May 30th, 2016 Buenos Aires, Argentina – Activa CRO, a…
The polio vaccine: Fast is good, isn’t it?
The polio vaccine field trials of 1954, sponsored by the National Foundation for Infantile Paralysis (March of Dimes), are among the largest and most publicized clinical trials ever undertaken.
Across the United States, 623 972 schoolchildren were injected with vaccine or placebo, and more than a million others participated as “observed” controls. The results, announced in 1955, showed good statistical evidence that Jonas Salk’s “killed- virus” preparation was 80-90% effective in preventing paralytic poliomyelitis.
The Salk inactivated poliovirus vaccine is one of the most rapid examples of bench-to-bedside translation in medicine. The key basic laboratory discoveries facilitating the development of the vaccine were made in the span of only 6 years, with optimization and safety testing completed in both animals and human volunteers during that timeline.
Such example of rapid translation can not only offer clues as to what factors can successfully drive and accelerate the translational process, but also what mistakes can occur (and thus should be avoided).
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.
Development of poliovirus vaccine
Several discoveries in the laboratory laid the foundation for the development of the first polio vaccine
- 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.
- 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.
- 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. This discovery won the trio the Noble Prize in Physiology or Medicine in 1954.
- Finally in 1953, Hammon showed that anti-polio 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 anti-polio antibody response should be protective against paralytic polio since passive immunization had proven effective.
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.
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.
Polio vaccine trial of 1954
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, 2ndgraders 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 diagnostic suspicion bias since it was known that the second graders were the inoculated group and this information could potentially influence the classification of equivocal cases of paralytic polio by 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.
The trails ended with a positive result, thus opening the door for mass vaccination in the US, and shortly the rest of the world followed
Lessons from the Salk polio vaccine: Factors for rapid translation and its dangers
As discussed above, between the Polio vaccine was in mass production and available to the public in a record six years from bench to bedside, including the largest clinical trial ever conducted.
Given the fact that medical discoveries take 15 to 17 years on average to get to the general population, the Salk polio vaccine is an example of amazingly fast translation.
However the process was not without drawbacks. in April 1955, soon after mass polio vaccination began in the United States, reports trickled in to the Surgeon General concerning 250 cases of “atypical” paralytic polio.
Patients presented with paralysis in the arm or leg in which they received the injection. These cases occurred in some polio vaccines lots produced by Cutter and Wyeth pharmaceutical companies, that carried insufficiently inactivated virus .
These incidents demonstrated the lack of oversight and safeguards put into place before the vaccine was made so widely available.
In response, the NIH 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.
Notwithstanding, 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, it showed a way that was soon to follow by regulatory authorities, with fast Track programs that would enable break throughs in science to reach as fast as possible to the ailing population, but allowing for risks to be minimized.
Dr Salk received mahy distinctions throughout his lifetime, including the prestigious US Presidential Medal of Freedom from President Jimmy Carter . He was never awarded the Nobel Prize, although he was presented as a candidate by many academic institutions……And the story of science continues……
This Article was written by Dr. Daniel Bernasconi, M.D