GACVS COVID19 Sub-committee
Extract from meeting of GACVS of 15-16 May 2023, published in the WHO Weekly Epidemiological Record of 11 August 2023
The GACVS COVID-19 Subcommittee was convened from December 2020 through November 2022, after which it was agreed that the Subcommittee would cease to exist, however GACVS would continue to review new COVID-19 vaccine safety data or concerns as part of its routine meetings and scope of work. This session included presentations on the safety of bivalent mRNA vaccines from the US Food and Drug Administration (FDA); child and adolescent myocarditis data from Germany’s Paul-Ehrlich-Institut (PEI); and Cohort Event Monitoring (CEM) studies for the COVID-19 vaccine (BIBP) (Sinopharm) presented by 2 Iranian research groups.
The presenter from the US FDA shared lessons learned in utilizing rapid cycle analysis to compare rates of selected adverse events following administration of bivalent mRNA vaccines compared with historical rates by age group. The only 2 signals that have arisen were known from the original vaccine formulations and expected: anaphylaxis among those aged 18–64 years for both BNT162b2 and mRNA-1273 bivalent vaccines and myocarditis/pericarditis among those aged 18–35 years for the BNT162b2 bivalent vaccine. Among paediatric populations, insufficient bivalent doses have been captured to commence formal analysis.
The presenter from PEI shared data from a study of children and adolescents aged 5 to less than 18 years with suspected myocarditis occurring within 21 days of COVID-19 vaccination. The study cohort included 56 patients through the end of 2022, 91% of whom were male and 89% of whom were admitted to hospital. Almost all participants received BNT162b2 vaccine and 52% experienced symptoms following dose 2. Approximately 88% received imaging by cardiac magnetic resonance imaging (cMRI). At the 3-month and 9–12-month follow-up, diagnostics revealed some residual changes interpreted as scarring after myocarditis demonstrable on cMRI in 37.5% of children though they lacked clinical symptoms. Cardiologists were concerned that this could potentially be associated with future arrhythmias and these children will be followed up for longer.
Two Iranian research groups presented data on CEM studies undertaken to assess the safety of COVID-19 vaccines. The first assessed the safety of the vaccine developed by Sinopharm's Beijing Institute of Biological Products (BIBP) in those aged less than 18 years using the WHO template for CEM. The main objectives included estimating the incidence of serious adverse events, AESI and reactogenicity within 7 days following each dose. More than 18 000 participants with a mean age of 11.9 years (range: 4.6–18.6 years) were enrolled from October 2021 to July 2022. Events were more commonly reported within the first day following vaccination and after dose 2. Pain at the injection site (53% participants) and headache (8.7% participants), both within one day of dose 2, were most commonly reported. Most local and systemic events did not interfere with participant activities. The incidence rate of COVID-19 breakthrough infection was estimated at 26.1 per 100 000 person-years. Ninety-one participants were hospitalized.
The second Iranian study was designed to assess the safety of a ChAdOx1-S [recombinant] (AstraZeneca) booster in individuals aged 18 years and older who received a COVID-19 vaccine (BIBP) primary series. The objectives included estimating the incidences of serious adverse events and AESI occurring within 3 months of the booster and of severe COVID-19 infection after a booster dose.
The study was interrupted, after which too few ChAdOx1-S [recombinant] boosters were being administered. Prior to the interruption, data were captured from 4133 individuals who were followed up more than 12 000 times. Within this cohort, 6 individuals were hospitalized. Their self-reported diagnoses included 2 cases of thromboses and one case of GBS. Going forward, the study will focus on 2 Iranian provinces, employing retrospective methods to follow up participants identified using linked hospitalization, death and immunization data.
Reviewing all COVID-19 vaccine safety updates presented at the meeting, GACVS expressed no new concerns regarding the safety of bivalent COVID-19 vaccines but acknowledged that new formulations of COVID-19 vaccines will continue to arrive, requiring ongoing surveillance. Regarding myocarditis, the Committee expressed no new concerns but stressed the importance of continued and long-term monitoring, particularly for children and adolescents, given the cMRI results shared by the PEI. The Advisory Committee acknowledged, however, that data availability will begin to decline with decreased uptake of COVID-19 vaccines, and consequently, it will become increasingly complex to make informed safety assessments for future formulations of COVID-19 vaccines. The Committee found the COVID-19 vaccine (BIBP) data important, acknowledging that the ChAdOx1-S [recombinant] booster study was not sufficiently powered to adequately assess the findings. The Committee stressed the importance of risk–benefit analyses and continued monitoring of the safety of COVID-19 vaccine (BIBP).
Extract from second joint meeting of GACVS and ACSoMP of 14-16 December 2022, published in the WHO Weekly Epidemiological Record of 3 March 2023
Updates on GACVS COVID-19 Subcommittee activities
After being established in December 2020, the GACVS COVID-19 Subcommittee had four meetings in the first half of 2021 and then mostly monthly meetings until its last meeting in November 2022. The Subcommittee issued 10 statements on safety issues related to COVID-19 vaccines, and reviewed 8 safety topics, including safety during pregnancy, vaccine booster doses and vaccination errors in children.
The signal identification and initial review process for the Subcommittee was organized by the WHO-HQ PVG team. Through weekly Situation Briefing Team meetings, the GACVS Secretariat generated a list of events, cases and potential signals from multiple sources, such as VigiBase data from the Uppsala Monitoring Centre (UMC), reports from other countries, publications, and an Early Warning System (EWS). The Medical Review Subgroup met to review identified events of interest and to decide on which to present to the Subcommittee for further assessment. The GACVS Secretariat then reviewed the cases of interest and added potential or confirmed signals to a watchlist of signals. Based on the watchlist and confirmed signals the Secretariat prepared the agenda for the next GACVS Subcommittee meeting. Once GACVS Subcommittee assessed safety data, provided advice on the overall safety of the COVID-19 vaccines. They also advised on additional monitoring needs and public communication of safety information, as required. Minutes of these meetings were recorded and when appropriate, GACVS Subcommittee statements were issued.
The PVG Team produced biweekly literature reviews on safety signals that were summarized to be used in the Subcommittee meetings. These literature reviews were summarized for specific topics and were used to inform the Subcommittee discussions. UMC provided VigiLyze summary analysis reports of safety signals by vaccine with the overall number of reports and numbers of serious and fatal reports, as well as numbers by gender and country.
Although the Subcommittee has been disbanded, the PVG Team will continue to monitor safety signals, in particular, the long-term impact of signals, such as COVID-19 vaccine-related myocarditis, pregnancy outcomes and Guillain-Barré syndrome, as well as the safety of new COVID-19 vaccines as they are rolled out. Safety concerns and issues will be presented to the whole GACVS. The GACVS COVID-19 Secretariat thanked the GACVS COVID-19 Subcommittee for their commendable efforts in providing WHO with impartial, high quality, scientific advice and recommendations on the COVID-19 vaccines issue bought to them.
Extract from GACVS meeting of 15 December 2021, published in the WHO Weekly Epidemiological Record of 11 March 2022
Review of signals
Since the last full GACVS meeting in June 2021, 7 meetings of the COVID-19 vaccine safety subcommittee have been held. The main signals reviewed were myocarditis and pericarditis with the mRNA vaccines and GuillainBarré syndrome with the adenovirus vector vaccine. The subcommittee also reviewed data for safety signals with 2 other vaccines, Sinopharm and Covaxin. The recommendations were shared with SAGE and have been published online.8
Future plans
In 2022 the GACVS COVID-19 vaccine safety subcommittee will have regular 90-minute meetings on the 4th Tuesday of every month, with additional emergency meetings, when required. Topics that will be reviewed include the safety of booster doses, both homologous and heterologous booster schedules, and safety in pregnant women. Other topics could include new COVID-19 vaccines that are authorized under EUL by WHO and safety in paediatric populations. Safety signals such as TTS and myocarditis could be reviewed again if new information becomes available.
Summary of topics to be prioritized for WHO, GACVS and COVID-19 GACVS subcommittee
The issues discussed during the meeting need to be prioritized, but, where possible, what will be done for COVID-19 vaccines should also be applied to issues with other vaccines. Formal and informal, internal and external working groups will be created to address the issues.
Capacity building is crucial, not only for the current COVID-19 pandemic but for the future, and this remains a priority, particularly providing support to the countries that are investigating AEFIs and AESIs for the first time. Although available resources will be largely used to address the many issues related to COVID-19 vaccines, it will be important not to neglect safety surveillance of other vaccines. New vaccines, such as nOPV2 and the malaria vaccine are being rolled out quickly in some countries, so it is important to ensure adequate safety surveillance is in place for these and other vaccines.
COVID-19 vaccines are being administered to increasingly younger children and surveillance is needed for specific safety signals, e.g., Kawasaki’s disease and febrile seizures in those aged 0 to 4. Also, as an increasing number of COVID-19 vaccines are being rolled-out, new signals must be identified and their relationship with the vaccines investigated rapidly. All AEFIs that have been reported since the rollout of COVID-19 vaccination should be systematically reviewed to identify any trends in specific populations or association with specific vaccines or vaccine platforms. The safety of the booster dose that is being given in many countries needs to be assessed, in particularly to see if any new signals appear and to assess any differences in homologous and heterologous boosters. While the initial reports of TTS were mainly from the western hemisphere and Australia, it is important to determine if this is due to a real difference in distribution or if it is due to underreporting. The safety of the different COVID-19 vaccines in pregnant and breastfeeding women, and their infants should be closely assessed via a systematic review of available data, for example from pregnancy registries. Uptake by pregnant women is low in Europe but in the US, it is about 35%. The data being collected on fertility and menstrual disorders following COVID-19 vaccination should be identified and reviewed. Further discussion about the importance of assessing the theoretical risk of VAED is needed. A subcommittee or working group within WHO will be set up to assess the available evidence and WHO will conduct a landscape analysis to map what is being done elsewhere for assessing VAED.
8 WHO News. Available from: https://www.who.int/news, accessed January 2022.
Extract from GACVS meeting of 8-9 June 2021, published in the WHO Weekly Epidemiological Record of 23 July 2021
The COVID-19 Subcommittee of the GACVS is a technical advisory body to WHO which aims to review, evaluate and interpret post-introduction COVID-19 vaccine safety data following the implementation of COVID-19 vaccines in different countries. In addition to the data from conventional sources – such as health and regulatory authorities, WHO regions, literature and the WHO global pharmacovigilance database (VigiBase) – the review includes data from surveillance, ongoing clinical studies and/or other observational studies . Meetings are short (1 hour) and each is dedicated to 1 topic, allowing for 1 or 2 presentations supporting the topic and with time for discussion, decision and statement preparation when relevant.
The objectives of the subcommittee are to review, evaluate and interpret post-introduction COVID-19 vaccine safety data in order to:
advise WHO on the safety of the different COVID-19 vaccines;
provide recommendations on post-introduction safety studies to investigate and/or validate emerging signals of risks with new COVID-19 vaccines; and
guide the development of COVID-19 vaccine-related safety advisories and communication materials on vaccine safety for Member States and for the WHO Vaccine Safety Network member websites.
The GACVS subcommittee has met regularly since February 2021, with 12 meetings between 25 February and 16 June.
Since its creation in December 2020 and up to the end of May 2021, the GACVS COVID-19 subcommittee issued 7 statements1 on different topics and different approved COVID-19 vaccines based on safety surveillance and driven by guidance needs – especially in low- and middle-income countries. They include:
22 January 2021: Review reports of deaths of very frail elderly individuals vaccinated with Pfizer BioNTech COVID-19 vaccine, BNT162b2.
8 March 2021: Review reports on influenza-like illness in individuals vaccinated with COVID-19 vaccines.
19 March 2021: Statement on safety signals related to the AstraZeneca COVID-19 vaccine.
7 April 2021: Interim statement on vaccine safety of AstraZeneca COVID-19 vaccine.
6 April 2021: Review of latest evidence of rare adverse blood coagulation events with AstraZeneca COVID-19 vaccine (Vaxzevria and Covishield).
19 May 2021: Statement on safety signals related to the Johnson & Johnson/Janssen COVID-19 vaccine.
26 May 2021: Review cases of mild myocarditis reported with COVID-19 mRNA vaccines.
Following the GACVS subcommittee review on Thrombosis with Thrombocytopenia Syndrome (TTS), it was decided to convene a group of clinical experts, including haematologists and other specialists, for advice on clinical diagnosis and case management. Subsequently WHO initiated the development of an interim Guidance document for clinical case management of Thrombosis with Thrombocytopenia Syndrome (TTS) following coronavirus disease (COVID-19) vaccination.2 This guidance document will be a living document and will be revised as further evidence emerges.
Coordinated by WHO’s Pharmacovigilance (PVG) team, a Guideline Development Group (GDG) has been established that includes global experts in internal medicine, epidemiology, haematology, immunology, neurology and neurosurgery. Key research questions have been formulated and the literature has been searched, reviewed and collated to a zero draft by a scientific rapporteur, coordinated by the GACVS and overseen by a guideline methodologist. A draft document that has been developed includes the scope and rationale, methodology, TTS case definition, TTS incidence, risk factors, pathophysiology, clinical presentation, laboratory diagnosis, clinical case management, prevention and lifestyle changes and vaccination in post-recovery TTS patients and the general population. Gaps in present information and possible issues for further research were also identified.
The key considerations for the guideline’s development are the balance between benefits and harms, resource requirements, the impact on equity, acceptability to all stakeholders, feasibility for immediate implementation and additional considerations. The GDG will aim for unanimous consensus. However, if consensus is not possible, the controversies will be described to help end-users understand the rationale. As far as is possible, visual tools aimed at frontline end-users will be provided, GDG perceptions of important variations in the evidence (e.g. effectiveness, acceptability or implementability) will be described and plausible consequences for which no evidence was found will be documented and reported. The GDG conclusions, including the TTS case definition and the good practices in the identification of TTS cases, will be presented to the GACVS. The guidance on good clinical practices in the treatment of TTS will be presented to the WHO Guidelines Review Committee for inputs prior to publication.
1 All GACVS statements (accessed 21 July 2021)
2 Guidance for clinical case management of thrombosis with thrombocytopenia syndrome (TTS) following vaccination to prevent coronavirus disease (COVID-19) (Interim guidance). Geneva: World Health Organization; 2021 (accessed 21 July 2021).
3 Peek Platform is being developed in collaboration with Link Along, a start-up company of the École Polytechnique Fédérale de Lausanne (EPFL), Switzerland.
4 Recall: the total number of documents. Increasing the number of documents that are captured improves the chances of detecting a weak signal.
5 Precision: the total number of relevant documents can be improved by using natural language processing to train the artificial intelligence to understand the meaning of a given text in order to classify the text accurately for analysis.
6 Vaccine-related events: vaccine reaction, media report or rumour, new study, temporary suspension, recall of vaccine and vaccine replacement.