In this study, we report on longitudinal kinetics of cellular immune subsets following SARS-CoV-2 infection in a cohort of hospitalized individuals and evaluate the interplay of these profiles with infecting viral variants, humoral immunity including neutralizing responses, vaccination history, and clinical outcomes. A cohort of 121 SARS-CoV-2–infected individuals exhibiting varying disease states were prospectively evaluated for lymphopenic profiles, antiviral humoral responses and infecting viral variants for a period of up to 90 d spanning the period of February 2021 to January 2022 (second and third waves of infection). A total of 51 participants received at least 1 vaccine dose of indigenous vaccines (Covishield or Covaxin) prior to recruitment. When stratified in terms of mortality, B and natural killer cells, in contrast to the T cell compartment, did not recover from nadir levels in nonsurvivors who were largely unvaccinated. No discriminatory signature was identified for nonsurvivors in terms of anti-nucleocapsid or anti-S1-RBD IgG chemiluminescent immunoassay profiles including GenScript S1-RBD assays. Evaluation of sVCAM and sMAdCAM revealed opposing dynamics that correlated with disease severity and convalescence respectively. Viral variant analysis revealed Delta and Omicron variants to comprise the majority of the infections, which reflected national transmission kinetics during the period of recruitment. Our results demonstrate the importance of monitoring circulating biomarkers for convalescence as well as mortality in COVID-19 progression. Delta variants of SARS-CoV-2 clearly demonstrated increased pathogenicity and warrants sustained viral surveillance for re-emergence of these strains. Our findings with respect to vaccination advocate for continued vaccine development and administration of COVID-19 vaccines.