Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host

Choi, Byong-Seok; Choudhary, Manish; Regan, James; Sparks, Jeffrey A.; Padera, Robert F.; Qiu, Xueting; Solomon, Isaac H.; Kuo, Hsiao Hsuan; Boucau, Julie; Bowman, Kathryn; Adhikari, Upasana Das; Winkler, Marisa L.; Mueller, Alisa A.; Hsu, Tiffany; Desjardins, Michaël; Baden, Lindsey R.; Chan, Betty; Walker, Bruce D.; Lichterfeld, Mathias; Brigl, Manfred; Kwon, Douglas S.; Kanjilal, Sanjat; Richardson, Eugene T; Jonsson, Helena; Alter, Galit; Barczak, Amy K.; Hanage, William P.; Yu, Xu G.; Gaiha, Gaurav D.; Seaman, Michael S.; Cernadas, Manuela; Li, Jonathan Z.

doi:10.1056/nejmc2031364

Cited by 1,212 publications

(1,245 citation statements)

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“…The persistently infected patient and his clinical time course are described in detail in ( 14 ). That paper also describes the Illumina deep sequencing of that patient at nine timepoints.…”

Section: Deep-sequencing Analysis Of Within-host Viral Genetic Diversmentioning

confidence: 99%

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

Starr

Greaney

Addetia

et al. 2020

Preprint

Self Cite

263

397

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Antibodies are becoming a frontline therapy for SARS-CoV-2, but the risk of viral evolutionary escape remains unclear. Here we map how all mutations to SARS-CoV-2's receptor-binding domain (RBD) affect binding by the antibodies in Regeneron's REGN-COV2 cocktail and Eli Lilly's LY-CoV016. These complete maps uncover a single amino-acid mutation that fully escapes the REGN-COV2 cocktail, which consists of two antibodies targeting distinct structural epitopes. The maps also identify viral mutations that are selected in a persistently infected patient treated with REGN-COV2, as well as in lab viral escape selections. Finally, the maps reveal that mutations escaping each individual antibody are already present in circulating SARS-CoV-2 strains. Overall, these complete escape maps enable immediate interpretation of the consequences of mutations observed during viral surveillance.

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Section: Deep-sequencing Analysis Of Within-host Viral Genetic Diversmentioning

confidence: 99%

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

Starr

Greaney

Addetia

et al. 2020

Preprint

Self Cite

263

397

View full text Add to dashboard Cite

show abstract

“…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 . The unprecedented scale of whole genome SARS-CoV-2 sequencing has enabled identification and epidemiological analysis of transmission.…”

Section: Introductionmentioning

confidence: 99%

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

Kemp

Meng

Ferriera

et al. 2020

Preprint

178

161

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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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“…Deletions in the N-terminal domain (NTD) of Spike S1 are also being increasingly recognised, both within hosts 7 and across individuals 8 . The evolutionary basis for the emergence of deletions is unclear at present, and could be related to escape from immunity or to enhanced fitness/transmission.…”

Section: Introductionmentioning

confidence: 99%

Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation

Kemp

Collier

Datir

et al. 2020

Preprint

160

145

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SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and amino acid variation in Spike is increasingly appreciated. Given both vaccines and therapeutics are designed around Wuhan-1 Spike, this raises the theoretical possibility of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences by both short and long read technologies over 23 time points spanning 101 days. Although little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days, N501Y in Spike was transiently detected at day 55 and V157L in RdRp emerged. However, following convalescent plasma we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility, but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type and appeared to compensate for the reduced infectivity of D796H. Consistent with the observed mutations being outside the RBD, monoclonal antibodies targeting the RBD were not impacted by either or both mutations, but a non RBD binding monoclonal antibody was less potent against ΔH69/ΔV70 and the double mutant. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with reduced susceptibility to neutralising antibodies.

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Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host

Cited by 1,212 publications

References 5 publications

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

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

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

Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation

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