The number of patients with COVID-19 has surged during the Omicron pandemic worldwide. It remains unclear whether and how previous SARS-CoV-2 infection and vaccine-induced humoral immunity can protect against Omicron BA.5 infection. We examined the association between preinfection anti–SARS-CoV-2 spike antibody titers and protection against Omicron BA.5 infection among the staff of a medical and research center in Tokyo, Japan.
A total of 2610 staff members participated in a serosurvey in June 2022 (baseline), were evaluated for anti–SARS-CoV-2 antibodies (spike and nucleocapsid proteins; Abbott Japan and Roche Diagnostics), and answered a questionnaire.1 Diagnosed infection was defined as a history of COVID-19 that was self-reported (confirmed against in-house COVID-19 registry), whereas undiagnosed infection was defined as antinucleocapsid seropositive at any of the first (July 2020) through sixth (June 2022: baseline) surveys among those without a history of COVID-19. In July 2022, a large epidemic caused by the Omicron BA.5 variant hit Japan. Using an in-house COVID-19 registry, we followed up the study participants for SARS-CoV-2 infection from baseline until the date of COVID-19 diagnosis, additional vaccination, or September 21, 2022, whichever occurred first. Additional methods can be found in the eMethods in Supplement 1. Written informed consent was obtained from all participants. This study was approved by the ethics committee of the National Center for Global Health and Medicine and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.
Of the 2610 participants at baseline (1845 [70.7%] female; median [IQR] age, 37 [28-48] years), 2401 (92.0%) had received 3-dose vaccinations, and 418 (16.0%) had previous SARS-CoV-2 infection. Of the 230 previously diagnosed infections, 202 (88.0%) occurred during the Omicron BA.1/BA.2 predominant epidemic. Those with previously diagnosed and undiagnosed infections had higher antispike antibody titers than infection-naive individuals (median titer, 29 528 [previously diagnosed], 24 556 [previously undiagnosed], and 4849 [infection naive]).
During the follow-up period (ie, Omicron BA.5 predominant wave), 288 participants were diagnosed with COVID-19; the incidence rate was 13.8 per 10 000 person-days. Higher antispike antibody titers were associated with higher protection against Omicron BA.5 infection (3.7% per 1000 titers; 95% CI, 3.3%-4.2%) (Table). Fifty percent protection was achieved at 17 000 AU/mL among previously infected participants and 27 000 AU/mL among infection-naive participants, respectively, and 80% protection was achieved at 50 000 AU/mL among previously infected participants but not among infection-naive participants (Figure).
Protection against Omicron BA.5 reinfection was 87.0% (95% CI, 68.0%-95.0%) in participants with previously diagnosed infections and 58.0% (95% CI, 28.0%-76.0%) among those with undiagnosed infections. The protection of the previous infection during the Omicron BA.1/BA.2 epidemic was 91.0% (95% CI, 73.0%-97.0%).
In vaccine recipients (mainly 3-dose) who had experienced the Omicron BA.1/BA.2 wave, we found that higher antispike antibody titers were associated with a lower risk of Omicron BA.5 infection, and the association was enhanced by previous infection (mainly occurred during the Omicron BA.1/BA.2 epidemic). In the current study, the antispike antibody titer required for a 50% reduction in the risk of infection during the Omicron BA.5 epidemic was lower among those with previous infection than among infection-naive individuals. These results are compatible with laboratory data showing that Omicron BA.1/BA.2 convalescent patients had higher neutralizing capacity against Omicron BA.5 than infection-naive 3-dose recipients.2,3 Limitations of this study include the lack of active surveillance during the study period and generalizability of the findings. These data suggest that preinfection spike antibody titers indicate the risk of Omicron BA.5 infection and that high protection can only be achieved with hybrid immunity from infection and 3-dose vaccination.
Accepted for Publication: January 31, 2023.
Published: March 16, 2023. doi:10.1001/jamanetworkopen.2023.3370
Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2023 Yamamoto S et al. JAMA Network Open.
Corresponding Author: Shohei Yamamoto, PhD, Department of Epidemiology and Prevention, Center for Clinical Sciences, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo 162-8655, Japan (syamamoto@hosp.ncgm.go.jp).
Author Contributions: Drs Yamamoto and Mizoue had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: Yamamoto, Mizoue.
Drafting of the manuscript: Yamamoto.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Yamamoto.
Obtained funding: Mizoue.
Administrative, technical, or material support: Mizoue, Ohmagari.
Supervision: Mizoue.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by grant 19K059 from the National Center for Global Health and Medicine COVID-19 Gift Fund, grant 2020-B-09 from the Japan Health Research Promotion Bureau Research Fund, and the grant 21A2013D from the National Center for Global Health and Medicine.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 2.
Additional Contributions: Mika Shichishima, National Center for Global Health and Medicine, Tokyo, Japan, contributed to data collection. The staff of the Laboratory Testing Department, National Center for Global Health and Medicine, Tokyo, Japan, contributed to measuring antibody testing. Abbott Japan and Roche Diagnostics provided reagents for anti–SARS-CoV-2 antibody assays. Ms Shichishima was not compensated beyond her regular salary.
1.Yamamoto
S, Maeda
K, Matsuda
K,
et al. Coronavirus disease 2019 (COVID-19) breakthrough infection and post-vaccination neutralizing antibodies among healthcare workers in a referral hospital in Tokyo: a case-control matching study.
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