Background: Despite the successes of several global vaccine platforms that have shown a tremendous promise in curbing the COVID-19 pandemic, waning immunity, and the emergence of variants of concern linked to rising breakthrough infections among vaccinees, have begun to highlight opportunities to improve vaccine platforms and deployment. Vaccination after infection, referred as hybrid immunity, points to the potential for more vigorous or distinct immunity primed by the infection and may confer enhanced protection from COVID-19.

Methods: With the system serology platform, we sought to define whether hybrid immunity may shape the functional humoral immune response to SARS-CoV-2 following BNT162b2 and mRNA1273 (mRNA-based), and AZ1222 and Ad26.COV2.S (vector-based( SARS-CoV-2 vaccination

Results: Each vaccine exhibited a unique functional humoral immune profile in the setting of naïve or hybrid immunity. However, hybrid immunity showed a unique augmentation in S2-domain specific functional humoral immunity that was poorly induced in the setting of naïve immune response.

Conclusions: These data highlight the immunodominant effect of the S1-domain in the setting of natural immunity, which is highly variable during viral evolution, and the importance of natural infection in breaking this immunodominance in driving immunity to the S2 region of the SARS-CoV-2 S2 domain that is more conserved across variants of concern.