When was the polio vaccine born?

When was the polio vaccine born?

When was the polio vaccine born?

The first developments of the vaccine

The first use of a poliovirus vaccine in the United States occurred in 1934, before the discovery of the existence of three types of poliovirus, types 1, 2, and 3. This unauthorized experimental vaccine contained a poliovirus obtained from the nervous tissue of a infected monkey, which was then ground up and mixed with formalin, a formaldehyde agent, in an attempt to inactivate the poliovirus without compromising 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.(1)

Following the publication of the results, health officials facing polio epidemics called for the vaccine to be tested on larger numbers of individuals. While some officials involved in the vaccine trials reported that the experimental poliovirus vaccine was effective in preventing polio, others blamed the polio cases on the vaccine itself. The vaccine trials were inadequately conducted and it was not possible to gather accurate information to determine the vaccine's effectiveness.(2-3)

While Park and Brodie conducted clinical trials of their inactivated poliovirus vaccine, John A. Kolmer, a Philadelphia pathologist, began testing his live virus vaccine. This experimental vaccine had been weakened with chemicals that included two highly toxic mercury-containing compounds, mercurophene and merthiolate.(4) After testing the live virus vaccine on monkeys, Kolmer vaccinated himself, his two sons, and 23 other children, before expanding its use to more than 10.000 people. Nine people who received his vaccine died and dozens were paralyzed.(5-6)

In the late 40s, research began to determine how many types of poliovirus were circulating in the environment. In 1949 a team led by Dr. David Bodian reported that there were at least 3 distinct types of poliovirus, but researchers continued to study strains of polio by collecting culture samples of throat, stool, and even nerve tissue from people who had developed polio or they were dead.(7) Between 1949 and 1951, more than $1,2 million was spent on poliovirus typing, most of which was used to purchase and transport monkeys for experimental purposes.(8)

Poliovirus researchers used monkeys for polio research, and during typing experiments, stool samples from people who had developed polio were injected into the monkeys' brains. The monkeys were monitored for symptoms of polio and, when these appeared, they were killed to harvest their poliovirus-infected spinal cords and brain tissue. Between 1949 and 1951, more than 17.000 monkeys were killed, but no other types of poliovirus were isolated.(9)

The researchers had already concluded that the poliovirus could be grown in the nervous tissue of monkeys, but they knew they could not use it to develop a vaccine because the nervous tissue of monkeys was known to cause inflammation of the spinal cord and brain (encephalomyelitis). in humans.(10) In 1949, however, a group of researchers at Children's Hospital in Boston, led by microbiologist John Enders, discovered that the poliovirus could also be grown in kidney, skin, and muscle tissue and in a test tube, rather than in the spinal cord or brain of a monkey.(11-12)

Once it was established that there were only three types of poliovirus and that cultures could be grown in test tubes in tissues other than the nervous tissues of monkeys, work began on a killed-virus vaccine.

At that time, however, research was already underway on a live attenuated poliovirus vaccine, led by Dr. Hilary Koprowski, a scientist at Lederle pharmaceuticals. In 1950, Koprowski tested his vaccine on institutionalized children residing in New York's Letchworth Village without permission from New York State officials. Koprowski reported that the children involved in the secret trial developed antibodies against poliovirus type 2 without suffering paralysis. His experiment, however, was criticized by fellow researchers who questioned the ethics of experimenting on children locked up in institutions.(13)

Salk's inactivated poliovirus vaccine

In 1950, Dr. Jonas Salk, a poliovirus researcher at the University of Pittsburgh, had begun work on a killed poliovirus vaccine derived from monkey kidney cells seeded with live poliovirus. Researchers working with Salk had discovered that monkey kidneys were ideal for developing cell cultures and that one monkey kidney could produce several thousand doses of poliovirus vaccine.(14)

The killed poliovirus vaccine would contain all 3 types of poliovirus selected from strains isolated in samples sent to laboratories from poliovirus patients. Salk selected type 1 from the Mahoney strain, isolated in 1941 and responsible for more than 80% 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 of polio in Egypt in 1943; and type 3 from the Saukett strain, isolated by Salk himself, from the feces of a child with polio.(15-16)

The selected strains were then inactivated with a process that used formaldehyde in a 250:1 ratio at a temperature of one degree Celsius. This process had to be perfect to ensure that the poliovirus could produce an immune response but was incapable of causing paralytic polio.(17-18)

The first tests of Salk's vaccine against killed poliovirus began in 1952 at two different Pennsylvania institutions: the D.T. Watson Home for Crippled Children and the Polk School for the Retarded and Feeble-Minded.(19) The Watson Home, an impressive facility for people recovering from paralytic polio, it was considered one of the best rehabilitation centers, and patients who received Salk's experimental vaccine were considered low risk due to previous exposure to polio. With this experiment, Salk tested each patient to determine which type of poliovirus was likely to cause the paralysis and then injected them with an experimental vaccine containing only that particular strain. The experiment was done to see if its vaccine could increase antibody levels even further than previously found and whether these would remain elevated for a prolonged period.(20)

The Polk School, however, housed individuals with intellectual disabilities and was considered a depressing, understaffed, and overcrowded institution. While some residents had measurable antibodies to at least one type of poliovirus, others had none, putting them at high risk of developing polio due to an experimental vaccine that was not properly inactivated.(21)

Salk continued to change the vaccine formulation during the testing process. Some formulations contained mineral oil, others did not. He tested a vaccine against only one type of poliovirus on some residents, while on others he gave a vaccine containing all 3 types. He also experimented with the process of inactivating the poliovirus. Salk reported that his killed vaccine was safe for human use and capable of producing an antibody response to all 3 types of poliovirus that persisted for several months.(22-23)

Coincidentally, 1952 also occurred as the worst poliovirus year in history, with over 57.000 reported cases in the United States and 3.000 deaths.(24) Some attributed the increase in reported cases to improved public health reporting systems and a more accurate diagnosis of polio by doctors, while others believed that population growth had simply increased the number of potentially susceptible individuals. Some have even speculated that DDT and other poisonous chemicals in widespread use could be the cause of the rise in polio.(25)

In March 1954, Salk appeared on the cover of Time magazine, and his photo was accompanied by an article reporting the success of the small vaccine experiments. His results had not yet been published in any medical journal, and Salk reported that his vaccine would not be available to the public until the next polio season.(26)

Preparations for a large-scale trial of the vaccine, which would begin in the early spring of 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, however, initially refused to accept this condition, because he believed that he would not be able to live with himself if a child who received the placebo contracted polio, which could have been prevented by his vaccine. Salk finally agreed to have a control group as part of the field trial after his former mentor, Thomas Francis, was chosen to evaluate the trial's results.(27)

Connaught Laboratories in Toronto grew live poliovirus for use in vaccines and shipped it to Parke-Davis Pharmaceuticals in Detroit for vaccine production.(28) Vaccine production problems occurred immediately and were blamed on the complex process needed to ensure inactivation of the poliovirus. Furthermore, Salk was still perfecting his vaccine product, even though it was supposed to be in the production stage for use in the vaccine field trials that were supposed to begin in 1954.(29)

In the fall of 1953, after several failed attempts by Parke-Davis to duplicate Salk's vaccine, other pharmaceutical companies were contacted to assist in vaccine development, including Cutter Laboratories, Eli Lilly, Wyeth, and Sharp and Dohme. Stricter quality controls were also established, requiring each batch of poliovirus vaccine to be triple tested - by the pharmaceutical company, Salk's laboratory and the Public Health Service - to ensure that the vaccine was safe and effective for use.(30)

Doubts about the safety of Salk's vaccine began to emerge, both from the media and other scientists. The developer of the oral poliovirus (OPV) vaccine, Dr. Albert Sabin, who was actively working on a competing vaccine, expressed his concerns regarding the size of the study population, the type 1 poliovirus strain selected for use in the vaccine and the speed with which the vaccine had gone from being a laboratory experiment to being injected into hundreds of thousands of children. Additionally, the media was told that some batches of vaccine were found to contain live poliovirus.(31)

Due to the negative publicity, an additional safeguard was initiated that required the vaccine manufacturer to produce eleven consecutive batches of vaccine free of live poliovirus before allowing a batch to be used by the public. Salk was also required to complete a smaller field trial, involving 5.000 children, to ensure the vaccine's safety before beginning mass vaccination trials.

Salk reported that his smaller test was successful, and large-scale clinical trials began on April 26, 1954. Some problems occurred during the clinical trial, including multiple doses given to a single child, reuse of needles among children, loss of records, and even illnesses and deaths following vaccination.(32)

The trial, which involved over 1,3 million children, of whom over 600.000 received at least one dose of vaccine, concluded in late spring 1954. However, it took almost a year before the results were evaluated and presented publicly. On April 12, 1955, at an official press conference timed specifically to discuss the results of the field trial, Dr. Thomas Francis reported that Salk's vaccine was 60 to 70 percent effective in preventing paralytic polio. (33-34-35) The 1954 vaccine, however, was ineffective in preventing nonparalytic polio.(36)

Within two hours of the announcement, the U.S. Department of Health, Education, and Welfare (HEW), a newly formed government agency that included the Public Health Service, voted to approve the vaccine. While it was not yet known whether Salk's vaccine would be approved for use, preparations had already been made to ensure the vaccine would be immediately available for commercial use. Six pharmaceutical companies had pre-produced 9 million vaccines, which were made available for use by the American public soon after approval.(37)

Soon after the vaccine's approval, safety provisions requiring each batch of vaccine to be triple tested were no longer enforced, and vaccine manufacturers were the only ones to screen their products.(38-39) As a result , the vaccine batches containing live poliovirus were not recalled and within 2 weeks the consequences were evident: recently vaccinated children began to develop polio.(40-41)

Cases of paralytic polio following vaccination have been reported in several states, including California and Idaho. All cases occurred within 10 days of vaccination, and paralysis often began in the limb where the shot was given, not in the lower extremities of the body as classically seen in paralytic polio. It was also discovered that most cases of paralysis occurred in children vaccinated with a poliovirus vaccine produced by Cutter Laboratories.(42)

Public health officials did not immediately stop the poliovirus vaccination program or stop Cutter Laboratories from manufacturing or distributing the poliovirus vaccine. Instead, on April 27 of that year, U.S. Surgeon General Leonard A. Scheele called executives at Cutter Laboratories and asked them to recall all poliovirus vaccines. Scheele publicly declared that there was no correlation between paralytic polio and the use of the vaccine, but few believed him. Polio has also occurred in people vaccinated with vaccines produced by both Eli Lilly and Wyeth, although less frequently.(43) Additionally, cases of polio have also been reported among family members of children who received the vaccine polio, particularly those who had received vaccines produced by Cutter Laboratories.(44)

The incidence of polio following vaccination continued to increase, and on May 8, 1955, Scheele ordered all poliovirus vaccination programs suspended until a review of the six poliovirus vaccine manufacturers was completed. Five days after Scheele blocked the use of all poliovirus vaccines, vaccines produced by Parke-Davis and Eli Lilly were cleared for use. Since doubts remained about the safety of the vaccine, there was much less demand for the vaccine.(45)

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 produced 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 superior called her "an alarmist."(46)

While batches of poliovirus vaccine produced during the 1954 field experiments were required to undergo rigorous testing before use, vaccines produced for commercial use were not, and after the vaccine was authorized for use, the Cutter Laboratories did not report the problems and simply discarded vaccine batches that were found to be contaminated with live poliovirus.(47)

The poliovirus vaccine produced by Cutter was found responsible for 40.000 cases of polio, including 200 cases of severe polio and 10 deaths.(48) It was referred to as “The Cutter Incident”.

In 1954, there were 18.308 cases of paralytic polio and 20.168 cases of non-paralytic polio. By 1955, the year Salk's vaccine was approved, the number had dropped to 13.850 cases of paralytic polio and 15.135 cases of nonparalytic polio.(49) Incidentally, the diagnosis criteria for polio have also changed. In 1953, there were no established criteria or guidelines for diagnosing polio. A scientific report published by a roundtable held in 1960 by the Illinois State Medical Society noted that:(50)

“Before 1954, every doctor who reported paralytic polio was doing a service to his patient by subsidizing the cost of hospitalization and making a commitment to the community by reporting a communicable disease. At the time, the diagnostic criteria of most health departments followed the World Health Organization definition: “Paralytic Spinal Poliomyelitis”: “Signs and symptoms of non-paralytic poliomyelitis with the addition of partial or complete paralysis of one or multiple muscle groups, detected in two tests at least 24 hours apart". Note that “two tests at least 24 hours apart” was all that was required. Laboratory confirmation and the presence of residual paralysis were not required. In 1955 the criteria were modified 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 field trials is still evident in most health departments: unless there is residual involvement at least 60 days after onset, a case of polio is not considered paralytic.”

The report goes on to state that:(51) “This change in definition meant that a new disease began to be reported in 1955, namely paralytic polio with a longer-lasting paralysis. Additionally, diagnostic procedures continued to be refined. Coxsackie virus infections and aseptic meningitis are been distinguished from paralytic poliomyelitis Before 1954 a large number of these cases were undoubtedly mislabeled as paralytic poliomyelitis. Thus, simply due to changes in diagnostic criteria, the number of paralytic cases was expected to decline in 1955-1957, regardless of the number. 'use of the vaccine or not. At the same time, the number of non-paralytic cases was expected to increase because any case of polio-like disease that could not be classified as paralytic poliomyelitis according to the new criteria was classified as non-paralytic poliomyelitis.

Although the Salk vaccine is credited with decreasing the number of polio cases soon after its approval in 1955, public health experts have noted that polio, like other infectious diseases, has natural variability and that in 1955 rates of infectious hepatitis, an infection with no vaccine at the time, also declined at a rate similar to that of polio.(52)

Furthermore, before the introduction of the Salk vaccine, a polio epidemic was considered to be 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 population. This change in definition artificially decreased the number of epidemics in the United States. Furthermore, little effort has been made to differentiate paralysis caused by poliovirus from that caused by other factors, such as enteroviruses (ECHO and Coxsackie), transverse myelitis, Guillain-Barre syndrome, DDT and arsenic toxicity, and still others.(53-54)

This is demonstrated by a study published in 1960 that reported a polio epidemic in Michigan and noted:(55)

“During a polio epidemic in Michigan in 1958, virological and serological studies were conducted on samples from 1.060 patients. Fecal samples 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 viruses in 3 cases. Sera from 191 patients from whom fecal samples could not be obtained showed no antibody changes in 123 cases, but showed diagnostic changes for poliovirus in 48, ECHO virus. in 14 and Coxsackie virus in 6. In a large number of paralytic and nonparalytic patients poliovirus was not the cause. Frequency studies demonstrated that there were no obvious clinical differences between Coxsackie virus, ECHO, and poliomyelitis infections Coxsackie virus and ECHO have been responsible for more cases of "nonparalytic poliomyelitis" and "aseptic meningitis" than the poliovirus itself. This, combined with the fact that two immunological types of poliovirus were involved in the epidemic, suggests the difficulties to be foreseen in future immunization programs".

Between 1955 and 1957, cases of paralytic and nonparalytic polio declined, but rates began to increase in 1958 and again in 1959. Public health officials quickly attributed the rise in polio rates to the lack of vaccination, but by 1958 vaccination rates had increased significantly compared to those recorded between 1955 and 1957.(56-57) Additionally, polio was reported in people who had received one or more doses of the vaccine, including those who had received three and four doses.(58)

In 1960, some poliovirus experts even speculated that use of the Salk vaccine might actually put a person at greater risk of paralytic polio, when a 1959 polio epidemic in Massachusetts reported that 47% of paralysis cases had occurred. occurred in people who had received three or more doses of vaccine.(59) In 1961, more than 47% of individuals who developed paralytic polio but recovered without residual paralysis and more than 27% who developed paralytic polio with paralysis remaining had received 3 doses of Salk vaccine.(60)

Many doctors chose to vaccinate infants and children with Salk's polio vaccine at the same time as the combined diphtheria, tetanus, and pertussis (DTP) 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.(61) The vaccine was approved for use in 1959, but was removed from the market in 1968 after several lawsuits found it caused serious injuries in children.(62-63) Additional combination vaccines containing DTP and polio were also approved for use in 1959, but by 1968 they had all been removed from the market.(64)

After 1963 and the approval of the live oral poliovirus vaccine (OPV), the use of IPV declined, and by 1968, only 2,7 million doses of IPV were distributed in the United States.(65) In 1969, the CDC published the first recommendations of the Advisory Committee on Immunization Practices (ACIP) and reported that the use of IPV has essentially been replaced by OPV due to this vaccine's ease of use, response superior immunity and lack of booster requirements.(66)

Development of the live oral poliovirus vaccine

Salk was not the only poliovirus vaccine researcher in the 1951s. Dr. Albert Sabin, another researcher who had begun work on a live-virus polio vaccine in XNUMX, was still actively developing his product when Salk's killed vaccine was approved for use in the United States.(67)

Sabin had always believed that a live-virus oral polio vaccine, attenuated enough to produce a mild infection but weak enough to cause no harm, was the only way to stop polio. Many scientists considered this live virus vaccine preferable because it could be administered orally and mimic the way poliovirus enters and replicates in the body. His vaccine would contain all 3 types of poliovirus strains and attenuate the virus by passing each one through the tissues of monkeys. The first trial of his live virus vaccine took place in 1954-1955 among adult inmates, and Sabin reported that all 30 inmates who received his vaccine had safely developed antibodies against all 3 types of polio. However, he was aware that his live virus vaccine could become virulent again and capable of causing polio.(68)

That's what happened when Lederle pharmaceutical researcher Dr. Hilary Koprowski was allowed to begin testing her live virus vaccine in Belfast, Northern Ireland. Early in the study, stool samples acquired after vaccinating the monkeys found poliovirus vaccine particles that had become problematic and even capable of producing paralysis. Once this was discovered, the vaccine trial was stopped.(69)

Sabin was also aware that he would not be able to conduct a large-scale trial of the vaccine in the United States, because that had already occurred. Polio cases, however, were increasing in the Soviet Union, and Russian researchers looked to the United States for information on the poliovirus vaccine. Russian scientists at the time were not convinced that Salk's vaccine was that effective, and producing and administering the vaccine was expensive. Additionally, sometimes the final product was not always acceptable for use due to manufacturing issues.(70)

Sabin was allowed to travel 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. At the end of the year, Russia declared the vaccine effective, and the Ministry of Health announced that all people under the age of 20 would receive Sabin's vaccine.(71)

Sabin was not the only researcher of live poliovirus vaccines in the 50s and 60s. Koprowski, who had initially failed to develop a safe oral polio vaccine in Belfast, continued to expand on his earlier work. By then, he was working for the Wistar Institute and had developed two distinct vaccines: the CHAT1 oral polio vaccine and the W-Fox3 oral polio vaccine. Koprowski's vaccines were used to mass vaccinate children in the Belgian Congo,(72) of Poland(73-74) and Croatia.(75) Double-blind, placebo-controlled studies of its 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,(76) before administering it to hundreds of thousands of individuals in South America.(77)

In 1960, Sabin and Cox received permission to proceed with vaccine trials in the United States.(78) Sabin chose to test his oral polio vaccine near his home in Cincinnati, Ohio, and administered his vaccine to nearly 200.000 people, even though most of the area had already received Salk's vaccine and polio was not more of a problem.(79-80)

Cox chose to conduct the trial in Dade County, Florida, and administered his trivalent oral polio vaccine to more than 400.000 people. The vaccine was declared effective and even preferred to Sabin's, as it contained all 3 types of polio in a single dose; however, 6 cases of severe polio occurred within 7 to 14 days of vaccination. As a result, Cox's vaccine did not receive approval for licensing.(81-82)

In August 1960, the U.S. Surgeon General approved the experimental production of Sabin's poliovirus vaccine.(83) Four major pharmaceutical companies, including Lederle Pharmaceutical, Cox's employer, announced plans to produce Sabin's vaccine.

Salk and Sabin were known rivals, with Sabin often criticizing Salk and his vaccine. Sabin was quick to declare the killed vaccine ineffective and, after “The Cutter Incident,” called for the complete removal of Salk's vaccine from the market.

With both vaccines authorized for use, the controversy and competition became even more heated. Additionally, doctors were unsure which vaccine was best for their patients and asked to receive information from a "neutral" source. In 1961, the American Medical Association (AMA) entered the polio vaccine debate and declared that its "Council on Drugs" would evaluate the situation and issue a report.

The chairman of the AMA's Drug Council, however, was the former chief medical officer of Pfizer Pharmaceuticals, one of four pharmaceutical companies involved in the production of Sabin's oral polio vaccine. In July 1961, the AMA officially recommended the use of Sabin's vaccine in place of the killed Salk vaccine, even though Sabin's vaccine had not yet been officially licensed.(84)

Sabin's Type 1 oral polio vaccine received approval for use within a month of the AMA's decision, and its Types 2 and 3 vaccines would receive authorization within a year. In the United States, 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(85) and Sweden.(86)

Sabin's Type 1 monovalent OPV was first authorized in August 1961, and two months later the Type 2 OPV was approved. In the spring of 1962, Sabin's Type 3 was approved and Subcommittee One of the Polio Control Advisory Committee recommended that each of the three types of OPV be administered sequentially in infants, starting with type 1 OPV between 6 weeks and 3 months of age. OPV type 3 was recommended 6 weeks later, followed by OPV type 2 after another 6 weeks. A fourth dose of trivalent OPV was recommended 6 months or more after administration of type 2 OPV. This schedule was similar for other age groups, except that a fourth dose of OPV was not recommended.(87)

Cases of paralysis after administration of the Sabin vaccine, as well as the Cox vaccine, are also reported, but public health officials express no concern.(88-89-90) In December 1962, the Special Advisory Committee on Oral Polio to the Surgeon General of the Public Health Service announced that communities should proceed with vaccination plans using all three types of OPV, with particular attention to the administration of the vaccine in children and young adults. Paralysis associated with OPV was noted in the report, but in nearly all cases public health officials said the majority of cases were inconclusive and that the risk of contracting polio from the vaccine was minimal.(91)

In 1962, Wistar Institute researcher Leonard Hayflick announced that he had developed an alternative to monkey kidney cells for use in the production of poliovirus vaccine.(92) Hayfield had developed a cellular substrate from human diploid lung fibroblasts - the famous WI-38 - taken from the lung cells of a 12-week fetus.(93) This cell line was apparently virus-free, and Hayfield believed it to be a safer option than monkey kidney cells with their known simian viruses, such as the recently discovered Simian Virus 40 (SV40) capable of causing cancer in small animals.(94)

Federal health regulatory agencies, however, were not convinced of the safety of this cell line and refused to make any changes to the production of the polio vaccine. Their rationale was that although this cell line appeared safe and free of adventitious ingredients, they did not believe there was enough evidence to show that it would remain that way.

Hayfield chose to distribute vials of his cell substrate to laboratories in Europe and even the Soviet Union. The first poliovirus vaccine made with WI-38 was approved for use in Yugoslavia in 1967, and approvals followed in the Soviet Union, Great Britain and France. The United States had to wait until 1972 to approve Diplovax; however, supply problems with the vaccine limited its use, and by 1976 it was no longer available in the United States.(95)

In 1969, the CDC published the first recommendations of the Advisory Committee on Immunization Practices (ACIP), and at that time OPV was considered the vaccine of choice, due to its ease of use, superior immune response, and lack of requirements for the recall.(96)

The use of OPV was again considered the preferred vaccine in both 1982 and 1987, when the CDC's ACIP committees updated their recommendations on the use of poliovirus vaccines. However, people with immunodeficiencies or conditions that impair the immune response, such as cancer patients or those undergoing corticosteroid treatments, have been recommended to receive IPV due to the potential risk of vaccine-induced paralysis.(97 -98)

Wild-type polio was declared eradicated in the United States in 1979; however, between 1980 and 1998, 152 cases of paralytic polio occurred in the United States. One hundred and forty-four of these cases were confirmed as vaccine-acquired paralytic polio (VAPP), 6 were imported and 2 cases were unknown.(99)

VAPP was associated with the use of OPV almost immediately after the introduction of the vaccine. When OPV was in use in the United States, 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 given as the first dose. At the June 1996 ACIP meeting, committee members voted to increase the use of IPV and to gradually decrease the use of OPV over the next 3 to 5 years because of the risk of VAPP.(100)

On June 17, 1999, the CDC's Advisory Committee on Immunization Practices (ACIP) voted to discontinue the use of OPV in the United States by January 2000.(101) OPV, however, continues to be used in some countries and continues to be the vaccine of choice in global campaigns to eradicate polio.(102)

SV40 and Poliovirus vaccine

All of the first poliovirus vaccines were made using monkey kidneys, primarily rhesus monkey kidneys. Monkey kidneys, like those of humans, filter contaminants from the body and therefore contain waste products that include bacteria, viruses, toxins and more. Early poliovirus researchers were aware that rhesus monkeys, even apparently healthy ones, were reservoirs of new 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 was killed and the kidneys were chopped up and placed in bottles containing a nutrient. This was the process by which the tissue cultures used in the development of the poliovirus vaccine began.(103)

Researchers, however, quickly realized that these unknown viruses found in monkey kidneys could cause damage and death to tissue cultures. The first simian virus, SV1, was isolated in February 1954 by Eli Lilly researcher Robert Hull after the virus caused the destruction of 17% of the company's tissue cultures.(104-105)

Hull began cataloging every new simian virus discovered, but little concern was 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 may be present. When Salk's vaccine was cleared for use in April 1955, researchers expressed no concern that the vaccine might also contain simian viruses or other contaminants.(106)

In 1959, National Institutes of Health (NIH) microbiologist Dr. Bernice Eddy, who had previously reported her concerns about the Cutter polio vaccine, was investigating the hypothesis that viruses might be capable of causing cancer . In 1959, Eddy and colleague Sarah Stewart discovered that a mouse virus could cause cancer in other small mammals.(107-108)

In his previous work at the NIH on vaccine safety testing, Eddy had been forced to discard hundreds of tissue cultures due to viral contamination. With the 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 him. Without the support of his superiors, Eddy began testing his theory by injecting newborn hamsters with ground-up and filtered rhesus monkey cell cultures, comparing them to a control group that had been injected with extracts of human and feline tumors.(109-110)

The hamsters that received the cat and human tumor extracts did not develop any problems; however, 70% of hamsters that received cultures of rhesus monkey kidney cells developed tumors and ultimately died from cancer. Most hamsters developed tumors later in life, which suggested that these tumors may have a long latency period.(111)

In July 1960, Eddy presented his findings to his boss, Joe Smadel, who was now responsible for vaccine safety testing within the Division of Biologic Standards (DBS), a new agency formed following the Cutter incident. Smadel rejected Eddy's findings and would not support any efforts to have his research published or publicized. Eddy, however, was not the only scientist working on culturing monkey kidney cells.(112)

In 1960, Merck, led by vaccine researcher Maurice Hilleman, was working on an inactivated poliovirus vaccine that would be more effective than Salk's formulation. Before the vaccine was approved, however, fellow researcher Ben Sweet discovered that during the testing phase of an adenovirus vaccine derived from rhesus kidney cells, the cells swelled and filled with holes. During his investigations, Sweet realized that the tissue cultures, while grown in rhesus monkey kidneys, were being tested on tissue cultures from African green monkey kidney, an entirely different species.(113)

This simian virus, now called virus 40 (SV40), was almost impossible to detect in its natural host - the rhesus monkey - but once transplanted into tissue cultures of another species and grown, the problems were visible. Sweet analyzed all of his adenovirus supplies and found that they were completely contaminated with this new virus. Sweet, at Hilleman's request, analyzed polio supplies from samples of Sabin's experimental OPV vaccine and found that they were also contaminated.(114-115)

In June 1960, Hilleman announced his findings and reported that the virus was almost always present in the kidney cells of rhesus monkeys, frequently in kidney cultures of cynomolgus monkeys, but rarely in African green monkeys.(116-117) Scientists who learned of Hilleman's findings expressed concern or dismissed the findings as irrelevant. Some claimed that because Sabin's vaccine had been administered to millions of individuals in the Soviet Union with no evidence of harm, the presence of this virus was not of concern. Others, however, have expressed concern about potential harmful effects that may not yet be known.(118)

In public, Hilleman began recommending the use of African green monkeys in vaccine development, while in private he expressed to Sabin his concerns about the long-term health implications this virus might have in people who received OPV of Sabin. Hilleman allegedly developed an antiserum against this virus and told Sabin that if he treated his supplies with this antiserum, the virus would be rendered harmless and safe for use in vaccine production.(119) When Eddy learned of Sweet and Hilleman's findings, he suspected that it was the same virus he had isolated a few months earlier. Eddy repeated his studies and, after completing a series of tests, was able to demonstrate that the cancer-causing virus he had discovered was actually SV40, the same virus isolated by Sweet and Hilleman. Despite Eddy's multiple attempts to demand that the DBS take action to ensure that all vaccines were free of SV40, no action was implemented.(120)

Concern about SV40 was initially limited to the oral poliovirus vaccine, which would soon be authorized for use in the United States. It was widely believed that the formaldehyde used in the inactivation process of the Salk vaccine would neutralize SV40 and make it safe from contaminants. But in the spring of 1961 this theory would be called into question when British researchers reported that SV40 was resistant to formaldehyde and that people who had received the Salk vaccine were found to have antibodies against SV40.(121)

The Public Health Service Polio Vaccine Technical Committee, a committee appointed by the U.S. surgeon general in 1955 after the Cutter incident, was called upon to evaluate these findings. In 1961, the committee consisted of eight scientists, including Salk and five members with close personal ties to the Salk vaccine. In May 1961, the committee reported that although the evidence was in favor of many lots of poliovirus vaccine containing SV40, there was no evidence that exposure to the virus was harmful. However, it decided that in the future all new Salk vaccines should be free of SV40, but that there was no need to recall potentially contaminated vaccines.(122)

However, within a month, Merck scientists had proof that SV40 could cause cancer in laboratory animals. On June 20, 1961, Hilleman presented his findings to the same commission and recommended that all inactivated poliovirus vaccines be withdrawn from the market until modifications were made to ensure that the vaccines did not contain SV40. Once again, the commission chose not to act and expressed no concern about the SV40 findings.(123)

On 30 June 1961, DBS proceeded to notify all poliovirus vaccine manufacturers that from 1 August 1961 they would be required to submit test results to confirm that each batch of poliovirus vaccine was free of live SV40 contaminants . SV40, however, could still be present if inactivated. It will take another two years before stricter requirements are placed on manufacturers regarding SV40. Again, no recall was issued and the contaminated vaccine batches remained in use until 1963.(124)

For many years, the common belief was that the techniques used to inactivate SV40 in the oral polio vaccine manufacturing process were sufficient to ensure that this contaminant was not present in the final product. In recent years, however, evidence has been presented demonstrating the presence of SV40 in OPV as late as the 90s.(125-126-127) Health officials have only acknowledged that between 1955 and 1963, nearly 100 million Americans who received IPV may have been exposed to SV40.(128)

By 1998, published medical research had detected the presence of SV40 in brain, bone, bladder and lung tumors.(129-130-131-132-133-134-135-136) Additionally, 45% of sperm from healthy men were found to contain SV40. The researchers concluded that “multiple strains of SV40 can infect humans”(137) and that SV40 infection can be spread via “blood transfusion and sexual transmission in the human population.”(138) 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 exposure to SV40 could lead to cancer in humans in natural conditions". It also concluded that “the evidence is inadequate to accept or reject a causal relationship between SV40-containing polio vaccines and cancer.”(139)

Between 1997 and 2005, attempts were made to deny any association between SV40 and the development of human cancer.(140-141)

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 meeting, attended by government scientists from the FDA, CDC, NIH, NIP, and NVPO, as well as independent non-government scientists working in laboratories around the world, was scheduled to allow for an open discussion about SV40 and about its possible connection with cancer. Several independent scientists presented data linking SV40 to cancer, but were rejected by government scientists who reported that they failed to find any association and that their data did not support an increased cancer risk in people who may have received poliovirus vaccines contaminated with SV40.(142)

In September 2003, the Subcommittee on Human Rights and Welfare of the United States Committee on Government Reform met to discuss SV40 and its link to rising cancer rates. Although U.S. public health officials acknowledged that live SV40 contaminated both inactivated and live polio vaccines between 1955 and 1963, they continued to deny that the simian virus that infected humans caused human tumors .(143)

The 2002 IOM committee recommended that further research be completed to determine whether there is a causal relationship between SV40 and cancer, but has published no further reports on this topic.

The vaccine controversy and the origin of HIV: a critical look at history

In the 80s, with the emergence of acquired immunodeficiency syndrome (AIDS) and its association with the human immunodeficiency virus (HIV), the scientific and medical world was rocked by a contamination scandal linked to oral vaccines against poliomyelitis (OPV). Over the years, heated debate has surrounded the possibility that HIV may have originated from poliovirus vaccination practices.

Various research and publications, which emerged in the early 90s, highlighted a worrying connection between OPV vaccines and Simic Immunodeficiency Virus (SIV). It has been suggested that some experimental oral polio vaccines, tested on children in Central Africa in the late 50s and early 60s, were produced using cells from chimpanzees and African green monkeys infected with SIV. According to these theories, HIV-1, which afflicts humanity today, could be the result of a hybrid monkey-human virus, arising from interspecies transmission of SIV following vaccinations with SIV-contaminated OPVs.[-144 146]

These statements have led to a deep reflection on the safety procedures adopted during the production of vaccines and on the transparency of information shared with the public and the scientific community. Nonetheless, in 2009, more extensive studies localized the origin of HIV-1 group M, the most prevalent strain of HIV, to central African chimpanzees, specifically identifying the SIV virus as the direct ancestor.[147]

The scientific community remains divided. Many scientists and vaccine manufacturers, as well as government health officials, continue to deny that SIV-contaminated OPV vaccines played a role in the genesis of HIV-1. However, a non-negligible segment of the scientific community argues otherwise, arguing that there is compelling evidence linking the use of these contaminated vaccines to the emergence of HIV among humans.[148]

The challenges of global polio eradication and the role of vaccines

In the global health landscape, the fight against polio remains one of the most difficult and complex priorities. Even today, most health officials continue to use the live oral poliovirus vaccine (OPV), containing poliovirus types 1 and 3, in campaigns to eradicate the disease. Since 2015, wild poliovirus type 2 has been declared eradicated and, as a result, has been rapidly removed from OPV to prevent outbreaks of vaccine-derived poliovirus (cVDPV2).[149]

Health experts had hoped that eliminating type 2 OPV would stop cVDPV2 epidemics. In cases where an epidemic was underway, it was thought that a monovalent type 2 vaccine (mOPV2) would be effective in stopping the spread. While this strategy has worked in many countries, in Africa it has led to an increase in the number of cVDPV2 cases, contrary to initial expectations.[-150 151]

This increase in cases forced health officials to acknowledge that the use of mOPV2 caused more cases of polio than would have happened without the vaccine. This admission has pushed the scientific community to look for safer alternative solutions. Currently, two new mOPV2 vaccines, developed through genetic engineering, are in early development. Researchers hope that these new vaccines will significantly reduce the risk of cVDPV2, improving the safety of vaccination campaigns.[-152 153]

Despite these efforts, public health officials recognize that total polio eradication will not be achieved until OPV is in use. However, there are concerns regarding the exclusive use of inactivated polio vaccine (IPV), as it may not be sufficient to maintain eradication status. Among the concerns are the inability of IPV to completely stop poliovirus transmission and the risk that some individuals may continue to transmit the virus for years.[-154 155]

This article is summarized and translated by National Vaccine Information Center.

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