Global public health faced a havoc turbulence in last couple of years due to SARS-CoV-2 or COVID-19 pandemic. During the period numerous outbreaks of SARS-CoV-2 mutants took place. However, as per epidemiological paradigms like infectivity and mortality, Variants of Concern (VOC) alpha (B.1.1.7), delta (B.1.6172) and omicron (B.1.1.529) turned out to be of pivotal importance. We have systematically analyzed human immune response considering these VOC infections, assessing diverse pathophysiological manifestations and corresponding perplexing mechanisms. Since the pandemic, the evolutionary interaction of different virus strains has significantly changed how corresponding human immune responses have developed. During the early waves, accumulating mutation and hypervariability at spike proteins were linked to enhanced virulence and infectivity. Later, though, other mutations helped to lessen pathogenicity while making up for it with noticeably higher transmissibility. This has greatly aided in the human population's ability to deal with the severe clinical symptoms of SARS-CoV-2 and has helped to restore global social protocols that were disturbed by the epidemic. Therefore, a thorough grasp of the evolutionary concepts underlying both the host and parasite systems was much appreciated to develop clinical interventions that effectively address global public health concerns.