Case study 4: The 1954 Salk Polio Vaccine Trials

Polio has practically been eradicated in the western world. In the first half of the twentieth century, however, it was a major public health problem. Over 500,000 cases of polio were reported between 1930 and 1950, and the actual number may have been con siderably higher.

Because polio attacks mostly children and because its effects can be so serious, eradication of the disease became a top public health priority in the United States. By the late 1940s it was known that polio is a virus and as such can best be treated by a vaccine which is itself made up of a virus. The vaccine virus can be a closely related virus that does not have the same harmful effects, or it can be the actual virus that produces the disease but which has been killed by a special treatment. The former is known as a live-virus vaccine, and the latter as a killed-virus vaccine. In response to either vaccine the body is known to produce antibodies which remain in the system and give the individual immunity against an attack by the real virus.

Both the live-virus and the killed-virus approaches have their advantages and disadvantages. The live-virus approach produces a stronger reaction and better immunity, but at the same time it is also more likely to cause a harmful reaction and in some cases even to produce the very disease it is supposed to prevent. The killed-virus approach is safer in terms of the likelihood of producing a harmful reaction, but it is also less effective in providing the desired level of immunity.

These facts are important because they help us understand the extraordinary amount of caution that went into the design of the experiment that tested the effectiveness of the polio vaccine. By 1953, several potential vaccines had been developed. one of the more promising of which was a killed-virus vaccine developed by Jonas Salk at the Unviersity of Pittsburgh. The killed-virus approach was chosen because there was a great potential risk in testing a live-virus vaccine in a large-scale experiment and a large-scale experinment was needed to collect enough information on polio (which in the 1950s had a rate of incidence among children of about 1 in 2000).

The testing of any new vaccine or drug creates many ethical dilemmas which have to be taken into account in the design of the experiment. With a killed-virus vaccine the risk of harmful consequence produced by the vaccine itself is small, so one possible approach could have been to distribute the vaccine widely among the population (ideally giving it to every child, but this was not possible because supplies were limited) and then follow up on whether there was a decline in the national incidence of polio in subsequent years. This is called the vital statistics approach and is the simplest way to test a vaccine. This is essentially the way the smallpox vaccine was determined to be effective. The problem with such an approach for polio is that polio is an epidemic type of disease, which means that there is a great variation in the incidence of the disease from one year to the next. In 1951, there were close to 60,000 reported cases of polio in the United States, but in 1952 the number of reported cases had dropped to almost half (around 35,000). Since no vaccine or treatment was being used at the time, the cause of the drop can only be attributed to the natural variablility that is typical of epidemic diseases. If a totally ineffective vaccine had been tested in 1951, the observed effect -- a significant drop in the incndence of polio in 1952 -- could have been incorrectly interpreted as a proof that the vaccine worked rather than to the real cause. The serious consequences of such a mistake are obvious.

The final decision on how best to test the effectiveness of the Salk vaccine was left to an advisory committee of doctors, public officials. and statisticians convened by the National Foundation for Infantile Paralysis and the Public Health Service. In order to isolate the cause under investigation (the Salk vaccine) from other possible causes of the desired effect (a reduction in the incidence of polio), it was decided that the experiment would be a controlled experiment involving a treatment group (those receiving the actual vaccine) and a control group (those receiving a shot of a harmless salt solution). An experiment of this kind is called a controlled placebo experiment. The reasons for using placebos go back to our desire that the treatment and control groups be as equal as possible in all respects, except of course that one group is receiving the vaccine and the other one isn't.

It is obvious that in a controlled placebo experiment it is always desirable that neither the members of the treatment group nor the members of the control group known to which of the two groups they belong. When this is the case the experiment is called a blind experiment. It is also desirable that the scientists conducting the experiment not know which individuals are given the actual treatment and which are given the placebo. The purpose of this is to make the observation, analysis and interpret ation of the results of the experiment as impratial as possible.

A controlled experiment in which neither the subjects nor the scientists conducting the experiment know which individuals are in the treatment group and which are in the control group is called a double-blind experiment. Making the Salk vaccine experiment double-blind was particularly important because polio is not an easy disease to diagnose -- it comes in many different forms and degrees. Sometimes it can be a borderlline call, and if the doctor collecting the information had had prior knowledge of whether the subject jad received the real vaccine or not, the diagnosis could have been subjectively tipped one way or the other.

With all this background we can now describe the actual details of the experiment. Approximately 750,000 children were randomly selected to participate in the study. Of these, about 340,000 declined to participate and another 8500 dropped out in the middle of the experiment. The remaining children were divided into two groups -- a treatment and a control group --with approximately 200,000 children in each group. The choice of which children were selected for te treatment group and which for the control group was made by random selection (so this is a randomized controlled experiment). Here are some of the results:

Number of
children
Number of reported
cases of polio
Number of paralytic
cases of polio
Number of fatal
cases of polio
Treatment group 200,745 82 33 0
Control group 201,2291621154
Declined to participate338,7781821210
Dropped out in the middle8,484210
TOTAL749,2364282704

While this table shows only a small part of the data collected by the Salk vaccine experiment, it can be readily seen that the difference between the treatment and control groups was significant and could rightfully be interpreted as a clear indication th at the vaccine was indeed effective.

Based on the data collected by the 1954 field trials, a massive inoculation campaign was put into effect. Today all children are routinely inoculated against polio, and polio has essentially been eradicated in the United States. A statistically designed experiment played a key role in this breakthrough.