To maximize the value of vaccine safety data in clinical trials given their relatively limited sample size, it is essential to standardize their collection, presentation and analysis when possible.
Given serious adverse events following immunization (AEFIs) are fortuitously rare, this need for globally accepted standard case definitions that allow for valid comparisons extend to individual case reports, surveillance systems, and retrospective epidemiologic studies.
This need for standardization was recognized by Dr. RobertChen at a vaccine conference in Brighton, England in 1999. Harald Heijbel, Ulrich Heininger, Tom Jefferson, and Elisabeth Loupi joined his call one year later to launch the Brighton Collaboration as an international voluntary organization, now with more than 750 scientific experts. It aims to facilitate the development, evaluation and dissemination of high-quality information about the safety of human vaccines.1
The goals of the Brighton Collaboration in the domain of case definitions have been to:
1. Develop standardized case definitions for specific AEFI’s
2. Prepare guidelines for their data collection, analysis and presentation for global use
3. Develop and implement study protocols for evaluation of case definitions and guidelines in clinical trials and surveillance systems.
4. Raise global awareness of their availability and to educate about their benefit, monitor their global use, and facilitate access.
Safety monitoring during clinical trials is a crucial component for vaccine development. Before a vaccine can receive regulatory approval for marketing, rigorous safety monitoring and reporting is required. In the CEPI funded vaccine development programs, the CEPI funded developers are the sponsors and responsible for safety monitoring of their products and have the responsibility to comply with regulatory requirements. Since CEPI funds several developers that develop vaccines for the same target, using different vaccines and platforms, harmonization of safety monitoring is essential to allow for meaningful analysis and interpretation of the safety profiles of CEPI funded vaccines.
CEPI has contracted with the Brighton Collaboration, through the Task Force for Global Health, to harmonize the safety assessment of CEPI-funded vaccines via its Safety Platform for Emergency vACcines(SPEAC) Project. As part of its landscape analysis of COVID-19, this document describes the methods and results SPEAC used to arrive at the list of adverse events of special interest (AESI).
Adverse events of special interest
An adverse event following immunization (AEFI) is defined as ‘any untoward medical occurrence which follows immunization, and which does not necessarily have a causal relationship with the usage of the vaccine. The adverse event may be any unfavorable or unintended sign, abnormal laboratory finding, symptom or disease.’2
‘Adverse Event of Special Interest’ (AESI) is further defined in Council for International Organizations of Medical Sciences (CIOMS) VII3 as:
“An adverse event of special interest (serious or non-serious) is one of scientific and medical concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid communication by the investigator to
the sponsor could be appropriate. Such an event might require further investigation in order to characterize and understand it. Depending on the nature of the event, rapid communication by the trial sponsor to other parties (e.g., regulators) might also be warranted.”
AESI can be specified in the Program Safety Analysis plan (PSAP) early in product development for safety planning, data collection, analysis and reporting on AESI data, and eventually form the base of AESI analysis in Reporting and Analysis Plan.
While the current CEPI vaccine development focus is primarily on phase 1 and 2 clinical trials, which will have very small total sample sizes (likely N < 1000), the ultimate goal is to have vaccines ready for use against emerging, epidemic diseases. Vaccine safety assessment needs therefore to be conducted 1) across the entire life cycle of vaccine development, approval and use, and 2) in a harmonized and standardized manner so that data are comparable across different trials and populations. Many if not most of the AESI identified as relevant to CEPI vaccine programs are likely to be rare events and may never occur in the context of a given trial. Nevertheless, we have to be prepared to maximize the utility of vaccine safety data in case they do occur.
To this end SPEAC has chosen to identify AESI that have been previously identified with immunization in general (e.g. anaphylaxis, Guillain Barré Syndrome) or vaccine platforms in particular (e.g., arthritis following recombinant vesicular stomatitis virus vectored vaccine). In addition, it is important to consider events that may occur during the clinical course or as a complication of the chosen target pathogen. Depending on the platform, a vaccine targeting that pathogen may induce an adverse event with a similar immunopathogenic mechanism; whether this occurs or not can only be assessed by studying this specific AESI (e.g., sensorineural hearing loss after Lassa Fever).