All Studies Meta Analysis

Emergence of SARS-CoV-2 Resistance with Monoclonal Antibody Therapy

Choudhary et al., medRxiv, doi:10.1101/2021.09.03.21263105, NCT04518410

Sep 2021

Post
Facebook

Source PDF All Studies Meta AnalysisMeta

Bamlanivimab/etesevimab

22nd treatment shown to reduce risk in May 2021, now with p = 0.00036 from 21 studies, recognized in 7 countries. Efficacy is variant dependent.

Lower risk for mortality, hospitalization, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 109 treatments. c19early.org

Analysis of ACTIV-2/A5401, showing the potential for rapid emergence of resistance during monoclonal antibody treatment, resulting in prolonged high level viral loads and clinical worsening. Treatment-emergent resistance mutations were more common after bamlanivimab 700mg (7% of 111 vs 0% of 112 participants, p=0.003).

Efficacy is highly variant dependent. In Vitro research suggests a lack of efficacy for omicron1-5.

Important missing comments or errors? Let us know.

1. Liu et al., Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2, bioRxiv, doi:10.1101/2021.12.14.472719.biorxiv.org, doi.org.

2. Sheward et al., Variable loss of antibody potency against SARS-CoV-2 B.1.1.529 (Omicron), bioRxiv, doi:10.1101/2021.12.19.473354.biorxiv.org, doi.org.

3. VanBlargan et al., An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by several therapeutic monoclonal antibodies, bioRxiv, doi:10.1101/2021.12.15.472828.biorxiv.org, doi.org.

4. Pochtovyi et al., In Vitro Efficacy of Antivirals and Monoclonal Antibodies against SARS-CoV-2 Omicron Lineages XBB.1.9.1, XBB.1.9.3, XBB.1.5, XBB.1.16, XBB.2.4, BQ.1.1.45, CH.1.1, and CL.1, Vaccines, doi:10.3390/vaccines11101533.mdpi.com, doi.org.

5. Haars et al., Prevalence of SARS-CoV-2 Omicron Sublineages and Spike Protein Mutations Conferring Resistance against Monoclonal Antibodies in a Swedish Cohort during 2022–2023, Microorganisms, doi:10.3390/microorganisms11102417.mdpi.com, doi.org.

Choudhary et al., 15 Sep 2021, preprint, 28 authors, trial NCT04518410 (history).

This Paper Bamlaniv../e..All

Emergence of SARS-CoV-2 Resistance with Monoclonal Antibody Therapy

Manish C Choudhary, Kara W Chew, Rinki Deo, James P Flynn, James Regan, Charles R Crain, Carlee Moser, Michael Hughes, Justin Ritz, Ruy M Ribeiro, Ruian Ke, Joan A Dragavon, Arzhang C Javan, Ajay Nirula, Paul Klekotka, Alexander L Greninger, Courtney V Fletcher, Eric S Daar, David A Wohl, Joseph J Eron, Judith S Currier, Urvi M Parikh, Scott F Sieg, Alan S Perelson, Robert W Coombs, MD Davey M Smith, MD Jonathan Z Li

doi:10.1101/2021.09.03.21263105

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Author contributions MCC, KC, RC, DMS, JZL conceptualized and performed the study, MCC, RD, JPF, JR, CC performed resistance analysis experiment; RMR, RK, ASP performed mathematical modeling; JD, AG performed viral load analysis; UP, SS performed serological analysis; CM, MH, JR performed statistical analysis.

References

Berg, Development of the RealTime SARS-CoV-2 quantitative Laboratory Developed Test and correlation with viral culture as a measure of infectivity, J Clin Virol, doi:10.1016/j.jcv.2021.104945

Campbell, Increased transmissibility and global spread of SARS-CoV-2 variants of concern as at June 2021, Euro Surveill, doi:10.2807/1560-7917.ES.2021.26.24.2100509

Chen, SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19, N Engl J Med, doi:10.1056/NEJMoa2029849

Chew, Conference on Retroviruses and Opportunistic Infections (Virtual

Choi, Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host, N Engl J Med, doi:10.1056/NEJMc2031364

Chou, Guentzel, Michels, Miner, Drew, Frequency of UL97 phosphotransferase mutations related to ganciclovir resistance in clinical cytomegalovirus isolates, J Infect Dis, doi:10.1093/infdis/172.1.239

Choudhary, Crain, Qiu, Hanage, Li, SARS-CoV-2 Sequence Characteristics of COVID-19 Persistence and Reinfection, Clin Infect Dis, doi:10.1093/cid/ciab380

Clavel, Hance, HIV drug resistance, N Engl J Med, doi:10.1056/NEJMra025195

Collier, Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies, Nature, doi:10.1038/s41586-021-03412-7

Degli-Angeli, Validation and verification of the Abbott RealTime SARS-CoV-2 assay analytical and clinical performance, J Clin Virol, doi:10.1016/j.jcv.2020.104474

Fajnzylber, SARS-CoV-2 viral load is associated with increased disease severity and mortality, Nat Commun, doi:10.1038/s41467-020-19057-5

Gottlieb, Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial, JAMA, doi:10.1001/jama.2021.0202

Gupta, Will SARS-CoV-2 variants of concern affect the promise of vaccines?, Nat Rev Immunol, doi:10.1038/s41577-021-00556-5

He, Temporal dynamics in viral shedding and transmissibility of COVID-19, Nat Med, doi:10.1038/s41591-020-0869-5

Ko, High-throughput, single-copy sequencing reveals SARS-CoV-2 spike variants coincident with mounting humoral immunity during acute COVID-19, PLoS Pathog, doi:10.1371/journal.ppat.1009431

Larder, Kemp, Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT), Science, doi:10.1126/science.2479983

Lee, Performance comparison of next generation sequencing analysis pipelines for HIV-1 drug resistance testing, Sci Rep, doi:10.1038/s41598-020-58544-z

Luan, Wang, Huynh, Enhanced binding of the N501Y-mutated SARS-CoV-2 spike protein to the human ACE2 receptor: insights from molecular dynamics simulations, FEBS Lett, doi:10.1002/1873-3468.14076

Mccallum, SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern, Science, doi:10.1126/science.abi7994

Mccarthy, Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape, Science, doi:10.1126/science.abf6950

Moore, Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level, Science

Pelegrin, Naranjo-Gomez, Piechaczyk, Antiviral Monoclonal Antibodies: Can They Be More Than Simple Neutralizing Agents?, Trends Microbiol, doi:10.1016/j.tim.2015.07.005

Plant, Manukyan, Sanchez, Laassri, Ye, Immune Pressure on Polymorphous Influenza B Populations Results in Diverse Hemagglutinin Escape Mutants and Lineage Switching, Vaccines, doi:10.3390/vaccines8010125

Sheet, Health, Providers, EMERGENCY USE AUTHORIZATION (EUA) OF BAMLANIVIMAB AND ETESEVIMAB

Sheet, Health, Providers, EMERGENCY USE AUTHORIZATION (EUA) OF CASIRIVIMAB AND IMDEVIMAB

Starr, Greaney, Dingens, Bloom, Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016, Cell Rep Med, doi:10.1016/j.xcrm.2021.100255

Starr, Prospective mapping of viral mutations that escape antibodies used to treat COVID-19, Science, doi:10.1126/science.abf9302

Takashita, Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2017-2018, Antiviral Res, doi:10.1016/j.antiviral.2020.104718

Truong, Increased viral variants in children and young adults with impaired humoral immunity and persistent SARS-CoV-2 infection: A consecutive case series, EBioMedicine, doi:10.1016/j.ebiom.2021.103355

Weinreich, REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19, N Engl J Med, doi:10.1056/NEJMoa2035002

Wolfel, Virological assessment of hospitalized patients with COVID-2019, Nature, doi:10.1038/s41586-020-2196-x

Zhou, Enhancement versus neutralization by SARS-CoV-2 antibodies from a convalescent donor associates with distinct epitopes on the RBD, Cell Rep, doi:10.1016/j.celrep.2021.108699

{ 'institution': [{'name': 'medRxiv'}], 'indexed': {'date-parts': [[2022, 1, 3]], 'date-time': '2022-01-03T17:26:58Z', 'timestamp': 1641230818693}, 'posted': {'date-parts': [[2021, 9, 15]]}, 'group-title': 'Infectious Diseases (except HIV/AIDS)', 'reference-count': 33, 'publisher': 'Cold Spring Harbor Laboratory', 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'short-container-title': [], 'accepted': {'date-parts': [[2021, 9, 15]]}, 'abstract': 'ABSTRACTResistance mutations to monoclonal antibody (mAb) ' 'therapy has been reported, but in the non-immunosuppressed population, it is unclear if ' 'in vivo emergence of SARS-CoV-2 resistance mutations alters either ' 'viral replication dynamics or therapeutic efficacy. In ACTIV-2/A5401, non-hospitalized ' 'participants with symptomatic SARS-CoV-2 infection were randomized to bamlanivimab (700mg or ' '7000mg) or placebo. Treatment-emergent resistance mutations were significantly more likely ' 'detected after bamlanivimab 700mg treatment than placebo (7% of 111 vs 0% of 112 ' 'participants, P=0.003). There were no treatment-emergent resistance mutations among the 48 ' 'participants who received bamlanivimab 7000mg. Participants with emerging mAb resistant virus ' 'had significantly higher pre-treatment nasopharyngeal and anterior nasal viral load. ' 'Intensive respiratory tract viral sampling revealed the dynamic nature of SARS-CoV-2 ' 'evolution, with evidence of rapid and sustained viral rebound after emergence of resistance ' 'mutations, and worsened symptom severity. Participants with emerging bamlanivimab resistance ' 'often accumulated additional polymorphisms found in current variants of concern/interest and ' 'associated with immune escape. These results highlight the potential for rapid emergence of ' 'resistance during mAb monotherapy treatment, resulting in prolonged high level respiratory ' 'tract viral loads and clinical worsening. Careful virologic assessment should be prioritized ' 'during the development and clinical implementation of antiviral treatments for ' 'COVID-19.', 'DOI': '10.1101/2021.09.03.21263105', 'type': 'posted-content', 'created': {'date-parts': [[2021, 9, 15]], 'date-time': '2021-09-15T11:45:12Z', 'timestamp': 1631706312000}, 'source': 'Crossref', 'is-referenced-by-count': 4, 'title': ['Emergence of SARS-CoV-2 Resistance with Monoclonal Antibody Therapy'], 'prefix': '10.1101', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-3192-7840', 'authenticated-orcid': False, 'given': 'Manish C.', 'family': 'Choudhary', 'sequence': 'first', 'affiliation': []}, {'given': 'Kara W.', 'family': 'Chew', 'sequence': 'additional', 'affiliation': []}, {'given': 'Rinki', 'family': 'Deo', 'sequence': 'additional', 'affiliation': []}, {'given': 'James P.', 'family': 'Flynn', 'sequence': 'additional', 'affiliation': []}, {'given': 'James', 'family': 'Regan', 'sequence': 'additional', 'affiliation': []}, {'given': 'Charles R.', 'family': 'Crain', 'sequence': 'additional', 'affiliation': []}, {'given': 'Carlee', 'family': 'Moser', 'sequence': 'additional', 'affiliation': []}, {'given': 'Michael', 'family': 'Hughes', 'sequence': 'additional', 'affiliation': []}, {'given': 'Justin', 'family': 'Ritz', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ruy M.', 'family': 'Ribeiro', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ruian', 'family': 'Ke', 'sequence': 'additional', 'affiliation': []}, {'given': 'Joan A.', 'family': 'Dragavon', 'sequence': 'additional', 'affiliation': []}, {'given': 'Arzhang C.', 'family': 'Javan', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ajay', 'family': 'Nirula', 'sequence': 'additional', 'affiliation': []}, {'given': 'Paul', 'family': 'Klekotka', 'sequence': 'additional', 'affiliation': []}, {'given': 'Alexander L.', 'family': 'Greninger', 'sequence': 'additional', 'affiliation': []}, {'given': 'Courtney V.', 'family': 'Fletcher', 'sequence': 'additional', 'affiliation': []}, {'given': 'Eric S.', 'family': 'Daar', 'sequence': 'additional', 'affiliation': []}, {'given': 'David A.', 'family': 'Wohl', 'sequence': 'additional', 'affiliation': []}, {'given': 'Joseph J.', 'family': 'Eron', 'sequence': 'additional', 'affiliation': []}, {'given': 'Judith S.', 'family': 'Currier', 'sequence': 'additional', 'affiliation': []}, {'given': 'Urvi M.', 'family': 'Parikh', 'sequence': 'additional', 'affiliation': []}, {'given': 'Scott F.', 'family': 'Sieg', 'sequence': 'additional', 'affiliation': []}, {'given': 'Alan S.', 'family': 'Perelson', 'sequence': 'additional', 'affiliation': []}, {'given': 'Robert W.', 'family': 'Coombs', 'sequence': 'additional', 'affiliation': []}, {'given': 'Davey M.', 'family': 'Smith', 'sequence': 'additional', 'affiliation': []}, {'given': 'Jonathan Z.', 'family': 'Li', 'sequence': 'additional', 'affiliation': []}, {'name': 'for the ACTIV-2/A5401 Study Team', 'sequence': 'additional', 'affiliation': []}], 'member': '246', 'reference': [ { 'key': '2021091610100424000_2021.09.03.21263105v1.1', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.1069660'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.2', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/vaccines8010125'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.3', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.2479983'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.4', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/infdis/172.1.239'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.5', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2020.104718'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.6', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJM2ra025195'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.7', 'doi-asserted-by': 'publisher', 'DOI': '10.1001/jama.2021.0202'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.8', 'unstructured': 'FACT SHEET FOR HEALTH CARE PROVIDERS: EMERGENCY USE AUTHORIZATION (EUA) ' 'OF CASIRIVIMAB AND IMDEVIMAB, < ' 'https://www.fda.gov/media/143892/download> (Accessed July 14, 2021).'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.9', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2029849'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.10', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.xcrm.2021.100255'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.11', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.abf9302'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.12', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.abi7994'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.13', 'unstructured': 'FACT SHEET FOR HEALTH CARE PROVIDERS: EMERGENCY USE AUTHORIZATION (EUA) ' 'OF BAMLANIVIMAB AND ETESEVIMAB, < ' 'https://www.fda.gov/media/145802/download> (Accessed July 14, 2021).'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.14', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ebiom.2021.103355'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.15', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMc2031364'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.16', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.abf6950'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.17', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/1873-3468.14076'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.18', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41577-021-00556-5'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.19', 'unstructured': 'Chew, K. W. et al. in Conference on Retroviruses and Opportunistic ' 'Infections (Virtual, March 6-10, 2021 (Abstract 396)).'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.20', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.ppat.1009431'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.21', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/cid/ciab380'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.22', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41591-020-0869-5'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.23', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2035002'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.24', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-020-2196-x'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.25', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.tim.2015.07.005'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.26', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.celrep.2021.108699'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.27', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-021-03412-7'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.28', 'doi-asserted-by': 'publisher', 'DOI': '10.2807/1560-7917.ES.2021.26.24.2100509'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.29', 'first-page': '97', 'article-title': 'An EUA for sotrovimab for treatment of COVID-19', 'volume': '63', 'year': '2021', 'journal-title': 'Med Lett Drugs Ther'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.30', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jcv.2020.104474'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.31', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jcv.2021.104945'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.32', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41467-020-19057-5'}, { 'key': '2021091610100424000_2021.09.03.21263105v1.33', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41598-020-58544-z'}], 'container-title': [], 'original-title': [], 'link': [ { 'URL': 'https://syndication.highwire.org/content/doi/10.1101/2021.09.03.21263105', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2021, 9, 16]], 'date-time': '2021-09-16T17:10:35Z', 'timestamp': 1631812235000}, 'score': 1, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2021, 9, 15]]}, 'references-count': 33, 'URL': 'http://dx.doi.org/10.1101/2021.09.03.21263105', 'relation': {}, 'published': {'date-parts': [[2021, 9, 15]]}, 'subtype': 'preprint'}

Late treatment
is less effective

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0