Viruses evolve as a result of mutation (misincorporations, insertions or deletions, and recombination) and natural selection for favorable traits such as more efficient viral replication, transmission, and evasion of host defenses. Newly selected traits may be linked in unpredictable ways and raise concern that virus spread and evolution could result in greater virulence (disease severity). The limited diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reported during 2020, ascribed to the 3′-5′ exonuclease proofreading function of nonstructural protein 14 (nsp14), led to the view that vaccines based on a single sequence of the viral spike (S) protein, which mediates host cell entry, would likely generate immune protection to all circulating variants (1). However, variants of SARS-CoV-2 with mutations in S have emerged around the world, posing potential challenges for vaccination and antibody-based therapies. The continued spread of SARS-CoV-2 creates the opportunity for accumulation of additional consequential mutations in S and throughout the viral genome.