Protocol template to be used as template for observational study protocols: cohort event monitoring (CEM) for safety signal detection after vaccination with COVID-19 vaccines

COHORT EVENT MONITORING (CEM) FOR SAFETY SIGNAL DETECTION AFTER VACCINATION WITH COVID‑19 VACCINES PROTOCOL TEMPLATE TO BE USED AS A TEMPLATE FOR OBSERVATIONAL STUDY PROTOCOLS ADDENDUM TO COVID-19 VACCINES: SAFETY SURVEILLANCE MANUAL – MODULE ON MONITORING AND RESPONDING TO ADVERSE EVENTS OF SPECIAL INTEREST (AESI)

COHORT EVENT MONITORING (CEM) FOR SAFETY SIGNAL DETECTION AFTER VACCINATION WITH COVID‑19 VACCINES ADDENDUM TO COVID-19 VACCINES: SAFETY SURVEILLANCE MANUAL – MODULE ON MONITORING AND RESPONDING TO ADVERSE EVENTS OF SPECIAL INTEREST (AESI) PROTOCOL TEMPLATE TO BE USED AS A TEMPLATE FOR OBSERVATIONAL STUDY PROTOCOLS Protocol template to be used as template for observational study protocols for cohort event monitoring (CEM) for safety signal detection after vaccination with COVID-19 vaccines. ISBN 978-92-4-002739-8 (electronic version) ISBN 978-92-4-002740-4 (print version) © World Health Organization 2021 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. 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Protocol template to be used as template for observational study protocols for cohort event monitoring (CEM) for safety signal detection after vaccination with COVID-19 vaccines. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/ about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. 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The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Acknowledgements The preparation of this protocol was commissioned by World Health Organization (WHO), coordinated by Christine Guillard with the support of Noha Iessa, in the Pharmacovigilance (PVG) team, within the Regulation and Prequalification department at WHO Headquarters, Geneva, Switzerland. This document is based on the principles described in the WHO COVID-19 vaccines: safety surveillance manual.1 It was developed under the guidance of the WHO Global Advisory Committee on Vaccine Safety (GACVS). Active surveillance protocols developed by United States Centers for Disease Control and Prevention (US CDC)2 and European Medicines Agency vACcine Covid-19 monitoring readinESS (EMA-ACCESS)3 projects were reviewed. Key aspects of these protocols were adapted to low- and middle-income country (LMIC) settings. Special acknowledgements to Steven Anderson, Barbara Law and Saad B. Omer, members of the Scientific Committee, who provided expert advice throughout the project. The protocol was written by Kaatje Bollaerts and Anke Stuurman with technical input from Wendy Hartig-Merkel, Omar Okasha, Elodie Sole, Thao Mai Phuong Tran from the P95 Excellence in Pharmacovigilance and Epidemiology team. The significant contributions of Bartholomew Dicky Akanmori, Don Ananda Chandralal Amarasinghe, Madhav Ram Balakrishnan, Oleg Benes, Jose Luis Castro, Amavi Edinam, Sujeet Jain, Houda Langar, Jayantha Bandula L. Liyanage, Helvert Felipe Molina Leon, Diadié Maiga, Sergio Raul Munoz Navarro, Irma Desiree Pastor, Jinho Shin from WHO regional offices and the pharmacovigilance (PVG) team in WHO headquarters are gratefully acknowledged. Sarah D. Bennett, Laura Conklin, Jane Gidudu and Zunera Gilani from the US CDC provided useful comments and advice. 1 Covid-19 vaccines: safety surveillance manual. (https://www.who.int/publications/i/item/10665338400, accessed 9 March 2021). 2 Centers for Disease Control and Prevention. V-safe active surveillance for COVID-19 vaccine safety 2020 [updated 19 November 2020; cited 2021-01-15], (https://www.cdc.gov/vaccinesafety/pdf/V-safe-Protocol-508.pdf, accessed 9 March 2021). 3 ACCESS (vACCinecovid-19 monitoring readinESS). Cohort event monitoring to assess safety of COVID-19 vaccines using patient reported events, a protocol template from the ACCESS project - EUPAS 38915. 2020 [updated 10 January 2021]. (https://vac4eu.org/wp-content/uploads/2021/02/3a.Cohort-event-monitoring-to-assess-safety-of-COVID-19- vaccines-using-patient-reported-events-a-protocol-template-from-the-ACCESS-project.pdf, accessed 9 March 2021) iiiCohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Introduction WHO has published the COVID-19 vaccines: safety surveillance manual to guide the processes for collecting, analysing and sharing safety data and information on COVID-19 vaccines within and across countries.4 To accompany this manual and facilitate the conduct of active safety surveillance studies using harmonized tools and methods, a protocol template for cohort event monitoring (CEM) studies has been developed. The present template protocol is for CEM studies of COVID-19 vaccines for the purpose of safety signal detection. The protocol synopsis was developed under the guidance of a scientific committee including former and current Global Advisory Committee on Vaccine Safety (GACVS) committee members, and reviewed by the GACVS during its meeting held on 1-3 December 2020.5 CEM is a flexible active safety surveillance study design that can be used for signal detection and evaluation. CEM has been successfully used in the context of the H1N1 influenza pandemic in 2009, both in high income countries (HICs) and low- and middle-income countries (LMICs).6 CEM is a prospective, observational, single-arm cohort study design for the early launch of a new medicine or vaccine. CEM studies are designed to capture all adverse events that occur in a defined group of individuals who are exposed to the new medicine or vaccine during routine clinical practice, in a defined period of time.7,8 Vaccinees are enrolled in the cohort at the moment they are vaccinated for the first time with the monitored vaccine. Demographic and medical information are recorded at this initial encounter. Vaccinees are then followed up at defined intervals. Any adverse events (AEs), of either any severity or of a defined severity, occurring after vaccination are recorded, regardless of whether they are suspected to be caused by the vaccine or not. By capturing these events, regardless of suspicion of causality, the CEM study has the potential to identify previously unrecognised and unsuspected adverse reactions to the vaccine.9 How to use this template to develop a CEM study protocol The protocol template should be completed by adapting it to the specific country(ies) and study population(s). The sections of the protocol template to be adapted have been marked with orange square brackets. 4 World Health Organization. Covid-19 vaccines: safety surveillance manual. Geneva2020. Last accessed 11 March 2021; Available from: https://www.who.int/publications/i/item/10665338400. 5 GACVS. Report of the meeting of the WHO Global Advisory Committee on Vaccine Safety (GACVS), 1–3 December 2020. WER. 2021;96:13-20. 6 Torre CM, Cary M, Borges FC, Ferreira PS, Alarcão J, Leufkens HG, et al. Intensive monitoring studies for assessing medicines: a systematic review. Front Med. 2019;6:147. 7 World Health Organization. A practical handbook on the pharmacovigilance of antimalarial medicines: World Health Organization; 2008. 8 Pal SN, Duncombe C, Falzon D, Olsson S. WHO strategy for collecting safety data in public health programmes: complementing spontaneous reporting systems. Drug Saf. 2013;36(2):75-81. doi: 10.1007/s40264-012-0014-6. 9 Suku CK, Hill G, Sabblah G, Darko M, Muthuri G, Abwao E, et al. Experiences and lessons from implementing cohort event monitoring programmes for antimalarials in four African countries: results of a questionnaire-based survey. Drug Saf. 2015;38:1115-26. iv PROTOCOL TEMPLATE It is important also to note that the adult informed consent form (ICF) template, provided in this template, and the informed consent process must be adapted to local situations, local languages and special populations (e.g., minors, pregnant women, elderly individuals lacking full capacity, migrants, prisoners) that require a tailored approach to consent. This includes possible surrogate decision-makers, such as parents or guardians for young children, or study advocates for inclusion of prisoners, or orphans and additional forms, such as assent forms, as well as tailoring to correspond to the study information provided to participants during the consent process. All protocols developed using this template should be reviewed by a scientific committee and by relevant ethics committees and institutional review boards, at a national level, or at the level of the study sites, or at the institution of the sponsor, as required by applicable laws and regulation. Suggested process • Step 1: Constitute a study coordination team consisting of representatives from the immunization programme, national regulatory authority, pharmacovigilance centre, chair of the national adverse events following immunisation (AEFI) committee, and academia. • Step 2: Identify the role and responsibilities of the different institutions, and nominate a person to lead and coordinate the process of protocol development and obtain the consensus of the study coordination team. Complete section 6 of the template with this information. • Step 3: Define the target population, identify study sites, review list of adverse events of special interest (AESI) for the COVID-19 vaccine(s) in use,10 and complete the protocol (including informed consent forms and data collection tools). If technical assistance from WHO is required at this stage, send an e mail request to gvsi@who.int and the WHO country office focal person. • Step 4: Discuss the draft protocol with the study coordination team and study site representatives to obtain their input and endorsement and then finalise the protocol. • Step 5: The final protocol should be reviewed by an independent scientific committee to ensure that it is scientifically sound, and should then be reviewed by the national ethics committee or the independent ethics committee (IEC) or institutional review board (IRB) of participating institution(s). • Step 6: Develop the study procedures, data management plan and statistical analysis plan. Disclaimer: WHO cannot accept any responsibility or liability for the conduct of studies by third parties that follow this protocol template. Studies conducted by third parties using this protocol template cannot be considered ‘WHO studies’ and the WHO logo cannot be used in studies that are not WHO studies. 10 Law B. SO2-D2.1.2 Priority List of COVID-19 Adverse events of special interest: Quarterly update December 2020. Safety Platform for Emergency vACcines (SPEAC); 2021. Last accessed 11 March 2021; Available from: https:// brightoncollaboration.us/wp-content/uploads/2021/01/SO2_D2.1.2_V1.2_COVID-19_AESI-update_V1.3.pdf vCohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Start of CEM study protocol template Cohort event monitoring (CEM) study for safety signal detection after vaccination with COVID‑19 vaccines Title page Abbreviated study title COVID-19-CEM-[COUNTRY]- [NUMBER] Full study title Cohort Event Monitoring (CEM) study for safety signal detection in [PRIORITY GROUP OF INTEREST] after vaccination with COVID-19 vaccines in [COUNTRY] Study ID Research question and objectives Country(ies) of study Protocol version Date of protocol version Protocol authors Title page Abbreviated study title COVID-19-CEM-[COUNTRY]- [NUMBER] Full study title Cohort Event Monitoring (CEM) study for safety signal detection in [PRIORITY GROUP OF INTEREST] after vaccination with COVID-19 vaccines in [COUNTRY] Study ID Research question and objectives Country(ies) of study Protocol version Date of protocol version Protocol authors 1Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines 1. Contents .....................................................................................................................................................2 2. List of tables..............................................................................................................................................4 3. List of figures ............................................................................................................................................4 4. Protocol sign-off ......................................................................................................................................5 5. Documentation of protocol amendments ..................................................................................6 6. Study team and responsibilities ......................................................................................................7 6.1 Study team .......................................................................................................................................7 6.2 Responsibilities ...............................................................................................................................7 7. Abbreviations ...........................................................................................................................................8 8. Synopsis ......................................................................................................................................................9 9. Background and rationale ................................................................................................................12 10. Objectives ................................................................................................................................................13 11. Methods ....................................................................................................................................................14 11.1 Study design ...................................................................................................................................14 11.2 Study population ..........................................................................................................................14 11.2.1 Inclusion criteria ................................................................................................................................ 14 11.2.2 Exclusion criteria................................................................................................................................ 14 11.2.3 Withdrawal from the study ............................................................................................................ 14 11.3 Study sites .......................................................................................................................................15 11.4 Study period ...................................................................................................................................15 11.4.1 Start of study and duration of follow-up ................................................................................... 15 11.4.2 Study completion and end of study ............................................................................................ 16 11.5 Sample sizes ...................................................................................................................................16 11.5.1 Sample size for overall cohort ....................................................................................................... 16 11.5.2 Sample size for reactogenicity subset ........................................................................................ 18 11.6 Study variables ..............................................................................................................................19 11.6.1 Exposure of interest ......................................................................................................................... 19 11.6.2 Study outcomes ................................................................................................................................. 20 11.6.2.1 Serious adverse events ........................................................................................................................20 11.6.2.2 Adverse events of special interest resulting in hospitalization ...................................................20 11.6.2.3 Reactogenicity .......................................................................................................................................20 11.6.2.4 Severe COVID‑19 disease ....................................................................................................................21 11.7 Study flow: data sources and data collection ......................................................................21 Contents01 2 PROTOCOL TEMPLATE 11.7.1 Vaccination and enrolment ............................................................................................................ 21 11.7.2 Vaccination during the follow-up period ................................................................................... 22 11.7.3 Follow-up .............................................................................................................................................. 22 11.7.4 Identification of AESIs and SAEs ................................................................................................... 22 11.7.5 Pregnancy ............................................................................................................................................ 22 11.7.6 Data collection at withdrawal/lost to follow-up ....................................................................... 22 11.8 Data analysis ..................................................................................................................................23 11.8.1 Descriptive analysis of demographics and baseline characteristics ................................. 23 11.8.2 Statistical analyses ............................................................................................................................ 23 12. Data management ...............................................................................................................................24 12.1 Data security ..................................................................................................................................25 12.2 Data transfer ..................................................................................................................................25 12.3 Source documents .......................................................................................................................25 12.4 Data retention and archiving ....................................................................................................25 13. Quality assurance, monitoring and reporting .........................................................................26 13.1 Monitoring ......................................................................................................................................26 13.2 Interim analyses and reporting ...............................................................................................26 13.3 Final analyses and reporting.....................................................................................................26 14. Study management .............................................................................................................................27 14.1 National pharmacovigilance centre/AEFI committee/national immunization programme manager/dedicated scientific committee ....................................................27 14.2 Changes to the protocol .............................................................................................................27 14.3 Management and reporting of adverse events/adverse reactions ..............................27 15. Ethical considerations ........................................................................................................................28 15.1 Guiding principles ........................................................................................................................28 15.2 Respecting participants’ autonomy ........................................................................................29 15.3 Participant confidentiality ..........................................................................................................29 15.4 Independent ethics committee/institutional review board ............................................29 16. Limitations ..............................................................................................................................................30 17. References ...............................................................................................................................................30 18. Appendices ..............................................................................................................................................32 Appendix 1 ...................................................................................................................................................32 Data dictionary .................................................................................................................................................... 32 Appendix 2 ...................................................................................................................................................42 Adverse events of special interest ................................................................................................................ 42 Appendix 3 ...................................................................................................................................................43 Relationships between study tables ............................................................................................................. 43 Appendix 4 ...................................................................................................................................................44 Adult informed consent form ......................................................................................................................... 44 Participant information sheet ......................................................................................................................... 44 3Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Protocol sign-off This protocol has been discussed, reviewed and approved by the Scientific Committee consisting of the following members: • [NAME] • [NAME] • [NAME] • [NAME] • [NAME] • [NAME] • [NAME] Protocol title: Cohort event monitoring (CEM) study for safety signal detection in [PRIORITY GROUP OF INTEREST] after vaccination with COVID-19 vaccines in [COUNTRY] Version: [Version number] I have reviewed and approved the protocol. Name of scientific committee member: ......................................................................................... Signature: ............................................................................................................................................ Date: .................................................................................................................................................... 04Table 1: Study sites with principal investigators and contact details ......................................15Table 2: Sample size required to rule out events with the indicated frequency if no event is observed with 95% confidence ...........................................................................16 Table 3: Sample size needed to rule out a relative risk if no event is observed within the risk window with 95% confidence. ................................................................17 Table 4: Sample size needed to rule out different levels of relative risk if no event is observed within the risk window with 95% confidence. Additional results correspond to different values of background rates.....................................18 Table 5: Sample size required to estimate reactogenicity prevalence with the indicated level of precision with 95% confidence interval using Clopper- Pearson exact calculation for the proportion. ...............................................................18 Fig 1: Probability of observing at least one event assuming a given event probability, by varying sample sizes up to 60,000. The horizontal dotted lined correspond to a 95% probability of observing at least one event. ...............17 Fig 2: Data collection and timing (a) for all study participants, and (b) additional data collection for participants in the reactogenicity subset; illustrated for two doses of COVID-19 vaccines 28 days apart (timing between doses may differ) ..................................................................................................................................19 List of tables02 List of figures03 4 PROTOCOL TEMPLATE Protocol sign-off This protocol has been discussed, reviewed and approved by the Scientific Committee consisting of the following members: • [NAME] • [NAME] • [NAME] • [NAME] • [NAME] • [NAME] • [NAME] Protocol title: Cohort event monitoring (CEM) study for safety signal detection in [PRIORITY GROUP OF INTEREST] after vaccination with COVID-19 vaccines in [COUNTRY] Version: [Version number] I have reviewed and approved the protocol. Name of scientific committee member: ......................................................................................... Signature: ............................................................................................................................................ Date: .................................................................................................................................................... 04 5Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Documentation of protocol amendments Version Version date Reason for new version 05 Study team and responsibilities 6.1 Study team Role Organisation Name Research team Principal investigator Project manager Data monitor Other research staff Study site(s) Investigator Study coordinator Other research staff Scientific committee Data owner Sponsor 6.2 Responsibilities Organisation/Capacity Responsibilities 0 6 PROTOCOL TEMPLATE Study team and responsibilities 6.1 Study team Role Organisation Name Research team Principal investigator Project manager Data monitor Other research staff Study site(s) Investigator Study coordinator Other research staff Scientific committee Data owner Sponsor 6.2 Responsibilities Organisation/Capacity Responsibilities 0 7Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Abbreviations AE Adverse event AESI Adverse event of special interest CDC Centers for Disease Control and Prevention CEM Cohort event monitoring CIOMS Council for International Organisations of Medical Sciences COVID-19 Coronavirus disease 2019 DMP Data management plan EMA European Medicines Agency GEP Good epidemiological practice ICF Informed consent form IEC Independent ethics committee IRB Institutional review board MedDRA Medical Dictionary for Regulatory Activities NIP National immunisation programme PT Preferred term SAE Serious adverse event SARS-CoV-2 Severe acute respiratory syndrome Coronavirus 2 SAP Statistical analysis plan SCRI Self-controlled risk interval SIR Standardized incidence ratio SPEAC Safety platform for emergency Vaccines VAED Vaccine-associated enhanced disease WHO World Health Organization 07 Synopsis Full title of study Cohort Event Monitoring (CEM) study for safety signal detection in [PRIORITY GROUP OF INTEREST] after vaccination with COVID-19 vaccines in [COUNTRY]. Background and rationale Vaccines approved for use in national immunisation programmes (NIPs), are considered safe and efficacious based on demonstrable evidence from randomized controlled clinical trials. They are, however, not completely free of risks, and occasional adverse events will inevitably occur following vaccination at the population level. Given vaccines are often recommended for otherwise healthy individuals, the key to success for NIPs is public trust in vaccine safety [1]. Thus, systematic vaccine safety surveillance is indispensable for ensuring safety of vaccines and public trust. COVID-19 vaccine pharmacovigilance should start simultaneously with the implementation of plans for immunisation with COVID-19 vaccines. This protocol describes a cohort event monitoring (CEM) study designed to capture adverse events occurring in a cohort of [PRIORITY GROUP OF INTEREST FOR THIS STUDY] vaccinated with [VACCINE/COVID-19 vaccines] during routine clinical practice in [COUNTRY] for the purpose of signal detection. Objectives The overall aim of this observational study is to monitor the safety of COVID-19 vaccines in [PRIORITY GROUP OF INTEREST FOR THIS STUDY] in [COUNTRY] for the purpose of safety signal detection as soon as the vaccine is used in routine vaccination programmes. Specific objectives 1. To estimate the incidence of serious adverse events (SAEs) in all enrolled vaccinated individuals after each COVID-19 vaccine dose, by COVID-19 vaccine brand. 2. To estimate the incidence of adverse events of special interest (AESIs) that result in hospitalisation in all enrolled vaccinated individuals after each COVID-19 vaccine dose, by COVID-19 vaccine brand. 3. To estimate the reactogenicity within 7 days following each COVID-19 vaccine dose within a subset of patients (‘reactogenicity subset’), by COVID-19 vaccine brand. 4. To estimate the incidence of severe COVID-19 in all enrolled vaccinated individuals, to assess the risk of vaccine-associated enhanced disease (VAED) at a population level. Study design Active COVID-19 vaccine safety surveillance through an observational prospective single-arm cohort study that will be conducted in vaccination centres in [COUNTRY]. Study period There will be an intensive enrolment period from the date of the study start until a predefined number of individuals have been enrolled. The time point for enrolment is first vaccination with any authorized COVID-19 vaccine in participating study sites. Each subject enrolled will be actively followed-up until 3 months after their last COVID-19 vaccine dose. The anticipated follow-up time for every individual is 3 months (for single dose vaccines) and about 4 months (for two-dose vaccines), assuming an interval of up to one month between the first and the second dose. 08 8 PROTOCOL TEMPLATE Synopsis Full title of study Cohort Event Monitoring (CEM) study for safety signal detection in [PRIORITY GROUP OF INTEREST] after vaccination with COVID-19 vaccines in [COUNTRY]. Background and rationale Vaccines approved for use in national immunisation programmes (NIPs), are considered safe and efficacious based on demonstrable evidence from randomized controlled clinical trials. They are, however, not completely free of risks, and occasional adverse events will inevitably occur following vaccination at the population level. Given vaccines are often recommended for otherwise healthy individuals, the key to success for NIPs is public trust in vaccine safety [1]. Thus, systematic vaccine safety surveillance is indispensable for ensuring safety of vaccines and public trust. COVID-19 vaccine pharmacovigilance should start simultaneously with the implementation of plans for immunisation with COVID-19 vaccines. This protocol describes a cohort event monitoring (CEM) study designed to capture adverse events occurring in a cohort of [PRIORITY GROUP OF INTEREST FOR THIS STUDY] vaccinated with [VACCINE/COVID-19 vaccines] during routine clinical practice in [COUNTRY] for the purpose of signal detection. Objectives The overall aim of this observational study is to monitor the safety of COVID-19 vaccines in [PRIORITY GROUP OF INTEREST FOR THIS STUDY] in [COUNTRY] for the purpose of safety signal detection as soon as the vaccine is used in routine vaccination programmes. Specific objectives 1. To estimate the incidence of serious adverse events (SAEs) in all enrolled vaccinated individuals after each COVID-19 vaccine dose, by COVID-19 vaccine brand. 2. To estimate the incidence of adverse events of special interest (AESIs) that result in hospitalisation in all enrolled vaccinated individuals after each COVID-19 vaccine dose, by COVID-19 vaccine brand. 3. To estimate the reactogenicity within 7 days following each COVID-19 vaccine dose within a subset of patients (‘reactogenicity subset’), by COVID-19 vaccine brand. 4. To estimate the incidence of severe COVID-19 in all enrolled vaccinated individuals, to assess the risk of vaccine-associated enhanced disease (VAED) at a population level. Study design Active COVID-19 vaccine safety surveillance through an observational prospective single-arm cohort study that will be conducted in vaccination centres in [COUNTRY]. Study period There will be an intensive enrolment period from the date of the study start until a predefined number of individuals have been enrolled. The time point for enrolment is first vaccination with any authorized COVID-19 vaccine in participating study sites. Each subject enrolled will be actively followed-up until 3 months after their last COVID-19 vaccine dose. The anticipated follow-up time for every individual is 3 months (for single dose vaccines) and about 4 months (for two-dose vaccines), assuming an interval of up to one month between the first and the second dose. 08 9Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Population Participants will be recruited among [PRIORITY GROUP OF INTEREST FOR THIS STUDY], vaccinated at [PLACE OF VACCINATION] participating in this CEM study. Study participation will be strictly voluntary. Inclusion criteria — Written informed consent; — [PRIORITY GROUP OF INTEREST FOR THIS STUDY] vaccinated with the first dose of any COVID-19 vaccine at one of the vaccination centres participating in the study. Exclusion criteria — Individuals already vaccinated with any COVID-19 vaccine before study enrolment, irrespective of the brand. — Individuals unable to comply with study procedures. The first 1,000 participants will be analysed in the reactogenicity subgroup analyses. Variables Exposure of interest Vaccination with the first dose of any of the COVID-19 vaccine brands that are available in [COUNTRY]. The COVID-19 vaccine brand, dose, date of vaccination and batch number will be recorded. Details on the second dose will also be collected if it is administered within 3 months of the first dose. Outcomes — SAEs (hospitalization, death) — AESIs that result in hospitalization — Reactogenicity — Severe COVID-19 disease Data sources Data collection is a mix of investigator site data entry and subject self-reported data through [A MOBILE APP/WEBLINKS/TELEPHONE CALLS/PAPER DIARY]. Sample size The target study size is 30,000 individuals vaccinated with one or more dose(s) of a COVID-19 vaccine. This study size can rule out events occurring with a frequency of at least 1 per 10,000 if no event is observed, with at least 95% confidence. For the reactogenicity subset, the target sample size is 1,000 individuals; the first 1,000 individuals enrolled will be included in this subset. 10 PROTOCOL TEMPLATE Data analyses Participation rates and demographic characteristics will be summarized using descriptive statistics. The mean/median and standard deviation/range will be summarized for age at enrolment, overall and stratified by sex and by country, when appropriate. Frequencies and percentages of outcomes will be provided by age group, sex and country when appropriate. Analyses of SAEs and AESIs will include all individuals, and analyses of reactogenicity will include the reactogenicity subset (the first 1,000 participants enrolled). The frequencies and proportions of individuals with identified SAEs and AESIs will be calculated by time since vaccination, in weeks. For proportions, 95% confidence intervals will be calculated using an exact method. For SAEs and for AESIs with an unknown risk window, observed-to-expected analyses will be performed. The observed incidences for AESIs and SAEs will be compared with expected incidences obtained from the most appropriate sources (e.g., clinical trials, epidemiological studies). The expected rates will be age- stratified, and standardized incidence ratios (SIRs) will be calculated. For acute AESIs with a known risk window, a self-controlled risk interval (SCRI) analysis will be performed. The control interval will be the follow-up time after the risk window for the AESI. For reactogenicity, the frequency and proportion of individuals with at least one solicited AE will be calculated overall, by event type and severity and by time since vaccination, in days. For proportions, 95% confidence intervals will be calculated using an exact method. For each type of reactogenic event and severity, the duration (in days) with their mean/median and standard deviation/range will be calculated. Observed-to-expected analyses will be performed. Incidence of severe COVID-19 disease (any COVID-19 disease diagnosed by a healthcare professional, laboratory-confirmed COVID-19, hospitalization for COVID-19, COVID-19 requiring intensive care unit (ICU) admission, COVID-19 disease resulting in death) will be calculated by dose, by timing between doses, and by time since each vaccination in months. It should be noted that the 3-month follow up period is unlikely to be sufficiently long to detect VAED. Periodic reporting Interim analyses will be performed weekly for the reactogenicity outcomes. For the other outcomes, interim analyses will be performed monthly. Ethics This non-interventional study will be conducted in accordance with the international ethical guidelines for epidemiology studies published by the Council for International Organizations of Medical Sciences (CIOMS) [2], the Declaration of Helsinki and its amendments [3], good epidemiological practice (GEP) guidelines and any applicable national laws and guidelines [SPECIFY AS APPROPRIATE]. Data protection and privacy regulations will be strictly observed in capturing, forwarding, processing, and storing individuals’ data. Written informed consent will be obtained from all participating individuals. The study protocol and informed consent forms will be reviewed and approved by [NAME OF ETHICS COMMITTEE(S)/NAME OF INSTITUTIONAL REVIEW BOARD(S)]. 11Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines purpose of signal detection. The site-specific protocol will include informed consent forms (ICFs) in [LOCAL LANGUAGE(S)]. A statistical analysis plan, and a data management plan will be developed. Findings regarding any study events, whether anecdotal, interim or final, will be communicated carefully and correctly, so as not to undermine trust in vaccines locally or globally. Anecdotal sharing should be prevented by reminding staff about confidentiality. However, even when official sharing aggregate interim and final findings occurs, it should be carefully done, particularly in the light of widespread and growing COVID-19 vaccine hesitancy. Steps must be taken to ensure correct local communication of the study results. To facilitate this, it is important to proactively estimate expected baseline incidence rates (without vaccination) for common study outcomes in the location and the specific population, to ensure that appropriate messaging of results is possible and to maintain trust in the vaccination programme. Objectives The overall aim of this observational study is to monitor the safety of COVID-19 vaccines in [PRIORITY GROUP OF INTEREST FOR THIS STUDY] in [COUNTRY] for the purpose of safety signal detection as soon as the vaccine is introduced. The specific objectives are to: 1. estimate the incidence of SAEs in all enrolled vaccinated individuals after each COVID-19 vaccine dose, by COVID-19 vaccine brand; 2. estimate the incidence of AESIs in all enrolled vaccinated individuals after each COVID-19 vaccine dose, by COVID-19 vaccine brand; 3. estimate the reactogenicity within 7 days after each COVID-19 vaccine dose, by COVID-19 vaccine brand; 4. estimate the incidence of severe COVID-19 disease, to assess the risk of VAED at a population level. 10 Background and rationale In December 2019, an outbreak of respiratory disease caused by a novel coronavirus strain was reported in Wuhan City, Hubei Province, China. The novel coronavirus was named ‘severe acute respiratory syndrome coronavirus 2’ (SARS-CoV-2), while the disease associated with it is referred to as COVID-19. The virus spread to different parts of China and an increasing number of countries worldwide and on 30 January 2020 the World Health Organization (WHO) announced that the outbreak was a public health emergency of international concern (PHIC). The development of safe and effective vaccines is key in containing the SARS-CoV-2 pandemic. Ensuring equitable access to vaccines across the globe is one of the key strategies to mitigate the public health and economic impact of the pandemic [Safety Surveillance Manual] [4]. Vaccine candidates against COVID-19 include traditional virus- and protein-based vaccines and newer platforms such as viral vector-based vaccines and nucleic acid vaccines. Vaccines approved for use in national immunization programmes (NIPs), are considered safe and efficacious based on demonstrable evidence from randomized controlled clinical trials. They are, however, not completely free of risks, despite rigorous safety evaluation during clinical development, and occasional adverse events will occur following vaccination at the population level. Given vaccines are often recommended for otherwise healthy individuals, the key to success of NIPs is public trust in vaccine safety [1]. Thus, systematic vaccine safety surveillance is indispensable for ensuring safety of vaccines and public trust of vaccines, across countries with various pharmacovigilance capacities. Once plans for immunization with COVID-19 vaccines are set- up, pharmacovigilance systems should start simultaneously, and specific COVID-19 vaccine safety surveillance should be implemented, as described in the WHO COVID-19 vaccines: safety surveillance manual [4]. Acknowledging that routine passive reporting systems might not be sufficient to allow rapid assessment and appropriate public health response during COVID-19 vaccine introduction, active safety surveillance is recommended. In [COUNTRY], vaccination with COVID-19 vaccines as part of the NIP is expected to start in [XXX]. It is expected that vaccination will take place with [VACCINE BRAND], a [VACCINE PLATFORM e.g. mRNA] vaccine, manufactured by [MANUFACTURER]. The vaccine is indicated for [AGE GROUP], and is contraindicated for persons with [CONTRAINDICATION]. [Any known safety concerns]. At the initiation of the COVID-19 NIP, there will be limited supplies of the COVID-19 vaccines. [PRIORITY GROUP OF INTEREST FOR THIS STUDY] will be (among) the first groups to be vaccinated, other priority groups are [PRIORITY GROUPS]. [PRIORITY GROUP OF INTEREST FOR THIS STUDY] will be primarily vaccinated at [PLACE OF VACCINATION]. As one or more vaccines may be used in [COUNTRY], identification of vaccine brand will be an important aspect of post-marketing pharmacovigilance activities. This protocol describes a cohort event monitoring (CEM) study designed to capture adverse events occurring in a cohort of [PRIORITY GROUP OF INTEREST FOR THIS STUDY] vaccinated with [VACCINE/COVID-19 vaccines] during routine clinical practice in [COUNTRY] for the 09 12 PROTOCOL TEMPLATE purpose of signal detection. The site-specific protocol will include informed consent forms (ICFs) in [LOCAL LANGUAGE(S)]. A statistical analysis plan, and a data management plan will be developed. Findings regarding any study events, whether anecdotal, interim or final, will be communicated carefully and correctly, so as not to undermine trust in vaccines locally or globally. Anecdotal sharing should be prevented by reminding staff about confidentiality. However, even when official sharing aggregate interim and final findings occurs, it should be carefully done, particularly in the light of widespread and growing COVID-19 vaccine hesitancy. Steps must be taken to ensure correct local communication of the study results. To facilitate this, it is important to proactively estimate expected baseline incidence rates (without vaccination) for common study outcomes in the location and the specific population, to ensure that appropriate messaging of results is possible and to maintain trust in the vaccination programme. Objectives The overall aim of this observational study is to monitor the safety of COVID-19 vaccines in [PRIORITY GROUP OF INTEREST FOR THIS STUDY] in [COUNTRY] for the purpose of safety signal detection as soon as the vaccine is introduced. The specific objectives are to: 1. estimate the incidence of SAEs in all enrolled vaccinated individuals after each COVID-19 vaccine dose, by COVID-19 vaccine brand; 2. estimate the incidence of AESIs in all enrolled vaccinated individuals after each COVID-19 vaccine dose, by COVID-19 vaccine brand; 3. estimate the reactogenicity within 7 days after each COVID-19 vaccine dose, by COVID-19 vaccine brand; 4. estimate the incidence of severe COVID-19 disease, to assess the risk of VAED at a population level. 10 13Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Methods 11.1 Study design Active COVID-19 vaccine safety surveillance through an CEM observational prospective single- arm cohort study that will be conducted through [PLACE OF VACCINATION] under the [NAME OF NATIONAL HEALTH AUTHORITIES]. Study participants will be actively followed up until 3 months after their last COVID-19 vaccine dose, if administered within 3 months of the first dose. The anticipated follow-up time for participants is 3 months (for single dose vaccines) and about 4 months for two-dose vaccines, assuming an interval of up to one month between the first and the second dose. 11.2 Study population Participants will be recruited among [PRIORITY GROUP OF INTEREST FOR THIS STUDY] vaccinated at [PLACE OF VACCINATION] participating in this CEM study. Study participation will be strictly voluntary. 11.2.1 Inclusion criteria • Written informed consent. • [PRIORITY GROUP OF INTEREST FOR THIS STUDY] vaccinated with the first dose of any COVID-19 vaccine at one of the vaccination centres participating in the study. 11.2.2 Exclusion criteria • Individuals already vaccinated with any COVID-19 vaccine before study enrolment, irrespective of the brand. • Individuals unable to comply with study procedures (illiterate, [to be completed as per study set up: e.g., use of mobile phone for data collection]). The first 1,000 individuals enrolled will be included in the reactogenicity subset. 11.2.3 Withdrawal from the study Participants will have the right to withdraw from the study for any reason at any time. A participant will be considered lost-to-follow-up after [NUMBER] unsuccessful attempts to contact them by phone, followed by [NUMBER] unsuccessful attempts to contact their next of kin. The attempts to contact will be documented. 11 14 PROTOCOL TEMPLATE All attempts will be made to determine the underlying reason for withdrawal and, where possible, the primary underlying reason will be recorded. Withdrawn participants and those lost-to-follow-up will not be replaced after the enrolment period has ended. Should a participant decide to withdraw from the study, data collected up to the time of withdrawal will not be withdrawn and will be used in the analyses. 11.3 Study sites [Paragraph describing the health facilities in which the study will be conducted] Study sites are defined as [groups of] vaccination centres where COVID-19 vaccines are administered to [STUDY POPULATION OF INTEREST]. Study sites will be selected based on [SELECTION CRITERIA TO BE LISTED, e.g., study population has access to secondary/tertiary hospitals with the capacity to diagnose the AESIs, size, population covered, vaccination coverage, access to computer for data collection at site-level, availability of sufficient human resources]. Table 1: Study sites with principal investigators and contact details Site Principal investigator Email Phone number 11.4 Study period 11.4.1 Start of study and duration of follow-up There will be an intensive enrolment period from the date of the start of the NIP until the predefined target number (study sample size) of enrolled individuals has been reached. The time point for enrolment will be first vaccination with any licensed COVID-19 vaccine in one of the participating sites. Study recruitment will be monitored during the study to assess whether recruitment goals are being reached. Each individual will be followed-up for 3 months after the first dose of COVID-19 vaccine. If a second dose is administered within 3 months of the first dose, the subject will be followed up till 3 months after the second dose. A 3-month follow-up period was chosen because this covers the most common risk windows for AESIs (42 days), with a similar amount of time after the risk window, to be used as a control period. 15Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines 11.4.2 Study completion and end of study Participants will be considered to have completed the study when they have completed the questionnaire 3 months after their last COVID-19 vaccine dose. End of study is defined as the point at which the last subject enrolled has reached the 3 months follow up period. 11.5 Sample sizes 11.5.1 Sample size for overall cohort To guide the decision for suitable sample sizes, sample sizes were calculated taking into consideration different event frequencies. Table 2 shows the sample sizes required to rule out an event with a given frequency with 95% confidence. If no event is observed with 30,000 participants, events with a frequency of 1 per 10,000 would be ruled out with 95% confidence. Studies conducted following the same protocol in different countries will provide strengthened evidence on COVID-19 vaccine safety. Table 2: Sample size required to rule out events with the indicated frequency if no event is observed with 95% confidence Sample size Event frequency 10,000 1 per 3,333 20,000 1 per 6,666 30,000 1 per 10,000 40,000 1 per 12,500 50,000 1 per 16,666 60,000 1 per 20,000 80,000 1 per 25,000 100,000 1 per 33,333 150,000 1 per 50,000 500,000 1 per 100,000 The probability of observing at least one event was calculated based on a binomial distribution as shown in Figure 1 (example shown for sample sizes up to 60,000). This figure shows the probabilities of observing at least one event in different scenarios corresponding to different sample sizes and event frequencies. The two vertical dotted lines correspond to sample sizes of 10,000 and 30,000, respectively. The horizontal dotted lines correspond to a 95% probability of observing at least one event. With a sample size of 10,000, it is likely (probability ~ 95%) to observe at least one event with an event frequency of 1 per 3,333. A sample size of 20,000 will enable to observe at least one event with an event frequency of 1 per 6,666 people whilst a sample size of 30,000 will enable to observe at least one event with an event frequency of 1 per 10,000 people, with 95% confidence. 16 PROTOCOL TEMPLATE Fig 1: Probability of observing at least one event assuming a given event probability, by varying sample sizes up to 60,000. The horizontal dotted lined correspond to a 95% probability of observing at least one event. The sample size required to rule out a given relative risk (RR) with 95% confidence if no event is observed in the risk window was calculated, taking into account the background incidence rate and the length of the risk window for some AESIs. For example, for an expected background rate for acute respiratory distress syndrome (ARDS) of 39 per 100,000 person-years [5, 6] and a risk window of 40 days, sample sizes of 34,300 and 13.700 subjects would be needed to rule out a RR of 2 and 5, respectively, with 95% confidence (Table 3). Table 3: Sample size needed to rule out a relative risk if no event is observed within the risk window with 95% confidence. AESI Risk window (days)* Background rate** (/100,000) Sample size needed for RR = 2 Sample size needed for RR = 5 Generalized convulsions 0-7 10 6,836,000 2,735,000 ARDS 2-42 39 34,300 13,700 Thrombosis 2-42 80 16,700 6,700 Acute aseptic arthritis 2-42 100 13,400 5,400 *Days post‑vaccination; **Using the lowest value in case of multiple references. Sources for background rates: generalized convulsions: [7]; acute respiratory distress syndrome (ARDS): [5, 6]; thrombosis [8]; acute aseptic arthritis: [9, 10]. Disclaimer: incidence rates provided are only rough estimates as they are not from systematic literature reviews 17Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines For some AESIs, a range of background rates were identified. Additional sample sizes for different rates within the background rates range were calculated (Table 4). Table 4: Sample size needed to rule out different levels of relative risk if no event is observed within the risk window with 95% confidence. Additional results correspond to different values of background rates. AESI Background rate (/100,000) Risk window Sample size needed for RR = 2 Sample size needed for RR = 5 Generalized convulsion 30 D0-D7 2,279,000 91,200 50 D0-D7 1,368,000 54,700 80 D0-D7 85,500 34,200 ARDS 90 D2-D42 14,900 6,000 150 D2-D42 8,900 3,600 193 D2-D42 7,000 2,800 Acute aseptic arthritis 500 D2-D42 2,700 1,100 1000 D2-D42 1,400 600 1600 D2-D42 900 400 Sources for background rates: generalized convulsion [7]; acute respiratory distress syndrome (ARDS) [5, 6]; acute aseptic arthritis: [9, 10] 11.5.2 Sample size for reactogenicity subset To guide the selection of the sample size for the reactogenicity subset, the precision was calculated for a range of prevalence values (Table 5). The precision was defined as the half-width of the 95% exact confidence interval calculated using the Clopper-Pearson exact method [11]. Based on a sample size of 1,000 participants, an anticipated prevalence of 5 to 10% can be estimated with 2% precision. The first 1,000 participants enrolled will be included in the reactogenicity subset analyses. Table 5: Sample size required to estimate reactogenicity prevalence with the indicated level of precision with 95% confidence interval using Clopper-Pearson exact calculation for the proportion. Sample size Precision (%) for different levels of reactogenicity prevalence 1 2 5 10 15 25 50 200 0.03 0.03 0.04 0.05 0.06 0.07 0.07 500 0.01 0.02 0.02 0.03 0.03 0.04 0.04 1,000 0.01 0.01 0.02 0.02 0.02 0.03 0.03 18 PROTOCOL TEMPLATE 11.6 Study variables Study staff will collect data for covariates and vaccination on the day of vaccination. All participants will complete questionnaires through [A MOBILE APP/WEBLINKS/TELEPHONE CALLS/PAPER DIARY] at weekly intervals for 3 months (D7, D14, …, Dd91, with D0 being the day of vaccination) after each vaccine dose administration (Figure 2a). Participants in the reactogenicity subset will also be followed-up daily from the day of vaccination until 7 days after each dose (D0, D1, … D7, with D0 being the day of vaccination) (Figure 2b). Fig 2: Data collection and timing (a) for all study participants, and (b) additional data collection for participants in the reactogenicity subset; illustrated for two doses of COVID-19 vaccines 28 days apart (timing between doses may differ) a) COVID-19 vaccine dose 1 Form E1 (Informed consent, contact details, covariates) Form E2 (Exposure) Form A3 (Follow-up ques�onnaire) to be completed weekly un�l 3 months a�er the second dose D10 D17 D114 D121 D128 D135 D142 D149 D156 D163 D170 D177 D184 D191 COVID-19 vaccine dose 2 Form E2 (Exposure) D20D21 D27 D214 D221 D228 D235 D242 D249 D256 D263 D270 D277 D284 D291 b) D17 D114 D121 D128 D135 D142 D149 D156 D163 D170 D177 D184 D191 COVID-19 vaccine dose 1 D10 COVID-19 vaccine dose 2 Form A2 (Reactogenicity ques�onnaire) to be completed daily from the day of vaccina�on un�l 7 days a�er each dose D20D21 D27 D214 D221 D228 D235 D242 D249 D256 D263 D270 D277 D284 D291 11.6.1 Exposure of interest Vaccination with the first dose of any of the COVID-19 vaccine brands that are available in [COUNTRY]. The COVID-19 vaccine brand, dose, date at vaccination and batch number will be recorded. If a second dose is administered within 3 months of the first dose, same details on the second dose will also be collected. 19Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines 11.6.2 Study outcomes 11.6.2.1 Serious adverse events SAEs that require over-night hospitalization or result in death will be identified. SAEs that result in in-patient hospitalizations will be reported by the participant or their next of kin, and SAEs that results in death will be reported by their next of kin (Appendix 1, form A3 and form E3). 11.6.2.2 Adverse events of special interest resulting in hospitalization The list of AESIs includes events that have a: • proven association with immunization that is true for most, if not all, vaccines; • proven association with a known vaccine platform or adjuvant that is being used in any COVID-19 vaccine; • theoretical concern based on immunopathogenesis of COVID-19 disease; • theoretical concern related to viral replication during COVID-19 infection; • theoretical concern that has been demonstrated in an animal model with one or more candidate vaccine platforms; or • emerging safety signal during vaccine development and/or deployment. Please refer to the WHO COVID-19 vaccines: safety surveillance manual [4]. [It should be noted that the list of relevant AESIs may evolve over time and vary across vaccine brands as results from clinical studies and other safety studies become available globally. The most up to date information should be taken into account when adapting this template protocol.] AESIs (listed in APPENDIX 2) that result in hospitalization will be identified among diagnoses reported by the participant (or their next of kin) during follow-up (Appendix 1, form A3 and form E3). 11.6.2.3 Reactogenicity The first 1,000 participants will be enrolled in the reactogenicity subset. Reactogenicity will be categorized as local or systemic reactogenicity. Local reactogenicity is defined as the presence of pain, redness, warmth, swelling, hardening/induration, haematoma, or itching at, or near, the injection site. Systemic reactogenicity is defined as the presence of fever, chills, headache, nausea, muscle ache, joint pain, or malaise. Local and systemic reactogenicity (including grade) will be solicited and recorded daily for 7 days following each vaccination (D0, D1, …, D7 where D0 is the day of vaccination). See form A2 in Appendix 1 for the daily reactogenicity questionnaire. Additionally, subjects in the reactogenicity subset will be asked to report retrospectively any systemic symptoms in the 3 days prior to enrolment (excluding the day of enrolment) (Appendix 1, form A1). 20 PROTOCOL TEMPLATE 11.6.2.4 Severe COVID‑19 disease Severe COVID-19 disease is defined as COVID-19 disease resulting in hospitalization, requiring intensive care, and/or resulting in death. Occurrence of COVID-19 disease will be solicited throughout follow-up to collect Information on (Appendix 1, Forms A3 and E3): • laboratory-confirmed diagnosis or not; • hospitalization for COVID-19 disease; • intensive care necessary or not; and • COVID-19 resulted in death. In view of the challenges in differentiating between VAED and severe COVID-19 on an individual level only severe COVID-19 will be solicited. The occurrence of severe COVID-19 after immunization will serve as trigger pointing towards potential cases of VAED. It should be noted that the recommended 3-month post vaccine follow up is unlikely to be sufficiently long to detect VAED. 11.7 Study flow: data sources and data collection Data will be collected at the time of enrolment, at time of vaccination, and during follow- up. Data collection by the study site staff at the time of enrolment and vaccination will take place through [AN ELECTRONIC TOOL OR OTHER MEANS] at the site. Data collection by the participants during follow-up will take place through [A MOBILE APP/WEBLINKS/TELEPHONE CALLS/PAPER DIARY]. All data variables are listed in Appendix 1, and a graphic summary is available in APPENDIX 3. 11.7.1 Vaccination and enrolment Potential participants will be informed about the study through [APPROPRIATE ROUTE, e.g. occupational health service department for healthcare workers, or study staff at vaccination centre], and study staff will be available to answer any questions. Enrolment will take place immediately after vaccination, the study staff will collect the signed ICF, complete the participants’ baseline information (demographic and medical) and contact information for the participant and their next of kin (Appendix 1, form E1), and record the details of vaccination (Appendix 1, form E2). A unique participant identifier will then be generated. To increase the quality of the self-reported data, participants will be asked to report any physician-made diagnoses and, if they are hospitalized, to provide data from their discharge report, if available. In addition, the participants will be asked to return to the same vaccination centre to receive their second dose of COVID-19 vaccine (if applicable). 21Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines 11.7.2 Vaccination during the follow-up period If participants receive a second COVID-19 vaccine dose during the follow-up period, details of the second vaccination are also collected (Appendix 1, form E2). 11.7.3 Follow-up The participants will complete the study questionnaires at predefined time points during follow-up. Reminders will be sent to participants who do not complete the questionnaire [TO DESCRIBE APPROPRIATE FORMAT AND FREQUENCY OF REMINDERS DEPENDING ON DATA COLLECTION TOOL AND ON TYPE OF QUESTIONNAIRE, e.g., push notification in app, SMS]. If the questionnaire is still not completed, the participant will be called by telephone. After [NUMBER] unsuccessful attempts to contact the participant by phone, their next of kin will be contacted. After [NUMBER] unsuccessful attempts to contact their next of kin, the participant will be considered as lost to follow-up. The online questionnaires will expire at the end of the day (time 23:59) preceding the next data collection point. It will be possible to complete reactogenicity questionnaires (Appendix 1, forms A1 and A2) until 23:59 every day, after which they expire. It will be possible to complete follow-up questionnaires (Appendix 1, forms A3) for one week, after which they expire. 11.7.4 Identification of AESIs and SAEs The diagnoses reported by the participants during follow-up will be coded using Medical Dictionary for Regulatory Activities (MedDRA) by [TO BE DEFINED BY STUDY TEAM]. SAES and AESIs will be identified using MedDRA codes by [TO BE DEFINED BY STUDY TEAM]. 11.7.5 Pregnancy Participants who are reported to be pregnant during follow-up will be referred to the [NATIONAL AEFI FOCAL POINT] for follow-up as per national guidelines. As per WHO recommendation, all pregnant women inadvertently exposed to COVID-19 vaccine should be followed up until delivery, and the pregnancy outcome documented. Please refer to the module on safety surveillance of pregnant and lactating women manual WHO’s COVID-19 vaccines: safety surveillance manual [4]. 11.7.6 Data collection at withdrawal/lost to follow-up If a participant withdraws from the study or is lost-to-follow-up, the follow-up for that participant will be terminated early and the date of and, if possible, the reason for withdrawal/ lost-to-follow-up will be recorded. 22 PROTOCOL TEMPLATE If a safety signal is detected, [DESIGNATED STUDY TEAM/NATIONAL AEFI FOCAL POINT/ NATIONAL PHARMACOVIGILANCE CENTER] may decide to contact the healthcare provider of participant with the potential safety issue, for further investigation through [APPROPRIATE NATIONAL ROUTES]. 11.8 Data analysis The analysis plan will be fully described in a written and approved statistical analysis plan (SAP). All analyses will be documented in the final study report. Missing data will be acknowledged in the analyses and interpretation of data. 11.8.1 Descriptive analysis of demographics and baseline characteristics Participation rates over time will be described. Demographic characteristics will be summarized. The mean/median and standard deviation/range will be given for age at enrolment, overall and stratified by sex and by country, when appropriate. Frequencies and percentages will be provided by age group, sex, and country, when appropriate. 11.8.2 Statistical analyses The analyses of SAEs and AESIs will include data for all participants, while analyses of reactogenicity will include only data from the participants in the reactogenicity subset. Participants that completed the follow-up forms but do not report any event(s) will be considered as participants without event(s). Diagnoses will be coded, using MedDRA preferred terms (PTs), by [TO BE DEFINED BY STUDY TEAM]. All analyses for AESIs will be at the PT levels. The frequency and proportion of participants reporting AESIs and SAEs will be calculated by time since vaccination (in weeks). For the proportions, 95% confidence intervals will be calculated using an exact method [11]. Observed-to-expected analyses will be performed for SAEs and AESIs with an unknown risk window. The observed incidences for AESIs will be compared with background rates from the most appropriate sources. Good quality national background rates will be used if available. If these are not available, good quality background rates from neighbouring countries with comparable healthcare systems will be used. If these are also not available, quality background rates obtained from the Centers for Disease Control and Prevention (CDC) or European Medicines Agency (EMA) will be used. Sensitivity analyses will be performed if deemed appropriate. The expected rate will be age-stratified, and the standardised incidence ratio (SIR) will be calculated. For acute AESIs with a known risk window (see APPENDIX 2t), self-controlled risk interval (SCRI) analyses will be performed. The control interval will consist of the follow-up time after the risk window for the acute outcomes. 23Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines For reactogenicity, the frequency and proportion of participants with at least one solicited AE will be calculated overall and by event type, by event type and severity, and by time since vaccination, in days. For the proportions, the 95% confidence intervals will be calculated using an exact method. For each type of event and severity, the duration (in days) will be calculated and their mean/median and standard deviation/range will be reported. Observed-to-expected analyses will be performed using the retrospectively collected data for the 3 days prior to vaccination and, when available, using data from control groups from appropriate clinical trial sources from the same or similar countries. The incidence of COVID-19 disease (any COVID-19 disease diagnosed by a healthcare professional, laboratory-confirmed COVID-19, hospitalization for COVID-19, COVID-19 requiring intensive care unit admission, COVID-19 resulting in death) will be calculated by dose, by timing between doses, and by time since each vaccination in months. Participants with COVID-19 symptom onset within [APPROPRIATE TIME INTERVAL] after vaccination may be excluded. Data management A data management plan (DMP) will be developed before data collection begins and will describe all functions, processes, and specifications for data collection, cleaning and validation. Study staff will enter data in [APPROPRIATE TOOL] at several time points. Study staff will enter data on informed consent, contact details and covariates at the time of enrolment, data on the exposure at the time of vaccination, [DATA FROM THE QUESTIONNAIRE IF COLLECTED THROUGH TELEPHONE/PAPER-BASED DIARIES], and any data obtained in the event of additional follow-up after initial non-response. [TO DESCRIBE SPECIFICATIONS OF MEANS OF DATA COLLECTION, SOFTWARE IF ANY, DATA STORAGE]. Participants will complete the questionnaires through [A MOBILE APP/WEBLINKS/TELEPHONE CALLS/PAPER DIARIES]. The questionnaires will be available in [LANGUAGE]. [SPECIFICATIONS OF MEANS OF DATA COLLECTION, SOFTWARE IF ANY, DATA STORAGE TO BE DESCRIBE]. For all electronic data entry, automated quality checks will detect out-of-range or anomalous data, where applicable. User testing of any data entry methods, whether electronic or on paper, will be performed prior to deployment. 12 24 PROTOCOL TEMPLATE 12.1 Data security [PROCESSES FOR ANONYMIZATION, ACCESS, STORAGE, AND DESTRUCTION OF RAW DATA TO BE DESCRIBE]. The key-coded data obtained from this study will be stored in a secured database located in [COUNTRY]. Data will be handled in accordance with all applicable data protection and privacy laws. No unauthorized persons will have access to the data. Data will be archived for [XXX] years, as per national regulations, and will then be destroyed. These security measures will also apply to the ICFs. 12.2 Data transfer [PROCESS FOR DATA TRANSFER INCLUDING SECURITIY TO BE DESCRIBE]. 12.3 Source documents The data sources for the exposure of interest will be [TO BE COMPLETED AS APPLICABLE]. The data source for covariates will be the participants. The data sources for the study outcomes will be the questionnaires completed by the participants (or their next of kin). 12.4 Data retention and archiving Documents that individually and collectively permit evaluation of the study conduct and the quality of the data produced will be retained for [TIME PERIOD AS APPLICABLE] in accordance with good pharmacoepidemiological practice guidelines [12] and [LOCAL REGULATIONS, to be detailed in the site-specific protocol]. This will include the analytical data, analyses programs, and all output generated. 25Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Study management This study will be performed by the investigator, with guidance, input, review and approval of the sponsor, including development of materials, recruitment, training and management of sites, electronic data capture and data management and analyses. The Investigator and all study staff will conduct the study in compliance with the [NAME ETHICS COMMITTEE/NAME of INSTITUTONAL REVIEW BOARD] approved version of this protocol. All personnel involved in the conduct of this study must be qualified by education, training and experience to perform their tasks. 14.1 National pharmacovigilance centre/ AEFI committee/national immunization programme manager/dedicated scientific committee The [NAME OF NATIONAL PHARMACOVIGLANCE CENTRE/AEFI COMMITTEE/NATIONAL IMMUNIZATION PROGRAMME MANAGER/DEDICATED SCIENTIFIC COMMITTEE (to be detailed in the site-specific protocol)] will oversee the implementation and smooth running of the project. They will provide scientific, statistical and technical expertise, as needed. 14.2 Changes to the protocol Changes to the protocol will be documented in written protocol amendments. Major amendments will usually require submission to the relevant institutional review board (IRB)/ independent ethics committee (IEC) for approval. In such cases, the amendment will be implemented only after approval has been obtained. Minor protocol amendments, including administrative changes, will be filed by the investigator at each participating site and will be submitted to the relevant IRB/IEC. Any amendment that could have an impact on an individual’s agreement to participate in the study will require the renewed informed consent prior to continued participation in the study. 14.3 Management and reporting of adverse events/adverse reactions The study team will ensure that the healthcare workers in charge of vaccine administration in study sites are familiar with the national AEFI reporting and management processes as per 14Quality assurance, monitoring and reporting 13.1 Monitoring A site initiation [VISIT (PREFERRED IF FEASIBLE)/TELEPHONE CALL] will be conducted to ensure the site is ready to start data collection. Study staff will be trained on the study procedures. [REMOTE/ON-SITE] monitoring of the study conduct will be performed throughout the study period to assess the accuracy and completeness of the data. The study site may be subject to a quality assurance visit. If so, the site will be contacted in advance to arrange a monitoring visit. The investigator and site staff will guarantee direct access to all study documents for quality assurance monitors. 13.2 Interim analyses and reporting Interim analyses will be performed by [TO BE DEFINED BY STUDY TEAM] on a weekly basis for the reactogenicity outcomes, as data will be collected daily. For the other outcomes, for which data will be collected weekly, interim analyses will be performed on a monthly basis. Should the rates of adverse event be different from the expected rates (as per clinical trials data and reported in the summary product characteristic of a given product), the study team will have to inform the national regulatory authorities for regulatory review. 13.3 Final analyses and reporting Final analyses will be performed and a full study report will be written within 4 weeks after database lock. Study results will be shared with the national regulatory authorities for regulatory review, and with the national immunization programme to inform policy decision. 13 26 PROTOCOL TEMPLATE Study management This study will be performed by the investigator, with guidance, input, review and approval of the sponsor, including development of materials, recruitment, training and management of sites, electronic data capture and data management and analyses. The Investigator and all study staff will conduct the study in compliance with the [NAME ETHICS COMMITTEE/NAME of INSTITUTONAL REVIEW BOARD] approved version of this protocol. All personnel involved in the conduct of this study must be qualified by education, training and experience to perform their tasks. 14.1 National pharmacovigilance centre/ AEFI committee/national immunization programme manager/dedicated scientific committee The [NAME OF NATIONAL PHARMACOVIGLANCE CENTRE/AEFI COMMITTEE/NATIONAL IMMUNIZATION PROGRAMME MANAGER/DEDICATED SCIENTIFIC COMMITTEE (to be detailed in the site-specific protocol)] will oversee the implementation and smooth running of the project. They will provide scientific, statistical and technical expertise, as needed. 14.2 Changes to the protocol Changes to the protocol will be documented in written protocol amendments. Major amendments will usually require submission to the relevant institutional review board (IRB)/ independent ethics committee (IEC) for approval. In such cases, the amendment will be implemented only after approval has been obtained. Minor protocol amendments, including administrative changes, will be filed by the investigator at each participating site and will be submitted to the relevant IRB/IEC. Any amendment that could have an impact on an individual’s agreement to participate in the study will require the renewed informed consent prior to continued participation in the study. 14.3 Management and reporting of adverse events/adverse reactions The study team will ensure that the healthcare workers in charge of vaccine administration in study sites are familiar with the national AEFI reporting and management processes as per 14 27Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines national guidelines. The study team will liaise with the national immunization programme/ national regulatory authorities to ensure that provisions are in place (including AEFI reporting forms, procedures, and training) for smooth implementation. Adverse events will be assessed at the level of the population. No individual causality assessment will be done as part of the study. Contact information of the participants and their healthcare providers will be collected, and consent will be sought to use this contact information in case the [NAME OF NATIONAL AEFI FOCAL POINT/NATIONAL PHARMACOVIGILANCE CENTER] needs to investigate any potential safety signals that arise from the study. The study team will be responsible to ensure that all SAEs detected and reported in the context of this study will also be reported through the routine AEFI surveillance system to the responsible organization within the health ministry (NPI/national regulatory authorities/ pharmacovigilance centre), to ensure appropriate healthcare, timely investigation, causality assessment and response as per the country’s protocol. [Describe mechanisms/processes to ensure that all serious adverse events detected and reported in the context of this study, are also reported through the routine AEFI surveillance system to the responsible institution within the health ministry (NPI/ national regulatory authorities / pharmacovigilance centre), to ensure timely investigation, causality assessment and response as per the country protocol]. Ethical considerations 15.1 Guiding principles To ensure the quality and integrity of research, this study will be conducted under the International Ethical Guidelines for Health related Research involving humans issued by the Council for International Organizations of Medical Sciences [2] , good epidemiological practice (GEP) guidelines, the ethical principles in the Declaration of Helsinki [3] and any applicable national laws, regulations and guidelines. This is an observational study without medical intervention or change in the clinical and diagnostic practices. Therefore, there will be no direct benefit to the participants. Nevertheless, there will be potentially important societal benefits from this vaccine safety study. COVID-19 vaccines are key to controlling the pandemic. Close monitoring of the first cohorts vaccinated 15 28 PROTOCOL TEMPLATE with COVID-19 vaccines will be important for these novel vaccines, to ensure safety and to maintain public confidence in vaccines. 15.2 Respecting participants’ autonomy The study will use self-reported data and data collected as part of healthcare provision at designated hospital(s). Participants will be informed about the study through [TO COMPLETE AS APPLICABLE] and will have the opportunity to ask questions to study staff. An ICF must be signed prior to the individual’s participation in the study (APPENDIX 4). When signing the ICF, individuals agree that the study team will be able to contact designated hospital(s) at which they may have sought care during the study period. The purpose of this contact is to obtain medical confirmation of the adverse event that led to the hospital visit. The study-specific ICF will spell out the purpose of the data collection, the foreseeable uses of the data, the intended goal of such use, who has access to the data, the conditions and duration of data storage, and the ways in which the participant can contact the custodian and remain informed about future use. The ICF will explain that individual’s participation is completely voluntary and that they can decide to withdraw at any time during the study. [The adult ICF template and process will need to be adapted for special populations (e.g., minors, pregnant women, elderly patients lacking full capacity, migrants, prisoners) that require a tailored approach to consent, including possible surrogate decision-makers (e.g. parents or guardians, adult children) or study advocates (e.g. for inclusion of prisoners, orphans) and additional forms (e.g., assent forms), as well as tailoring some details provided to participants during consent]. 15.3 Participant confidentiality No data whatsoever will be used, either alone or in conjunction with any other information to establish the identity of any of the participants from whom data were obtained. All parties will ensure protection of participant personal data and will not include participant’s names on any study forms, reports, publications, or in any other disclosures, except where required by law. Local data protection and privacy regulations [TO BE DETAILED IN THE SITE SPECIFIC PROTOCOL] will be observed in capturing, forwarding, processing, and storing patient data. 15.4 Independent ethics committee/ institutional review board Participating study sites will submit the site-specific protocols to [NAME OF ETHICS COMMITTEE(S)/ NAME OF INSTITUTIONAL REVIEW BOARD(S), following local regulations - to be detailed in the site-specific protocol] and will comply with any national ethics committee requirements. Informed consent will be required from all participants or legal representatives. 29Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Limitations The exclusion of individuals who have already been vaccinated with COVID-19 vaccine precludes the possibility to monitor effects of repeat vaccinations as part of this study. The study is limited to sites located in areas where the study population has access to secondary or tertiary hospitals with the capacity to diagnose the AESIs. Consequently, populations in rural areas with only community clinics will be excluded. References [1] World Health Organization. Vaccine safety basics learning manual. Geneva, Switzerland: WHO; 2013. [2] Council for International Organizations of Medical Sciences. International ethical guidelines for epidemiological studies Geneva, Switzerland: CIOMS; 2009. Last accessed 9 March 2021; Available from: https://cioms.ch/publications/product/international-ethical-guidelines- for-epidemiological-studies/. [3] World Medical Association. WMA Declaration of Helsinki - ethical principles for medical research involving human subjects. 2013. Last accessed 9 March 2021; Available from: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles- for-medical-research-involving-human-subjects/. [4] World Health Organization. Covid-19 vaccines: safety surveillance manual. Geneva2020. Last accessed 11 March 2021; Available from: https://www.who.int/publications/i/ item/10665338400. [5] Li G, Malinchoc M, Cartin-Ceba R, Venkata CV, Kor DJ, Peters SG, et al. Eight-year trend of acute respiratory distress syndrome: a population-based study in Olmsted County, Minnesota. Am J Respir Crit Care Med. 2011;183:59-66. [6] Eworuke E, Major JM, McClain LIG. National incidence rates for Acute Respiratory Distress Syndrome (ARDS) and ARDS cause-specific factors in the United States (2006–2014). J Crit Care. 2018;47:192-7. 16 17 30 PROTOCOL TEMPLATE [7] Sturkenboom M, Braeye T, van der Aa L, Danieli G, Dodd C, Duarte-Salles T, et al. Advance database characterisation and fit for purpose assessment for multi-country studies on the coverage, benefits and risks of pertussis vaccinations. Vaccine. 2020;38:B8-B21. [8] Waheed SM, Kudaravalli P, Hotwagner DT. Deep vein thrombosis. Treasure Island (FL): StatPearls Publishing; 2020. Last accessed 17 March 2021; Available from: https://www. ncbi.nlm.nih.gov/books/NBK507708/. [9] Prieto-Alhambra D, Judge A, Javaid MK, Cooper C, Diez-Perez A, Arden NK. Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. Ann Rheum Dis. 2014;73:1659-64. [10] Roddy E, Choi HK. Epidemiology of gout. Rheum Dis Clin North Am. 2014;40:155-75. [11] Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika. 1934;26:404-13. [12] Public Policy Committee ISoP. Guidelines for good pharmacoepidemiology practice (GPP). Pharmacoepidemiol Drug Saf. 2016;25:2-10. [13] Law B. SO2-D2.1.2 Priority List of COVID-19 Adverse events of special interest: Quarterly update December 2020. Safety Platform for Emergency vACcines (SPEAC); 2021. Last accessed 11 March 2021; Available from: https://brightoncollaboration.us/wp-content/ uploads/2021/01/SO2_D2.1.2_V1.2_COVID-19_AESI-update_V1.3.pdf. 31Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Appendices Appendix 1 Data dictionary Variable name Type Values and coding Question to be asked Data from electronic tool Table 1: Participant’s information Form E1: Participant registration, informed consent, contact, and covariates siteID Type of variable at discretion of site [needs to be unique] Unique and persistent identifier for each site subjectID Type of variable at discretion of site [needs to be unique] Unique and persistent identifier for each participant subjName Text Name of participant consent Numeric (binary) 0 = No 1 = Yes Informed consent provided reactoSubset Numeric (binary) 0 = No 1 = Yes Is the participant part of the reactogenicity subset? Subject contact details subjPhone Numeric Participant’s phone number NOKname Text Name of next of kin NOKphone Numeric Phone number of next of kin Subject covariates subjDoB Date dd/mm/yyyy Date of birth of participant subjSex Numeric (multinomial) 0 = Male 1 = Female 2 = Other Sex of participant subjPreg Numeric (multinomial) 0 = No 1 = Yes 2 = Not applicable Is the participant pregnant 18 32 PROTOCOL TEMPLATE Variable name Type Values and coding Question to be asked subjLact Numeric (multinomial) 0 = No 1 = Yes 2 = Not applicable Is the participant breastfeeding? subjMedHist Numeric (multinomial) 0 = No medical history 1 = Chronic respiratory disease or asthma 2 = Chronic heart disease 3 = Chronic liver disease 4 = Chronic renal disease 5 = Diabetes 6 = Immunocompromised/ immunosuppressed 7 = Obesity 8 = Allergy Medical history, presence of diseases? subjPriorCovid Numeric (multinomial) 0 = No 1 = Yes, laboratory confirmed 2 = Probable but not laboratory-confirmed Previous COVID-19 disease subjPriorRxn Numeric (multinomial) 0 = No 1 = Yes 2 = Do not know History of reaction to vaccination subjPriorRxn Text Indicate which vaccine and describe reaction (Only filled in if subjPriorRxn == 1) subjSocioE Numeric (multinomial) (classes to be defined locally) Socioeconomic class Data from electronic tool Table 2: Vaccine exposure information Table 2 can be linked to Table 1 by subjectID Form E2: Subject exposure dose 1 & 2 doseID Numeric 1 = 1st vaccination 2 = 2nd vaccination 1st or 2nd dose of vaccine vaccDate Date dd/mm/yyyy Date of vaccination vaccTime Time HH:MM Time of vaccination vaccBrand Numeric (multinomial) 1 – to list all brand/ manufacturers available in the country Vaccine brand and manufacturer vaccBatch Text Vaccine batch number vaccDiluent Numeric (binary) 0 = No 1 = Yes Was a separate diluent required? 33Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Variable name Type Values and coding Question to be asked vaccDiluentBrand Numeric (multinomial) 1 – to list all brand/ manufacturers available in the country Diluent brand and manufacturer (Only filled in if vaccDiluent == 1) vaccDiluentBatch Text Diluent batch number (Only filled in if vaccDiluent == 1) vaccOther Numeric (binary) 0 = No 1 = Yes Co-administration of vaccine against any disease other than COVID vaccOtherDis Text Specify which disease was vaccinated against (Only filled in if vaccOther == 1) Data from the app Table 3: Pre-vaccination reactogenicity Table 3 can be linked to Table 1 by subjectID Trigged only if reactoSubset == 1 & prevaccFU == 1 Form A1: Reactogenicity (pre-vaccination) preLogID Numeric Numbers from 1 to 7 Unique ID for the record of pre-vaccination reactogenicity preLogDate Date dd/mm/yyyy Date of record preFebrile Numeric (binary) 0 = No 1 = Yes Did you feel febrile in the past 3 days? preTempY Numeric (binary) 0 = No 1 = Yes Did you measure your temperature in the past 3 days? preTemp Numeric (multinomial) 1 = Below 38.0°C (below 100.4°F) 2 = 38.0°C to 38.4°C (100.4°F to 101.12 °F) 3 = 38.5°C to 38.9°C (101.3°F to 102.02°F) 4 = Higher than 39.0°C (higher than 102.2°F) What was your temperature? (Only filled in if preTempY == 1) preTempWhere Numeric (multinomial) 1 = Oral (in the mouth) 2 = Rectum (in the anus) 3 = Armpit 4 = Ear 5 = Forehead Where did you measure the temperature? (Only filled in if preTempY == 1) preNausea Numeric (binary) 0 = No 1 = Yes Did you feel nauseous in the past 3 days, or did you vomit? 34 PROTOCOL TEMPLATE Variable name Type Values and coding Question to be asked preNauseaSev Numeric (multinomial) 1 = The nausea/vomiting did not interfere with my activities 2 = The nausea/vomiting somewhat interfered with my activities 3 = The nausea/vomiting was considerable and prevented my daily activities How severe was the nausea/vomiting? (Only filled in if preNausea == 1) preMalaise Numeric (binary) 0 = No 1 = Yes Did you experience general malaise in the past 3 days (feeling of weakness, not feeling well)? preMalaiseSev Numeric (multinomial) 1 = The malaise did not interfere with my activities 2 = The malaise somewhat interfered with my activities 3 = The malaise was considerable and prevented my daily activities How severe was the general malaise? (Only filled in if preMalaise == 1) preChill Numeric (binary) 0 = No 1 = Yes Did you have chills in the past 3 days? preChillSev Numeric (binary) 1 = The chills did not interfere with my activities 2 = The chills somewhat interfered with my activities 3 = The chills were considerable and prevented my daily activities How severe were the chills? (Only filled in if preChill == 1) preHeadache Numeric (binary) 0 = No 1 = Yes Did you have a headache in the past 3 days? preHeadacheSev Numeric (multinomial) 1 = The headache did not interfere with my activities 2 = The headache somewhat interfered with my activities 3 = The headache was considerable and prevented my daily activities How bad was the headache? (Only filled in if preHeadache == 1) prePain Numeric (binary) 0 = No 1 = Yes Did you have joint pain in the past 3 days? prePainSev Numeric (multinomial) 1 = The joint pain did not interfere with my activities 2 = The joint pain somewhat interfered with my activities 3 = The joint pain was considerable and prevented my daily activities How bad was the joint pain? (Only filled in if prePain == 1) preMuscle Numeric (binary) 0 = No 1 = Yes Did you have muscle aches in the past 3 days? 35Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Variable name Type Values and coding Question to be asked preMuscleSev Numeric (multinomial) 1 = The muscle aches did not interfere with my activities 2 = The muscle aches somewhat interfered with my activities 3 = The muscle aches were considerable and prevented my daily activities How bad were the muscle aches? (Only filled in if preMuscle == 1) preTired Numeric (binary) 0 = No 1 = Yes Did you feel tired (fatigued) in the past 3 days? preTiredSev Numeric (multinomial) 1 = The tiredness did not interfere with my activities 2 = The tiredness somewhat interfered with my activities 3 = The tiredness was considerable and prevented my daily activities How bad was the tiredness? Data from the app Table 4: Post-vacc dose ID Trigged only if reactoSubset == 1 posDoseID Numeric (binary) 1 = 1st vaccine dose 2 = 2nd vaccine dose [unique per each subject] Identifier if the subsequent record is for reactogenicity after the 1st or 2nd vaccine dose Table 5: Post-vaccination reactogenicity Table 5 can be linked to Table 4 by posDoseID Trigged only if reactoSubset == 1 Form A2: Reactogenicity (post-vaccination) posLogID Numeric Numbers from 1 to 8 [unique per each posDoseID per each subjectID] ID for the record of pre- vaccination reactogenicity corresponding to each date posLogDate Date dd/mm/yyyy Date of record posInjectPain Numeric (binary) 0 = No 1 = Yes Did you have pain at the injection site today? posPainSev Numeric (multinomial) 1 = The pain did not interfere with my activities 2 = The pain somewhat interfered with my activities 3 = The pain was considerable and prevented my daily activities How much pain did you have? (Only filled in if posInjectPain == 1) posRedness Numeric (binary) 0 = No 1 = Yes Was your skin red around the injection site today? 36 PROTOCOL TEMPLATE Variable name Type Values and coding Question to be asked posRedBig Numeric (multinomial) 1 = Less than 2.,5 cm 2 = 2.5 to 5.0 cm 3 = 5.1 to 10 cm 4 = More than 10 cm 5 = Unknown/not measured How big was the red area? (Only filled in if posRedness == 1) posSwell Numeric (binary) 0 = No 1 = Yes Did you have swelling around the injection site on today? posSwellBig Numeric (multinomial) 1 = Less than 2.5 cm 2 = 2.5 to 5.0 cm 3 = 5.1 to 10 cm 4 = More than 10 cm 5 = Unknown/not measured How big was the swelling? (Only filled in if posSwell == 1) posHard Numeric (binary) 0 = No 1 = Yes Was the area around the injection site hard (induration) today? posHardBig Numeric (multinomial) 1 = Less than 2.5 cm 2 = 2.5 to 5.0 cm 3 = 5.1 to 10 cm 4 = More than 10 cm 5 = Unknown/not measured How big was the hardened area? (Only filled in if posHard == 1) posBruise Numeric (binary) 0 = No 1 = Yes Did you have a bruise (haematoma) around the injection site today? posBruiseBig Numeric (multinomial) 1 = Less than 2.5 cm 2 = 2.5 to 5.0 cm 3 = 5.1 to 10 cm 4 = More than 10 cm 5 = Unknown/not measured How big was the bruise? (Only filled in if posBruise == 1) posWarm Numeric (binary) 0 = No 1 = Yes Was the area around the injection site warm today? posWarmSev Numeric (multinomial) 1 = The warmth did not interfere with my activities 2 = The warmth somewhat interfered with my activities 3 = The warmth was considerable and prevented my daily activities How severe was the warmth? (Only filled in if posWarm == 1) posItch Numeric (binary) 0 = No 1 = Yes Did you have an itch around the injection site today? posItchSev Numeric (multinomial) 1 = The itch did not interfere with my activities 2 = The itch somewhat interfered with my activities 3 = The itch was considerable and prevented my daily activities How severe was the itch? (Only filled in if posItch == 1) 37Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Variable name Type Values and coding Question to be asked posFebrile Numeric (binary) 0 = No 1 = Yes Did you feel febrile today? posTempY Numeric (binary) 0 = No 1 = Yes Did you measure your temperature today? posTemp Numeric (multinomial) 1 = Below 38.0°C (below 100.4°F) 2 = 38.0°C to 38.4°C (100.4°F to 101.12°F) 3 = 38.5°C to 38.9°C (101.3°F to 102.02°F) 4 = Higher than 39.0 °C (higher than 102.2°F) What was your temperature? (Only filled in if posTempY == 1) posTempWhere Numeric (multinomial) 1 = Oral (in the mouth) 2 = Rectum (in the anus) 3 = Armpit 4 = Ear 5 = Forehead Where did you measure the temperature? (Only filled in if posTempY == 1) posNausea Numeric (binary) 0 = No 1 = Yes Did you feel nauseous today, or did you vomit? posNauseaSev Numeric (multinomial) 1 = The nausea/vomiting did not interfere with my activities 2 = The nausea/vomiting somewhat interfered with my activities 3 = The nausea/vomiting was considerable and prevented my daily activities How severe was the nausea/vomiting? (Only filled in if posNausea == 1) posMalaise Numeric (binary) 0 = No 1 = Yes Did you experience general malaise today (feeling of weakness, not feeling well)? posMalaiseSev Numeric (multinomial) 1 = The malaise did not interfere with my activities 2 = The malaise somewhat interfered with my activities 3 = The malaise was considerable and prevented my daily activities How severe was the general malaise? (Only filled in if posMalaise == 1) posChill Numeric (binary) 0 = No 1 = Yes Did you have chills today? posChillSev Numeric (binary) 1 = The chills did not interfere with my activities 2 = The chills somewhat interfered with my activities 3 = The chills were considerable and prevented my daily activities How severe were the chills? (Only filled in if posChill == 1) posHeadache Numeric (binary) 0 = No 1 = Yes Did you have a headache today? 38 PROTOCOL TEMPLATE Variable name Type Values and coding Question to be asked posHeadacheSev Numeric (multinomial) 1 = The headache did not interfere with my activities 2 = The headache somewhat interfered with my activities 3 = The headache was considerable and prevented my daily activities How bad was the headache? (Only filled in if posHeadache == 1) posPain Numeric (binary) 0 = No 1 = Yes Did you have joint pain today? posPainSev Numeric (multinomial) 1 = The joint pain did not interfere with my activities 2 = The joint pain somewhat interfered with my activities 3 = The joint pain was considerable and prevented my daily activities How bad was the joint pain? (Only filled in if posPain == 1) posMuscle Numeric (binary) 0 = No 1 = Yes Did you have muscle aches today? posMuscleSev Numeric (multinomial) 1 = The muscle aches did not interfere with my activities 2 = The muscle aches somewhat interfered with my activities 3 = The muscle aches were considerable and prevented my daily activities How bad were the muscle aches? (Only filled in if posMuscle == 1) posTired Numeric (binary) 0 = No 1 = Yes Did you feel tired (fatigued) today? posTiredSev Numeric (multinomial) 1 = The tiredness did not interfere with my activities 2 = The tiredness somewhat interfered with my activities 3 = The tiredness was considerable and prevented my daily activities How bad was the tiredness? (Only filled in if posTired == 1) Data from the app (and the electronic tool if participant did not complete the follow-up questionnaire in the app) Table 6: FU identifier Table 6 can be linked to Table 1 by subjectID Form E3: Follow-up questionnaire fuID Numeric 1 = FU one week after 1st dose 2 = FU one week after 2nd dose 3 = FU one month after 2nd FU 4 = FU one month after 3rd FU --- [needs to be unique for each subjectID] Identifier of the follow-up questionnaire 39Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Variable name Type Values and coding Question to be asked fuBySujb Numeric (binary) 0 = No 1 = Yes Form completed by participant (via the app) or site staff (via the electronic tool)? fuWhyLoss Numeric (multinomial) 0 = No reason given 1 = The study takes too much time 2 = Not interested anymore 4 = Death 5 = Other Reason for no completed- follow-up form. (Only if fuBySujb == 1) fuWhyDeath Text Reason for death (Only if fuWhyLoss == 4) fuMedCare Numeric (multinomial) 0 = No 1 = 1 times 2 = 2 times etc How many times did the participant seek medical care between [date X and date Y]? (e.g., at a local health centre, or hospital) Table 7: FU information Table 7 can be linked to Table 6 by fuID Triggered by fuMedCare > 0 Form A3: Follow-up questionnaire fuHosp Numeric (binary) 0 = No 1 = Yes Were you hospitalized since [date of last contact]? (Only if fuEventType == 3) fuHospDate Date mm/dd/yyyy What was the date of hospital admission? (Only if fuHosp == 1) fuHospOut Numeric (binary) 0 = No 1 = Yes Have you been discharged from hospital? (Only if fuHosp == 1) fuHospOutDate Date dd/mm/yyyy What was the date of hospital discharge (Only if fuHosp == 1 and fuHospOut == 1) fuReason Text Indicate reason for your hospitalization fuDiag Text Indicate diagnosis by healthcare provider, if available fuReport Picture/ Attachment Take a picture/attach your discharge report, if available fuHospID Text Name and place of hospital 40 PROTOCOL TEMPLATE Variable name Type Values and coding Question to be asked fuCovid Numeric (binary) 0 = No 1 = Yes Were you diagnosed with COVID-19 disease by a healthcare professional? fuCovidTest Numeric (multinomial) 0 = No 1 = Yes 2 = I do not know Was the diagnosis based on a laboratory test (for the virus causing COVID-19 disease or antibodies against COVID-19 disease) (Only if fuCovid == 1) fuCovidSympOnset Date dd/mm/yyyy What was the date of symptom onset? (Only if fuCovid == 1) fuCovidICU Numeric (binary) 0 = No 1 = Yes Was admission to the intensive care unit necessary? (Only if fuCovid == 1) fuPreg Numeric (multinomial) 0 = No 1 = Yes 2 = Not applicable Are you pregnant? (Only if subjSex == 1 or 2) Data from electronic tool Table 8: Site information Table 8 can be linked to Table 1 by siteID SiteID Type of variable at discretion of site [needs to be unique] Unique and persistent identifier for each site siteName Text Name of the site siteCountry Text Site country siteLocation Text Location of the site sitePI Text Site principal investigator SiteContact Text Contact information for the site 41Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Appendix 2 Adverse events of special interest Adverse events of special interest (AESIs) and their risk windows, based on SPEAC list, version December 2020 [13]. No. Body system AESI Risk interval 1 Cardiac Acute cardiovascular injury D1-D42 2 Dermatologic Chilblain like lesions D1-D42 3 Dermatologic Single organ cutaneous vasculitis D1-D42 4 Dermatologic Erythema multiforme D1-D42 5 Endocrine Pancreatitis D1-14 6 Endocrine Subacute thyroiditis D1-42 7 Gastrointestinal Acute liver injury D1-D42 8 Hematologic Coagulation disorder (thromboembolism) D1-D42 9 Hematologic Thrombocytopenia D1-D42 10 Immunologic Vaccine-associated enhanced disease (VAED) Unknown 11 Immunologic Multisystem inflammatory syndrome in children (MIS-C) [TO REMOVE IN STUDIES LIMITED TO ADULTS] D1-D42 12 Immunologic Anaphylaxis D0-D7 13 Musculoskeletal Acute aseptic arthritis D1-D42 14 Musculoskeletal Rhabdomyolysis D1-D7* 15 Neurologic Acute disseminated encephalomyelitis (ADEM) D1-D42 16 Neurologic Bell’s palsy D1-D42 17 Neurologic Generalized convulsion D1-D42 18 Neurologic Guillain-Barré syndrome (GBS) D1-D42 19 Neurologic Meningoencephalitis D1-D42 20 Renal Acute renal injury D1-D42 21 Respiratory Acute respiratory distress syndrome D1-D42 *Sensitivity analysis with a risk interval 1‑14 days may be considered 42 PROTOCOL TEMPLATE Appendix 3 Relationships between study tables The following figure shows the relationship between the tables described in Appendix 1: Data Dictionary. su bj ec tID sit eI D su bj Na m e, co ns en t, re ac to Su bs et , p re va cc FU , su bj Ph on e, N O KN am e, su bj Ho sp , h os pC on ta ct , su bj Do B, su bj Se x, su bj Pr eg , su bj La ct , s ub jM ed Hi st , su bj Pr io rC ov id , s ub jS oc io E. Ta bl e 1: S ub je ct in fo rm ati on d os eI D su bj ec tID va cc Da te , v ac cT im e, va cc Br an d, v ac cB at ch , va cc Di lu en t, va cc Di lu en tB ra nd , va cc Di lu en tB at ch , va cc O th er , v ac cO th er Di s. Ta bl e 2: V ac ci ne e xp os ur e in fo pr eL og ID su bj ec tID pr eL og Da te , p re Fe br ile , pr eT em pY , p re Te m p, pr eT em pW he re , p re Na us ea , pr eN au se aS ev , p re M al ai se , pr eM al ai se Se v, p re Ch ill , pr eC hi llS ev , p re He ad ac he , pr eH ea da ch eS ev , p re Pa in , pr eP ai nS ev , p re M us cle , pr eM us cle Se v, p re Ti re d, pr eT ire dS ev . Ta bl e 3: P re -v ac ci na ti on re ac to ge ni ci ty Tr ig ge d on ly if re ac to Su bs et = = 1 & p re va cc FU = = 1 p os Lo gI D po sD os eI D po sL og Da te , p os In jP ai n, po sP ai nS ev , p os Re dB ig , po sS w el l, po sS w el lB ig , po sH ar d, p os Ha rd Bi g, po sB ru ise , p os Br ui se Bi g, po sW ar m , p os W ar m Se v, po sIt ch , p os Itc hS ev , po sF eb ril e, p os Te m pY , po sT em p, p os Te m pW he re , po sN au se a, p os Na us ea Se v, po sM al ai se , p os M al ai se Se v, po sC hi ll, p os Ch ill Se v, po sH ea da ch e, po sH ea da ch eS ev , … Ta bl e 5: P os t- va cc in ati on re ac to ge ni ci ty po sD os eI D su bj ec tID Ta bl e 4: P os t- va cc do se I D Tr ig ge d on ly if re ac to Su bs et = = 1 fu ID su bj ec tID fu By Su bj , fu W hy Lo ss , fu W hy De at h, fu M ed Ca re . Ta bl e 6: F U id en ti fi er fu Ca re ID fu ID fu Ev en tT yp e, fu Ho sp , fu Ho sp W ar d, fu Ho sp Da te , fu Ho sp O ut , fu Ho sp O ut Da te , fu Ca re Da te , f uC ar eH os p, fu Ca re Ho sp , fu Ca re De pa rt , f uD ia g, fu Di ag Ad d, fu Di ag Te xt , fu Ca re Na m e, fu Ca re Ad re s, fu Co vi d, fu Co vi dT es t, fu Co vi dI CU , fu Pr eg . Ta bl e 7: F U in fo rm ati on Tr ig ge d on ly if fu M ed Ca re > 0 si te ID sit eN am e, sit eC ou nt ry , sit eL oc ati on , sit eP I, sit eC on ta ct . Ta bl e 8: S ite in fo rm ati on 1 ∞ ∞ ∞ ∞ ∞ ∞ 1 1 1 1 1 ∞ 1 43Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines Appendix 4 Adult informed consent form [The adult ICF template and process should be adapted for special populations (e.g., minors, pregnant women, elderly patients lacking full capacity, migrants, prisoners) that require a tailored approach to consent, including possible surrogate decision-makers (e.g., parents, adult children) or study advocates (e.g., for inclusion of prisoners, orphans) and additional forms (e.g., assent forms), as well as tailoring to the details provided to participants during consent]. Participant information sheet You are visiting this vaccination centre to receive the first dose of COVID-19 vaccine as part of routine care. This vaccination centre is participating in observational research to monitor the safety of COVID-19 vaccines in [POPULATION OF INTEREST]. This study is taking place in [NUMBER] vaccination centres in [COUNTRY]. Around 30,000 persons vaccinated with COVID-19 vaccine will be included in the study and followed up for 3 months after the last dose of COVID-19 vaccine for specific health events of interest. The study sponsor is [STUDY SPONSOR], and the principal investigators are [PRINCIPAL INVESTIGATORS]. If you participate in the study, data will be collected from you by interview at the time of enrolment and through regular questionnaires throughout the study period. By participating in the study you agree: • to complete the study questionnaires [THOUGH MOBILE/WEBLINK/TELEPHONE] (weekly after each COVID-19 vaccine dose, until 3 months after the second COVID-19 vaccine dose) (or more frequently if selected for the reactogenicity subset); • to be contacted by phone in case of non-response, if no answer is received, your next of kin can be contacted; • that the [NATIONAL AEFI FOCAL POINT/NATIONAL PHARMACOVIGILANCE CENTER, to be detailed in the protocol] may contact your healthcare provider if further investigation is required; • that, in the event you learn you are pregnant during the study, the [NATIONAL AEFI FOCAL POINT/NATIONAL PHARMACOVIGILANCE CENTER, to be detailed in the protocol] may follow you until the time of delivery, to monitor the safety of COVID-19 vaccines administered during pregnancy. This study will not lead to any changes in your routine care. You will not be receiving any intervention (vaccine, drug, other) as part of the study. So, there will be no direct benefit to you from this research. However, information gathered from individuals vaccinated with COVID-19 vaccines will contribute to the safety surveillance of COVID-19 vaccines. Your individual identity will be protected because the final information used for the research study will not bear your name, contact details or any other personal information about you 44 PROTOCOL TEMPLATE that will allow you to be identified. The vaccination centre will assign a responsible person to use and store the research data in a safe place. The key-coded data obtained from this study will be stored in a secured database located in [COUNTRY]. Your personal data will always be handled in accordance with all applicable data protection and privacy laws. All information about you as an individual is confidentially and will be protected and only communicated to authorized persons. Any information collected from other physicians will be handled in the same confidential manner as those collected by the study doctor. Data will be archived for [XXX] years, as per national regulations, and will then be destroyed. Should you decide to withdraw from the study, data collected up until the time of the time of withdrawal will be used in the analyses. If you are willing to participate in this study that will monitor the safety of COVID-19 vaccines, please sign and date this form. You are free to contact [XXX] to understand how your information will be used. If at any time you do not wish to share your information, you are free to contact [XXX] and withdraw from this study. You also have the choice to say no and opt out of this research. Not participating, or withdrawing from this study, will not impact your access to healthcare. 45Cohort event monitoring (Cem) for safety signal deteCtion after vaCCination with Covid‑19 vaCCines I have read the above information, or it has been read to me. I have had the opportunity to ask questions about it and all questions have been answered to my satisfaction. I consent voluntarily to be a participant in this study. Print name of participant ............................................................................................................................................................... Signature of participant Date ........................................................... (Day/month/year) Statement by the researcher/person taking consent: I have accurately read out the information sheet to the potential participant. I confirm that the participant was given every opportunity to ask questions about the study, and all the questions asked by the participant have been answered correctly and to the best of my ability. I confirm that the individual has not been coerced into giving consent, and the consent has been given freely and voluntarily. A copy of this informed consent form has been provided to the participant. Print name of researcher/person taking the consent ................................................................... Signature of researcher/ person taking the consent Date ........................................................... (Day/month/year) 46 PROTOCOL TEMPLATE

COVID‑19 VACCINES: SAFETY SURVEILLANCE MANUAL