| Summary: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause serious illness in older adults and people with chronic underlying medical conditions; however, children and young people are often asymptomatic or with mild symptoms. We evaluated the presence of specific antibodies (Abs) response against Human coronavirus NL63 (HCoV-NL63) S protein epitopes (NL63-RBM1, NL63-RBM2_1, NL63-RBM2_2, NL63-RBM3, NL63-SPIKE<sub>541–554</sub>, and NL63-DISC-like) and SARS-CoV-2 epitopes (COV2-SPIKE<sub>421–434</sub> and COV2-SPIKE<sub>742–759</sub>) in plasma samples of pre-pandemic, mid-pandemic, and COVID-19 cohorts by indirect ELISA. Moreover, a competitive assay was performed to check for cross reactivity response between COV2-SPIKE<sub>421–434</sub> and NL63-RBM3 among patients with a definitive diagnosis of SARS-CoV-2. Immune reaction against all SARS-CoV-2 and HCoV-NL63 epitopes showed a significantly higher response in pre-pandemic patients compared to mid-pandemic patients. The results indicate that probably antibodies against HCoV-NL63 may be able to cross react with SARS-CoV-2 epitopes and the higher incidence in pre-pandemic was probably due to the timing of collection when a high incidence of HCoV-NL63 is reported. In addition, the competitive assay showed cross-reactivity between antibodies directed against COV2-SPIKE<sub>421–434</sub> and NL63-RBM3 peptides. Pre-existing HCoV-NL63 antibody response cross reacting with SARS-CoV-2 has been detected in both pre- and mid-pandemic individual, suggesting that previous exposure to HCoV-NL63 epitopes may produce antibodies which could confer a protective immunity against SARS-CoV-2 and probably reduce the severity of the disease.
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