contain all 3 poliovirus types selected from strains isolated in the samples submitted to laboratories from poliovirus patients. Salk selected type 1 from the Mahoney strain, isolated in 1941 and responsible for over 80 percent of all cases of paralytic polio; type 2 from the Middle East Forces strain, isolated from the spinal tissue of a British soldier who died from polio in Egypt in 1943; and type 3 from the Saukett strain, isolated by Salk himself, from the stool of a child with polio.
The selected strains were then inactivated by a process that used formaldehyde in a 250:1 ratio at a temperature of one degree Celsius. This process was required to be perfect to ensure that the poliovirus could produce an immune response but be incapable of causing paralytic polio.
Early testing of Salk’s killed poliovirus vaccine began in 1952 at two different institutions in Pennsylvania – the D.T. Watson Home for Crippled Children and the Polk School for the Retarded and Feeble-Minded. The Watson Home, a stately facility for persons recovering from paralytic polio, was considered one of the best rehabilitation centers, and patients administered Salk’s experimental vaccine were considered at low risk due to previous exposure to polio. With this experiment, Salk tested each patient to determine what poliovirus type had likely caused the paralysis and then injected them with an experimental vaccine containing only that particular strain. This experiment was done to see whether his vaccine could raise antibody levels even higher than what was previously found and whether they would remain elevated for an extended period.
The Polk School, however, housed individuals with intellectual disabilities, and was considered a depressing institution that was poorly staffed and overcrowded. While some residents had measurable antibody to at least one type of poliovirus, others did not, and this put them at a high-risk for developing polio from an incorrectly inactivated experimental vaccine.
Salk continued to change his vaccine formulation during the vaccine trial process. Some formulations contained mineral oil while others did not. He tried a single type poliovirus vaccine on some residents and gave others a vaccine containing all 3 types. He even experimented with the process by which the poliovirus was inactivated. Salk reported that his killed vaccine was safe for human use and capable of producing an antibody response to all 3 poliovirus types that persisted for several months.
Coincidentally, the worst poliovirus year in history also occurred in 1952, with over 57,000 reported cases in the United States, and 3,000 deaths. Some attributed the rise in reported cases to improved public health reporting systems and more accurate physician diagnosis of polio while others believed the rise in population simply increased the number of potentially susceptible individuals. Some people even suggested that DDT and other poisonous chemicals in widespread use might be causing an increase in polio.
In March 1954, Salk appeared on the cover of Time magazine and an article accompanied his photo which reported on the success of the small vaccine trials. His findings had not yet been published in any medical journal and Salk reported that his vaccine would not be available for the public before the next polio season.
Preparations for a large-scale vaccine trial that would begin in the early part of the spring in 1954 began after the publicity Salk received in Time magazine. The Vaccine Advisory Committee, the committee charged with overseeing the trials, wanted a double-blind placebo study to ensure that the vaccine was indeed safe and effective. Salk, on the other hand, initially refused to agree to this condition, as he felt that he would not be able to live with himself if a child who received the placebo contracted polio and it could have been prevented by his vaccine. Salk eventually agreed to have a control group as part of the field trial after his former mentor, Thomas Francis, was selected to evaluate the trial’s results.
Connaught Laboratories in Toronto cultivated the live poliovirus for use in the vaccines and shipped them to Parke-Davis pharmaceuticals in Detroit for vaccine production. Vaccine manufacturing problems occurred immediately and were blamed on the complex process involved to ensure that the poliovirus was inactivated. Additionally, Salk was still refining his vaccine product even though it was supposed to be in the manufacturing stages for use in the vaccine field trials slated to begin in 1954.
By the fall of 1953, after several failed attempts by Parke-Davis to consistently duplicate Salk’s vaccine, additional pharmaceutical companies were approached to assist in vaccine development, including Cutter Laboratories, Eli Lilly, Wyeth, and Sharp and Dohme. Stricter quality controls were also established and would require each batch of poliovirus vaccine be triple-tested – by the pharmaceutical company, by Salk’s lab, and by the Public Health Service – to ensure that the vaccine was safe and effective for use.
Questions about the safety of Salk’s vaccine began to surface, by both the media and by other scientists. Oral poliovirus vaccine (OPV) developer, Dr. Albert Sabin, who was actively working on a rival vaccine, voiced concerns about the size of the study population, the poliovirus type 1 strain selected for use in the vaccine, and the speed at which the vaccine had gone from being an experiment in a laboratory, to one expected to be injected into hundreds of thousands of children. Further, the media was told that certain vaccine batches were found to contain live poliovirus.
Due to the negative publicity, an additional safeguard was initiated that would require the vaccine manufacturer to produce eleven consecutive vaccine lots free of live poliovirus prior to allowing the use of one lot by the public. Salk was also required to complete a smaller field test involving 5,000 children to ensure that the vaccine was safe prior to starting the mass vaccination trial.
Salk reported his smaller vaccine trial as successful and on April 26, 1954, the large-scale clinical trial began. Problems did occur during the clinical trial and included the administration of multiple doses to a single child, the reuse of needles between children, the loss of records, and even illness and death following vaccination.
The trial, which involved over 1.3 million children of whom over 600,000 received at least one dose of vaccine, ended in late spring of 1954. It took, however, nearly a year for the results to be evaluated and publicly presented. On April 12, 1955, at an official press conference scheduled specifically to discuss the outcomes of the field trial, Dr. Thomas Francis reported Salk’s vaccine to be between 60 and 70 percent effective at preventing paralytic polio. The 1954 vaccine was, however, reported to be ineffective at preventing non-paralytic polio.
Within 2 hours of the announcement, the U.S Department of Health, Education, and Welfare (HEW), a newly formed government agency which encompassed the Public Health Service, voted to approve the vaccine for use. Even though it was not yet known if Salk’s vaccine would be approved for use, preparations had already been made to ensure that the vaccine would be available immediately for commercial use. Six pharmaceutical companies had manufactured 9 million vaccines in advance and these vaccines became available for use by the American public right after approval.
Immediately following the vaccine’s approval, the safety provisions which required each vaccine lot to be triple-tested were no longer enforced, and vaccine manufacturers were the only ones screening their products. As a result, vaccine lots containing live poliovirus were not caught and within 2 weeks, the consequences would be apparent – when recently vaccinated children began developing polio.
Cases of paralytic polio following vaccination were reported in several states including California and Idaho. All cases occurred within 10 days of vaccination and paralysis frequently began in the limb where the injection had been administered – not in the lower limbs of the body as what was classically seen with paralytic polio. It was also discovered that most cases of paralysis had occurred in children vaccinated with a poliovirus vaccine manufactured by Cutter Laboratories.
Public health officials did not immediately halt the poliovirus vaccination program or even stop Cutter Laboratories from manufacturing or distributing the poliovirus vaccine. Instead, U.S. Surgeon General Leonard A. Scheele called Cutter Laboratories executives on April 27th and requested that they recall all their poliovirus vaccines. Publicly, Scheele stated that there was no correlation between paralytic polio and use of the vaccine, but few believed him. Polio had also occurred in persons vaccinated with vaccines manufactured by both Eli Lilly and Wyeth, though less frequently. Additionally, cases of polio were also reported among family members of children who were administered the polio vaccine, particularly those who received vaccines made by Cutter Laboratories.
The incidence of polio following vaccination continued to rise and by May 8, 1955, Scheele ordered that all poliovirus vaccination programs be halted until a review of the six poliovirus vaccine makers could be completed. Five days after Scheele halted use of all poliovirus vaccines, the vaccines manufactured by Parke-Davis and Eli Lilly were cleared for use. As questions remained about the safety of the vaccine, the demand for the vaccine was much less.
What was not known at the time of this incident was that National Institutes of Health (NIH) microbiologist, Dr. Bernice Eddy, had reported to her NIH supervisors that vaccines manufactured by Cutter Laboratories in 1954-1955 were causing paralysis in laboratory monkeys. NIH director, Dr. William Sebrell chose to ignore Eddy’s findings and her immediate supervisor called her “an alarmist”.
While lots of poliovirus vaccine manufactured during the 1954 field trials were required to undergo strict testing prior to use, vaccines made for commercial use were not and after the vaccine was licensed for use, Cutter Laboratories would not report problems and would simply discard vaccine lots found to be contaminated with the live poliovirus.
The poliovirus vaccine manufactured by Cutter was found to be responsible for 40,000 cases of polio – including 200 cases of severe polio and 10 deaths.
There were 18,308 cases of paralytic polio and 20,168 cases of non-paralytic polio in 1954. In 1955, the year that Salk’s vaccine received approval, this number had decreased to 13,850 paralytic cases and 15,135 non-paralytic cases. Incidentally, diagnosing criteria for polio also changed. In 1953, there were no set criteria or guidelines for the diagnosing of poliomyelitis. A scientific report published from a panel discussion held in 1960 by the Illinois State Medical Society noted that:
“Prior to 1954 any physician who reported paralytic poliomyelitis was doing his patient a service by way of subsidizing the cost of hospitalization and was being community-minded in reporting a communicable disease. The criterion of diagnosis at that time in most health departments followed the World Health Organization definition: “Spinal paralytic poliomyelitis: “Signs and symptoms of nonparalytic poliomyelitis with the addition of partial or complete paralysis of one or more muscle groups, detected on two examinations at least 24 hours apart.” Note that “two examinations at least 24 hours apart” was all that was required. Laboratory confirmation and presence of residual paralysis was not required. In 1955 the criteria were changed to conform more closely to the definition used in the 1954 field trials: residual paralysis was determined 10 to 20 days after onset of illness and again 50 to 70 days after onset. The influence of the field trials is still evident in most health departments; unless there is residual involvement at least 60 days after onset, a case of poliomyelitis is not considered paralytic”
This report also went on to state that:
“This change in definition meant that in 1955 we started reporting a new disease, namely, paralytic poliomyelitis with a longer lasting paralysis. Furthermore, diagnostic procedures have continued to be refined. Coxsackie virus infections and aseptic meningitis have been distinguished from paralytic poliomyelitis. Prior to 1954 large numbers of these cases undoubtedly were mislabeled as paralytic poliomyelitis. Thus, simply by changes in diagnostic criteria, the number of paralytic cases was predetermined to decrease in 1955-1957, whether or not any vaccine was used. At the same time, the number of nonparalytic cases was bound to increase because any case of poliomyelitis-like disease which could not be classified as paralytic poliomyelitis according to the new criteria was classified as nonparalytic poliomyelitis.”
While Salk’s vaccine is credited with decreasing the number of polio cases immediately following its 1955 approval, public health experts noted that polio, like other infectious diseases, have natural variability, and in 1955, rates of infectious hepatitis, an infection with no vaccine at the time, also declined at a similar rate as polio.
Additionally, prior to the introduction of the Salk vaccine, an epidemic of polio was considered 20 or more cases of polio per 100,000 population. After the Salk vaccine became available, a polio epidemic was defined as 35 cases per 100,000. This definition change artificially decreased the number of epidemics in the U.S. Further, there were few efforts made to differentiate between paralysis cause by the poliovirus or paralysis caused by other factors such as enteroviruses (ECHO and Coxsackie), transverse myelitis, Guillain-Barre Syndrome, DDT and arsenic toxicity, and more.
This is evidenced by a study published in 1960 which reported on a polio epidemic in Michigan that noted:
“During an epidemic of poliomyelitis in Michigan in 1958, virological and serologic studies were carried out with specimens from 1,060 patients. Fecal specimens from 869 patients yielded no virus in 401 cases, poliovirus in 292, ECHO (enteric cytopathogenic human orphan) virus in 100, Coxsackie virus in 73, and unidentified virus in 3 cases. Serums from 191 patients from whom no fecal specimens were obtainable showed no antibody changes in 123 cases but did show changes diagnostic for poliovirus in 48, ECHO viruses in 14, and Coxsackie virus in 6. In a large number of paralytic as well as nonparalytic patients poliovirus was not the cause. Frequency studies showed that there were no obvious clinical differences among infections with Coxsackie, ECHO, and poliomyelitis viruses. Coxsackie and ECHO viruses were responsible for more cases of "nonparalytic poliomyelitis" and "aseptic meningitis" than was poliovirus itself. This, added to the fact that two immunological types of the poliovirus were involved in the epidemic, suggests the difficulty to be anticipated in future programs of immunization.”
Between 1955 and 1957, cases of both paralytic and non-paralytic polio decreased, however, rates began to increase in 1958 and again in 1959. Public health officials quickly blamed the rise in polio rates on a lack of vaccination – yet by 1958, vaccination rates had significantly increased from those reported between 1955 and 1957. Further, polio was being reported in persons who had received one or more vaccine doses, including those who had received three and four doses.
By 1960, some poliovirus experts were even hypothesizing that the use of the Salk vaccine might actually put a person at a higher risk of paralytic polio, when a 1959 polio epidemic in Massachusetts reported that 47 percent of the cases that involved paralysis had occurred in persons who had received three or more vaccine doses. By 1961, over 47 percent of individuals who developed paralytic polio but recovered without residual paralysis and over 27 percent who had developed paralytic polio with residual paralysis had received 3 doses of the Salk vaccine.
Many doctors were opting to vaccinate infants and children with Salk’s poliovirus vaccine at the same time as the combination diphtheria, pertussis, and tetanus vaccine (DTP), a vaccine which had been in use since the 1940s. As a result, Parke-Davis pharmaceuticals developed Quadrigen, a combination vaccine containing DTP and Salk’s inactivated poliovirus vaccine. The vaccine was approved for use in 1959 but was removed from the market in 1968 after multiple lawsuits found that it caused severe injuries in children. Additional combination vaccines containing DTP and polio were also approved for use in 1959, but by 1968, all had been removed from the market.
By 1962, approximately 400 million doses of Salk’s IPV vaccine had been administered in the U.S., but public health officials estimated that most children had not received the four recommended vaccine doses. Polio in persons who had received 3 and 4 IPV doses were still occurring sporadically but public health officials reported that most cases occurred among under-vaccinated and unvaccinated individuals.
The first dose of IPV was recommended at 6 weeks to 3 months of age, with 2 more doses recommended at least 6 weeks apart. A fourth dose was also recommended, and this dose was supported to be administered at least 6 months after the third dose. The same schedule was also recommended for use in other age groups.
After 1963, and the approval of the live oral poliovirus vaccine (OPV), IPV usage decreased and in 1968, only 2.7 million IPV doses were distributed in the U.S. In 1969, the CDC published its first Advisory Committee on Immunization Practices (ACIP) recommendations and reported that IPV use had essentially been replaced by OPV due this vaccine’s ease of use, superior immune response, and lack of booster requirements.
Live Oral Poliovirus Vaccine Development
Salk was not the only poliovirus vaccine researcher in the 1950s. Dr. Albert Sabin, another researcher who had begun working on a live-virus polio vaccine by 1951, was still actively developing his product when Salk’s killed vaccine was approved for use in the U.S.
Sabin had always believed that a live-virus oral polio vaccine, attenuated enough to produce a mild infection but weak enough not to cause harm, was the only way to stop polio. Many scientists also considered this live-virus vaccine to be preferential because it could be administered orally and mimic the way that the poliovirus enters and replicates in the body. His vaccine would contain all 3 types of poliovirus strains and he attenuated the virus by passing each one through the tissue of monkeys. The first testing of his live-virus vaccine took place in 1954- 1955 among adult prisoners, and Sabin reported that all 30 prisoners who received his vaccine safely developed antibodies to all 3 types of polio. He was, however, aware that his live-virus vaccine could revert to being virulent and capable of causing polio.
This, in fact, was what had occurred when Lederle pharmaceutical researcher, Dr. Hilary Koprowski was permitted to begin testing his live-virus vaccine in Belfast, Northern Ireland. Early in the study, stool samples acquired post-vaccination of monkeys found poliovirus vaccine particles that had become problematic and even capable of producing paralysis. When this was discovered, the vaccine trial was halted.
Sabin was also aware that he would not be able to run a large-scale vaccine trial in the U.S. because this had already occurred. Polio cases, however, were increasing in the Soviet Union, and researchers from Russia were looking to the U.S. for information on the poliovirus vaccine. Russian scientists at the time were not convinced that Salk’s vaccine was all that effective, and production and administration of the vaccine was expensive. Further, at times, the final product was not always acceptable for use due to manufacturing issues.
Sabin was permitted to go to the Soviet Union to continue work on his vaccine and in 1959, millions of Russian children were vaccinated with Sabin’s live-virus vaccine. By the end of the year, Russia declared the vaccine effective and their health ministry announced that all persons under the age of 20 years would receive Sabin’s vaccine.
Sabin was not the only live-virus poliovirus vaccine researcher in the 1950s and early 60s. Koprowski, who had initially failed to develop a safe oral polio vaccine in Belfast, continued to expand on his earlier work. By this time, he was working for the Wistar Institute and had developed 2 separate vaccines – the CHAT-type1 oral polio vaccine and the W-Fox- type 3 oral polio vaccine. Koprowski’s vaccines were used to mass vaccinate children in the Belgian Congo, Poland and Croatia. Double-blind placebo-controlled studies of his experimental vaccine were not completed, and in most cases, government officials mandated the vaccine without even knowing whether it was safe or effective.
Additionally, a team of scientists from Lederle Pharmaceuticals led by Dr. Herald Cox, Koprowski’s former boss, tested another experimental oral polio vaccine on a small group of volunteers in Minnesota in 1958, before administering it to hundreds of thousands of individuals in South America.
In 1960, Sabin and Cox were granted permission to proceed with vaccine trials in the U.S. Sabin chose to test his oral polio vaccines near his home in Cincinnati, Ohio and administered his vaccine to nearly 200,000 people – even though most in the area had already received the Salk vaccine and polio was no longer an issue.
Cox chose to run his trial in Dade County, Florida, and administered his trivalent oral polio vaccine to over 400,000 individuals. The vaccine was reported as effective and even preferred over Sabin’s vaccine as it contained all 3 types of polio in a single dose; however, 6 cases of severe polio occurred within 7-14 days of vaccination. As a result, Cox’s vaccine failed to receive approval for licensing.
The U.S. Surgeon General approved Sabin’s poliovirus vaccine to be manufactured on a trial basis in August 1960. Four major pharmaceutical companies, including Cox’s employer, Lederle pharmaceutical, announced plans to manufacture Sabin’s vaccine.
Salk and Sabin were known rivals, with Sabin a frequent critic of Salk and his vaccine. Sabin was quick to discount the killed vaccine as ineffective and after the ‘Cutter Incident,’ he had called for the complete removal of the Salk vaccine from the market.
With both vaccines licensed for use, the controversy and competition became even more fierce. Also, doctors were not sure what vaccine would be best for their patients and were requesting to have information provided to them from a ‘neutral’ source. In 1961, the American Medical Association (AMA) entered the polio vaccine discussions and stated that their “Council on Drugs” would evaluate the situation and issue a report.
The chair of the AMA’s Council on Drugs, however, was the former medical director of Pfizer pharmaceuticals, one of the four drug companies involved in the manufacturing of Sabin’s oral poliovirus vaccine. In July 1961, the AMA officially recommended that Sabin’s vaccine be used instead of Salk’s killed vaccine, even though Sabin’s vaccine had not yet been officially licensed.
Sabin’s type 1 oral poliovirus vaccine received approval for use within a month of the AMA’s decision and his type 2 and type 3 vaccines would receive licensing within a year. In the U.S., Sabin’s oral polio vaccine would replace Salk’s killed vaccine; however, Salk’s vaccine would still be used globally, in countries such as the Netherlands, and Sweden.
Sabin’s monovalent type 1 OPV was first licensed in August of 1961 and two months later, his type 2 OPV received approval. By the spring of 1962, Sabin’s type 3 had received approval and Subcommittee One of the Advisory Committee on Poliomyelitis Control recommended that in infants, each of the three types of OPV be administered sequentially, beginning with type 1 OPV between 6 weeks and 3 months of age. Type 3 OPV was recommended 6 weeks later, followed by type 2 OPV after another 6 weeks. A fourth dose of a trivalent OPV was recommended 6 months or more after administration of the type 2 OPV. This schedule was similar for other age groups except that a fourth OPV dose was not recommended.
Reports of paralysis after administration of Sabin’s vaccine, like Cox’s vaccine, were also being reported, but public health officials did not express concern. By December of 1962, the Special Advisory Committee on Oral Poliomyelitis to the Surgeon General of the Public Health Service announced that communities should move forward with vaccination plans using all three types of OPV, with a special focus on vaccine administration in children and young adults. OPV associated paralysis was noted in the report but in nearly all cases, public health officials stated that most cases were inconclusive and the risk of acquiring polio from the vaccine was small.
In 1962, Wistar Institute researcher Leonard Hayflick announced that he had developed an alternative to monkey kidney cells for use in the production of the poliovirus vaccine. Hayfield had developed a cell substrate from human diploid lung fibroblasts – WI-38- taken from the lung cells of a 12-week-old female fetus. This cell line was reportedly free of viruses and Hayfield believed it to be a safer option to monkey kidney cells with their known simian viruses- such as the recently discovered Simian Virus 40 (SV40), which was found capable of causing cancer in small animals.
Federal health regulatory agencies, however, were not convinced that this cell line would be safe and declined to make any changes to polio vaccine production. Their rationale was that while this cell line appeared safe and free of adventitious ingredients, they did not feel there was enough evidence that could prove that it would remain so.
Hayfield chose to distribute vials of his cell substrate to laboratories in Europe and even the Soviet Union. The first poliovirus vaccine produced using WI-38 was approved for use in Yugoslavia in 1967, and approvals followed in the Soviet Union, Great Britain, and France. It took until 1972 for the U.S. to approve Diplovax; however, issues with supply of the vaccine limited its use, and by 1976, it was no longer available in the U.S.
In 1969, the CDC published its first Advisory Committee on Immunization Practices (ACIP) recommendations, and at this time OPV was considered the preferred vaccine, due to the ease of use, superior immune response, and lack of booster requirements.
The use of OPV was again considered the preferred vaccine in both 1982 and 1987, when the CDC’s ACIP committees updated their recommendations for the use of poliovirus vaccines. Persons with immunodeficiencies or with conditions which altered their immune response such as those with cancer or those undergoing corticosteroid treatments were, however, recommended to receive IPV due to the potential risk of vaccine-induced paralysis.
Wild-type polio was declared eradicated in the U.S. in 1979; however, between 1980 and 1998, there were 152 cases of paralytic polio in the U.S. One hundred and forty-four of these cases were confirmed as vaccine acquired paralytic polio (VAPP), 6 were imported, and 2 cases were unknown.
VAPP was associated with the use of OPV nearly immediately following the vaccine’s introduction. When OPV was in use in the U.S., VAPP was estimated to occur at a rate of one case per 2.4 million doses, or one case per 750,000 doses, if OPV was administered as the first dose. At the June 1996 ACIP meeting, committee members voted to increase the use of IPV and to gradually decrease OPV usage over the next 3-5 years because of the risk of VAPP.
On June 17, 1999, the CDC’s Advisory Committee on Immunization Practices (ACIP) voted to stop the use of OPV in the U.S., by January of 2000. OPV, however, remains in use in certain countries, and continues to be the preferred vaccine for use in global campaigns aimed at eradicating polio.
Current Poliovirus Vaccines and Recommendations in the United States
In 2000, two IPV products were licensed for use in the U.S. – Poliovax and IPOL. These two vaccines remain licensed for use in the U.S; however, Poliovax, which contains all 3 poliovirus types grown on MRC-5 human diploid cells, has been discontinued by the manufacturer. At this time, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended that all children receive 4 doses of IPV at 2, 4, 6-18 months, and 4-6 years.
IPOL is an inactivated poliovirus vaccine containing all 3 poliovirus types grown on monkey kidney cells (Vero cells), a cell line derived from African green monkey kidneys in the 1960s. Additional ingredients include calf bovine serum albumin, 2-phenoxyethanol, formaldehyde, polymyxin B, neomycin, and streptomycin. This vaccine was licensed for use in the U.S. without any clinical trials that involved a placebo-control group, and safety studies were limited to monitoring children for only 3 days post- administration.
On December 13, 2002, the FDA approved Pediarix, a combination vaccine containing diphtheria, tetanus, acellular pertussis (DTaP), hepatitis B (Hep B), and poliovirus vaccine (IPV) manufactured by GlaxoSmithKline. The poliovirus vaccine in Pediarix contains the same quantity and strains of poliovirus type 1, 2, and 3 found in IPOL. Following approval, ACIP recommended the vaccine for use but noted that its use caused higher fever rates when compared to rates of those who received the vaccine doses separately. Additionally, when administered as recommended at 2, 4, and 6 months, an infant who received the birth dose of Hep B vaccine would be given an extra fourth Hep B dose. This, however, was declared acceptable by ACIP.
In June 2008, Pentacel, a combination vaccine manufactured by Sanofi Pasteur containing DTaP, Haemophilus Influenzae Type B (HIB), and IPV, received FDA approval for use in infants and toddlers. When administered as recommended at 2, 4, 6, and 15-18 months, an additional IPV dose would be given, because all children are recommended to receive another IPV dose between 4-6 years of age per CDC’s guidelines. Again, this extra fifth IPV dose was declared acceptable by ACIP.
Also, in June 2008, the FDA approved Kinrix, a combination vaccine manufactured by GlaxoSmithKline containing DTaP and IPV. This vaccine was approved for use in children aged 4 through 6 years as a fifth booster dose of DTaP and a fourth booster dose of IPV who had previously received either INFANRIX DTaP and/or Pediarix combination vaccine containing DTaP, Hep B, and IPV. ACIP quickly recommended this vaccine for use and stated that it could be used in children whose previous vaccine type was not known even though safety and immunogenicity data of interchanging DTaP vaccine brands was not known.
On March 24, 2015, the FDA approved Quadracel, a combination vaccine containing DTaP and IPV. This vaccine, manufactured by Sanofi Pasteur, was approved for use in children 4 through 6 years of age who had previously received DAPTACEL DTaP vaccine and/or Pentacel combination vaccine containing DTaP, HIB, and IPV. Quadracel was also recommended for use by ACIP and again, the committee stated that even though data on safety and immunogenicity of interchanging vaccine brands was limited, the vaccine could be used when the DTaP brand type previously used was not known.
On December 21, 2018, the FDA approved VAXELIS, a combination 6 in 1 vaccine containing DTaP, HIB, Hep B, and IPV as a 3-dose series for use in children 6 weeks through 4 years of age. This vaccine, manufactured through a joint partnership between Sanofi Pasteur and Merck (MCM Vaccine Company), is not expected to be available for use until 2021; however, ACIP has already voted to recommend the vaccine as an option for use through its Vaccines For Children (VFC) program, to be administered at 2, 4, and 6 months of age. The use of VAXELIS in children who receive the recommended birth dose of Hep B vaccine will result in an extra fourth Hep B dose.
SV40 and Poliovirus vaccine
All early poliovirus vaccines were made using monkey kidneys, and primarily from the kidneys of rhesus monkeys. Kidneys from monkeys, like those of humans, filter contaminates from the body and therefore contain waste products that include bacteria, viruses, toxins and more. Early poliovirus researchers were aware that rhesus monkeys, even those who were seemingly healthy, were reservoirs for novel viruses. Monkey kidneys, however, were readily available at the time due to the widespread use of monkeys in poliovirus research. Once removed from the body, the monkey would be killed, and the kidneys would be chopped up and placed into bottles containing a nutrient. This was the process by which the tissue cultures used in poliovirus vaccine development began.
Researchers, however, quickly realized that these unknown viruses found in monkey kidneys could cause damage and death to the tissue cultures. The first monkey virus (simian virus), SV1, was isolated in February 1954 by researcher Robert Hull of Eli Lilly after the virus had caused the destruction of 17 percent of the company’s tissue cultures.
Hull began to catalogue each newly discovered simian virus, but few concerns were expressed about the possible presence of these viruses in the poliovirus vaccine. It was believed that the formaldehyde used to inactivate the poliovirus would also kill any other viruses that might be present. When Salk’s vaccine was licensed for use in April of 1955, researchers did not express any concerns about the possibility that the vaccine might also contain simian viruses or other contaminants.
By 1959, National Institutes of Health (NIH) microbiologist, Dr. Bernice Eddy, who had previously reported her concerns regarding the Cutter poliovirus vaccine, was researching the hypothesis that viruses might be capable of causing cancer. In 1959, Eddy and fellow researcher Sarah Stewart discovered that a mouse virus could cause cancer in other small mammals.
Through her previous work at NIH on vaccine safety testing, Eddy had been forced to discard hundreds of tissue cultures due to viral contamination. With her recent discovery that viruses could cause cancer in other species, the idea that a simian virus (SV) might be capable of causing cancer was now of interest to her. Without support from her superiors, Eddy began testing her theory by injecting newborn hamsters with ground up and filtered rhesus monkey cell cultures and compared them with a control group who were injected with human and feline tumor extracts.
Hamsters who received the cat and human tumor extracts did not develop any issues; however, 70 percent of hamsters who received rhesus monkey kidney cell cultures developed tumors and eventually died from cancer. Most hamsters developed tumors later in their lives, which suggested that these tumors might have a long latency period.
In July of 1960, Eddy presented her findings to her boss, Joe Smadel, who was now in charge of vaccine safety testing within the Division of Biologic Standards (DBS), a new agency formed following the Cutter Incident. Smadel dismissed Eddy’s findings and would not support any efforts to have her research published or publicized. Eddy, however, was not the only scientist looking at monkey kidney cell cultures.
By 1960, Merck, headed by vaccine researcher Maurice Hilleman, was working on an inactivated poliovirus vaccine that would be more effective than Salk’s vaccine formulation. Prior to the vaccine’s approval, however, fellow researcher Ben Sweet discovered that during the testing phase of a rhesus kidney cell derived adenovirus vaccine, the cells would balloon in size and fill with holes. During his investigation, Sweet realized that while the tissue cultures were being cultivated in rhesus monkey kidneys, they were being tested on African green monkey kidney tissue cultures – a completely different species.
This simian virus, now referred to as simian virus 40 (SV40), was almost impossible to locate in its natural host – the rhesus monkey – but once transplanted into tissue cultures from another species and grown out, problems were visible. Sweet tested all his adenovirus stock and discovered that it was completely contaminated with this new virus. Sweet, at the request of Hilleman, tested the polio seed stock from samples of Sabin’s experimental OPV vaccine, and found that it was also contaminated.
In June 1960, Hilleman announced his findings and reported that this virus was nearly always present in the rhesus monkey kidney cells, frequently found in kidney cultures from the cynomolgus monkey, but rarely seen in African green monkeys. Scientists who heard about Hilleman’s findings either expressed concerns or else dismissed the findings as inconsequential. Some stated that since Sabin’s vaccine had been administered to millions of individuals in the Soviet Union without evidence of harm, the presence of this virus was not concerning. Others, however, voiced concerns of the potential harmful effects that might not yet be known.
Publicly, Hilleman began recommending that African green monkeys be used in vaccine development while privately expressing to Sabin his concerns over the long-term health implications that this virus might have in persons who had received Sabin’s OPV. Hilleman had reportedly developed an antiserum against this virus and told Sabin that if he treated his seed stock with this antiserum, the virus would be rendered harmless and safe for use in vaccine production.
When Eddy heard about Sweet and Hilleman’s findings she suspected that this was the same virus that she had isolated several months earlier. Eddy repeated her studies and after completing a yearlong series of tests, she was able to prove that the cancer-causing virus that she had discovered was in fact SV40 – the same virus isolated by Sweet and Hilleman. Despite multiple attempts by Eddy to request that the DBS act to ensure that all vaccines were free of SV40, no initiatives were implemented.
The concern over SV40 was initially limited to the oral poliovirus vaccine which was soon to be licensed for use in the U.S. It was widely believed that the formaldehyde used in the inactivation process of the Salk vaccine would neutralize SV40 and render it safe from contaminants. But by the spring of 1961, this theory would be challenged when researchers from Britain reported that SV40 was resistant to formaldehyde and that persons who had received the Salk vaccine had been found to have antibodies to SV40.
The Public Health Service’s Technical Committee on Poliomyelitis Vaccine, a committee appointed by the U.S. Surgeon General in 1955 after the Cutter Incident, was asked to weigh in on these findings. In 1961, the committee consisted of eight scientists, and included Salk and five members with close personal ties to the Salk vaccine. In May 1961, this committee reported that while evidence supported that many poliovirus vaccine lots contained SV40, there was no proof that exposure to the virus was harmful. They did, however, decide that going forward, all new Salk vaccines would need to be free of SV40 but that no recall of potentially contaminated vaccines was necessary.
Yet within the month, Merck scientists had proof that SV40 could cause cancer in laboratory animals. On June 20th, 1961, Hilleman presented his findings to the same committee and recommended that all inactivated poliovirus vaccines be taken off the market until changes could be made to ensure that the vaccines did not contain SV40. Once again, the committee chose not to act, and did not express any concern over the SV40 findings.
On June 30, 1961, the DBS went ahead and notified all poliovirus vaccine manufacturers that beginning on August 1, 1961, they would be required to show test results to confirm that each poliovirus vaccine lot was free of live SV40 contaminants. SV40, however, could still be present if it was inactivated. It would be another two years before stricter requirements involving SV40 would be required of manufacturers. Again, no recall was issued and contaminated vaccine lots remained in use until 1963.
For many years, the common belief was that the techniques used to inactivate SV40 in the manufacturing process of the oral polio vaccine were enough to ensure that this contaminant was not present in the final product. In recent years, however, evidence has been presented to show that SV40 was in the OPV until the 1990s. Health officials have only acknowledged that between 1955 and 1963, nearly 100 million Americans who received IPV may have also been exposed to SV40.
By 1998, published medical research had noted the presence of SV40 in brain, bone, bladder and lung cancers. Further, 45 percent of sperm from healthy men were also found to contain SV40. Researchers concluded that “multiple SV40 strains can infect humans” and that SV40 infection may be spread by “blood transfusion and sexual transmission in the human population.” In 2002, the Institute of Medicine (IOM) concluded that “the biological evidence is strong that SV40 is a transforming virus” and that “the biological evidence is of moderate strength that SV40 exposure could lead to cancer in humans under natural conditions”. It also concluded that "the evidence is inadequate to accept or reject a causal relationship between SV40-containing polio vaccines and cancer."
Between 1997 and 2005, efforts were made to deny any association between SV40 and the development of human cancer.
On January 27-28, 1997, the National Institutes of Health (NIH) hosted a Workshop on Simian Virus-40 (SV40): A Possible Human Polyomavirus in Bethesda, Maryland. This gathering, which included government scientists from the FDA, CDC, NIH, NIP and NVPO, as well as independent non-government scientist working in labs globally, was scheduled to allow for an open discussion on SV40 and its possible connection to cancer. Several independent scientists presented data which linked SV40 to cancer, but they were dismissed by government scientists who reported that they were unable to find any association and that their data did not support an increased risk of cancer in persons who may have received SV40 contaminated poliovirus vaccines.
In September 2003, the Subcommittee on Human Rights and Wellness of the U.S. House Government Reform Committee met to discuss SV40 and its link to the rising rates of cancer. While U.S public health officials acknowledged that live SV40 did contaminate both inactivated and live polio vaccines between 1955 and 1963, they continued to deny that the monkey virus infecting humans was causing human cancers.
The 2002 IOM committee recommended that additional research be completed to determine whether a causal relationship exists between SV40 and cancer but have not published any further reports on this subject.
Simian Immunodeficiency Virus, Human Immunodeficiency Virus and Poliovirus Vaccines
In the 1980’s, after acquired immune deficiency syndrome (AIDS) emerged and was associated with the human immunodeficiency virus (HIV), the live oral polio vaccine (OPV) was associated with another monkey virus contamination scandal as a search for the origins of HIV began. Beginning in the early 1990s, several hypotheses were published in the mainstream media and medical literature. Some authors provided evidence that experimental live oral polio vaccines tested on children in central Africa in the late 1950’s and early 1960’s had been produced using monkey cells from chimpanzees or African green monkeys infected with simian immunodeficiency virus (SIV). They alleged that the HIV-1 virus currently circulating among humans is a hybrid monkey-human virus that was created when there was a cross-species transmission of SIV from non-human African primates to humans in Africa via SIV-contaminated oral polio vaccines.
By 2009, the origins of HIV-1 group M, the most prevalent form circulating in humans, was traced to a monkey virus (SIV), residing in chimpanzees in central Africa. While most scientists and vaccine manufacturers involved in the research and development of live polio vaccines and government health officials defending the use of OPV continue to deny that SIV contaminated oral polio vaccines were involved in the creation of HIV-1, those who disagree maintain that there is good evidence to the contrary.
Global Vaccine Use
A live-virus oral poliovirus vaccine (OPV) containing type 1 and type 3 poliovirus continues to be used by most health officials in campaigns aimed at eradicating polio. Wild poliovirus type 2 was declared eradicated in 2015 and health officials moved quickly to remove this strain from the OPV because it was known to cause cases and outbreaks of circulating vaccine-derived poliovirus (cVDPV2).
Health experts believed that the removal of type 2 poliovirus from the OPV would eventually stop cVDPV2 outbreaks, and that in instances where an outbreak was occurring, a monovalent OPV type 2 (mOPV2) vaccine could be used to halt the spread of cVDPV2. While circulation of cVDPV2 appeared to stop in many countries after an mOPV2 vaccine was used, the opposite occurred in Africa.
In Africa, use of mOPV2 caused an increase in the number of cases of cVDPV2 and health officials were forced to admit that its use caused more cases of polio than likely would have occurred if they had not used the vaccine.
Global health officials hope that the two new mOPV2 vaccines currently under development will receive quick approval for use in countries experiencing cVDPV2 outbreaks. Both mOPV2 vaccines are in the early stages of development and made through genetic engineering and vaccine researchers believe that these novel vaccines will lower the risk of cVDPV2.
Public health officials acknowledge that polio will not be eradicated until OPV is no longer in use; however, experts are not certain whether the exclusive use of IPV will be able to maintain eradication status. Concerns include the vaccine’s inability to fully halt poliovirus transmission, and the fact that some individuals can shed the poliovirus for years.
IMPORTANT NOTE: NVIC encourages you to become fully informed about Polio and the Polio vaccine by reading all sections in the Table of Contents, which contain many links and resources such as the manufacturer product information inserts, and to speak with one or more trusted health care professionals before making a vaccination decision for yourself or your child. This information is for educational purposes only and is not intended as medical advice.