<p><em>Severe acute respiratory syndrome coronavirus 2</em> (SARS-CoV-2) is the causal agent of the COVID-19 pandemic. Two mRNA vaccines based on the spike protein S have been authorized by the Food and Drug Administration. Antibody-based diagnostic test detect antibodies developed against protein S. Mutations in the genome of SARS-CoV-2 might compromise the precision of diagnostic tests and the efficacy of vaccines and antiviral drugs. We recently profiled genomic variation in human coronaviruses SARS[1]CoV, SARS-CoV-2, and <em>Middle East respiratory syndrome coronavirus</em> (MERS-CoV). As in all species of the genus Betacoronavirus, the genome is hyper variable, and mutations are not random. The most variable cistron codes for the spike S protein. Hyper variation in protein S has the potential to affect the efficacy of vaccines, the reliability of antibody-based diagnostic test, and predicts potential for repeated SARS-CoV-2 infections. Here we review the basics of coronavirus biology and genomic variation, and link them to diagnostic tests, vaccines, and antiviral drugs.</p>
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