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Pharmacovigilance leaders from major vaccine developers describe the learnings from the coronavirus disease 2019 (COVID-19) pandemic in the area of pharmacovigilance and pharmacoepidemiology. The authors aim to raise awareness of the co-operation among vaccine developers, highlight common challenges, advocate for solutions, and propose recommendations for the future in the areas of real-world safety and effectiveness, safety reporting and evaluation, and regulatory submissions. To enable timely evaluation of real-world safety and effectiveness, multi-sponsor study platforms were implemented, resulting in quicker recruitment over wide geographical areas. Future gains could be derived by developing geographically flexible, common protocols and/or joint company-sponsored studies for multiple vaccines and a collective strategy to build low/middle-income country (LMIC) sentinel sites. Safety reporting, signal detection and evaluation was particularly challenging given the unprecedented number of adverse events reported. New methods were required to manage increased report volume while maintaining the ability to quickly identify and respond to new data that could impact the benefit-risk profile of each vaccine. Worldwide health authority submissions, requests for information and differing regulatory requirements imposed significant burden on regulators and industry. Industry consensus on the safety reporting requirements and joint meetings with regulatory authorities markedly reduced this burden for all stakeholders. The most impactful innovations should be undertaken rapidly and expanded to other vaccines and therapeutics, with a multi-stakeholder approach. The authors of this paper make future recommendations and have launched an initiative named BeCOME (Beyond COVID Monitoring Excellence) with a focus on actions in each of the highlighted areas., (© 2023. The Author(s).)

Introduction: Quantitative benefit-risk models (qBRm) applied to vaccines are increasingly used by public health authorities and pharmaceutical companies as an important tool to help decision makers with supporting benefit-risk assessment (BRA). However, many publications on vaccine qBRm provide insufficient details on the methodological approaches used. Incomplete and/or inadequate qBRm reporting may affect result interpretation and confidence in BRA, highlighting a need for the development of standard reporting guidance., Objectives: Our objective was to provide an operational checklist for improved reporting of vaccine qBRm., Methods: The consolidated standards of reporting quantitative Benefit-RIsk models applied to VACcines (BRIVAC) were designed as a checklist of key information to report in qBRm scientific publications regarding the assessed vaccines, the methodological considerations and the results and their interpretation., Results: In total, 22 items and accompanying definitions, recommendations, explanations and examples were provided and divided into six main sections corresponding to the classic subdivisions of a scientific publication: title and abstract (items 1-2), introduction (items 3-4), methods (items 5-15), results (items 16-17), discussion (items 18-20) and other (items 21-22)., Conclusions: The BRIVAC checklist is the first initiative providing an operational checklist for improved reporting of qBRm applied to vaccines in scientific articles. It is intended to assist authors, peer-reviewers, editors and readers in their critical appraisal. Future initiatives are needed to provide methodological guidance to perform qBRm while taking into account the vaccine specificities.

Introduction: Understanding the balance between the benefits and risks of vaccination is essential to ensure informed and adequate public health decision making. Quantitative benefit-risk models (qBRm) represent useful tools to help decision makers with supporting benefit-risk assessment throughout the lifecycle of a medical product. However, few initiatives have been launched to harmonise qBRm approaches, specifically for vaccines., Objectives: The aim of this paper was to identify publications about qBRm applied to vaccines through a systematic literature review, and to describe their characteristics., Methods: Medline, Scopus and Institute for Scientific Information Web of Knowledge databases were searched to identify articles in English, published from database inceptions up to December 2019. The search strategy included the combination of three key concepts: 'benefit-risk', 'modelling' and 'vaccines'. Data extracted included the modelling context and the methodological approaches used., Results: Of 3172 publications screened, 48 original publications were included. Most of the selected studies were published over the past decade and focused on rotavirus (15), dengue (10) and influenza (6) vaccines. The majority (30) of studies reported analyses related to high-income countries. The methodology of the studies differed, particularly in modelling techniques, benefit-risk measures, and sensitivity analyses. The present work also pointed out a high level of variability in the quality of reporting across studies, with particular regard to input parameters and methodological approaches., Conclusions: This review provides an extensive list of qBRm applied to vaccines. Discrepancies across studies were identified during our review. While the number of published qBRm studies is increasing, no reporting guidance for qBRm applied to vaccines is currently available. This may affect decision makers' confidence in the results and their benefit-risk assessment(s); therefore, the development of such reporting guidance is highly needed.

Introduction: New vaccines are launched based on their benefit-risk (B/R) profile anticipated from clinical development. Proactive post-marketing surveillance is necessary to assess whether the vaccination uptake and the B/R profile are as expected and, ultimately, whether further public health or regulatory actions are needed. There are several, typically not integrated, facets of post-marketing vaccine surveillance: the surveillance of vaccination coverage, vaccine safety, effectiveness and impact., Objective: With this work, we aim to assess the feasibility and added value of using an interactive dashboard as a potential methodology for near real-time monitoring of vaccine coverage and pre-specified health benefits and risks of vaccines., Methods: We developed a web application with an interactive dashboard for B/R monitoring. The dashboard is demonstrated using simulated electronic healthcare record data mimicking the introduction of rotavirus vaccination in the UK. The interactive dashboard allows end users to select certain parameters, including expected vaccine effectiveness, age groups, and time periods and allows calculation of the incremental net health benefit (INHB) as well as the incremental benefit-risk ratio (IBRR) for different sets of preference weights. We assessed the potential added value of the dashboard by user testing amongst a range of stakeholders experienced in the post-marketing monitoring of vaccines., Results: The dashboard was successfully implemented and demonstrated. The feedback from the potential end users was generally positive, although reluctance to using composite B/R measures was expressed., Conclusion: The use of interactive dashboards for B/R monitoring is promising and received support from various stakeholders. In future research, the use of such an interactive dashboard will be further tested with real-life data as opposed to simulated data.

Introduction: We investigated a signal of solid organ transplant (SOT) rejection after immunisation with (AS03) A/H1N1 2009 pandemic influenza vaccines., Methods: Potential immunological mechanisms were reviewed and quantitative analyses were conducted. The feasibility of pharmacoepidemiological studies was explored., Results: Overall results, including data from a pharmacoepidemiological study, support the safety of adjuvanted (AS03) pandemic influenza vaccination in SOT recipients. The regulatory commitment to evaluate the signal through a stepwise investigation was closed in 2014., Conclusion: Lessons learned highlight the importance of investigating plausible biological mechanisms between vaccines and potentially associated adverse outcomes, and the importance of selecting appropriate study settings and designs for safety signal investigations.

Introduction: Measles, mumps, rubella, and varicella combination vaccines (MMRV) facilitate varicella vaccination uptake compared with separate administration of measles, mumps, and rubella vaccine (MMR) with varicella vaccine (V). However, the risk of developing febrile convulsions (FC) is higher in children vaccinated with MMRV., Objectives: The aim was to demonstrate how to put the increased FC risk associated with MMRV into perspective by comparing it with the lower V-coverage risk associated with MMR + V., Methods: FC and varicella burdens were measured by total numbers or duration of hospitalisations. A model, based on several assumptions and integrating parameters from heterogeneous data sources relevant to Germany, was developed to evaluate hospitalisation ratios (HRs; ratios between yearly numbers of varicella-related hospitalisation days prevented by MMRV and yearly numbers of FC-related hospitalisation days attributed to MMRV, both compared with MMR + V). A sensitivity analysis estimated HR under different scenarios beyond the German experience., Results: For parameter values compatible with the German experience, where MMRV (Priorix-Tetra™, GSK, Belgium) was introduced in 2006, the model predicted that transitioning from MMR + V to MMRV would induce 225 vaccine-related FC hospitalisation days whilst preventing 1976 varicella-related hospitalisation days per year. The HR estimated by Monte Carlo simulations was 8.5 (95 % confidence interval: 1.99-25.22). A sensitivity analysis on two key parameters suggested that transitioning from MMR + V to MMRV would be favourable in situations where MMRV use would significantly impact varicella vaccination uptake., Conclusions: MMRV use instead of MMR + V can substantially reduce the number of hospitalisation days, despite increased FC risk when MMRV is used as a first dose of measles-containing vaccine.

Purpose: We evaluated the use of logistic regression to model the probabilities of spontaneously reported vaccine-event pairs being adverse reactions following immunization (ARFI), using disproportionality and unexpectedness of time-to-onset (TTO) distributions as predictive variables and the presence of events in the global product information as a dependent variable., Methods: We used spontaneous reports of adverse events from eight vaccines and their labels as proxies for ARFIs. Three logistic regressions were built to predict ARFIs based on different combinations of the proportional reporting ratio (PRR; disproportionality measure) and two Kolmogorov-Smirnov (KS) tests ('between vaccines' and the 'between events') of TTO distribution: model 1, using the PRR estimate and its 95% lower confidence interval (CI) limit; model 2, using the p values of the two KS tests; and model 3, using the PRR (point estimate and lower CI limit) and both KS tests. The performance of the regressions (model fit statistics, calibration, and discrimination) was measured on 100 bootstrap samples., Results: Model 3, using two quantified causality criteria, provided the best performance for all measures. The p value of the 'between vaccines' KS test was the most significant predictive factor. Model 1 had the worst performance., Conclusions: Logistic regression allows estimation of the probability of a vaccine-event pair being an ARFI using two causality criteria at the population level assessed in spontaneous report data: the strength of association (disproportionality measure) and temporality (TTO distribution tests). Logistic regression combines and weights these causality criteria based on their respective ability to predict known safety issues.