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1.
Immunity ; 2022.
Article in English | ScienceDirect | ID: covidwho-1778211

ABSTRACT

Summary The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize Omicron variant remains unclear. We assessed affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naïve individuals. Compared to other variants of concern, Omicron evaded recognition of a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron-RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all individuals analysed. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provide some protection against the Omicron variant in vaccinated individuals.

2.
EBioMedicine ; 77: 103934, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1739673

ABSTRACT

BACKGROUND: SARS-CoV-2 lineages are continuously evolving. As of December 2021, the AY.4.2 Delta sub-lineage represented 20 % of sequenced strains in the UK and had been detected in dozens of countries. It has since then been supplanted by Omicron. The AY.4.2 spike displays three additional mutations (T95I, Y145H and A222V) in the N-terminal domain when compared to the original Delta variant (B.1.617.2) and remains poorly characterized. METHODS: We compared the Delta and the AY.4.2 spikes, by assessing their binding to antibodies and ACE2 and their fusogenicity. We studied the sensitivity of an authentic AY.4.2 viral isolate to neutralizing antibodies. FINDINGS: The AY.4.2 spike exhibited similar binding to all the antibodies and sera tested, and similar fusogenicity and binding to ACE2 than the ancestral Delta spike. The AY.4.2 virus was slightly less sensitive than Delta to neutralization by a panel of monoclonal antibodies; noticeably, the anti-RBD Imdevimab showed incomplete neutralization. Sensitivity of AY.4.2 to sera from vaccinated individuals was reduced by 1.3 to 3-fold, when compared to Delta. INTERPRETATION: Our results suggest that mutations in the NTD remotely impair the efficacy of anti-RBD antibodies. The spread of AY.4.2 was not due to major changes in spike fusogenicity or ACE2 binding, but more likely to a partially reduced neutralization sensitivity. FUNDING: The work was funded by Institut Pasteur, Fondation pour la Recherche Médicale, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute, Labex IBEID, ANR/FRM Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal, Humanized , Antibodies, Viral , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins
3.
Nature ; 604(7905): 330-336, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1692583

ABSTRACT

The animal reservoir of SARS-CoV-2 is unknown despite reports of SARS-CoV-2-related viruses in Asian Rhinolophus bats1-4, including the closest virus from R. affinis, RaTG13 (refs. 5,6), and pangolins7-9. SARS-CoV-2 has a mosaic genome, to which different progenitors contribute. The spike sequence determines the binding affinity and accessibility of its receptor-binding domain to the cellular angiotensin-converting enzyme 2 (ACE2) receptor and is responsible for host range10-12. SARS-CoV-2 progenitor bat viruses genetically close to SARS-CoV-2 and able to enter human cells through a human ACE2 (hACE2) pathway have not yet been identified, although they would be key in understanding the origin of the epidemic. Here we show that such viruses circulate in cave bats living in the limestone karstic terrain in northern Laos, in the Indochinese peninsula. We found that the receptor-binding domains of these viruses differ from that of SARS-CoV-2 by only one or two residues at the interface with ACE2, bind more efficiently to the hACE2 protein than that of the SARS-CoV-2 strain isolated in Wuhan from early human cases, and mediate hACE2-dependent entry and replication in human cells, which is inhibited by antibodies that neutralize SARS-CoV-2. None of these bat viruses contains a furin cleavage site in the spike protein. Our findings therefore indicate that bat-borne SARS-CoV-2-like viruses that are potentially infectious for humans circulate in Rhinolophus spp. in the Indochinese peninsula.


Subject(s)
COVID-19 , Chiroptera , Angiotensin-Converting Enzyme 2 , Animals , Humans , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry
4.
Nature ; 602(7898): 671-675, 2022 02.
Article in English | MEDLINE | ID: covidwho-1616994

ABSTRACT

The SARS-CoV-2 Omicron variant was first identified in November 2021 in Botswana and South Africa1-3. It has since spread to many countries and is expected to rapidly become dominant worldwide. The lineage is characterized by the presence of around 32 mutations in spike-located mostly in the N-terminal domain and the receptor-binding domain-that may enhance viral fitness and enable antibody evasion. Here we isolated an infectious Omicron virus in Belgium from a traveller returning from Egypt. We examined its sensitivity to nine monoclonal antibodies that have been clinically approved or are in development4, and to antibodies present in 115 serum samples from COVID-19 vaccine recipients or individuals who have recovered from COVID-19. Omicron was completely or partially resistant to neutralization by all monoclonal antibodies tested. Sera from recipients of the Pfizer or AstraZeneca vaccine, sampled five months after complete vaccination, barely inhibited Omicron. Sera from COVID-19-convalescent patients collected 6 or 12 months after symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titres 6-fold to 23-fold lower against Omicron compared with those against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and, to a large extent, vaccine-elicited antibodies. However, Omicron is neutralized by antibodies generated by a booster vaccine dose.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , Immune Evasion/immunology , Immunization, Secondary , SARS-CoV-2/immunology , Adult , Antibodies, Monoclonal/immunology , /immunology , Belgium , COVID-19/immunology , COVID-19/transmission , /immunology , Convalescence , Female , Humans , Male , Mutation , Neutralization Tests , Phylogeny , SARS-CoV-2/classification , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Travel
5.
Immunity ; 54(12): 2893-2907.e5, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1433403

ABSTRACT

In addition to serum immunoglobulins, memory B cell (MBC) generation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is another layer of immune protection, but the quality of MBC responses in naive and coronavirus disease 2019 (COVID-19)-recovered individuals after vaccination remains ill defined. We studied longitudinal cohorts of naive and disease-recovered individuals for up to 2 months after SARS-CoV-2 mRNA vaccination. We assessed the quality of the memory response by analysis of antibody repertoires, affinity, and neutralization against variants of concern (VOCs) using unbiased cultures of 2,452 MBCs. Upon boosting, the MBC pool of recovered individuals expanded selectively, matured further, and harbored potent neutralizers against VOCs. Although naive individuals had weaker neutralizing serum responses, half of their RBD-specific MBCs displayed high affinity toward multiple VOCs, including delta (B.1.617.2), and one-third retained neutralizing potency against beta (B.1.351). Our data suggest that an additional challenge in naive vaccinees could recall such affinity-matured MBCs and allow them to respond efficiently to VOCs.


Subject(s)
/immunology , COVID-19/immunology , Precursor Cells, B-Lymphoid/immunology , RNA, Messenger/genetics , SARS-CoV-2/physiology , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Antibody Affinity , Cells, Cultured , Convalescence , Humans , Immunization, Secondary , Immunologic Memory , Mass Vaccination , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
6.
Nature ; 596(7871): 276-280, 2021 08.
Article in English | MEDLINE | ID: covidwho-1301174

ABSTRACT

The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India1-5. Since then, it has become dominant in some regions of India and in the UK, and has spread to many other countries6. The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), which contain diverse mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein that may increase the immune evasion potential of these variants. B.1.617.2-also termed the Delta variant-is believed to spread faster than other variants. Here we isolated an infectious strain of the Delta variant from an individual with COVID-19 who had returned to France from India. We examined the sensitivity of this strain to monoclonal antibodies and to antibodies present in sera from individuals who had recovered from COVID-19 (hereafter referred to as convalescent individuals) or who had received a COVID-19 vaccine, and then compared this strain with other strains of SARS-CoV-2. The Delta variant was resistant to neutralization by some anti-NTD and anti-RBD monoclonal antibodies, including bamlanivimab, and these antibodies showed impaired binding to the spike protein. Sera collected from convalescent individuals up to 12 months after the onset of symptoms were fourfold less potent against the Delta variant relative to the Alpha variant (B.1.1.7). Sera from individuals who had received one dose of the Pfizer or the AstraZeneca vaccine had a barely discernible inhibitory effect on the Delta variant. Administration of two doses of the vaccine generated a neutralizing response in 95% of individuals, with titres three- to fivefold lower against the Delta variant than against the Alpha variant. Thus, the spread of the Delta variant is associated with an escape from antibodies that target non-RBD and RBD epitopes of the spike protein.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/virology , Convalescence , Immune Evasion/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/epidemiology , COVID-19 Vaccines/administration & dosage , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , France , Humans , India/epidemiology , Male , Middle Aged , Neutralization Tests , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
7.
Cell ; 184(5): 1201-1213.e14, 2021 03 04.
Article in English | MEDLINE | ID: covidwho-1062272

ABSTRACT

Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.


Subject(s)
B-Lymphocytes/immunology , COVID-19/immunology , Immunologic Memory , Adult , COVID-19/physiopathology , Flow Cytometry , Germinal Center/cytology , Humans , Lymphocyte Activation , Middle Aged , Severity of Illness Index , Single-Cell Analysis , Spike Glycoprotein, Coronavirus/chemistry
9.
Sci Transl Med ; 12(559)2020 09 02.
Article in English | MEDLINE | ID: covidwho-724557

ABSTRACT

It is of paramount importance to evaluate the prevalence of both asymptomatic and symptomatic cases of SARS-CoV-2 infection and their differing antibody response profiles. Here, we performed a pilot study of four serological assays to assess the amounts of anti-SARS-CoV-2 antibodies in serum samples obtained from 491 healthy individuals before the SARS-CoV-2 pandemic, 51 individuals hospitalized with COVID-19, 209 suspected cases of COVID-19 with mild symptoms, and 200 healthy blood donors. We used two ELISA assays that recognized the full-length nucleoprotein (N) or trimeric spike (S) protein ectodomain of SARS-CoV-2. In addition, we developed the S-Flow assay that recognized the S protein expressed at the cell surface using flow cytometry, and the luciferase immunoprecipitation system (LIPS) assay that recognized diverse SARS-CoV-2 antigens including the S1 domain and the carboxyl-terminal domain of N by immunoprecipitation. We obtained similar results with the four serological assays. Differences in sensitivity were attributed to the technique and the antigen used. High anti-SARS-CoV-2 antibody titers were associated with neutralization activity, which was assessed using infectious SARS-CoV-2 or lentiviral-S pseudotype virus. In hospitalized patients with COVID-19, seroconversion and virus neutralization occurred between 5 and 14 days after symptom onset, confirming previous studies. Seropositivity was detected in 32% of mildly symptomatic individuals within 15 days of symptom onset and in 3% of healthy blood donors. The four antibody assays that we used enabled a broad evaluation of SARS-CoV-2 seroprevalence and antibody profiling in different subpopulations within one region.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Serologic Tests/methods , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19 , COVID-19 Testing , Cohort Studies , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Enzyme-Linked Immunosorbent Assay/methods , Female , Flow Cytometry/methods , France/epidemiology , Healthy Volunteers , Humans , Immunoprecipitation/methods , Luciferases , Male , Middle Aged , Neutralization Tests , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , SARS-CoV-2 , Seroepidemiologic Studies , Spike Glycoprotein, Coronavirus/immunology , Young Adult
10.
C R Biol ; 343(1): 33-39, 2020 Jun 05.
Article in English | MEDLINE | ID: covidwho-677826

ABSTRACT

SARS-CoV-2 epidemics raises a considerable issue of public health at the planetary scale. There is a pressing urgency to find treatments based upon currently available scientific knowledge. Therefore, we tentatively propose a hypothesis which hopefully might ultimately help save lives. Based on the current scientific literature and on new epidemiological data which reveal that current smoking status appears to be a protective factor against the infection by SARS-CoV-2 [1], we hypothesize that the nicotinic acetylcholine receptor (nAChR) plays a key role in the pathophysiology of Covid-19 infection and might represent a target for the prevention and control of Covid-19 infection.


L'épidémie de SARS-Cov-2 pose un problème considérable de santé publique à l'échelle planétaire. Il y a urgence extrême de découvrir des traitements qui se fondent sur les connaissances scientifiques disponibles. Nous proposons donc une hypothèse plausible mais provisoire qui puisse le moment venu contribuer à sauver des vies. Elle se fonde sur la littérature scientifique disponible et sur des données épidémiologiques nouvelles qui révèlent que le statut de fumeur parait être un facteur de protection contre l'infection par SARS-Cov-2 [1]. Nous proposons l'hypothèse que le récepteur nicotinique de l'acétylcholine (nAChR) joue un rôle critique dans la pathophysiologie de l'infection Covid-19 et puisse représenter une cible pour la prévention et le contrôle de l'infection.


Subject(s)
Coronavirus Infections/physiopathology , Coronavirus Infections/therapy , Nicotine/therapeutic use , Nicotinic Agonists/therapeutic use , Pneumonia, Viral/physiopathology , Pneumonia, Viral/therapy , Receptors, Nicotinic , COVID-19 , Coronavirus Infections/prevention & control , Humans , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Smoking , Transdermal Patch
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