Vaccination Induces Stronger Spike Immunity and Better Protection Against SARS-CoV-2 Infection in COVID-19 Recovered Subjects than in Naïve Individuals

Background; As the Covid-19 pandemic remains uncontrolled despite the introduction of multiple vaccines, it is essential to identify populations with the highest risk of being infected or re-infected.Methods: To address this question, Spike-specific humoral and cellular immunity were compared in several groups of subjects from different cohorts, 6 months post-infection or post-vaccination in naïve or previously infected individuals (convalescents).Findings: Vaccinated convalescent subjects have significantly higher Spike-specific antibody levels, serum neutralization capacity, and memory T cell frequency than naïve vaccinated or unvaccinated convalescent individuals. This advantage is independent of the vaccination regimen post infection (ChAdOx1, BNT162b2 one dose, BNT162b2 two doses). Moreover, it correlates with a lower frequency of breakthrough infections recorded in the convalescent vaccinated group (N=1/2572) compared to vaccinated without prior infection (N=112/10614), in a two-month real life monitoring during the fifth Covid-19 wave dominated by the Delta variant.Interpretation: Hybrid immunity conferred by vaccination following infection is greatly superior to all other forms of immunity. These results suggest that vaccinated individuals with no history of prior infection should be prioritized for booster doses 6 months post initial vaccination and that monitoring of spike-specific immunity is required for vaccines follow-up.Trial Registration Details: The study was registered on ClinicalTrials.gov (NCT04341142).Funding Information: This study was supported by ANRS-MIE (Emergen study), REACTing (Research and ACTion targeting emerging infectious diseases)-INSERM, the Fondation AnBer (http://fondationanber.fr/).and institutional grants from INSERM, CNRS, UCBL1, and ENS de Lyon.Declaration of Interests: Philippe Vanhems declared the following conflict of interest: grants and consulting fees by SANOFI, PFIZER, MSD, Astellas since 2018. Christelle Compagnon and Karen Brengel-Pesce are employees of Biomerieux. The other authors have no conflict of interest to declare.Ethics Approval Statement: The use and analysis of data from the occupational health medical file were authorized after a regulatory declaration to the National Commission for Information Technology and Civil Liberties (CNIL) according to the reference methodology (declaration MR004 n° 20-121 of April 30th 2020). Written informed consent was obtained from all participants; ethics approval was obtained from the national review board for biomedical research in April 2020 (Comité de Protection des Personnes Sud Méditerranée I, Marseille, France; ID RCB 2020-A00932-37).