Extract from the first joint meeting of WHO GACVS and WHO ACSoMP, published in the WHO Weekly Epidemiological Record of 26 August 2022

Since the beginning of 2022 4 safety topics have been reviewed by the GACVS COVID-19 sub-committee:

• interim results from a cohort event monitoring (CEM) study for safety signal detection after vaccination with different COVID-19 vaccines;
  
• safety of COVID-19 vaccines in children and adolescent groups including the risk of myocarditis;
• safety of COVID-19 vaccine booster doses, including heterologous vaccination;
• COVID-19 vaccine safety during pregnancy and pregnancy outcomes.

Following a sub-committee recommendation, the Pharmacovigilance team has been updating the emergency interim guideline for the case management of thrombosis with thrombocytopenia syndrome (TTS) following vaccination to prevent coronavirus disease (COVID-19). The updates take into account scientific evidence that became available between July 2021 and November 2021. A section on TTS management in pregnant and breastfeeding women and another on public and patient-centred communications about TTS have been added. The updated guidance is expected to be published soon.

Three emerging safety signals are being reviewed to assess if they should be presented to the GACVS COVID-19 sub-committee:

• transverse myelitis;
• hearing loss and tinnitus;
• acute hepatitis.

In addition, several other safety signals are being monitored and the long-term impact of myocarditis, pregnancy outcomes and Guillain-Barré syndrome (GBS) is being monitored continuously, as recommended by the sub-committee.

Full report of the first joint meeting of WHO GACVS and WHO ACSoMP, published in the WHO Weekly Epidemiological Record of 26 August 2022

Extract from GACVS meeting of 1-3 December 2020, published in the WHO Weekly Epidemiological Record of 22 January 2021

This session heard an update on the vaccine safety surveillance plans of the European Medicines Agency and the United States Centres for Disease Control and Prevention, a review of the WHO COVID-19 vaccines safety surveillance manual, an overview of the recommended list of adverse events of special interest (AESI) for COVID-19 vaccines and feedback on the proposed template protocol for surveillance of these AESI. The Committee also discussed the procedure for reviewing the safety profile of COVID-19 vaccines. The following salient themes emerged from the robust discussion.

Europe and the USA appear to be well positioned to implement vaccine safety surveillance programmes of unprecedented magnitude. Concern was expressed, however, that low- and middle-income countries (LMIC) might find it more difficult to implement some of the studies that are being designed in Europe and the USA.

 The COVID-19 vaccine safety surveillance manual was developed by working groups led by GACVS members and other experts with diverse expertise from all WHO regions. A first draft was submitted for public consultation in early October 2020. All comments were reviewed, and the document was revised accordingly. The aim of the manual is to guide the processes for collecting, analysing and sharing safety data and information on COVID-19 vaccines within and across countries. It builds on the principles described in the Global Vaccine Safety Blueprint (GVSB),² the WHO global manual on surveillance of adverse events following immunization³ and the Council for International Organizations of Medical Sciences (CIOMS) guide to active vaccine safety surveillance.⁴ For ease of use, the manual is divided into an executive summary and nine modules that can be consulted individually and which contain hyperlinks to relevant sections of other modules. The manual will be available on the WHO website with relevant training materials and will be updated as frequently as required.

GACVS endorsed the document, commending the extensive, high-quality work and the efforts to ensure that it is well aligned with current vaccine development and implementation scenarios within countries. The Committee recognized that it is a “living document”. It recommended the development of a specific module for surveillance of COVID-19 vaccine safety in pregnant and lactating women.

A synopsis was presented of template protocols with different and complementary methods that are being developed for active surveillance of AESI associated with COVID-19 vaccines in LMIC. The synopsis described 2 methods:

- a cohort event monitoring protocol that can be quickly implemented to monitor the groups that are first vaccinated (e.g. health care workers, high-risk groups) for generation and validation of AESI signals and

- a sentinel surveillance protocol that can be used to recognize and evaluate signals of rare adverse events.

Background rates of AESI vary considerably among populations and areas due to differences in disease frequency and health care utilization. In view of changes in health-seeking behaviour during the COVID-19 pandemic, background rates assessed before (if these data are available) and during the pandemic should be considered for appropriate study design.

The Committee highlighted the importance of aligning this work with other initiatives to enable comparison of data for different study groups.

The Committee discussed the procedures proposed by WHO for reviewing the safety profile of COVID-19 vaccines before and after their introduction in countries.

GACVS agreed that a subcommittee be established to review, evaluate and interpret post-introduction data on COVID19 vaccine safety, as these become available from different sources, to:

- advise WHO on the safety of the different COVID19 vaccines;

- provide recommendations on safety studies, to investigate and/or validate emerging safety signals; and

- guide the development of COVID19 vaccines safety advisories and communiques on vaccine safety for Member States.

The subcommittee will include members of the GACVS, external experts and nominees from the office of the WHO Chief Scientist. The terms of reference for the scope of the work, deliverables and working arrangements for the subcommittee were discussed and approved.

³  Global manual on surveillance of adverse events following immunization. Geneva: World Health Organization; 2014.

⁴  CIOMS guide to active vaccine safety surveillance. Geneva: Council for International Organizations of Medical Sciences; 2017 (accessed December 2020).

Full report of GACVS meeting of 1-3 December 2020, published in the WHO Weekly Epidemiological Record of 22 January 2021

COVID-19 vaccines in the pipeline and potential safety issues

SAGE is establishing a working group on COVID-19 vaccines to review the evidence on candidate vaccines, provide guidance for prediction models to determine the optimal target age groups and populations, update target product profiles and prepare policy advice for SAGE on accelerated use of vaccines, early allocation of limited vaccine supplies, equitable access to vaccination and vaccine safety. It is expected to issue its initial policy advice in October 2020. The usual timeline for vaccine development has accelerated markedly, and it is hoped that it will be reduced to the minimum feasible, namely 12–18 months. This will require assessment of risks and benefits, securing funding and emergency licensing approval worldwide and scaling up manufacturing capacity at the same time as vaccine development, rather than sequentially.

Seven vaccine technology platforms are currently being considered for COVID-19 vaccine development: live attenuated virus, inactivated virus, virus vector, virus like particles, protein subunits, mRNA and DNA. Most vaccines in development are based on protein or viral vectors. Only the live attenuated and vector-based vaccines can be delivered as a single vaccination rather than as a primary vaccination with one or more booster doses. WHO and the London School of Hygiene and Tropical Medicine publish frequently updated summaries of vaccine development.^{3, 4}

Twelve candidate vaccines had entered phase I and/or phase II clinical trials by the end of May 2020.1 A Chinese recombinant adenovirus type-5 vectored vaccine has been shown to be tolerated and immunogenic in humans 28 days after vaccination,⁵ while the University of Oxford–Astra Zeneca chimpanzee adenovirus (ChAd)-vectored vaccine showed good results in animal testing, although the reduced prevalence of SARS-CoV-2 in the United Kingdom is complicating the clinical trial in humans. Animal testing is continuing in parallel with phase II trials, and both public and private developers report to the WHO working group on animal models.

Information about the adjuvants used in the candidate vaccines is available only from individual manufacturers, and new adjuvant systems are being developed. A number of vaccine developers have committed themselves to making licensed adjuvants available for use with novel vaccines developed by others.

GACVS members asked to be kept informed of the activities of the SAGE working group and noted the need for guidance on compassionate use of the earliest vaccines before formal licensure, in line with WHO guidance on emergency use listing. They drew attention to possible beneficial, non-specific effects of existing vaccines with a proven safety profile, e.g. BCG and measles vaccines. They further stressed the importance of effective public communication and of obtaining as much information as possible from the trials being conducted by private-sector vaccine developers.

³ See https://www.who.int/who-documents-detail/draft-landscape-of-covid-19-candidate-vaccines.

⁴ See https://www.lshtm.ac.uk/research/centres/vaccine-centre/covid-19.

⁵ Zhu FC, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. ScienceDirect. 2020 (https://doi.org/10.1016/S0140-6736(20)31208-3, accessed 5 June 2020).

Pharmacovigilance preparedness for launch of a COVID-19 vaccine

Adverse events of special interest in the context of COVID-19 vaccine introduction

Identification and assessment of AESI are a high priority, because, when their frequency after vaccination increases, they represent potential risks, which will change in the benefit–risk balance of the vaccine or may require prompt communication with the public by regulatory or public health authorities.

Designating an event as an AESI has the advantage that countries can then prepare, with case definitions, collect information on background rates, collate relevant scientific literature, set up collaborations with relevant partners and establish platforms and strategies to assess signals rapidly. When a signal is identified, it might have to be investigated further through active surveillance, such as in risk quantification studies, hospital-based monitoring, population-based studies with large health care databases and reviews of various data sources, such as electronic health records, claims data and other sources of health care data.

SPEAC has created an initial list of AESI related to vaccination in general, viral vector platforms and manifestations of COVID-19 disease.

Since 2000, the Brighton Collaboration has issued over 60 case definitions for “adverse events following immunization” (AEFI), with 3 levels of evidence, which provide guidance on collecting and reporting harmonized data on vaccine safety.

Benefit–risk assessment

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was established in 2008 to allow stakeholders to anticipate potential safety issues, interpret safety data and improve public acceptance of vaccines. The Group has developed standardized templates to facilitate the communication of complex information, increase transparency and comparability and serve as a checklist for risk management. These templates assist national regulatory authorities and other stakeholders in assessing the benefit–risk profiles of specific vaccines. Three viral vector vaccine templates have been developed to date, with information on the wild-type virus, the viral vector itself and the final recombinant viral vector vaccine in animals and humans, its toxicology, potency and an overall assessment of adverse events and risks.

As many candidate COVID-19 vaccines are not based on a viral vector, V3SWG is preparing templates for RNA/DNA, protein subunit, inactivated vaccine and live attenuated vaccine platforms, as well as a module on maternal vaccination. The templates include information on adjuvants, where appropriate. The templates will be available on the Brighton Collaboration website.

Leveraging the 3 levels of WHO and its global partners for pharmacovigilance preparedness

WHO has collated information from its regional offices about the lessons learnt from the epidemics of H1N1 influenza and Ebola virus disease. The regional offices and global partners can thus support countries in planning vaccine use and safety. National immunization programmes and national regulatory authorities must be prepared to collect information on AESI, independently of their link with vaccination. This may place an additional strain on already overstretched programmes in some countries, and WHO regional offices could reduce the burden on countries by organizing work-sharing and information exchange with other countries in the region.

The action necessary for vaccine safety preparedness at global level includes monitoring the safety and benefit–risk profile of COVID-19 vaccines, disseminating case definitions and ensuring a syndromic approach to the identification of safety signals and theoretical concerns, guiding national plans to respond to safety signals in a robust, efficient manner.

A preparedness plan for introduction of the COVID-19 vaccine must be developed at regional level, with a synchronized surveillance system for AESI and AEFI, engagement with vaccine safety experts and effective management of vaccine hesitancy, risk communication and issues of demand.

Each country should have a framework plan for introducing COVID-19 vaccination, and the risk management plan recommended by the national regulatory authority must be implemented and communicated, including active and enhanced passive AEFI and AESI surveillance nationwide. Target populations for initial introduction and special populations should be identified, and safety surveillance should be established for these groups. Guidance on monitoring the safety of COVID-19 vaccines should be available at all levels. Vaccine hesitancy and the expectations of various constituencies should be anticipated and managed from the perspective of vaccine safety.

National preparedness for vaccine safety must be aligned with vaccination strategies, risk management plans and national AEFI surveillance, and pharmacovigilance should be adapted to include both available data and emerging information. Stakeholder engagement can be strengthened by defining their roles, by including risk communication in the preparedness and response plan and establishing a database of scientific literature from low- and middle-income countries. The ability of national regulatory authorities to evaluate safety and efficacy and to license novel vaccines should be strengthened. The roles and responsibilities of all stakeholders in planning, data collection, analysis and reporting on AESI must be clearly defined. National and international collaboration and exchanges of information are key aspects of effective management of vaccine safety.

Specifically for vaccination against COVID-19, the maturity of the existing AEFI surveillance system should be assessed, and routine AEFI surveillance that may have been interrupted by COVID-19 activities and other challenges should be reactivated and/or strengthened. The vaccine safety preparedness plan, response plans, the necessary infrastructure (including cold-chain capacity at all levels), capacity-building, procedures for recording vaccination, quality assurance and sharing of data should be prepared and established before vaccine deployment.