Generic protocol for ECDC studies of COVID-19 vaccine effectiveness against confirmed SARS-CoV-2 using healthcare worker cohorts, version 2.0

The end of 2019 saw the emergence of a novel virus associated with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). As of 20 July 2022, 157.6 million cases and 1.1 million deaths have been reported in the European Union (EU) and the European Economic Area (EEA) [1].

As of week 45 2022, six vaccines (Comirnaty, Spikevax Vaxzevria, Jcovden (previously COVID-19 Vaccine Janssen), Valneva and Nuvaxovid) 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 others are under rolling review. In addition, four adapted bivalent vaccines are authorised for use (Comirnaty Original/Omicron BA.1, Comirnaty Original/Omicron BA.4-5, Spikevax bivalent Original/Omicron BA.1, and Spikevax bivalent Original/Omicron BA.4-5 [2].

In 2020, the European Commission emphasised the importance of continuously monitoring the safety and effectiveness of vaccines in the EU/EEA and called on ECDC and EMA to develop a structured post-authorisation monitoring platform for vaccines, prioritising COVID-19 vaccines. In November 2020, the European Commission proposed to the European Parliament and the Council of the EU a change to the mandates of EMA and ECDC in the context of its COVID-19 lessons learned package and the creation of a European Health Union, empowering the two agencies to jointly coordinate independent vaccine monitoring studies.

As a result, ECDC started building infrastructure to perform COVID-19 vaccine effectiveness (VE) studies at the end of 2020, utilising the lessons learned from other VE studies. The infrastructure aims to build a system to regularly monitor VE and perform studies in different settings, and depending on the setting, to provide information on different outcomes (severe disease, moderate disease, infection transmission, etc). Many critical questions remain about the effectiveness of COVID-19 vaccines in real-world settings. These questions can only be answered in post-marketing VE studies.

This generic protocol for ECDC studies describes the design and methods for a prospective multi-country cohort study of hospital-based healthcare workers (HCWs) to evaluate the effectiveness of COVID-19 vaccine in preventing laboratory-confirmed SARS-CoV-2 infection. The combination of data from multiple sites aims at providing sufficient statistical power to meet both the overarching primary objective and a range of more specific secondary objectives. This protocol has been adapted to the rapid vaccine roll-out for COVID-19 in many countries and accommodates the establishment of HCW cohorts subsequent to the implementation of vaccination programmes.

All HCWs eligible to be vaccinated with a COVID-19 vaccine can be enrolled in the study, including those who have already been vaccinated with a primary COVID-19 vaccination course, those who have received booster dose(s), those who intend or do not intend to be vaccinated, and those who are not sure whether to be vaccinated. At enrolment, study participants complete a baseline enrolment survey about demographics, clinical comorbidities, and work- and community-related behaviours related to infection risk. In addition, a baseline serology sample and a respiratory swab should be collected from participants.

During the course of the study, participants should be actively followed for suspected COVID-19 infection through regular monitoring:

• Molecular testing: participants should provide a weekly sample, either a nasopharyngeal swab collected by trained HCWs (or self-swab following training) or a self-taken saliva sample, which should be tested for SARS-CoV-2 by RT-PCR. Alternative sampling schedules (e.g. bi-weekly nasopharyngeal swabs) are discussed in the protocol, but these will limit the sensitivity of detecting infection and hence estimates of VE against asymptomatic infection. Site investigators should select for genetic sequencing all or a representative proportion of SARS-CoV-2 confirmed infections in participants.
• Questionnaire survey: participants should complete a brief weekly survey reporting the appearance of any COVID-19-related symptoms and any changes in high-risk exposures to infection (both professional and personal).
• Serology: serum samples should be collected periodically (at enrolment and thereafter every 6–8 weeks) from participants. Serum samples should be tested for antibodies against SARS-CoV-2 by serological testing algorithms that can distinguish between vaccine-induced and infection-induced antibodies.

This generic protocol is primarily intended to guide the implementation of ECDC-funded studies. However, ECDC encourages the active endorsement and implementation of this protocol also beyond ECDC-funded studies to strengthen the evidence base for future policy decisions. The use of consistent protocols will facilitate the comparability of study results across studies, countries, and study sites.

The second version of the protocol includes the lessons learnt from the studies performed until end of July 2022, comments from the site investigators and recommendations from the first technical meetings of the VEBIS HCW project.