Impact of First SARS-CoV-2 Infection Variant on Serological Responses Against Omicron: Findings From the SIREN Study

Introduction: Despite the existing hybrid immunity, a sharp increase in SARS-CoV-2 reinfections was observed worldwide following Omicron variant emergence. We investigated whether the first infecting variant indelibly shapes serological responses against Omicron (BA.1 and BA.2) reinfection. Methods: Participants with a sequence-confirmed Alpha (n = 23) or Delta (n = 10) first infection before third vaccine dose (V3) that subsequently had a BA.1 or BA.2 reinfection were selected. Sera were tested for anti-SARS-CoV-2 spike (anti-S) and live virus microneutralisation (LV-N) against Ancestral, Alpha, Delta, Omicron BA.1 and BA.2. Antibody responses and waning post-V3 were compared by first infection variant using mixed-effect models, as well as inferred titres days before reinfections. Individual's neutralisation responses were compared 12 weeks post-V3, among those with Alpha and Delta primary infection. Results: After V3, those with Delta first infection had higher LV-N Omicron BA.1 titres (fold difference (FD) = 2.7, p = 0.05) compared to Alpha primary infection. Participants with Delta first infection presented higher LV-N BA.1 (FD = 1.89, p = 0.004) and LV-N BA.2 (FD = 2.06, p = 0.001) titres pre-Omicron reinfections. Individuals' neutralisation responses against Ancestral were higher than any other subsequent variants, regardless of first infection variant. Conclusions: A previous Delta SARS-CoV-2 infection induced a higher serological response against a subsequent Omicron infection when compared to Alpha first infections.