SARS-CoV-2 escapes neutralization by South African COVID-19
Jan 20, 2021 10:11:19 GMT
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Post by Deleted on Jan 20, 2021 10:11:19 GMT
SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma
www.biorxiv.org/content/10.1101/2021.01.18.427166v1
Abstract
SARS-CoV-2 501Y.V2, a novel lineage of the coronavirus causing COVID-19, contains multiple mutationswithin two immunodominant domains of the spike protein. Here we show that this lineage exhibitscomplete escape from three classes of therapeutically relevant monoclonal antibodies. Furthermore501Y.V2 shows substantial or complete escape from neutralizing antibodies in COVID-19 convalescentplasma. These data highlight the prospect of reinfection with antigenically distinct variants and mayforeshadow reduced efficacy of current spike-based vaccines.
Discussion
SARS-CoV-2, the virus responsible for the COVID-19 pandemic is evolving, with new lineages beingreported all over the world. Amongst previous lineages, D614G was shown to have faster growth in vitro,enhanced transmission in small animals, and has subsequently become globally dominant28-30. N501Y hasbeen shown to increase affinity for the human ACE2 receptor, which together with the repeated andindependent evolution of 501Y containing lineages25,26,31, strongly argues for enhanced transmissibility ofthese new variants. Here we show that the 501Y.V2 lineage, that contains nine spike mutations, andrapidly emerged in South Africa during the second half of 2020, is largely resistant to neutralizingantibodies elicited by infection with previously circulating lineages. This suggests that, despite the manypeople who have already been infected with SARS-CoV-2 globally and are presumed to have accumulatedsome level of immunity, new variants such as 501Y.V2 pose a significant re-infection risk.
While higher titres of neutralizing antibodies are common in hospitalized individuals, however most SARSCoV-2 infected people develop moderate neutralization titres3-5. Therefore, the data herein suggest thatmost individuals infected with previous SARS-CoV-2 lineages will have minimal or no detectableneutralization activity against 501Y.V2. This dramatic effect on plasma neutralization can be explained bythe dominance of RBD-directed neutralizing antibodies10,11,13. These data are supported by studiesshowing reduced plasma neutralization titres mediated by the E484K change alone23,24. Importantly, herewe show that the K417N change also has a crucial role in viral escape, effectively abrogating neutralizationby a well-defined, multi-donor class of VH3-53/66 germline restricted public antibodies that comprisesome of the most common and potent neutralizing antibodies to SARS-CoV-211,17.
The marked loss of neutralization against 501Y.V2 compared to the RBD-only chimeric virus demonstratesthe 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 resistance22, we also define an importantrole for a relatively small, three amino acid deletion in the 501Y.V2 NTD domain that completely disruptsa dominant public antibody response to the N5-loop supersite20-22. This deletion predominates among501Y.V2 variants, and occurs either alone or with an R246I substitution that has also been shown toabrogate neutralization by several NTD-directed neutralizing antibodies22.
A recently identified lineage in Brazil also has changes at key positions shown here to affect neutralizingantibodies (417T, 484K in RBD and 18F, 20N in NTD - the last mutation adding a glycosylation sequon)25.Our 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 subsequentselection for two distinct 501Y lineages with key mutations conferring neutralization resistance stronglyargues 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 likelyoccurred 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 theworld. The sporadic emergence of escape mutations in long-term viral shedders, includingimmunocompromised individuals, may also contribute to the emergence of neutralization resistantviruses32. Altogether, these data highlight the need for increased, ongoing surveillance and sequencingduring the SARS-CoV-2 pandemic.
Crucially, it is from these same public antibody responses thatmany therapeutic strategies currently underdevelopment have been derived8,9,33. The overwhelming majority of monoclonal antibodies already on the path to licensure target residues K417 or E484 and will therefore be ineffective against 501Y.V2.Amongst these antibodies, some have already been granted emergency use authorization in the USA(Regeneron Pharmaceuticals and Eli Lilly and Company). In addition, a next generation of potentneutralizing antibodies that target the NTD N5-loop supersite have been suggested for clinical development but are also likely to be futile against 501Y.V2.
These data also have implications for the effectiveness of SARS-CoV-2 vaccines, which are principallybased on immune responses to the spike protein. Neutralizing antibodies have repeatedly beendemonstrated as the primary correlate of protection for most vaccines, including those designed toprevent infection with respiratory pathogens34. Despite neutralization escape, we show here that asignificant proportion of non-neutralizing, RBD binding antibodies remain active against 501Y.V2. Whileantibody effector functions elicited by infection and vaccination have been implicated in protecting fromreinfection and disease35,36, the role of non-neutralizing antibodies and the efficacy of T cell responses to501Y.V2 remain to be elucidated. Ultimately, the correlates of protection against SARS-CoV-2 infectionand 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 neutralizingantibodies highlight the urgent requirement for rapidly adaptable vaccine design platforms, and the needto identify less mutable viral targets for incorporation into future immunogens.
www.biorxiv.org/content/10.1101/2021.01.18.427166v1
Abstract
SARS-CoV-2 501Y.V2, a novel lineage of the coronavirus causing COVID-19, contains multiple mutationswithin two immunodominant domains of the spike protein. Here we show that this lineage exhibitscomplete escape from three classes of therapeutically relevant monoclonal antibodies. Furthermore501Y.V2 shows substantial or complete escape from neutralizing antibodies in COVID-19 convalescentplasma. These data highlight the prospect of reinfection with antigenically distinct variants and mayforeshadow reduced efficacy of current spike-based vaccines.
Discussion
SARS-CoV-2, the virus responsible for the COVID-19 pandemic is evolving, with new lineages beingreported all over the world. Amongst previous lineages, D614G was shown to have faster growth in vitro,enhanced transmission in small animals, and has subsequently become globally dominant28-30. N501Y hasbeen shown to increase affinity for the human ACE2 receptor, which together with the repeated andindependent evolution of 501Y containing lineages25,26,31, strongly argues for enhanced transmissibility ofthese new variants. Here we show that the 501Y.V2 lineage, that contains nine spike mutations, andrapidly emerged in South Africa during the second half of 2020, is largely resistant to neutralizingantibodies elicited by infection with previously circulating lineages. This suggests that, despite the manypeople who have already been infected with SARS-CoV-2 globally and are presumed to have accumulatedsome level of immunity, new variants such as 501Y.V2 pose a significant re-infection risk.
While higher titres of neutralizing antibodies are common in hospitalized individuals, however most SARSCoV-2 infected people develop moderate neutralization titres3-5. Therefore, the data herein suggest thatmost individuals infected with previous SARS-CoV-2 lineages will have minimal or no detectableneutralization activity against 501Y.V2. This dramatic effect on plasma neutralization can be explained bythe dominance of RBD-directed neutralizing antibodies10,11,13. These data are supported by studiesshowing reduced plasma neutralization titres mediated by the E484K change alone23,24. Importantly, herewe show that the K417N change also has a crucial role in viral escape, effectively abrogating neutralizationby a well-defined, multi-donor class of VH3-53/66 germline restricted public antibodies that comprisesome of the most common and potent neutralizing antibodies to SARS-CoV-211,17.
The marked loss of neutralization against 501Y.V2 compared to the RBD-only chimeric virus demonstratesthe 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 resistance22, we also define an importantrole for a relatively small, three amino acid deletion in the 501Y.V2 NTD domain that completely disruptsa dominant public antibody response to the N5-loop supersite20-22. This deletion predominates among501Y.V2 variants, and occurs either alone or with an R246I substitution that has also been shown toabrogate neutralization by several NTD-directed neutralizing antibodies22.
A recently identified lineage in Brazil also has changes at key positions shown here to affect neutralizingantibodies (417T, 484K in RBD and 18F, 20N in NTD - the last mutation adding a glycosylation sequon)25.Our 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 subsequentselection for two distinct 501Y lineages with key mutations conferring neutralization resistance stronglyargues 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 likelyoccurred 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 theworld. The sporadic emergence of escape mutations in long-term viral shedders, includingimmunocompromised individuals, may also contribute to the emergence of neutralization resistantviruses32. Altogether, these data highlight the need for increased, ongoing surveillance and sequencingduring the SARS-CoV-2 pandemic.
Crucially, it is from these same public antibody responses thatmany therapeutic strategies currently underdevelopment have been derived8,9,33. The overwhelming majority of monoclonal antibodies already on the path to licensure target residues K417 or E484 and will therefore be ineffective against 501Y.V2.Amongst these antibodies, some have already been granted emergency use authorization in the USA(Regeneron Pharmaceuticals and Eli Lilly and Company). In addition, a next generation of potentneutralizing antibodies that target the NTD N5-loop supersite have been suggested for clinical development but are also likely to be futile against 501Y.V2.
These data also have implications for the effectiveness of SARS-CoV-2 vaccines, which are principallybased on immune responses to the spike protein. Neutralizing antibodies have repeatedly beendemonstrated as the primary correlate of protection for most vaccines, including those designed toprevent infection with respiratory pathogens34. Despite neutralization escape, we show here that asignificant proportion of non-neutralizing, RBD binding antibodies remain active against 501Y.V2. Whileantibody effector functions elicited by infection and vaccination have been implicated in protecting fromreinfection and disease35,36, the role of non-neutralizing antibodies and the efficacy of T cell responses to501Y.V2 remain to be elucidated. Ultimately, the correlates of protection against SARS-CoV-2 infectionand 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 neutralizingantibodies highlight the urgent requirement for rapidly adaptable vaccine design platforms, and the needto identify less mutable viral targets for incorporation into future immunogens.