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Serum anti-nucleocapsid antibody level induced after primary infection is an immunological surrogate of protection against SARS-CoV-2 re-infection in hybrid immunity holders


Background In 2024, there was quite high seroprevalence of anti-spike (S) protein antibodies against SARS-CoV-2 in Japanese adults, owing to the high vaccination coverage by spike-based vaccines. Nevertheless, the COVID-19 epidemic continues, albeit with low rates of severe illness, and hybrid immunity holders are becoming more common in these populations. It is necessary to determine the immunological protection correlates against SARS-CoV-2 re-infection in individuals with hybrid immunity because the currently available immune correlates were established by analyzing individuals possessing vaccine-induced immunity only. Methods We conducted an ad hoc prospective cohort study to measure serum anti-SARS-CoV-2 antibody levels in 4,496 Japanese adults as part of the national COVID-19 seroepidemiological survey. This ad hoc study evaluated the correlation between anti-S and anti-nucleocapsid (N) antibody levels at the first visit and their effectiveness in infection prevention until the second visit, including undiagnosed re-infections during the Omicron BA.5 epidemic period from December 2022 to March 2023. Findings We assessed the combined effect of anti-N and anti-S antibody levels and found that the reduced infection risk associated with anti-S antibody levels was limited. Contrastingly, higher levels of anti-N antibodies were strongly linked to a reduced infection risk in the entire cohort and in individuals with hybrid immunity. Interpretation We demonstrate a high correlation between reduced re-infection risk in hybrid immunity holders and high serum anti-N antibody levels, highlighting its potential as an immunological surrogate of protection against SARS-CoV-2 re-infection. The findings indicate that individuals with hybrid immunity are protected by a distinct form of immunity, beyond the presence of serum anti-S antibodies, which correlates with serum anti-N antibody levels. Funding The national COVID-19 seroepidemiological survey as a public health investigation was funded by the Ministry of Health, Labour and Welfare of Japan (MHLW). The ad hoc study based on the survey data as a research activity was funded by the Japan Agency for Medical Research and Development (AMED).