Pre-infection neutralizing antibodies, Omicron BA.5 breakthrough infection, and long COVID: a propensity score-matched analysis

Importance Investigating the role of pre-infection humoral immunity against Omicron BA.5 infection risk and long COVID development is critical to inform public health guidance. Objective To investigate the association between pre-infection immunogenicity after the third vaccine dose and the risks of Omicron BA.5 infection and long coronavirus disease. Design, Setting, and Participants This nested case-control analysis was conducted among tertiary hospital staff in Tokyo, Japan who donated blood samples in June 2022 (1 month before Omicron BA.5 dominant wave onset [July–September 2022]) approximately 6 months after receiving the third dose of the historical monovalent coronavirus disease 2019 mRNA vaccine. Exposures Live virus-neutralizing antibody titers against Wuhan and Omicron BA.5 (NT50) and anti-SARS-CoV-2 spike protein antibody titers with Abbott (AU/mL) and Roche (U/mL) assays at pre-infection. Main Outcomes and Measures Symptomatic SARS-CoV-2 breakthrough infections during the Omicron BA.5 dominant wave vs. undiagnosed controls matched using a propensity score. Incidence of long COVID (persistent symptoms ≥4 weeks after infection) among breakthrough infection cases. Results Anti-spike antibody titers were compared between 243 breakthrough infection cases and their matched controls among the 2360 staff members who met the criteria. Neutralizing antibodies in 50 randomly selected matched pairs were measured and compared. Pre-infection anti-spike and neutralizing antibody titers were lower in breakthrough cases than in undiagnosed controls. Neutralizing antibody titers against Wuhan and Omicron BA.5 were 64% (95% CI: 42–77) and 72% (95% CI: 53–83) lower, respectively, in breakthrough cases than in undiagnosed controls. Individuals with previous SARS-CoV-2 infections were more frequent among undiagnosed controls than breakthrough cases (19.3% vs. 4.1%), and their neutralizing antibody titers were higher than those of infection-naïve individuals. Among the breakthrough cases, pre-infection antibody titers were not associated with the incidence of long COVID. Conclusions and Relevance Pre-infection immunogenicity against SARS-CoV-2 may play a role in protecting against the Omicron BA.5 infection, but not in preventing long COVID. Question Does pre-infection anti-SARS-CoV-2 humoral immunity protect against Omicron BA.5 infection and long-COVID development? Findings Pre-infection neutralizing antibody titers against Omicron BA.5 were lower in subsequent Omicron BA.5 breakthrough infection cases than in matched controls in this nested case-control study of healthcare workers who received the third dose of historical COVID-19 mRNA vaccines approximately 6 months prior. Pre-infection antibody titers could not predict the incidence of long COVID among breakthrough infection cases. Meaning Higher pre-infection humoral immunity approximately 6 months after the third vaccination may correlate with protection against Omicron BA.5 infection but not against long-COVID development. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the NCGM COVID-19 Gift Fund (grant number 19K059), Japan Health Research Promotion Bureau Research Fund (grant number 2020-B-09), and National Center for Global Health and Medicine (grant number 21A2013D). Abbott Japan and Roche Diagnostics provided reagents for the anti-SARS-CoV-2 antibody assays. ### 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: Written informed consent was obtained from all participants. This study was approved by the National Center for Global Health and Medicine, Japan (NCGM) ethics committee (approval number: NCGM-G-003598). 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.