Younger age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new infection and/or increased disease severity. Demographic trends from the recent COVID waves, which are believed to be driven by new SARS-CoV-2 variants, indicate that the aforementioned epidemiological barriers are being breached and a larger number of younger and healthy individuals are developing severe disease. The new SARS-CoV-2 variants have key mutations that can induce significant changes in the virus-host interactions. Recent studies report that, some of these mutations, singly or in a group, enhanced key mechanisms, such as binding of the receptor-binding domain (RBD) of the viral spike protein with the ACE2 receptor in the host cells, increased glycosylation of spike protein at antigenic sites, and proteolytic cleavage of the spike protein, leading to improved host cell entry and replication of the virus. The putative changes in the virus-host interactions imparted by the mutations in the RBD sequence can potentially be the reason behind the breach of the observed epidemiological barriers. Susceptibility for contracting SARS-CoV-2 infection and the disease outcomes are known to be influenced by host expressions of ACE2 and other proteases. The new variants can act more efficiently, and even on the lower concentrations of the viral entry receptor and associated proteases, thus can have more efficient host cell entry and greater replication resulting in higher viral load and prolonged viral shedding, and widespread tissue injury, and severe inflammation leading to increased transmissibility and lethality. Furthermore, the accumulating evidence that multiple new variants show reduced neutralization by natural and vaccine acquired antibodies, indicating repeated and vaccine breakthrough infections may arise as serious health concerns in the ongoing pandemic.