A vaccine undergoes a comprehensive regime of testing, and its use is subject to continuous vigilance throughout its lifecycle to ensure safety, efficacy and quality. The evaluation begins at the pre-clinical stage of vaccine development and progresses stepwise through to the licensed vaccine.

Clinical trials are the primary process for testing vaccine safety and efficacy in humans. They are run in a stepwise or phased manner, but before any medicine is administered to humans it undergoes rigorous pre-clinical testing. In the case of vaccines, this includes an in-depth toxicological assessment in animals. Typically, animals are administered a dose of vaccine, which at least matches the highest dose proposed for human trials. Animals are observed for any adverse reactions focusing on undesirable inflammatory responses. Subsequently, a full autopsy will be undertaken to examine organs for signs of adverse effects alongside analysis of relevant samples, taken throughout the study, to measure the immune response to the vaccine. On successful completion of the study a vaccine developer applies to a national regulator to run phase I clinical trials.

Phase I, or first in human trials, are typically run in a small number of healthy adults and are primarily designed to ensure the vaccine does not cause serious adverse events. Additionally, the studies may be used to identify an appropriate dose of the vaccine that evokes an immune response. Once completed the vaccine progresses to phase II clinical trials. These evaluate the safety of the vaccine in a larger population, usually hundreds of people, as well as providing crucial information on optimal dosing and appropriate vaccination regimes. Critically these trials include a control group, are randomised with participants arbitrarily assigned to a group and ideally are double-blinded so neither the participant or the researcher know who has been administered the developmental vaccine or the control. Phase III trials follow and involve thousands to tens of thousands of participants comprising a range of age groups, from infants to elderly, providing a comprehensive safety profile of the vaccine. Importantly these trials enrol a sufficient number of the target population to be powered to provide statistically significant safety and effectiveness results. In phase III trials, groups may be included to assess concomitant administration with other routine vaccines; for example, to determine whether a candidate paediatric vaccine interferes with other vaccines in an infant immunisation programme.

Once the candidate vaccine has completed the clinical trials, the manufacturer submits a dossier to the relevant regulatory authority for authorisation to administer the vaccine in the population in its jurisdiction. The dossier is an in-depth report containing analysis of clinical studies, and descriptions of manufacturing and quality processes. The assessors review all data and make a recommendation on whether the vaccine should be used in humans and any limitations that apply.

Upon authorisation, both the vaccine manufacturer and the regulatory authority implement post-licensure surveillance based on a previously agreed risk management plan. Batch release testing of every vaccine lot is also undertaken to ensure the consistency of every batch with those shown to be safe and effective in clinical trials. The manufacturer is required to run an exhaustive panel of quality tests as described in the marketing authorisation (licence). Test results are submitted along with sample of each batch to the national control laboratory, such as the National Institute for Biological Standards and Control (NIBSC) in the UK, who review manufacturer’s data and run independent tests focussing on vaccine safety and potency. On successful completion of all tests the vaccine batch is issued with a certificate permitting it to be marketed in the designated country. Pharmacovigilance (part of phase IV trials) is performed by the manufacturer and the national regulator. Pharmacovigilance is the detection, assessment and prevention of adverse events caused by the vaccine. Whilst thorough, the evidence of safety of a vaccine prior to its authorisation is limited to a relatively small group of people, over a narrow time period with a small number of batches. It is possible that changes occur during product manufacture which are undetected by the QC testing, or administration with another medicine causes an adverse-event, or there may be rare underlying conditions in patients which results in an adverse event which were not identified in the trials. Identifying an adverse reaction from a vaccine requires data from multiple sources including physicians, pharmacists and patients. In the UK, members of the public and healthcare professionals can report suspected safety issues or adverse reactions via the Yellow Card scheme. Data from all sources is combined by the regulators and manufacturers in real-time to identify any potential issues at the earliest possible moment allowing effective intervention.

The first clinical trials occurred centuries ago building the foundations for the intensive testing regime applied to vaccines today. As new state of the art methods and technologies are developed with improved sensitivities, efficiencies and capabilities so they are adopted by regulators, control laboratories and manufacturers to ensure ever-improving safety and surveillance mechanisms are in place to continually protect public health.