key: cord-0880969-gxs5ucq3
authors: Vellas, Camille; Del Bello, Arnaud; Debard, Alexa; Steinmeyer, Zara; Tribaudeau, Laure; Ranger, Noémie; Jeanne, Nicolas; Martin-Blondel, Guillaume; Delobel, Pierre; Kamar, Nassim; Izopet, Jacques
title: Influence of treatment with neutralizing monoclonal antibodies on the SARS-CoV-2 nasopharyngeal load and quasispecies
date: 2021-09-16
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.09.008
sha: 29a140ac8fb33ef50b75a0e32b2085ddbb539445
doc_id: 880969
cord_uid: gxs5ucq3

OBJECTIVES: We aimed to evaluate the impact of neutralizing monoclonal antibodies (mAbs) treatment and to determine whether the mAbs selective pressure could facilitate the proliferation of virus variants with spike protein mutations that might attenuate mAb effectiveness. PATIENTS AND METHODS: We therefore evaluated the impact of mAbs on the nasopharyngeal (NP) viral load and virus quasispecies of mAb-treated patients using single molecule real time sequencing (Pacific Biosciences). The mAbs used were: Bamlanivimab alone (4 patients), Bamlanivimab/Etesevimab (23 patients), and Casirivimab/Imdevimab (5 patients). RESULTS: The NP SARS-CoV-2 viral load of mAb-treated patients decreased from 8.2 log(10) copies/ml before administration to 4.3 log(10) copies/ml 7 days after administration. Five immunocompromised patients given Bamlanivimab/Etesevimab were found to have mAbs activity-reducing spike mutations. Two patients harbored SARS-CoV-2 variants with a Q493R spike mutation 7 days after administration, as did a third patient 14 days after administration. The fourth patient harbored a variant with a Q493K spike mutation 7 days post-treatment, and the fifth patient had a variant with a E484K spike mutation on day 21. The emergence of the spike mutation was accompanied by stabilization or rebound of the NP viral load in 3/5 patients. CONCLUSION: Two-mAb therapy can drive the selection of resistant SARS-CoV-2 variants in immunocompromised patients. Patients given mAbs should be closely monitored and measures to limit virus spread reinforced.

(NP) viral load and virus quasispecies of mAb-treated patients using single molecule real time 38 sequencing (Pacific Biosciences). The mAbs used were: Bamlanivimab alone (4 patients), 39

Bamlanivimab/Etesevimab (23 patients), and Casirivimab/Imdevimab (5 patients). 40

The NP SARS-CoV-2 viral load of mAb-treated patients decreased from 8.2 log10 41 copies/ml before administration to 4.3 log10 copies/ml 7 days after administration. Five 42 immunocompromised patients given Bamlanivimab/Etesevimab were found to have mAbs 43 activity-reducing spike mutations. Two patients harbored SARS-CoV-2 variants with a 44 Q493R spike mutation 7 days after administration, as did a third patient 14 days after 45 administration. The fourth patient harbored a variant with a Q493K spike mutation 7 days 46 post-treatment, and the fifth patient had a variant with a E484K spike mutation on day 21. 47

The emergence of the spike mutation was accompanied by stabilization or rebound of the NP 48 viral load in 3/5 patients. patients and 2.47 log10copies/ml [IQR: 2.14-3.31] for controls (p=0.03) ( Figure S1 ). 119 120

We followed-up with spike-sequencing 23 (78%) mAb-treated patients. We detected 122

no key mutation associated with reduced mAb activity in treated patients on day 0 (Table S2) . 123 J o u r n a l P r e -p r o o f However, several spike-haplotypes appeared over time in 2 (50%) Bamlanivimab-treated 124 patients, 5 (31%) Bamlanivimab/Etesevimab-treated patients and one (33%) 125

Casirivimab/Imdevimab-treated patient (Table S2) 

B am lan iv im ab 7 0 0 m g + E te s e v im a b 1 4 0 0 m g no sequence low viral load no sequence low viral load

SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline

US Food Drug and Administration. Fact Sheet For Health Care Providers Emergency 202

Use Authorization (Eua) Of Bamlanivimab And Etesevimab n.d

US Food Drug and Administration. Fact Sheet For Health Care Providers Emergency 204

Use Authorization (Eua) Of REGEN-COV (Casirivimab and Imdevimab) n.d

SARS-CoV-2 variants, spike mutations and immune escape

Human neutralizing antibodies elicited 209 by SARS-CoV-2 infection

CoV-2 variants B.1.351 and B.1.1.7. Nature

SARS-CoV-2 variant P.1 to antibody neutralization

Complete map of SARS-CoV-2 RBD 218 mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-219

SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual 223 antibodies

Escape from 225 neutralizing antibodies by SARS-CoV-2 spike protein variants

SARS-CoV-2 501Y.V2 variants 228 lack higher infectivity but do have immune escape

SARS-COV-2 Spike Protein Escape Mutation Q493R after Treatment for COVID-19

Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral

Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial

Neutralizing Antibody Cocktail, in Outpatients with Covid-19

The monoclonal 241 antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in 242 preclinical and human studies