By Elizabeth Ohneck, PhD
April 26th marked the 60th anniversary of the initiation of the Salk inactivated poliovirus vaccine trial. This trial serves as a standard for today’s clinical trials and resulted in the licensing of a broadly effective vaccine against polio. The trial was not without its controversies, reminding us that debate over vaccination is nothing new. However, circumstances and attitudes of the time allowed the trial to achieve a level of success and public support that would likely be impossible in today’s climate, and makes this trial stand out from any other vaccine trials, both before and since.
Poliomyelitis is an acute viral disease that primarily affects young children. Poliovirus attacks the central nervous system, resulting in partial or full paralysis and possibly death. Survivors often suffered from paralysis into adulthood. In the early 1900s, polio was considered a “warm weather disease,” with severe outbreaks occurring in the summer. President Franklin D. Roosevelt, who suffered from polio as an adult, founded the National Foundation for Infantile Paralysis (NFIP), later known as March of Dimes, in 1938 as an organization of scientists and volunteers to assist victims through recovery and fund development of a vaccine against polio.
Much of the scientific community at the time believed a vaccine containing a live but attenuated version of poliovirus was the only feasible option. Attempts to develop vaccines with poliovirus that had been chemically killed by formalin had actually led to cases of vaccine-associated polio in earlier studies due to incomplete killing of the virus. Jonas Salk, a researcher at the University of Pittsburg, however, believed the killed virus to be safer than a live virus and devoted much time and effort to understanding and improving the formalin inactivation process. Supported by the NFIP, Salk developed an inactivated virus vaccine that proved successful and safe in animal models and small human trials. The next step was to demonstrate the efficacy of the vaccine in a large-scale field trial, a project the NFIP eagerly undertook.
The design of the trial was a battle of ethics, logistics, and statistics. Salk and leaders at the NFIP supported an observed control study, in which second graders who volunteered would be vaccinated, and the frequency of polio compared to the frequency in first and third graders, who would not receive an injection, but simply be observed for occurrence of polio. This observed control design would require fewer resources and less manpower than an injected placebo. More importantly, this design avoided any ethical issues regarding an invasive action with no possible benefit to the recipient. Salk and others felt parents would be more likely to volunteer their children if they were guaranteed that the injection at least had the potential to protect their children from polio.
To avoid potential bias, Thomas Francis, Jr., a well-respected epidemiologist and virologist from the University of Michigan, was brought on as an impartial party to serve as director of the trial. Francis’ participation, however, was dependent on the use of saline placebo controls in the study. He and other critics of the observed control design argued that without placebo controls, true blinding is impossible – everyone would know which children received the vaccine, potentially biasing analysis of the results. In addition, the vaccinated and unvaccinated groups under the observed control design would not be directly comparable to each other. The test group would consist of all children in the second grade willing to participate. It would be impossible to know, however, which of the observed first and third graders would have participated if given the option. It was previously documented that participants were more likely to come from families having greater education and income. Prior epidemiological data indicated that children with lower socioeconomic status were more likely to be resistant to polio due to increased likelihood of previous asymptomatic infection. The mix of children from these differing socioeconomic conditions in the observed control group would result in an incidence of polio artificially low compared to what the incidence would be in an unvaccinated sample of the test group. The use of placebo controls would limit study observations to willing participants only, allowing direct comparison of polio frequency, and would allow a double-blind format, limiting bias of the results.
Health departments in several states had already signed on for the trial under the observed control design and were in agreement with Salk over unnecessary saline injections of children. Other state health departments, however, refused to participate unless a placebo control design was used. In the end, it was decided to carry out both studies, with 11 states participating in the placebo control trial, and an additional 33 states carrying out the observed control design. The first injection was given on April 26, 1954, and vaccinations continued through June; data collection continued well into the fall.
On April 12, 1955, not even one full year after the initiation of the trial, Thomas Francis announced the results in front of a large group of eager journalists and scientists. According to the data from the placebo control study, the inactivated virus vaccine was 70% effective in preventing poliomyelitis. While the observed control study data pointed in a similar direction, the estimate of efficiency was only 62.5%, likely due to the differences between the vaccinated and observed groups described above. Regardless, the overall positive results were celebrated, and Salk’s vaccine was licensed the same day.
The Salk vaccine trial solidified the double-blind, placebo control design as the standard of clinical field trails. But was anything gained from the observed control experiments? It could be argued that despite the lower calculated efficiency, the observed control portion of the trial did provide supporting evidence that the inactivated vaccine was effective in reducing the incidence of polio. Critics will argue, however, that because the control group was not directly comparable to the test group, this data is statistically irrelevant. Inarguably, the observed control trial provided further information on safety of the vaccine, expanding the population available to monitor for reactions and side effects. As we know from debates over vaccination occurring today, safety is a primary concern, and a larger trial size can highlight the infrequency of complications, affirming vaccine safety. Finally, the increased participation in the trial due to the observed control study made the trial a national event. The inclusion of both study types made the trial appealing to health departments in a total of 44 states, resulting in broad public awareness, high rates of participation, and successful vaccination of a large number of children.
Would such a trial be possible in today’s scientific and social climate? The Salk polio vaccine trial was unique in that it was funded and organized by a voluntary organization rather than a government agency or the pharmaceutical industry. The trial was paid for through small donations, and carried out by parents, school administrators, and heath professionals who volunteered for the effort. To raise sufficient funds through private donations and recruit enough volunteers for a large-scale field trial today seems nearly impossible when the necessity and safety of vaccination is a hotly contested issue, and technology and media make it just as easy to encourage movements against such projects as to rally support. In addition, the point of contact with children participants was schools; because children regularly attended school, appointments could be easily kept, ensuring a high rate of trial completion. Today, privacy and other legal issues would prohibit such an approach. Finally, public anxiety over polio outbreaks was high, leading to enthusiastic support for any preventative measure. In modern times, fear of side effects can be nearly as strong as fear of the disease itself, spurring the debate over whether vaccinations are “worth” the risks. Has this shift in concern occurred because complications have become more frequent or more severe? Or simply because these infrequent events are more easily publicized? Are we less fearful of life-threatening communicable diseases because successful vaccination programs and advances in medical care have lead to reduced prevalence, so we no longer remember the severe symptoms and consequences of these diseases?
The Salk polio vaccine trial left a large legacy. It advanced vaccine research by improving the method and understanding of formalin inactivation. The internal comparison of the dual study designs allowed validation of the double-blind, placebo control model as the standard for clinical trials. In addition, the trial serves as a useful academic model in the teaching of controls, experimental design, and statistical analysis methods. The success of the trial bolstered public support of medical research. Most importantly, the introduction and widespread use of the Salk vaccine lead to a dramatic decrease in polio cases, from an average of over 45,000 cases per year in the U.S. in the two years leading up to the trial to just over 900 cases per year by 1962. Yet no clinical trial has since come close to reaching the level of support, participation, and success. How does this reflect on today’s society? Is there any disease for which the potential of a vaccine would stir within us the desire and enthusiasm to contribute our time, our money, and ourselves to the effort of vaccine development?