Incidence and Determinants of Symptomatic and Asymptomatic SARS-CoV-2 Breakthrough Infections After Booster Dose in a Large European Multicentric Cohort of Health Workers-ORCHESTRA Project
Authors: Porru Stefano , Monaco Maria Grazia Lourdes , Spiteri Gianluca , Carta Angela , Caliskan Gulser , Violán Concepción , Torán-Monserrat Pere , Vimercati Luigi , Tafuri Silvio , Boffetta Paolo , Violante Francesco Saverio , Sala Emma , Sansone Emanuele , Gobba Fabriziomaria , Casolari Loretta , Wieser Andreas , Janke Christian , Tardon Adonina , Rodriguez-Suarez Marta Maria , Liviero Filippo , Scapellato Maria Luisa , dell’Omo Marco , Murgia Nicola , Mates Dana , Calota Violeta Claudia , Strhársky Jozef , Mrázová Mariana , Pira Enrico , Godono Alessandro , Magnano Greta Camilla , Negro Corrado , Verlato Giuseppe ,   Orchestra WP5 Working Group, Pezzani Maria Diletta , Tacconelli Evelina , Gibellini Davide , Lotti Virginia , Carrasco-Ribelles Lucí Amalia , Cácers Eva María Martínez , Prado Julia Garcia , Lamonja-Vicente Noemí , De Maria Luigi , Stefanizzi Pasquale , Sponselli Stefania , Caputi Antonio , Abedini Mahsa , Ditano Giorgia , Asafo Shuffield S. , Collatuzzo Giulia , De Palma Giuseppe , Modenese Alberto , Rossi Giorgia , Glieca Francesca , Vivoli Daniela , Hoelscher Michael , Castelletti Noemi , Reinkemeyer Christina , Le Thi Thu Giang , Fernandez-Tardon Guillermo , Arcos-Gonzalez Pedro Ignacio , Jimeno-Demuth Francisco José , Natal-Ramos Carmen , Moretto Angelo , Mason Paola , Pavanello Sofia , Volpin Anna , Muzi Giacomo , Gambelunghe Angela , Folletti Ilenia , Fiordi Tiziana , Neamtu Andra , Perseca Ovidiu , Staicu Catalin Alexandru , Voinoiu Angelica , Fabiánová Eleonóra , Nedela Roman , Bérešová Jana Oravec , Palcová Lenka , Mansour Ihab , Ciocan Catalina , Franceschi Andrea , Filon Francesca Larese , Cegolon Luca 
Published: July 2023

Abstract
Background
SARS-CoV-2 breakthrough infections (BI) after vaccine booster dose are a relevant public health issue.

Methods
Multicentric longitudinal cohort study within the ORCHESTRA project, involving 63,516 health workers (HW) from 14 European settings. The study investigated the cumulative incidence of SARS-CoV-2 BI after booster dose and its correlation with age, sex, job title, previous infection, and time since third dose.

Results
13,093 (20.6%) BI were observed. The cumulative incidence of BI was higher in women and in HW aged < 50 years, but nearly halved after 60 years. Nurses experienced the highest BI incidence, and administrative staff experienced the lowest. The BI incidence was higher in immunosuppressed HW (28.6%) vs others (24.9%). When controlling for gender, age, job title and infection before booster, heterologous vaccination reduced BI incidence with respect to the BNT162b2 mRNA vaccine [Odds Ratio (OR) 0.69, 95% CI 0.63–0.76]. Previous infection protected against asymptomatic infection [Relative Risk Ratio (RRR) of recent infection vs no infection 0.53, 95% CI 0.23–1.20] and even more against symptomatic infections [RRR 0.11, 95% CI 0.05–0.25]. Symptomatic infections increased from 70.5% in HW receiving the booster dose since < 64 days to 86.2% when time elapsed was > 130 days.

Conclusions
The risk of BI after booster is significantly reduced by previous infection, heterologous vaccination, and older ages. Immunosuppression is relevant for increased BI incidence. Time elapsed from booster affects BI severity, confirming the public health usefulness of booster. Further research should focus on BI trend after 4th dose and its relationship with time variables across the epidemics.