Lessons from the Salk Polio Vaccine: Methods for and Risks of Rapid Translation
Abstract
The Salk inactivated poliovirus vaccine is one of the most rapid examples of bench‐to‐bedside translation in medicine. In the span of 6 years, the key basic lab discoveries facilitating the development of the vaccine were made, optimization and safety testing was completed in both animals and human volunteers, the largest clinical trial in history of 1.8 million children was conducted, and the results were released to an eagerly awaiting public. Such examples of rapid translation cannot only offer clues to what factors can successfully drive and accelerate the translational process but also what mistakes can occur (and thus should be avoided) during such a swift process. In this commentary, we explore the translational path of the Salk polio vaccine from the key basic science discoveries to the 1954 Field Trials and delve into the scientific and sociopolitical factors that aided in its rapid development. Moreover, we look at the Cutter and Wyeth incidents after the vaccine’s approval and the errors that led to them. Clin Trans Sci 2010; Volume 3: 182–185
Overview of Poliovirus
Poliovirus is a small RNA virus that infects the host through ingestion. The ingested virus first infects oropharyngeal epithelial cells and small intestine enterocytes. From there, virions can directly enter the host blood stream and peripheral nerves to infect distal organs including anterior horn cells in the central nervous system. 1 While poliovirus infection causes a classic viral prodrome (fever and sore throat), 1–2% will develop the classic presentation of paralytic polio–flaccid asymmetric limb paralysis, high fever, and intense muscle pain. 1 During the acute stage of paralytic polio, the patient’s respiratory muscles may be temporarily paralyzed leading to respiratory arrest and death. If the patient survived this initial paralysis, the respiratory muscles usually recovered enough strength to return to independent ventilation. As with other affected muscle groups, incomplete recovery could still result in good residual function. In 1927, Drinker and Shaw at Harvard University developed the first iron lung to permit breathing during this initial period of paralysis, thus allowing the patient to at least survive this disease. 2 , 3
The first recorded US outbreak of paralytic polio was in Vermont in 1894 involving 132 cases ( Figure 1 ). 3 The first major US epidemic was in 1916 involving 27,000 cases and 6,000 deaths. From the 1930s through the 1950s, the annual number of cases of paralytic polio increased from 10,000 up to 30,000 with an epidemic in 1952 involving almost 60,000 cases. 4 , 5
Development of Poliovirus Vaccine
Several discoveries in the laboratory laid the foundation for the development of the first polio vaccine ( Figure 1 ). In 1908, Landsteiner and Popper demonstrated using porcelain size exclusion filters that polio paralysis was caused by something smaller than a bacterium. This study concluded that a virus must be responsible for polio and hence a vaccine should be the goal of future research. 6
In 1949, Bodian, Morgan, and Howe classified three different classes of poliovirus (Types I, II, and III) based on the immunologic responses of monkeys to 14 different polio strains. This finding indicated that any poliovirus vaccine would need to be trivalent (containing inactivated virus from each of these three distinct viral groups) in order to be maximally effective. 7
Also in 1949, Enders, Weller, and Robbins developed a method to culture poliovirus in media lacking neural tissue. Previous poliovirus culturing techniques required human embryonic brain tissue, which raised health concerns if such viral stocks would be used to create poliovirus vaccine. 8 This discovery won the trio the Noble Prize in Physiology or Medicine in 1954.
Finally in 1953, Hammon showed that antipolio immunoglobulin protected against paralytic polio in several epidemic areas in the United States. This randomized 13‐week study showed a 4‐fold decrease in the incidence of paralytic polio in immunoglobulin recipients compared to gelatin controls. Thus, generating an antipolio antibody response should be protective against paralytic polio since passive immunization had proven effective. 9
With this information in hand, Jonas Salk began working on a poliovirus vaccine at the University of Pittsburgh. Dr. Salk was recruited after working under Dr. Thomas Francis at NYU School of Medicine on the testing of an inactivated influenza vaccine. 10 Using Type I, II, and III poliovirus inactivated in a 1:250 concentration of formalin, Salk safely inactivated poliovirus for a vaccine without destroying its immunogenicity. 11 , 12
Polio Vaccine Trials
The first human pilot studies were conducted nearby in Alleghany County, Pennsylvania in the spring of 1953 and involved 15,000 people—mostly children. Using the generation of serum antibodies against the three types of poliovirus as an outcome, this pilot study optimized the vaccine vehicle, injection schedule, and inoculation dose. These studies demonstrated a 4‐ to 16‐fold increase in serum polio titers after vaccination and the additional benefits of booster injections. 11 , 13 , 14
The success of these pilot studies led to the immediate launching of the largest clinical trial in human history—the 1954 Field Trials. Designed by Salk’s mentor Dr. Francis, 1.8 million children in the United States, Canada, and Finland were recruited for this experiment. In fact, this trial was so large that the entire process required over 300,000 volunteers to carry out. 3 , 10
The trial design was unique in that two different clinical trials were conducted simultaneously based on the control groups used for each study region. In the observed control trial involving 1.08 million children, 2nd graders in a region were vaccinated (after obtaining consent) and observed while the 1st and 3rd graders were observed without any intervention whatsoever (no consent required). While this trial design was the original design of the trial oversight committee, this design did have several epidemiologic flaws. There was an inherent selection bias since one group needed consent while the control group did not (e.g., poorer parents were less likely to give consent; their children were also less likely to get paralytic polio). Moreover, there also could be a diagnostic suspicion bias since it was known that the 2nd graders were the inoculated group and this information could potentially influence the classification of equivocal cases of paralytic polio by the trial staff. Additionally, this design did not allow direct measurement of the actual effectiveness of the vaccine since any confounding placebo effect was not being considered. Accordingly, a placebo‐controlled trial was conducted at the same time in a smaller group of 750,000 children. Students from the 1st, 2nd, and 3rd grades in these regions were all consented for injection in this double‐blind study. Half of these consented students were given the polio vaccine and the other half received a placebo injection in an alternating fashion. Thus, this smaller trial was far more rigorous in design and less susceptible to the biases described above. 15 , 16 , 17 , 18
On April 12, 1955, the results of the 1954 Field Trials were released to the public at a national press conference at the University of Michigan. 10 The vaccine was shown to be virtually as safe as placebo. In areas of the United States where the trials were conducted, the incidence of paralytic polio dropped by nearly 20% compared to previous years while there was a little change in the incidence of paralytic polio in other parts of the country. The vaccine demonstrated a 72% effectiveness against paralytic polio in the placebo‐controlled trial. 15 , 16 , 17 , 18 Within days, five pharmaceutical companies mass produced the vaccine and vaccination clinics were quickly organized nationwide. 10 , 19
Lessons from the Salk Polio Vaccine: Factors for Rapid Translation and its Dangers
In summary, in 1949 the two key scientific discoveries were made that allowed for the development of Salk’s polio vaccine and by the summer of 1955 the vaccine was in mass production and available to the public. In this interval of 6 years, all safety testing and human studies were completed, including the largest clinical trial ever conducted ( Figure 1 ). Given the fact that medical discoveries take 17 years on average to go from bench‐to‐bedside, the Salk polio vaccine is an example of amazingly fast translation. 20 In this case, a couple of factors helped the Salk vaccine make the journey so quickly, however the process was not without drawbacks.
Previous work on influenza
One major factor that facilitated polio vaccine’s rapid translation was the techniques used to create and test the polio vaccine were largely the same techniques developed to create the inactivated influenza vaccine in the 1940s. During World War I, the Spanish Flu pandemic killed tens of millions of people worldwide and heavily affected US troops on the Western front in Europe. As a result, the US military became intensely interested in an influenza vaccine to protect and potentially give an advantage to US troops during wartime. In the development of an influenza vaccine, the observation that a family of virus strains causing the same disease could contain different immunologic types was first made (e.g., Influenza A and B) and the formalin‐inactivation process for viral vaccine production was developed and refined. As a result, much of the time‐consuming laboratory work to develop methods for vaccine production was already complete. Many of the lessons learned by Jonas Salk under the tutelage of Thomas Francis about testing of viral vaccines readily applied as well. 3
Sociopolitical factors
In the case of polio vaccine, massive sociopolitical forces drove nearly every aspect of the translational process. Unlike some other diseases, poliovirus did not seem influenced by gender, socioeconomic class, or sexual orientation. However, the virus disproportionately afflicted children more than older individuals. The images of large iron lung facilities housing those struggling to breathe and permanently paralyzed children in braces walking to and from school struck a national chord. Parents and communities were strongly motivated to fight this disease in any way possible. A major paralytic polio epidemic in 1952, just 2 years before the 1954 Field Trials, was also likely fresh in parents’ minds as they agreed to have their children participate in this national experiment. 4 , 5
Moreover, paralytic polio took the national stage in 1932 when Franklin D. Roosevelt was elected President of the United States. President Roosevelt developed paralytic polio in 1921 at the age of 39 and lived with its effects for the rest of his life. He became a national advocate for polio research including raising money for treatment and research at his annual birthday bashes. These efforts evolved into the National Foundation of Infantile Research (NFIP) in 1938. This foundation (later renamed the March of Dimes) became a national grassroots organization devoted to raising money to fund the care of polio victims and research for a cure. This foundation funded Dr. Salk’s recruitment to the University of Pittsburgh to begin his work on a polio vaccine and NFIP completely oversaw and funded the 1954 Field Trials. Thus, a national clinical trial was funded by the donations of a concerned nation—one dime at a time. The announcement of the success of the Salk vaccine at the University of Michigan was made on the 10th anniversary of President Roosevelt’s death to honor his advocacy. 10
Cutter and Wyeth incidents
Regretfully, the story of polio vaccine was not without tragedy. In April 1955, soon after mass polio vaccination began in the United States, reports trickled in to the Surgeon General concerning atypical cases of paralytic polio. Several paralytic polio cases were reported in California in patients who had received the polio vaccine about a week earlier but the paralysis only affected the arm or leg in which they received the injection. Each of these cases occurred in polio vaccine produced by Cutter pharmaceutical company. The Surgeon General immediately pulled all Cutter polio vaccine, but it was too late; nearly 400,000 children had been inoculated with Cutter polio vaccine and 250 cases of atypical paralytic polio occurred. There were also reports of the Wyeth pharmaceutical company polio vaccine causing paralysis and death in several children in the northeastern United States. 19 , 21
It was soon discovered that some lots of Cutter and Wyeth polio vaccine were insufficiently inactivated with formalin leading to live polio virus in more than 100,000 doses. In fact, 16 lots of Cutter polio vaccine were retested and the first six lots produced were positive for live polio virus. These incidents demonstrated the lack of oversight and safeguards put into place before the vaccine was made so widely available. 12 , 19 , 21
In response, the National Institutes of Health and Public Health Services developed minimal safety and potency standards for all polio vaccine in the United States and a Technical Committee on Poliomyelitis Vaccine was established in May 1955. This permanent committee tested and reviewed all polio vaccine lots and advised the Public Health Service as to which lots should be released for public use. Public trust in the new miracle polio vaccine was greatly shaken after these incidents and vaccination rates dropped nationwide. Many state health boards actually launched public relation campaigns to reassure the public and encourage polio vaccination once again. 12 , 21
Conclusions
The introduction of the Salk polio vaccine represents one of the most important events in translational science. While the process was not without serious consequence as a result of its rapid translation, Salk’s inactivated poliovirus vaccine progressed from bench‐to‐bedside to the community within 6 years. Much of the driving force behind the very rapid implementation was social—the widespread fear of paralytic polio and the impact that annual epidemics had on communities across the United States leading to the establishment of a national, publicly funded foundation to oversee and support development and testing of a vaccine. Moreover, the public opinion of vaccination was clearly one of hope. By the 1950s, vaccinations had led to widespread protection against serious and potentially fatal diseases like smallpox and influenza. At that time, vaccination was also the only weapon in the medical arsenal against viral diseases.
The culture surrounding vaccinations has significantly changed in the past half century. Vaccinations against a host of different diseases are considered standard medical practice in the United States. Currently, the Centers for Disease Control recommends all US children and adolescents be vaccinated against diseases caused by 15 bacterial and viral pathogens (Cornyebacterium diphtheriae, Bordetella pertussis, Clostridium tetani, poliovirus, rotavirus, Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis, hepatitis A and B viruses, measles, mumps, rubella and varicella zoster viruses, and influenza virus [annual]) in addition to human papillomavirus vaccine for all adolescent females. 22 Some of these diseases are rarely seen in the United States today (e.g., diphtheria), some are usually mild (e.g., rotavirus, varicella), and some have a lag time of many years between infection and disease (e.g., human papillomavirus). As a result, the benefits of many of these vaccines are less directly apparent than the immediate benefits of a poliovirus vaccine in the 1950s (e.g., human papillomavirus). In spite of this, it should be noted that these changes have not prevented the recent testing and widespread implementation of new vaccinations like those against Streptococcus pneumoniae and rotavirus in the United States. Thus, while the landscape around vaccines may have changed over the past half century, new vaccinations are still being developed, tested, and brought into routine clinical practice.
Acknowledgements
This work was supported in part by F30DK084671 from the National Institute of Diabetes and Digestive and Kidney Diseases and UL1RR024150 from the National Center of Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center of Research Resources, or the National Institutes of Health.
Notes
This Historical Perspectives in Translation Medicine commentary was developed as part of the Case Studies in Translation course taught at Mayo Graduate School, Mayo Clinic College of Medicine as part of the Clinical & Translational Sciences track. This course analyzes different medical discoveries from bench‐to‐bedside to highlight factors that accelerate or slow the translational process from the laboratory to the hospital to generalized community medical practice. The goal of the course is for students in the masters and Ph.D. program in Clinical & Translational Sciences to critically evaluate the translational process and generate options to accelerate this process without compromising scientific integrity, subject safety, or public trust.
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