Core protocol for ECDC studies of COVID-19 vaccine effectiveness against hospitalisation with Severe Acute Respiratory Infection, laboratory-confirmed with SARS-CoV-2 or with seasonal influenza - Version 3.0

The end of 2019 saw the emergence of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19). As of October 2023, almost 276 million cases and more than

2.2 million deaths had been reported in the WHO European Region [1]. As of October 2023, eight vaccines (Comirnaty, COVID-19 Vaccine Valneva, Nuvaxovid [previously Novavax], Spikevax [previously COVID-19 vaccine Moderna], Vaxzevria [previously AstraZeneca], Jcovden [previously Covid-19 Vaccine Janssen], VidPrevtyn Beta [from Sanofi] and Bimervax [previously COVID-19 Vaccine HIPRA]), Nuvaxovid (NVX-CoV2373) and six adapted vaccines (Comirnaty Original/Omicron BA.1, Spikevax bivalent Original/Omicron BA.1, Comirnaty Original/Omicron BA.4-5, Spikevax bivalent Original/Omicron BA.4-5, Comirnaty Omicron XBB.1.5 and Spikevax XBB.1.5 have been authorised by the European Commission based on the scientific opinion of the European Medicines Agency (EMA) for use in the European Union, and many others are under rolling review [2].

Influenza viruses undergo frequent genetic and antigenic changes. The influenza vaccine is reformulated each year and annual re-vaccination is recommended. Observed influenza vaccine effectiveness (IVE) varies from year to year between population sub-groups (age groups, risk groups) and differs for the various influenza types, subtypes and genetic clades, and outcomes measured. Immunological correlates of protection are not well defined. In 2017, the EMA formally adopted new guidelines on influenza vaccines covering, inter alia, post-authorisation studies of vaccine effectiveness, including brand-specific IVE data [3].

The available vaccine products currently in use for EU/EEA immunisation programmes, the target groups for vaccination and the vaccination coverage all vary across countries. New vaccines are being developed for which limited or no effectiveness data are yet available in the EU. A comparison by vaccine type (adjuvanted vs non- adjuvanted, live attenuated vs inactivated, egg- vs cell-based, high vs standard dose), group (split virion, subunit, etc.) and product could provide essential information for vaccine recommendations and health economic assessments.

In 2020, the European Commission stressed the importance of continuously monitoring the safety and effectiveness of vaccines in the EU/EEA in the post-authorisation phase, with particular emphasis on COVID-19 vaccines in the context of the ongoing pandemic [4]. The 2018 ‘Council Recommendation on Strengthened Cooperation against Vaccine-preventable Diseases’ already called on the European Centre for Disease Prevention and Control (ECDC) and EMA to cooperate to ensure the continued monitoring of vaccines and vaccination in use in EU/EEA vaccination programmes [5]. This request was subsequently formalised as part of the extended EMA regulatory mandate [6] and ECDC’s newly amended mandate [7], requiring the two agencies to develop a structured and independent post-authorisation vaccine monitoring platform, initially prioritising COVID-19 vaccines. ECDC and EMA officially established and launched the platform in May 2022, with the intention of bringing together public health and regulatory experts to discuss the studies needed to generate real-life evidence on the safety and effectiveness of vaccines in use in EU/EEA immunisation programmes.

From 2020, ECDC began building the infrastructure to perform COVID-19 vaccine effectiveness (CVE) studies, using the lessons learned from other vaccine effectiveness studies already conducted. One such study was the ECDC- funded I-MOVE (Influenza – Monitoring Vaccine Effectiveness in Europe) project, under which influenza vaccine effectiveness (IVE) has been measured in Europe using primary care sentinel surveillance systems since the 2007/08 influenza season [3,4]. The infrastructure will be used to build a system that regularly monitors vaccine effectiveness and performs studies, including impact and burden of disease studies, in different settings.

Depending on the setting, information will be provided on different outcomes (severe disease, moderate disease, transmission, etc). The overall project is called VEBIS (Vaccine Effectiveness, Burden and Impact Studies) and it includes different networks of study sites/countries/infrastructures, where the multi-country studies are conducted.

This core protocol for ECDC studies of VE against hospitalisation with severe acute respiratory infection (SARI) laboratory-confirmed with SARS-CoV-2 or with influenza, version 3.0, represents an update to the main elements for a multi-country hospital-based study of COVID-19 vaccine effectiveness in patients hospitalised with SARI, initially published as version 1.0 [5], updated to version 2.0 [6]. This version includes updates on methodology for CVE pooled analyses The larger sample size achieved by combining data from multiple sites will provide more statistical power to meet more specific objectives. The protocol can be implemented for COVID-19 and/or influenza.

The proposed method is a case-control study using a test negative design. The study population consists of individuals of all ages, belonging to the target group for COVID-19 or influenza vaccination, hospitalised with SARI symptoms and no contra-indication for being vaccinated with the vaccine of interest. It would be beneficial if countries test for all other respiratory viruses (as appropriate depending on time of year).

This core protocol is primarily intended to guide the implementation of ECDC-funded studies. However, ECDC encourages using this protocol as a basis to conduct vaccine effectiveness studies in countries not currently planning to participate in ECDC-funded studies. The use of consistent protocols will facilitate the comparability of study results across studies, countries and study sites.