Virology

More virulent (see Zhou et al. and Daniloski et al.), now globally dominant, “G614” strain that began spreading in Europe and the U.S. East Coast in February-March 2020 (see Korber et al.). This mutation is a change of the amino acid at position 614, from aspartic acid (D) to glycine (G), thus the “D614G” mutation. The D614G mutation marks the evolution of the initial “D614” (Wuhan) strain to the more prevalent “G614” or “614G” strain. Human neutralizing antibodies cross-react to both strains (see Klumpp-Thomas et al.). For more background on the G614 strain, see Baric. For more evidence on the phenotypic traits and fitness of the G614 strain see van Dorp et al., Hou et al., Volz et al., and Plante et al. For discussion of its role in second wave infections see Long et al. For a summary of some of these papers and others on the G614 strain, see Nature News as well as this well written explanation.

• ORFΔ3b Mutation: Lam et al. Loss of ORF3b in the Circulating SARS-CoV-2 Strains. Emerg Microbes Infect. Nov 2020.
  Globally circulating mutation that lack a full-length form of orf3b (known as orfΔ3b). Approximately 24% of circulating sequences carry orfΔ3b. Emergence of this variants coincides with the emergence of the G614 strain. SARS-CoV-2 orfΔ3b does not block interferon production, unlike full-length orf3b. Thus, these Δ3b variants have lost the ability to block the antiviral activity of interferons, but the effect of this on virulence has yet to be determined.

In late 2020 and early 2021, three new prevalent circulating variants with 614G backgrounds were identified, 501Y.1 (lineage B.1.1.7) in the UK and Europe, 501Y.V2 (lineage B.1.351) in South Africa, and 501Y.V3 (lineage P.1) in Brazil and Japan (see Martin et al.* and O’Toole et al.). All variants share a common mutation: N501Y (asparagine [N] to tyrosine [Y] at position 501) in the spike protein receptor binding domain. However, these variants arose independently and are genetically distinct. The N501Y mutation appears to increase transmissibility via increasing ACE2 receptor binding affinity (See Starr et al. and Gu et al.). The N501Y mutation alone is not believed to result in vaccine (see Xie et al.* and Gu et al.) or neutralizing antibody (see Haynes et al.*) resistance, however the multiple mutations within each of these variants appear to cause a small reduction in neutralizing antibody titers—see each variant below for more info as well as this summary.

501Y.V1 variant (B.1.1.7 lineage) accounts for a rapidly increasing proportion of infections in the UK, Europe, and the U.S. and has an unusually large number of genetic changes, particularly in the spike protein (see Rambaut et al.*). This variant is estimated to have emerged in September 2020 and has quickly become the dominant circulating variant in England (see Public Health England Reports). 501Y.V1 has likely been circulating in the U.S. since mid-November (see Firestone et al. and Larsen et al.*) and is expected to become the predominant variant in the U.S. in March (see Galloway et al. and Washington et al.*). For known 501Y.V1 cases in the U.S. see CDC: US Cases Caused by Variants. Preliminary analysis in the UK found that this variant is significantly more transmissible than previous circulating variants, with a potential to increase the reproductive number (R) by 0.4 or greater with an estimated increased transmissibility of ~56% or greater (see Davies et al., Volz et al.*, Graham et al.*, and Vöhringer et al.*, MRC GIDA Report, ECDC Threat Assessment, and CDC FAQ)—possibly due to a longer duration of acute infection (see Kissler et al.*)—and an increase in viral load (see Calistri et al., Golubchik et al.* and Kidd et al.). This variant does not appear to cause more severe disease in children (see Brookman, et al.). There is a realistic possibility that 501Y.V1 is associated with an increased risk of death (see Glint et al.*, NERVTAG Update, Challen et al., and Horby et al.). A number of recent studies appears to indicate varying degrees of antibody resistance to this variant and a small reduction in natural and mRNA vaccine-elicited antibody titers by either K417N, or E484K, or N501Y mutations (see Chen et al., Supasa et al., Rees-Spear et al., Tada et al.*, Skelly et al.*, Wang P et al.*, Xie et al., and Wang Z et al.*), however overall this variant is susceptible to neutralizing antibodies elicited by ancestral spike vaccines (see Shen et al.). Pfizer-BioNTech found that their vaccine (BNT162b2) elicited immune sera that had slightly reduced (~20%) efficacy but overall largely preserved neutralizing titers against B.1.1.7 lineage pseudovirus, indicating that this variant will not escape vaccine-mediated protection (see Liu et al., Muik et al., and Xie et al.). Moderna found that their vaccine (mRNA-1273) produces neutralizing titers against 501Y.V1 with no reduction in those titers relative to prior variants (see Wu et al.). Oxford-AstraZeneca found that virus neutralization activity by vaccine (ChAdOx1 nCoV-19) induced antibodies was 9-fold lower against the B.1.1.7 variant but that vaccine efficacy was ~10% less for B.1.1.7 compared to non-B.1.1.7 lineages at 74.6% and 84.0% in 120 cases, respectively (see Emary et al.*). Novavax similarly found a 10% reduction in their vaccine (NVX-CoV2373) efficacy compared to the G614 strain at 85.6% vs 95.6%, respectively. In February 2021, natural appearance of the E484K mutation (see below) on the B.1.1.7 background was observed in the UK, which will result in a reduction in neutralizing antibody efficacy (see Collier et al.).

501Y.V2 variant (B.1.351 lineage) has mainly to date been observed in South Africa and has a distinct set of genetic changes characterized by N501Y, E484K (see below), and K417N mutations in the spike protein (see KRISP Briefing and CAPRISA Update). The combination of significantly increased transmissibility from the N501Y mutation and the immunoevasive effects of the E484K mutation, make this a particularly concerning variant (see Pearson et al.*, Greaney et al., and Moyo-Gwete et al.*). Convalescent, therapeutic monoclonal, and mRNA vaccine-elicited antibody neutralization efficacy appears to be significantly reduced by this variant indicating that 501Y.V2 may escape the neutralizing antibody response elicited by prior natural infection or vaccination (see Chen et al., Cele et al.*, Wibmer et al., Zhou et al., Li et al., Tada et al.*, Skelly et al.*, Stamatatos et al.*, Wang P et al.*, Cele et al.*, and Wang Z et al.*). Moderna found that this variant causes a six-fold reduction in neutralizing titers relative to prior variants, however, neutralizing titer levels remained above levels that are expected to be protective (see Wu et al.). For the Pfizer-BioNTech vaccine, moderate effects on neutralization efficacy have been observed with these mutations, however not by enough to negate protection (see Liu et al. and Xie et al.). Novavax reported a vaccine efficacy of 60% against 501Y.V2 (vs 89% overall efficacy; see Shinde et al.*), while Johnson & Johnson reported a 57% efficacy (vs 66–72% overall efficacy), and Oxford-AstraZeneca, in a small underpowered trial, found a 10.4% efficacy (vs 62% overall efficacy) leading to South Africa suspending administration of the ChAdOx1 nCoV-19 vaccine (see Madhi et al.).

501Y.V3 variant (P.1 lineage, a descendent of the B.1.1.28 lineage) has mainly been found circulating in Manaus, north Brazil, but has been identified in the U.S., is characterized by N501Y, E484K (see below), and K417T mutations in the spike protein (see Faria et al.* and Faria et al.*). As with 501Y.V2, the combination of the N501Y mutation and immunoevasive E484K mutation, make this a particularly concerning variant and emerging data appears to indicate that this variant may resist neutralizing antibody responses (see Chen et al., Wang P et al.*, Wu et al., and Wang Z et al.*).

• E484K Mutation: Greaney AJ, et al. Comprehensive Mapping of Mutations in the SARS-CoV-2 Receptor-Binding Domain That Affect Recognition by Polyclonal Human Plasma Antibodies. Cell Host Microbe. Feb 2021. (Author Summary)
Immunoevasive E484K mutation (glutamic acid [E] to lysine [K] at position 484) of the spike protein receptor binding domain. This mutation impacts binding and neutralization by polyclonal serum antibodies targeting the receptor binding domain causing neutralization by some sera to be reduced by greater than 10-fold (see Chen et al., Wibmer et al., Tada et al.*, Skelly et al.*, Wang P et al.*, Wu et al., Xie et al., Weisblum et al., Wang Z et al.*, Greaney et al., Andreano et al.*, Liu et al.*, and Naveca et al.*). This mutation has been found in viral lineages in South Africa, Brazil, Japan, Europe, and New York namely B.1.351 (501Y.V2), P.1 (501Y.V3), B.1.1.248 (a descendent of B.1.1.28), B.1.525, and B.1.526 (see West et al.*, Nonka et al.*, Voloch et al.*, and Faria et al.*).

For information on the associated ΔH69/V70 mutation, which is also found in the below N439K variant and throughout the U.S. and may play a role in increased transmissibility, see Kemp et al.*, Kemp et al., and Larsen et al.*. For context on the potential significance of the associated P681H mutation—located immediately adjacent to the furin cleavage site, a known location of biological significance (see Johnson et al.)—see Hoffmann et al. For information on the S477N mutation see Singh et al., Liu et al., Chen et al., and West et al.*

Immunoevasive N439K mutation (asparagine [N] to lysine [K] at position 439) of the spike protein receptor binding domain, which is a key target of antibodies against the virus (see Thomson et al.). This variant has been observed to escape the activity of neutralizing antibodies, including those from convalescent sera and manufactured monoclonal antibodies. The N439K variant has emerged independently at least twice and now appears to be present in ~9% of infections in Europe. For more information on this and other immunoevasive variants (i.e. Zoonotic Y453F [lineage B.1.1.298]), see Greaney et al. and Starr et al.).

Note: Despite widespread incorrect media reports on the findings of Basavaraju et al., there remains virtually no evidence of SARS-CoV-2 widely circulating in the U.S. prior to January 19, 2020. Rather, these findings likely represent cross-reactivity with other endemic human coronaviruses. For more, see this explanation by Virologist Trevor Bedford.

*Not Peer Reviewed.