Facing new COVID-19 waves, the effectiveness of BBIBP-CorV has been noted to be low in countries whose populations were already administered two doses of the vaccine. Heterologous vaccination using ChAdOx1-S/BNT162b2 elicited higher immunogenicity compared with homologous immunization. BBIBP-CorV/BNT162b2 combination is worth testing. In this pilot prospective cohort study conducted at Makassed General Hospital, Beirut, Lebanon, from February 17, 2021, to June 30, 2021, we tested the safety and immunogenicity of a BNT162b2 booster dose in COVID-19-naïve individuals who had received two doses of the BBIBP-CorV vaccine. Heterologous booster vaccination was found to be safe and well tolerated. It was significantly associated with higher anti-spike IgG geometric mean titers compared to that after homologous BNT162b2 immunization in COVID-19-naïve individuals [(8040 BAU/mL, 95% confidence interval (CI), 4612–14 016) vs (1384 BAU/mL, 95% CI, 1063–1801), respectively, ( P < 0.0001)]. In countries with limited access to mRNA vaccines and where populations have already received BBIBP-CorV, mixing BBIBP-CorV/BNT162b2 is seen to overcome the low immunogenicity induced by BBIBP-CorV alone, thus potentially providing protection against emerging variants.