A SARS-CoV-2 vaccine candidate would likely match all currently circulating variants

Significance The rapid spread of the virus causing COVID-19, SARS-CoV-2, raises questions about the possibility of a universally effective vaccine. The virus can mutate in a given individual, and these variants can be propagated across populations and time. To understand this process, we analyze 18,514 SARS-CoV-2 sequences sampled since December 2019. We find that neutral evolution, rather than adaptive selection, can explain the rare mutations seen across SARS-CoV-2 genomes. In the immunogenic Spike protein, the D614G mutation has become consensus, yet there is no evidence of mutations affecting binding to the ACE2 receptor. Our results suggest that, to date, the limited diversity seen in SARS-CoV-2 should not preclude a single vaccine from providing global protection. The magnitude of the COVID-19 pandemic underscores the urgency for a safe and effective vaccine. Many vaccine candidates focus on the Spike protein, as it is targeted by neutralizing antibodies and plays a key role in viral entry. Here we investigate the diversity seen in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequences and compare it to the sequence on which most vaccine candidates are based. Using 18,514 sequences, we perform phylogenetic, population genetics, and structural bioinformatics analyses. We find limited diversity across SARS-CoV-2 genomes: Only 11 sites show polymorphisms in >5% of sequences; yet two mutations, including the D614G mutation in Spike, have already become consensus. Because SARS-CoV-2 is being transmitted more rapidly than it evolves, the viral population is becoming more homogeneous, with a median of seven nucleotide substitutions between genomes. There is evidence of purifying selection but little evidence of diversifying selection, with substitution rates comparable across structural versus nonstructural genes. Finally, the Wuhan-Hu-1 reference sequence for the Spike protein, which is the basis for different vaccine candidates, matches optimized vaccine inserts, being identical to an ancestral sequence and one mutation away from the consensus. While the rapid spread of the D614G mutation warrants further study, our results indicate that drift and bottleneck events can explain the minimal diversity found among SARS-CoV-2 sequences. These findings suggest that a single vaccine candidate should be efficacious against currently circulating lineages.