More than a year after the emergence of COVID-19, significant regional differences in terms of morbidity persist, showing lower incidence rates in central Africa. The work reported here aims to test for a pre-pandemic natural immunity among populations in this region. To identify such pre-existing immunity, sera samples collected before the emergence of COVID-19 were tested to detect IgG antibodies reacting against SARS-CoV-2 proteins of major significance. Sera samples from blood donors of France were used as control. The results showed a statistically significant difference for antibodies prevalence between the samples collected in central Africa and the control samples. Our results suggest that in the central African sub-region the populations have been potentially pre-exposed before the COVID-19 pandemic to the antigens of a SARS-CoV-2-like virus.