19
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Characterisation of the antibody-mediated selective pressure driving intra-host evolution of SARS-CoV-2 in prolonged infection

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Neutralising antibodies against the SARS-CoV-2 spike (S) protein are major determinants of protective immunity, though insufficient antibody responses may cause the emergence of escape mutants. We studied the humoral immune response causing intra-host evolution in a B-cell depleted, haemato-oncologic patient experiencing clinically severe, prolonged SARS-CoV-2 infection with a virus of lineage B.1.177.81. Following bamlanivimab treatment at an early stage of infection, the patient developed a bamlanivimab-resistant mutation, S:S494P. After five weeks of apparent genetic stability, the emergence of additional substitutions and deletions within the N-terminal domain (NTD) and the receptor binding domain (RBD) of S was observed. Notably, the composition and frequency of escape mutations changed in a short period with an unprecedented dynamic. The triple mutant S:Delta141-4 E484K S494P became dominant until virus elimination. Routine serology revealed no evidence of an antibody response in the patient. A detailed analysis of the variant-specific immune response by pseudotyped virus neutralisation test, surrogate virus neutralisation test, and immunoglobulin-capture enzyme immunoassay showed that the onset of an IgM-dominated antibody response coincided with the appearance of escape mutations. The formation of neutralising antibodies against S:Delta141-4 E484K S494P correlated with virus elimination. One year later, the patient experienced clinically mild re-infection with Omicron BA.1.18, which was treated with sotrovimab and resulted in an increase in Omicron-reactive antibodies. In conclusion, the onset of an IgM-dominated endogenous immune response in an immunocompromised patient coincided with the appearance of additional mutations in the NTD and RBD of S in a bamlanivimab-resistant virus. Although virus elimination was ultimately achieved, this humoral immune response escaped detection by routine diagnosis and created a situation temporarily favouring the rapid emergence of various antibody escape mutants with known epidemiological relevance.

          Author summary

          In the immunocompromised host, prolonged infection and insufficient antibody responses favour the emergence of highly mutated SARS-CoV-2 variants. To better understand the selective pressure exerted by antiviral antibodies, we characterised the variant-specific humoral immune response and resulting intra-host evolution of SARS-CoV-2 in a B-lymphocyte-depleted patient experiencing severe infection.

          Treatment with a monoclonal antibody early in infection led to the selection and outgrowth of resistant virus. As their B-cell function recovered, the patient mounted an IgM-dominated antiviral antibody response, the onset of which closely correlated with the appearance of additional escape mutations within the spike protein. The strength and breadth of this antibody response gradually increased, resulting in the selection of a variant carrying several escape mutations within spike. The formation of neutralising antibodies against this variant resulted in virus elimination.

          Our study provides new insights into the selection process of viral escape mutants in immunocompromised patients. The resuming humoral immunity against SARS-CoV-2 can be dominated by IgM. This immune response is poorly detectable with routine diagnostic procedures yet may trigger and drive substantial viral intra-host evolution. Determination of antiviral antibody responses and correlating them with intra-host evolution may provide a better picture of the adaptability of currently circulating SARS-CoV-2 variants.

          Related collections

          Most cited references114

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          A new coronavirus associated with human respiratory disease in China

          Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health 1–3 . Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing 4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China 5 . This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR

            Background The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur. Aim We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available. Methods Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavirus, making use of synthetic nucleic acid technology. Results The workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control material is made available through European Virus Archive – Global (EVAg), a European Union infrastructure project. Conclusion The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection

              Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.
                Bookmark

                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: MethodologyRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: ValidationRole: Writing – review & editing
                Role: Data curationRole: ResourcesRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: ValidationRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: ValidationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: ResourcesRole: Writing – review & editing
                Role: Funding acquisitionRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                PLOS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                15 October 2024
                October 2024
                : 20
                : 10
                : e1012624
                Affiliations
                [1 ] Institute of Virology Muenster, University of Muenster, Muenster, Germany
                [2 ] Institute of Hygiene, University Hospital Muenster, University of Muenster, Muenster, Germany
                [3 ] Department of Medicine A, Haematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
                [4 ] Department of Medicine B for Gastroenterology, Hepatology, Endocrinology and Clinical Infectiology, University Hospital Muenster, Muenster, Germany
                Leiden University Medical Center: Leids Universitair Medisch Centrum, NETHERLANDS, KINGDOM OF THE
                Author notes

                The authors have declared that no competing interests exist.

                ‡ PRT and JEK also contributed equally to this work.

                Article
                PPATHOGENS-D-24-00273
                10.1371/journal.ppat.1012624
                11508484
                39405332
                752293d6-bcd6-49cf-ae7c-18f8de49c981
                © 2024 Schoefbaenker et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 February 2024
                : 28 September 2024
                Page count
                Figures: 7, Tables: 0, Pages: 27
                Funding
                Funded by: Ministerium für Arbeit, Gesundheit und Soziales des Landes Nordrhein-Westfalen (DE)
                Award ID: CPS-1-1G and 76.06.04-20/2024-6626
                Award Recipient :
                Funded by: University of Muenster
                ° This study was partially funded by the Ministry of Labour, Health, and Social Affairs of the state of North Rhine-Westphalia, Germany (grants CPS-1-1G and 76.06.04-20/2024-6626 to SL). The Institute of Virology is part of the Virus Alliance North Rhine-Westphalia, which is supported by the Ministry of Culture and Science, NRW, Germany. We acknowledge support from the Open Access Publication Fund of the University of Muenster. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Antibodies
                Biology and Life Sciences
                Immunology
                Immune System Proteins
                Antibodies
                Medicine and Health Sciences
                Immunology
                Immune System Proteins
                Antibodies
                Biology and Life Sciences
                Biochemistry
                Proteins
                Immune System Proteins
                Antibodies
                Biology and life sciences
                Organisms
                Viruses
                RNA viruses
                Coronaviruses
                SARS coronavirus
                SARS CoV 2
                Biology and life sciences
                Microbiology
                Medical microbiology
                Microbial pathogens
                Viral pathogens
                Coronaviruses
                SARS coronavirus
                SARS CoV 2
                Medicine and health sciences
                Pathology and laboratory medicine
                Pathogens
                Microbial pathogens
                Viral pathogens
                Coronaviruses
                SARS coronavirus
                SARS CoV 2
                Biology and life sciences
                Organisms
                Viruses
                Viral pathogens
                Coronaviruses
                SARS coronavirus
                SARS CoV 2
                Biology and Life Sciences
                Immunology
                Vaccination and Immunization
                Medicine and Health Sciences
                Immunology
                Vaccination and Immunization
                Medicine and Health Sciences
                Public and Occupational Health
                Preventive Medicine
                Vaccination and Immunization
                Research and Analysis Methods
                Immunologic Techniques
                Immunoassays
                Enzyme-Linked Immunoassays
                Biology and Life Sciences
                Immunology
                Immune Response
                Antibody Response
                Medicine and Health Sciences
                Immunology
                Immune Response
                Antibody Response
                Biology and Life Sciences
                Immunology
                Immune Response
                Medicine and Health Sciences
                Immunology
                Immune Response
                Biology and Life Sciences
                Immunology
                Immunity
                Humoral Immunity
                Humoral Immune Response
                Medicine and Health Sciences
                Immunology
                Immunity
                Humoral Immunity
                Humoral Immune Response
                Biology and Life Sciences
                Microbiology
                Microbial Evolution
                Viral Evolution
                Biology and Life Sciences
                Evolutionary Biology
                Organismal Evolution
                Microbial Evolution
                Viral Evolution
                Biology and Life Sciences
                Microbiology
                Virology
                Viral Evolution
                Custom metadata
                vor-update-to-uncorrected-proof
                2024-10-25
                All experimental results not displayed in the main text have been attached as supplementary information. All raw sequence data are deposited at the NCBI SRA under bioproject number PRJNA1120916.
                COVID-19

                Infectious disease & Microbiology
                Infectious disease & Microbiology

                Comments

                Comment on this article

                scite_
                0
                0
                0
                0
                Smart Citations
                0
                0
                0
                0
                Citing PublicationsSupportingMentioningContrasting
                View Citations

                See how this article has been cited at scite.ai

                scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

                Similar content66

                Most referenced authors4,256