key: cord-0296712-xroal37z authors: MARTINUZZI, E.; BOUTROS, J.; BENZAQUEN, J.; GLAICHENHAUS, N.; HOFMAN, P.; MARQUETTE, C. H. title: Escape of SARS-CoV-2 variant Omicron to mucosal immunity in vaccinated subjects. date: 2022-05-07 journal: nan DOI: 10.1101/2022.05.03.22274517 sha: b0cda81a70f0259fa0f580e852acc6a0c379cfa3 doc_id: 296712 cord_uid: xroal37z Omicron s escape to vaccine-induced systemic antibody responses has been shown in several studies in Omicron-infected patients and vaccine controls. In the present study we compared mucosal antibody response to Omicron to mucosal antibody response to ancestral strain and Delta variant. This was done on nasal epithelial lining fluid (NELF) prospectively collected in 84 otherwise healthy healthcare workers who had never exhibited PCR-documented COVID-19 and had received three doses of the Pfizer-BioNTech COVID-19 mRNA vaccine. NELF was collected prior to Omicron detection in the geographical area of inclusion. We show that NELF antibodies from vaccinated individuals were less efficient at inhibiting the binding of the Omicron Spike protein to ACE-2 compared to those of Delta or the ancestral strain. These findings may explain the increased risk of onward transmission of Omicron, consistent with its successful global displacement of Delta in countries with a high vaccination coverage. Omicron s escape to vaccine-induced systemic antibody responses has been shown in several studies in Omicron-infected patients and vaccine controls. In the present study we compared mucosal antibody response to Omicron to mucosal antibody response to ancestral strain and Delta variant. This was done on nasal epithelial lining fluid (NELF) prospectively collected in 84 otherwise healthy healthcare workers who had never exhibited PCR-documented COVID-19 and had received three doses of the Pfizer-BioNTech COVID-19 mRNA vaccine. NELF was collected prior to Omicron detection in the geographical area of inclusion. We show that NELF antibodies from vaccinated individuals were less efficient at inhibiting the binding of the Omicron Spike protein to ACE-2 compared to those of Delta or the ancestral strain. These findings may explain the increased risk of onward transmission of Omicron, consistent with its successful global displacement of Delta in countries with a high vaccination coverage. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Since it was first reported on November 24 th 2021 and classified as a variant of concern two days later 1 , the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant Omicron (B.1.1.529) has spread throughout the world 1,2 , rapidly replacing other circulating variants including Delta. The growth advantage of Omicron over Delta was observed not only in countries with low vaccination coverage such as South Africa, but also in those in which more than 90% of individuals where vaccinated such as Norway 3 . In keeping with the higher transmissibility of Omicron, two recent studies in English and Norwegian households have shown that the secondary attack rate was higher when the variant of the index case was Omicron compared to Delta 4,5 . While protection from severe forms of COVID-19 in vaccinated adults is mediated at least in part by SARS-CoV-2-specific antibodies, lessons drawn from other mucosal pathogens suggest that mucosal antibodies and especially secretory immunoglobulin A (sIgA) are those that efficiently block transmission of respiratory viruses such as SARS-CoV-2 9 . Therefore, we hypothesize that Omicron disseminates more rapidly than Delta in vaccinated subjects because it escapes vaccine-induced mucosal immune responses. To test this hypothesis, we prospectively collected nasal epithelial lining fluid (NELF) in a cohort of 84 otherwise healthy healthcare workers (Centre Hospitalier Universitaire de Nice) who had never exhibited PCR-documented COVID-19 and had received three doses of the Pfizer-BioNTech COVID-19 mRNA vaccine 10 to 131 days before NELF collection. In all subjects NELF was collected prior to Omicron detection in the geographical area of inclusion, i.e. between December 14 and December 31 2021. All subjects signed an informed consent to participate in this work. This study was approved by the CPP Sud Méditerranée V ethics committee (ClinicalTrial.gov identifier: NCT04418206). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Workbench 3·0 software. NELF antibodies were assessed for their ability to inhibit the binding of a soluble ACE2 to Spike of the ancestral SARS-CoV-2 strain and its Delta and Omicron variants using the multiplex V-PLEX® SARS-CoV-2 Panel 13 ACE2 Kit as described 10 . NELF were diluted 10-fold before being assessed for binding inhibition. Data were acquired on the V-PLEX® Sector Imager 2400 plate reader and analyzed using the Discovery Workbench 3·0 software (MSD). Diluent alone was used as a blank. The percentage inhibition was calculated according to manufacturer's instructions. This assay has been shown to correlate with assays for viral neutralization. We found that mucosal IgG and IgA bound less efficiently to the Omicron Spike protein compared to those of Delta or the Wuhan ancestral strain ( Figure 1A, 1B) . NELF antibodies from vaccinated individuals were also less efficient at inhibiting the binding of the Omicron Spike protein to ACE-2 compared to those of Delta or the ancestral strain ( Figure 1C ). Our results show that Omicron escapes vaccine-induced mucosal antibody response more efficiently than Delta. This may explain the increased risk of onward transmission of Omicron, consistent with its successful global displacement of Delta in countries with a high vaccination coverage. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Heavily mutated Omicron variant puts scientists on alert Modelling the potential consequences of the Omicron SARS-CoV-2 variant in England. medRxiv Comparative transmission of SARS-CoV-2 Omicron (B.1.1.529) and Delta (B.1.617.2) variants and the impact of vaccination: national cohort study Secondary Attack Rates for Omicron and Delta Variants of SARS-CoV-2 in Norwegian Households Omicron and Delta variant of SARS-CoV-2: A comparative computational study of spike protein Seroprevalence of SARS-CoV-2 after the second wave in South Africa in HIV-infected and uninfected persons: a cross-sectional household survey Considerable escape of SARS-CoV-2 Omicron to antibody neutralization Mucosal Immunity in COVID-19: A Neglected but Critical Aspect of SARS-CoV-2 Infection A Single Dose of the Pfizer-BioNTech COVID-19 mRNA Vaccine Induces Airway Immunity in SARS-CoV-2 Naive and COVID-19 Convalescent Subjects. medRxiv The authors thank the subjects who volunteered in this study, the medical and paramedical personnel involved in their recruitment and follow-up. The authors have declared no competing interests.All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 7, 2022. ; https://doi.org/10.1101/2022.05.03.22274517 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 7, 2022. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 7, 2022. ; https://doi.org/10.1101/2022.05.03.22274517 doi: medRxiv preprint