ABSTRACT:
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INTRODUCTION:
Vietnam faced five distinct waves of COVID-19 between January 2020 and June 2023. Understanding SARS-CoV-2 variant dynamics is critical for timely public health responses, especially in resource-limited settings. This study aims to characterize the molecular epidemiology of SARS-CoV-2 in southern Vietnam over time and assess the evolution and spread of variants in relation to national control strategies and pandemic phases. *

METHODS:
Nasopharyngeal swabs were collected from patients with confirmed COVID-19 across 20 southern provinces between January 2020 and June 2023. Whole genome sequencing was performed using Illumina and Oxford Nanopore platforms. Variants were classified by pandemic phase, and lineage-specific mutations were described. Epidemiologic data and public health interventions were contextualized to interpret viral evolution. *

RESULTS:
A total of 2207 genomes were sequenced, revealing temporal shifts in variant dominance, particularly Delta and Omicron variants and an average mutation count of 52,5 per sample. Mutational analysis revealed increasing diversity over time, with lineage-specific substitutions and deletions identified. The implementation of strict lockdowns, vaccination campaigns, and a shift from zero-COVID to risk-adapted strategies strongly influenced viral transmission and diversity. *

CONCLUSIONS:
This study demonstrates that adaptive genomic surveillance is both feasible and effective in resource-constrained settings. It underscores the critical role of real-time genomic data in pandemic response and advocates for sustained investment in capacity building, infrastructure and global collaboration, offering a scalable model for future preparedness in low-and middle-income countries.