Background:Antibodies are a measure of immunity after primary infection, which may help protect against further SARS-CoV-2 infections. They may also provide some cross-protection against SARS-CoV-2 variants. There are limited data on antibody persistence and, especially, cross-reactivity against different SARS-CoV-2 variants after primary infection in children.Methods:We initiated enhanced surveillance in 18 secondary schools to monitor SARS-CoV-2 infection and transmission in September 2020. Students and Staff provided longitudinal blood samples to test for variant-specific SARS-CoV-2 antibodies using in-house receptor binding domain assays. We recruited 1189 students and 1020 staff; 160 (97 students, 63 staff) were SARS-CoV-2 nucleocapsid-antibody positive at baseline and had sufficient serum for further analysis.Results:Most participants developed sustained antibodies against their infecting [wild-type (WT)] strain as well as cross-reactive antibodies against the Alpha, Beta and Delta variants but at lower titers than WT. Staff had significantly lower antibodies titers against WT as cross-reactive antibodies against the Alpha, Beta and Delta variants than students (allP< 0.01). In participants with sufficient sera, only 2.3% (1/43) students and 17.2% (5/29) staff had cross-reactive antibodies against the Omicron variant; they also had higher antibody titers against WT (3042.5; 95% confidence interval: 769.0–12,036.2) than those who did not have cross-reactive antibodies against the Omicron variant (680.7; 534.2–867.4).Conclusions:We found very high rates of antibody persistence after primary infection with WT in students and staff. Infection with WT induced cross-reactive antibodies against Alpha, Beta and Delta variants, but not Omicron. Primary infection with WT may not be cross-protective against the Omicron variant.