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

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. Significance Statement SARS-CoV-2 infections after vaccination with COVID-19 mRNA vaccines with the ancestral spike antigen induce high serum neutralizing responses against Omicron sub-lineages, which are antigenically distant from the ancestral antigen. In individuals with breakthrough infections, the exposure interval from vaccination to infection is critical for the induction of serum cross-neutralizing activity. We used statistical modeling to estimate the serum neutralizing response to Omicron sub-lineages corrected for the influence of different exposure intervals between vaccination and breakthrough infection in individuals with pre-Omicron and Omicron breakthrough infections. This enabled us to assess fairly the effects of exposure to distinct antigens on inducing serum cross-neutralizing responses with the ideal exposure interval, and revealed the clinical significance of optimizing the dose interval in COVID-19 booster vaccination. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by a Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI) grant 21K20768 (to SMi), by Ministry of Health Labour and Welfare (MHLW) grants 20HA2001 (to TS), and 21HA2005 (to TS), and by Japan Agency for Medical Research and Development (AMED) grants JP21fk0108104 (to TS), JP22fk0108637 (to TS), and JP22fk0108141(to TS). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the National Institute of Infectious Diseases gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. The code used to estimate the increase in NTs during the interval from the second vaccination to the third exposure are provided at the GitHub repository.