Use of the Case-Control Approach in Vaccine Evaluation: Efficacy and Adverse Effects

The least ambiguous method with which to estimate the protective effect of a vaccine and to assess possible adverse effects associated with its use is a double-blind randomized controlled trial (RCT). Double-blindness, ensuring that neither trial participants nor those assessing vaccine effects know who has received the vaccine under evaluation and who has received the comparison product, should eliminate bias. Randomization should ensure, if the study is sufficiently large, that the vaccinated and unvaccinated groups are similar with respect to risk factors, other than vaccination, for the disease and adverse reactions under study. That is, randomization controls for both known and unknown factors that might otherwise confound the measurement of vaccine effects. If the vaccine is designed to protect from a disease for which there is currently no effective vaccine, the comparison product may be a placebo or, if a placebo injection is considered unacceptable, another vaccine which is not expected to have an impact on the endpoints the trial is designed to assess. If, however, a partially effective vaccine already exists, ethical considerations may dictate that this be used as the comparison product. In such circumstances, the assessments of efficacy and adverse effects are made relative to the existing product, and absolute estimation of effects is precluded. Once an RCT of a vaccine has been conducted and the vaccine has been shown to be efficacious, further such trials may be considered unethical, especially after the vaccine has been introduced into public health use. However, it is often of interest to know not only whether a vaccine is effective in the context of a trial but also what its efficacy is under routine conditions,