As variants of the pathogen that causes COVID-19 spread around the world, estimates of infectiousness and lethality of newly emerging strains are important. Here we report a predictive model that associates molecular motions and vibrational patterns of the virus spike protein with infectiousness and lethality. The key finding is that most SARS-CoV-2 variants are predicted to be more infectious and less lethal compared to the original spike protein. However, lineage B.1.351 (Beta variant) is predicted to be less infectious and more lethal, and lineage B.1.1.7 (Alpha variant) is predicted to have both higher infectivity and lethality, showing the potential of the virus to mutate towards different performance regimes. The relatively more recent lineage B.1.617.2 (Delta variant), although contains a few key spike mutations other than D614G, behaves quite similar to the single D614G mutation in both vibrational and predicted epidemiological aspects, which might explain its rapid circulation given the prevalence of D614G. This work may provide a tool to estimate the epidemiological effects of new variants, and offer a pathway to screen mutations against high threat levels. Moreover, the nanomechanical approach, as a novel tool to predict virus-cell interactions, may further open up the door towards better understanding other viruses.