BACKGROUND

High spike-based vaccine coverage led to a high seroprevalence of anti-spike (S) antibodies against SARS-CoV-2 in Japanese adults in 2024. Nevertheless, the COVID-19 epidemic continues, and individuals with hybrid immunity are becoming more common in these populations.

METHODS

We conducted a prospective cohort study to measure serum anti-SARS-CoV-2 antibody levels in 4496 Japanese adults as part of the national seroepidemiological survey. This study evaluated the correlation between first-visit anti-SARS-CoV-2 antibody levels and their effectiveness in providing protection until the second visit during the Omicron BA.5 epidemic.

RESULTS

Reduced symptomatic infection risk was found to be associated with anti-S antibody, anti-nucleocapsid (N) antibody, and BA.5 neutralizing antibody levels. However, the reduced asymptomatic infection risk associated with anti-S antibody or BA.5 neutralizing antibody levels was limited. In contrast, higher anti-N antibody levels were strongly linked to a reduced asymptomatic infection risk. Furthermore, higher anti-N antibody levels were also associated with a reduced risk of re-infection in individuals with hybrid immunity.

CONCLUSION

These observations highlight the potential of anti-N antibody level as a correlate of protection against SARS-CoV-2 asymptomatic infection and re-infection. The findings indicate that individuals with hybrid immunity have a distinct protective immunity against both symptomatic and asymptomatic infection beyond serum anti-S and neutralizing antibodies against circulating viral strains, which correlate with serum anti-N antibodies.