Complementary Roles of RT-PCR and Next-Generation Sequencing in Post-Vaccination SARS-CoV-2 Infection: Clinical Diagnosis, Genomic Characterization, and Surveillance

SARS-CoV-2 infection after vaccination remains a clinical and public-health challenge because protection against infection may vary with time since vaccination, host factors, previous infection, and ongoing viral evolution. Although vaccination substantially reduces the risk of severe COVID-19, post-vaccination infections may still occur and may be mild, atypical, or asymptomatic. This narrative review examines the complementary roles of reverse-transcription polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) in the diagnosis, genomic characterization, and surveillance of post-vaccination SARS-CoV-2 infection. RT-PCR remains the first-line method for confirming acute infection because it is rapid, widely available, and clinically actionable, although its clinical performance depends on appropriate specimen collection and timing. NGS complements RT-PCR by providing viral genomic characterization, including lineage assignment, mutation detection, investigation of suspected transmission clusters, and population-level surveillance. Sequencing may provide additional value in selected settings, particularly suspected reinfection, persistent infection in selected immunocompromised patients, outbreak investigations, and representative or event-triggered genomic surveillance. Its use should therefore be guided by a predefined clinical, epidemiological, or surveillance objective rather than applied routinely to all post-vaccination infections. An integrated strategy combining first-line RT-PCR with objective-driven sequencing can preserve diagnostic efficiency while providing genomic information when it is most likely to influence patient-level investigation, infection-control assessment, or public-health surveillance.