Prospective mapping of viral mutations that escape antibodies used to treat COVID-19

Starr, Tyler N; Greaney, Allison J; Addetia, Amin; Hannon, William W; Choudhary, Manish; Dingens, Adam S.; Li, Jonathan Z.; Bloom, Jesse D.

doi:10.1101/2020.11.30.405472

Cited by 258 publications

(426 citation statements)

References 31 publications

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“…Despite this critical interaction and related mutational constraints, it appears the RBD can tolerate mutations in this region 3,4 , raising the real possibility of virus escape from vaccines and monoclonal antibodies. Spike mutants exhibiting reduced susceptibility to monoclonal antibodies have been identified in in vitro screens 5,6 . Some of these have been found in clinical isolates 7 .…”

Section: Introductionmentioning

confidence: 99%

Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70

Kemp

Meng

Ferriera

et al. 2020

Preprint

175

156

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SARS-CoV-2 Spike amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition. Here we report recurrent emergence and significant onward transmission of a six-nucleotide deletion in the S gene, which results in loss of two amino acids: H69 and V70. Of particular note this deletion, 𝚫H69/V70, often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F. One of the 𝚫H69/V70+ N501Y lineages, B.1.1.7, is comprised of over 4000 SARS-CoV-2 genome sequences from the UK and includes eight other S gene mutations: RBD (N501Y and A570D), S1 (𝚫H69/V70 and 𝚫144/145) and S2 (P681H, T716I, S982A and D1118H). Some of these mutations have presumably arisen as a result of the virus evolving from immune selection pressure in infected individuals and at least one, lineage B.1.1.7, potentially from a chronic infection. Given our recent evidence that delH69/V70 enhances viral infectivity (Kemp et al. 2020), its effect on virus fitness appears to be independent to the RBD changes. Enhanced surveillance for the delH69/V70 deletion with and without RBD mutations should be considered as a priority. Permissive mutations such as delH69/V70 have the potential to enhance the ability of SARS-CoV-2 to generate new variants, including vaccine escape variants, that would have otherwise significantly reduced viral infectivity.

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Section: Introductionmentioning

confidence: 99%

Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70

Kemp

Meng

Ferriera

et al. 2020

Preprint

175

156

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“…The biggest question is what our work implies about possible antigenic evolution by SARS-CoV-2. While it is impossible to know if SARS-CoV-2 will evolve similarly to 229E, it is ominous that mutations affecting neutralization by antibodies or sera are already present at low frequencies among circulating SARS-CoV-2 (Greaney et al, 2020;Kemp, 2020;Liu et al, 2020b;McCarthy et al, 2020;Starr et al, 2020b;Thomson, 2020;Weisblum et al, 2020) even though most of the human population is still naive and so presumably exerting little immune pressure on the virus. But two facts provide hope even in light of our observation that human coronaviruses evolve to escape neutralizing immunity.…”

Section: Discussionmentioning

confidence: 99%

A human coronavirus evolves antigenically to escape antibody immunity

Eguia

Crawford

Stevens-Ayers

et al. 2020

Preprint

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There is intense interest in antibody immunity to coronaviruses. However, it is unknown if coronaviruses evolve to escape such immunity, and if so, how rapidly. Here we address this question by characterizing the historical evolution of human coronavirus 229E. We identify human sera from the 1980s and 1990s that have neutralizing titers against contemporaneous 229E that are comparable to the anti-SARS-CoV-2 titers induced by SARS-CoV-2 infection or vaccination. We test these sera against 229E strains isolated after sera collection, and find that neutralizing titers are lower against these “future” viruses. In some cases, sera that neutralize contemporaneous 229E viral strains with titers >1:100 do not detectably neutralize strains isolated 8–17 years later. The decreased neutralization of “future” viruses is due to antigenic evolution of the viral spike, especially in the receptor-binding domain. If these results extrapolate to other coronaviruses, then it may be advisable to periodically update SARS-CoV-2 vaccines.

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“…These implications are supported by experimental results recently described in preprint form that examined the ability of artificially-generated single site mutations to escape recognition by a panel of 10 antibodies not considered above. 25 In some cases, the mutations considered in that work were the same as the naturally occurring mutations considered above, and they were shown to reduce the ability of an antibody to bind ACE2 and to neutralize the variant virus.…”

Section: Discussionmentioning

confidence: 99%

The Potential for SARS-CoV-2 to Evade Both Natural and Vaccine-induced Immunity

Shang

Axelsen

2020

Preprint

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SARS-CoV-2 attaches to the surface of susceptible cells through extensive interactions between the receptor binding domain (RBD) of its spike protein and angiotensin converting enzyme type 2 (ACE2) anchored in cell membranes. To investigate whether naturally occurring mutations in the spike protein are able to prevent antibody binding, yet while maintaining the ability to bind ACE2 and viral infectivity, mutations in the spike protein identified in cases of human infection were mapped to the crystallographically-determined interfaces between the spike protein and ACE2 (PDB entry 6M0J), antibody CC12.1 (PDB entry 6XC2), and antibody P2B-2F6 (PDB entry 7BWJ).Both antibody binding interfaces partially overlap with the ACE2 binding interface. Among 16 mutations that map to the RBD:CC12.1 interface, 11 are likely to disrupt CC12.1 binding but not ACE2 binding. Among 12 mutations that map to the RBD:P2B-2F6 interface, 8 are likely to disrupt P2B-2F6 binding but not ACE2 binding. As expected, none of the mutations observed to date appear likely to disrupt the RBD:ACE2 interface.We conclude that SARS-CoV-2 with mutated forms of the spike protein may retain the ability to bind ACE2 while evading recognition by antibodies that arise in response to the original wild-type form of the spike protein. It seems likely that immune evasion will be possible regardless of whether the spike protein was encountered in the form of infectious virus, or as the immunogen in a vaccine. Therefore, it also seems likely that reinfection with a variant strain of SARS-CoV-2 may occur among people who recover from Covid-19, and that vaccines with the ability to generate antibodies against multiple variant forms of the spike protein will be necessary to protect against variant forms of SARS-CoV-2 that are already circulating in the human population.

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Prospective mapping of viral mutations that escape antibodies used to treat COVID-19

Cited by 258 publications

References 31 publications

Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70

Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70

A human coronavirus evolves antigenically to escape antibody immunity

The Potential for SARS-CoV-2 to Evade Both Natural and Vaccine-induced Immunity

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