Pre-licensure vaccine safety

Vaccines, like other pharmaceutical products, undergo extensive testing and review for safety, immunogenicityImmunogenicityThe power of an antigen to induce an immune response., and efficacyVaccine efficacyThe potential of a vaccine to protect from a disease in controlled clinical trials. Expressed as a percent. in the laboratory, in animals, and in three phases of clinical trialsClinical trialA systematic study of a medical intervention in human subjects (including patients and other volunteers) in order to discover or verify the effects of and/or identify any adverse reaction to the intervention. Clinical trials also study the absorption, distribution, metabolism, and excretion of the products with the objective of ascertaining their efficacy and safety. Clinical trials are generally classified into Phases I to IV. Phase IV trials are studies performed after the licensure and introduction of pharmaceutical products. They are carried out to expand the evidence base of the product characteristics for which the marketing authorization was granted. in human subjects before licensure.

Monitoring adverse vaccine reactionsVaccine reaction (also referred to as adverse vaccine reaction or adverse reaction)A classification of AEFI referring to events caused or precipitated by the vaccine when given correctly, caused by the inherent properties of the vaccine. is a major safety component of pre-licensure clinical trials.

In the table below you can see the different steps including clinical trials and further assessment that a vaccine must go through before entering the market. Look at the various sample sizes of the clinical trial phases and compare them to the classification of frequency of common and rare adverse events on this module’s page Adverse events: Frequency and severity. Note that even trials in Phase III are not generally designed to detect very rare reactions or reactions with vague or delayed onset. Larger studies, often at prohibitive cost and risk to delay vaccine availability, are necessary to detect very rare conditions that might result from vaccination.

Clinical trials and assessment of vaccine safety

  Activity Sample size (estimates) Detection of Adverse events
Common Rare
Introduction Involves making the vaccine available for use.
Clinical Trial
Phase I
Test the safety and immunogenicity of a vaccine candidate in a few low-risk individuals (usually healthy adults) to determine tolerability. 10 – 100 +/-
Clinical Trial
Phase II
Monitor safety, potential side effects, immune response, and determine optimum dosage and schedule. 100 – 1,000 +
Clinical Trial
Phase III
Address clinical efficacy in disease prevention and provide further safety information from more heterogeneous populations and longer times of observation. 1,000 – 10,000 +
Submission The vaccine application is submitted to regulatory authorities for approval to market.

Key point

Pre-licensure studies often identify common and acute undesirable reactions that occur with a frequency greater than 1 in 10 000 vaccinations, depending on total sample size of the study.

The sensitivity of detection of uncommon or rare adverse events, or those with delayed onset, or occurring in particular populations (such as HIV positives,  malnourished individuals, etc)  is, however, low in these trials.

As a result, continuous post-licensure monitoring of vaccine safety is needed to identify and evaluate such adverse events hence the importance of effective vaccine pharmacovigilance system in all countries.