Methodological frontiers in vaccine safety: qualifying available evidence for rare events, use of distributed data networks to monitor vaccine safety issues, and monitoring the safety of pregnancy interventions

Abstract

While vaccines are rigorously tested for safety and efficacy in clinical trials, these trials do not include enough subjects to detect rare adverse events, and they generally exclude special populations such as pregnant women. It is therefore necessary to conduct postmarketing vaccine safety assessments using observational data sources. The study of rare events has been enabled in through large linked databases and distributed data networks, in combination with development of case-centred methods. Distributed data networks necessitate common protocols, definitions, data models and analytics and the processes of developing and employing these tools are rapidly evolving. Assessment of vaccine safety in pregnancy is complicated by physiological changes, the challenges of mother-child linkage and the need for long-term infant follow-up. Potential sources of bias including differential access to and utilisation of antenatal care, immortal time bias, seasonal timing of pregnancy and unmeasured determinants of pregnancy outcomes have yet to be fully explored. Available tools for assessment of evidence generated in postmarketing studies may downgrade evidence from observational data and prioritise evidence from randomised controlled trials. However, real-world evidence based on real-world data is increasingly being used for safety assessments, and new tools for evaluating real-world evidence have been developed. The future of vaccine safety surveillance, particularly for rare events and in special populations, comprises the use of big data in single countries as well as in collaborative networks. This move towards the use of real-world data requires continued development of methodologies to generate and assess real world evidence.

Attitudes, Intentions and Readiness Towards COVID-19 Vaccines: a Survey of Staff and Students Within a New Zealand Vocational Tertiary Institute

“…One possibility for the high rate of agreement with this statement is that many people misunderstood or were not aware of the government's public health messages informing them that the COVID-19 vaccination is safe to have when pregnant or breastfeeding. Vaccine hesitancy may be higher in certain 'special populations' like pregnant women in part due to concerns they are not sufficiently represented in clinical trials (Dodd et al, 2021;Skirrow et al, 2022). However, we acknowledge, it is not incorrect for pregnant and breastfeeding women to discuss any vaccinations with a doctor or midwife to ensure the safety of their baby.…”

From program suspension to the pandemic: A qualitative examination of Australia’s vaccine pharmacovigilance system over 10 years

“…Data linkage is a central vaccine pharmacovigilance approach in several other countries, including the US [36], UK [37], Denmark and Sweden [38], where data can be used to both identify signals and test hypotheses, including in real time through rapid cycle analysis within the US Vaccine Safety Datalink [39]. Hypothesis testing through the conduct of observational studies, such as cohort and self-controlled case series analyses, enables comparison of vaccinated and unvaccinated cohorts and the estimation of risk, and contributes to causality assessment [2,12].…”

“…Subject to necessary ethics and governance approvals for all participating countries and data sources, the GVDN seeks to combine data from multiple settings to study AESI at a global level. Globally, distributed data networks are being implemented with common protocols, analytics and case definitions to assess vaccine safety using real world data, particularly for rare and population-specific events [12].…”

“…Concurrently, other expert commentators echoed concerns around governance and transparency and highlighted the inherent limitations of spontaneous (passive) reporting systems (SRS), the need for complementary active surveillance systems and the potential for use of large linked databases for pharmacovigilance [6]. Large linked databases are used in a number of developed countries to investigate safety signals identified through spontaneous reporting systems, with epidemiological studies comparing risk in vaccinated and unvaccinated cohorts; these data may also be used in near real time to monitor vaccine safety [12]. All recommendations of the Horvath Review were addressed by Government within the implementation timeframe; however, no formal report or evaluation of the response was completed [10].…”

Background rate estimations for thrombosis with thrombocytopaenia: challenges in evaluating rare safety signals following vaccination in real time during a pandemic

“… 3–5 Postregulatory emergency use or full approval of COVID-19 vaccines, as with all vaccines and medicines, requires monitoring for safety signals and to assess safety in any subpopulations unable to be studied in the clinical study programme. 6 …”