Estimating serum cross-neutralizing responses to SARS-CoV-2 Omicron sub-lineages elicited by pre-Omicron or Omicron breakthrough infection with exposure interval compensation modeling

Abstract

Understanding the differences in serum cross-neutralizing responses against SARS-CoV-2 variants, including Omicron sub-lineages BA.5, BA.2.75, and BQ.1.1, elicited by exposure to distinct antigens is essential for developing COVID-19 booster vaccines with enhanced cross-protection against antigenically distinct variants. However, fairly comparing the impact of breakthrough infection on serum neutralizing responses to several variants with distinct epidemic timing is challenging because responses after breakthrough infection are affected by the exposure interval between vaccination and infection. We assessed serum cross-neutralizing responses to SARS-CoV-2 variants, including Omicron sub-lineages, in individuals with breakthrough infections before or during the Omicron BA.1 epidemic. To understand the differences in serum cross-neutralizing responses after pre-Omicron or Omicron breakthrough infection, we used Bayesian hierarchical modeling to correct the cross-neutralizing responses for the exposure interval between vaccination and breakthrough infection. The exposure interval required to generate saturated cross-neutralizing potency against each variant differed by variant, with variants more antigenically distant from the ancestral strain requiring a longer interval. Additionally, Omicron breakthrough infection was estimated to have higher impact than booster vaccination and pre-Omicron breakthrough infection on inducing serum neutralizing responses to the ancestral strain and Omicron sub-lineages. However, the breadth of cross-neutralizing responses to Omicron sub-lineages, including BQ.1.1, after Omicron or pre-Omicron breakthrough infection with the ideal exposure interval were estimated to be comparable. Our results highlight the importance of optimizing the interval between vaccine doses for maximizing the breadth of cross-neutralizing activity elicited by booster vaccines with or without Omicron antigen.

SARS-CoV-2 Related Antibody-Dependent Enhancement Phenomena In Vitro and In Vivo

“…A broadly neutralizing antibody that has potent cross-reactivity against a wide variety of variants was reported in HIV infected individuals [152]. A long exposure interval is required to generate crossneutralizing potency against different variants antigenically distant from the ancestral strain [153]. The ratio between protective anti-S antibody and detrimental anti-N antibody in each individual [154] may affect the clinical relevance with breakthrough infection or re-infection.…”