SARS-CoV-2 501Y.V2, a novel lineage of the coronavirus causing COVID-19, contains multiple mutations within two immunodominant domains of the spike protein.

In a paper recently published on it’s shown that this lineage exhibits complete escape from three classes of therapeutically relevant monoclonal antibodies.

Furthermore 501Y.V2 shows substantial or complete escape from neutralizing antibodies in COVID-19 convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and may foreshadow reduced efficacy of current spike-based vaccines.

While higher titres of neutralizing antibodies are common in hospitalized individuals, however most SARSCoV-2 infected people develop moderate neutralization titres. Therefore, the data herein suggest that most individuals infected with previous SARS-CoV-2 lineages will have minimal or no detectable neutralization activity against 501Y.V2.

This dramatic effect on plasma neutralization can be explained by
the dominance of RBD-directed neutralizing antibodies. These data are supported by studies showing reduced plasma neutralization titres mediated by the E484K change alone. Importantly, here it’s shown that the K417N change also has a crucial role in viral escape, effectively abrogating neutralization by a well-defined, multi-donor class of VH3-53/66 germline restricted public antibodies that comprise some of the most common and potent neutralizing antibodies to SARS-CoV-2.

The marked loss of neutralization against 501Y.V2 compared to the RBD-only chimeric virus demonstrates the important role that mutations in the NTD play in mediating immune escape. While the L18F change (found in 501Y.V2) has previously been linked to neutralization resistance, was also defined an important role for a relatively small, three amino acid deletion in the 501Y.V2 NTD domain that completely disrupts a dominant public antibody response to the N5-loop supersite. This deletion predominates among 501Y.V2 variants, and occurs either alone or with an R246I substitution that has also been shown to abrogate neutralization by several NTD-directed neutralizing antibodies

A recently identified lineage in Brazil also has changes at key positions shown here to affect neutralizing antibodies (417T, 484K in RBD and 18F, 20N in NTD – the last mutation adding a glycosylation sequon).

These data suggest that this lineage is also likely to exhibit significant levels of neutralization resistance, making both lineages of considerable public health concern. The independent emergence and subsequent selection for two distinct 501Y lineages with key mutations conferring neutralization resistance strongly argues for selection by neutralizing antibodies as the dominant driver for SARS-CoV-2 spike diversification.

The relatively rapid acquisition of a comprehensive suite of neutralization escape mutations likely occurred because of the large number of commonly shared public antibodies (eg: VH3-53/66, VH1-2, VH1-24) to both the RBD and NTD of spike, together with high levels of SARS-CoV-2 transmission around the world.

The sporadic emergence of escape mutations in long-term viral shedders, including immunocompromised individuals, may also contribute to the emergence of neutralization resistant viruses.

Altogether, these data highlight the need for increased, ongoing surveillance and sequencing during the SARS-CoV-2 pandemic.

These data also have implications for the effectiveness of SARS-CoV-2 vaccines, which are principally based on immune responses to the spike protein. Neutralizing antibodies have repeatedly been demonstrated as the primary correlate of protection for most vaccines, including those designed to prevent infection with respiratory pathogens.

Despite neutralization escape, we show here that a significant proportion of non-neutralizing, RBD binding antibodies remain active against 501Y.V2. While antibody effector functions elicited by infection and vaccination have been implicated in protecting from reinfection and disease, the role of non-neutralizing antibodies and the efficacy of T cell responses to 501Y.V2 remain to be elucidated.

Ultimately, the correlates of protection against SARS-CoV-2 infection and severe COVID-19 disease remain undetermined and rely upon ongoing large-scale clinical trials. Nevertheless, the speed and scope of 501Y.V2 mediated immune escape from pre-existing neutralizing antibodies highlight the urgent requirement for rapidly adaptable vaccine design platforms, and the need to identify less mutable viral targets for incorporation into future immunogens.

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