OBJECTIVE: SARS-CoV-2 transmission and epidemic potential is related to the population\' immunity levels. As such, assessing different regions\' preexisting immune response to SARS-CoV-2 is important to understand the transmission potential of emerging SARS-CoV-2 variants. DESIGN: In 975 serum samples from Vietnam (2014 to 2019), anti-SARS-CoV-2 IgG levels were determined by ELISA. Plaque reduction neutralization test (PRNT) was performed using Wuhan strain and variants of concern (VOCs). Cross-reactivity was confirmed by analyzing B-cell receptor (BCR) repertoire sequences and identifying BCR repertoire sequences-derived T-cell epitopes. RESULTS: Overall, 20.9% (n=76/364) and 9.2% (n=7) demonstrated SARS-CoV-2 neutralizing activity (PRNT(50)) against the Wuhan and alpha strain, respectively. Neutralizing activity against beta, gamma, and delta strains was absent (PRNT(50)<5) in all samples. Cross-reactive epitopes against SARS-CoV-2 and other coronaviruses spike proteins were detected in the N-terminal domain (NTD), S2, and RBD regions. CONCLUSION: Following BCR and major histocompatibility complex analysis, TCR-recognized epitope motif (TREM) among pathogenic coronaviruses and coronaviruses spike proteins were the top TREM peptide, suggesting that pre-existing immunity against SARS-CoV-2 in Vietnam was due to exposure to common cold coronaviruses. With limited immunity against emerging VOCs, further monitoring and control of the epidemic, along with COVID-19 vaccine programs against VOCs, are necessary.