The SARS-CoV-2 Y453F mink variant displays a pronounced increase in ACE-2 affinity but does not challenge antibody neutralization

Abstract

SARS-CoV-2 transmission from humans to animals has been reported for many domesticated species, including farmed minks. The identification of novel spike gene mutations appearing in minks has raised major concerns about potential immune evasion and challenges for the global vaccine strategy. One genetic variant, known as “cluster-five”, arose among farmed minks in Denmark and resulted in a complete shutdown of the world’s largest mink production. However, the functional properties of this new variant are not established. Here we present functional data on the cluster-five variant, which contains a mutation resulting in a Y453F residue change in the receptor-binding domain (RBD) of the spike protein. Using an ELISA-based ACE-2/RBD inhibition assay, we show that the Y453F variant does not decrease established humoral immunity from previously infected individuals nor affect the neutralizing antibody response in a vaccine mouse model based on the original Wuhan strain RBD or spike as antigens. However, biolayer interferometry analysis demonstrates that it binds the human ACE-2 receptor with a four-fold higher affinity compared to the original strain suggesting an enhanced transmission capacity and a possible challenge for viral control. These results also indicate that the rise in frequency of the cluster-five variant in mink farms might be a result of the fitness advantage conferred by the receptor adaptation rather than evading immune responses.

The Spike of Concern—The Novel Variants of SARS-CoV-2

“…Y453 forms an electrostatic interaction with H34 in hAce2 and lies at the bottom of the concave binding site next to L452 (mutated in USA B.1.429 and Indian B.1.617 Spike) (Figures 4a and 5f). The Y453F mutation arose several times independently in different sub-lineages, was found as an escape mutant in in vitro experiments [69], and increases hAce2 affinity four-fold [70] (Table 2). The mutation may be linked with viral replication in minks and the repeated transition from humans to mink and back [66,71].…”

Structural basis for accommodation of emerging B.1.351 and B.1.1.7 variants by two potent SARS-CoV-2 neutralizing antibodies

“…However, the frequent mutation K417N resulted in escape of the prevalent VH3-53-derived antibody class ( Wang et al., 2021b ), and may be selected predominantly by antibody pressure. Despite the ability of 1–57 and 2–7 to still potently neutralize emerging strains that carry N501Y, K417N, and E484K mutations, we observed that individual mutations at 452, 494, 477, and 439 ( Figure 4 B)—which may affect 1–57 and 2–7 recognition—do not or only weakly enhance ACE2 binding ( Bayarri-Olmos et al., 2021 ; Lopez et al, 2021 ; Starr et al., 2020 ; Thomson et al., 2020 ; Tian et al, 2021 ; Zahradník et al, 2021 ) ( Figure S4 E). Thus, these mutations may undergo weak selection pressure for enhancing ACE2 binding affinity.…”

Novel SARS-CoV-2 Variants in Italy: The Role of Veterinary Public Health Institutes

“…Some domestic animal species, including cats, ferrets, and notably, minks, have been demonstrated to be susceptible to SARS-CoV-2 infection, while others, such as pigs and chickens, are not. In this perspective, SARS-CoV-2 surveillance in animals [8] is a fundamental task, ruled by veterinary public health institutes such IZSAM, to characterize potential novel viral variants with hazard to humans [9][10][11][12].…”