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Various safe and effective COVID-19 vaccines utilizing different platforms (mRNA, adenovirus vector, inactivated virus-based) are available against SARS-CoV-2 infection. A prime-boost regimen (administration of two doses) is recommended to induce an adequate and sustained immune response. Most of these vaccines follow a homologous regimen (the same type of vaccine as priming and booster doses). However, there is a growing interest in a heterologous prime-boost vaccination regimen to potentially help address concerns posed by fluctuating vaccine supplies, serious adverse effects (anaphylaxis and thromboembolic episodes following adenovirus-based vaccines), new emerging virulent strains, inadequate immune response in immunocompromised individuals, and waning immunity. Various studies have demonstrated that heterologous prime-boost vaccination may induce comparable or higher antibody (spike protein) titers and a similar reactogenicity profile to the homologous prime-boost regimen. Based on these considerations, the Center for Disease Control and Prevention has issued guidance supporting the “mix-and-match” heterologous boost COVID-19 vaccine strategy.