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Seroepidemiological data are useful to estimate the spread of SARS-CoV-2 infection, which can contribute to the planning and evaluation of measures against coronavirus disease 2019 (COVID-19). As the target of mRNA vaccine is spike protein, anti-nucleocapsid antibody (Ig-N) has been used to monitor natural infection after vaccine rollout.
we compared the proportion of Ig-N positives among the patients with PCR or
antigen-confirmed COVID-19 (sensitivity) across different periods and vaccine doses. We measured Ig-N (total Ig) using the Roche Elecsys® Anti-SARS-CoV-2 N assay, which can reliably detect mature Ig-N over 6 months.
In this cohort, we identified 224 patients who were infected for the first time after the second or third dose of mRNA vaccine, mainly BNT162b2 (Pfizer-BioNTech), and subsequently attended a serosurvey without receiving the additional dose. All the infections were mild or asymptomatic.
Patients who were infected within 2 months after the booster (during Omicron BA.1 epidemic) showed a higher proportion of asymptomatic infection (14%) and significantly lower Ig-N index (median, 7.4) and sensitivity (78%), as compared with other groups (sensitivity, 94–100%) (Fig. 1). In contrast, patients who were infected 4 to 5 months after the booster (during Omicron BA.2 epidemic) had Ig-N index (median, 18.6) and sensitivity (97%) comparable to those who were infected before vaccination rollout or after the second dose (during Delta or Omicron BA.1 epidemic). Similarly, patients who were infected 5 to 8 months after the second vaccine had high index (median, 15.1) and sensitivity (96%). These results support that the level of immunity (largely determined by vaccine dose and time since vaccination), rather than Omicron sub-variant, accounts for the discrepancy in test performance.
Earlier serological studies in the pre-vaccine era showed that anti-SARS-CoV-2 Ig-N detection rate is higher among symptomatic patients than asymptomatic patients.
In the present analysis among patients who were infected within 2 months after the booster, however, the sensitivity did not change (78%) after excluding asymptomatic cases. Among vaccine recipients who might have acquired strong immunity during short period after the booster, the presence of symptoms may not reflect SARS-CoV-2 Ig-N production.
In this well-defined cohort with repeat serological assessments and rigorous registration of COVID-19, the performance of the Roche Ig-N assay was decreased by approximately 20-percentage points for the breakthrough infections occurred within 2 months after the booster dose, whereas it performed well for those occurred 3 months or more after the second or third dose. The decreased performance observed shortly after the booster needs to be considered in the planning of seroepidemiological study and interpretation of the results.
Written informed consent was obtained from all participants, and the study procedure was approved by the NCGM Ethics Committee (approval number: NCGM-G-003598).
This work was supported by the NCGM COVID-19 Gift Fund (grant number 19K059 ) and the Japan Health Research Promotion Bureau Research Fund (grant number 2020-B-09 ). Roche Diagnostics provided reagents for anti-SARS-CoV-2 antibody assays.
Declaration of Competing Interest
All authors: No reported conflicts of interest.
We thank Mika Shichishima for her contribution to data collection and the staff of the Laboratory Testing Department for their contribution to measuring antibody testing.
Updated US infection- and vaccine-induced SARS-CoV-2 seroprevalence estimates based on blood donations, July 2020-December 2021.