Background: COVID-19 pandemic 2 nd wave catastrophic effect in the state of Chhattisgarh,India, from where no exclusive genomic data yet published, has prompted us to undertake thisstudy to unearth the causative variant.

Methods: Whole-genome sequencing of SARS-CoV-2 isolated from COVID-19 infected ninevaccinated healthcare workers (HCW), thirty mild/moderate, seventeen severe, and twenty-sevendeceased patients, was performed.

Findings: The significant predominance of the SARS-CoV-2 variant of concern (VOC), Delta(lineage B.1.617.2) identified in sixty-four (77.1%) cases in contrast to B.1 and its sublineage ineleven (13.2%), variant of interest (VOI), Kappa (lineage B.1.617.1) in five (6.0%) and anotherVOC Alpha (lineage B.1.1.7) in three (3.6%) cases respectively (p<0.05, χ 2 =162.49). 88.8%vaccine breakthrough, 60% mild/moderate, 94.4% severe and 81.5% dead patients were infectedby Delta. Kappa presents exclusively in mild/moderate, Alpha in vaccine breakthrough,mild/moderate, and dead patient and B.1 and its sublineages in mild, severe, and dead patientcategories. Delta variant spike mutation of T19R, G142D, E156G, L452R, and deletion ( F157and R158) helps in escaping antibody response, T478K and D614G enhance viral affinity withACE2 receptor while P681R and D950N result in higher replication and transmissibility bycleaving S1/S2 at furin site.

Interpretation: We conclude that Delta variant predominant role along with co-occurrence of Kappa, Alpha, and B.1 variant during COVID-19 2 nd wave pandemic in Chhattisgarh may pose apotential threat of future outbreak through hybrid variant evolution. Thus, intensive genomicsurveillance for monitoring variant evolution and a more efficacious vaccine against the Deltaand Alpha variants are required.