File:Currently Known Mutations of SARS-CoV-2 (49913240613).jpg

The novel coronavirus is getting ever more novel.

TLDR; SARS-CoV-2 mutates regularly, and we are seeing location-based virus evolution during the lockdown period. A single mutation could impact the universality of any vaccine, antibody therapy or drug targeting the binding domain. It also creates the possibility of repeat infections, like the seasonal flu. Gain-of-function mutations have already occurred (D614G), and the new variants are more virulent (614G becomes the leading strain in any new region into which it is introduced within a matter of weeks) and may mediate repeat infections. Some mutations are in regions that might impact antibody binding (V367F). Recombination (S943P) can enable multiple fitness-enhancing mutations to assemble within the same strain making it more pathogenic than the distinct original strains.

<a href="https://www.prellisbio.com" rel="noreferrer nofollow">Prellis Bio</a> pulled together this table of currently known mutations of SARS-CoV-2, and I asked if I could share. Here are some examples from recent pre-print papers (with attendant caveats):

From Los Alamos National Lab analysis in <a href="https://www.biorxiv.org/content/10.1101/2020.04.29.069054v1" rel="noreferrer nofollow">BioRxiv</a>, May 2020 (and <a href="https://www.news-medical.net/news/20200504/Research-detects-a-more-dangerous-SARS-CoV-2-mutation.aspx" rel="noreferrer nofollow">news summary</a>):“Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2”

“We have developed an analysis pipeline to facilitate real-time mutation tracking in SARS-CoV-2, focusing initially on the Spike protein because it mediates infection of human cells and is the target of most vaccine strategies and antibody-based therapeutics. To date we have identified fourteen mutations in Spike that are accumulating. The mutation Spike D614G is of urgent concern; it began spreading in Europe in early February, and when introduced to new regions it rapidly becomes the dominant form. Also, we present evidence of recombination between locally circulating strains, indicative of multiple strain infections.

Although the observed diversity among pandemic SARS-CoV-2 sequences is low, its rapid global spread provides the virus with ample opportunity for natural selection to act upon rare but favorable mutations. This is analogous to the case of influenza. If the pandemic fails to wane, this could exacerbate the potential for antigenic drift and the accumulation of immunologically relevant mutations in the population during the year or more it will take to deliver the first vaccine.

• D614G (a G-to-A base change at position 23,403 in the Wuhan reference strain) is increasing in frequency at an alarming rate, indicating a fitness advantage relative to the original Wuhan strain that enables more rapid spread. We were concerned that if the D614G mutation can increase transmissibility, it might also impact severity of disease. Patients carrying the G614 mutation had higher viral loads… a significant difference was observed.

• S943P (a double base mutation: AGT (S) -> CCT (P)) is located in the fusion core region, and is of particular interest as it is spreading via recombination. Recombination requires simultaneous infection of the same host with different viruses, and the two parental strains have to be distinctive enough to manifest in a detectable way in the recombined sequence. Both criteria were met in Belgium."

From <a href="https://www.biorxiv.org/content/10.1101/2020.05.04.075911v1.full.pdf" rel="noreferrer nofollow">BioRxiv India</a>, May 2020, on that same D614G mutation with additional distinct biological properties: "D614G rapidly outcompeted other pre-existing subtypes, including the ancestral. We assessed that D614G mutation generates an additional serine protease (Elastase) cleavage site near the S1-S2 junction of the Spike protein. We also identified that a single nucleotide deletion (delC) is extremely rare in East Asians but is common in Europeans and North Americans. The delC allele facilitates entry of the 614G subtype into host cells, thus accelerating the spread of 614G subtype in Europe and North America where the delC allele is common. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare."

From <a href="https://www.biorxiv.org/content/10.1101/2020.03.15.991844v4.full" rel="noreferrer nofollow">BioRxiv</a>, April 2020: “Emergence of RBD mutations in circulating SARS-CoV-2 strains enhancing the structural stability and human ACE2 receptor affinity of the spike protein”

"Spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the critical determinant of viral tropism and infectivity. Three mutant types displayed higher human ACE2 affinity, and probably higher infectivity, one of which (V367F) was validated by wet bench. The RBD mutation analysis provides insights into SARS-CoV-2 evolution. The emergence of RBD mutations with increased human ACE2 affinity reveals higher risk of severe morbidity and mortality during a sustained COVID-19 pandemic, particularly if no effective precautions are implemented."

From the <a href="https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02344-6" rel="noreferrer nofollow">Journal of Translational Medicine</a>, April 2020: “Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase (RdRp) variant”

“SARS-CoV-2 is an RNA coronavirus responsible for the pandemic of COVID-19. RNA viruses are characterized by a high mutation rate, up to a million times higher than that of their hosts. Mutation rate drives viral evolution and genome variability, thereby enabling viruses to escape host immunity and to develop drug resistance.

Methods: We analyzed 220 genomic sequences from the GISAID database derived from patients infected by SARS-CoV-2 worldwide from December 2019 to mid-March 2020.

Results: We characterized 8 novel recurrent mutations of SARS-CoV-2. America. We noticed for the first time a silent mutation in RdRp gene in England (UK) on February 9th, 2020 while a different mutation in RdRp, changing its amino acid composition, emerged on February 20th, 2020 in Italy (Lombardy). The SARS-CoV-2 RdRp (also named nsp12) is a key component of the replication/transcription machinery. RdRps are considered among primary targets for antiviral drug development, against a wide variety of viruses [e.g., Remdesivir]. Naturally occurring mutations can lead to drug resistance phenomena, with a significant loss in the binding affinity of these molecules to the RdRp.