Non-cognate ligands of hepatitis C virus envelope broadly neutralizing antibodies induce virus-neutralizing sera in mice
IntroductionThe persistent rise in new Hepatitis C virus (HCV) infections threatens WHO efforts to eliminate HCV infection by 2030. Although direct-acting antiviral (DAA) drugs are efficacious, access remains limited, reinfections occur, and perinatal infections continue to pose long-term complicati...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1624299/full |
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| author | Stephen Ian Walimbwa Stephen Ian Walimbwa Shiv Bharadwaj Petr Kosztyu Lucie Vankova Milan Kuchar Eliska Kopecna Roman Effenberg Lukas Drasar Leona Raskova Kafkova Petr Maly Milan Raska |
| author_facet | Stephen Ian Walimbwa Stephen Ian Walimbwa Shiv Bharadwaj Petr Kosztyu Lucie Vankova Milan Kuchar Eliska Kopecna Roman Effenberg Lukas Drasar Leona Raskova Kafkova Petr Maly Milan Raska |
| author_sort | Stephen Ian Walimbwa |
| collection | DOAJ |
| description | IntroductionThe persistent rise in new Hepatitis C virus (HCV) infections threatens WHO efforts to eliminate HCV infection by 2030. Although direct-acting antiviral (DAA) drugs are efficacious, access remains limited, reinfections occur, and perinatal infections continue to pose long-term complications. Therefore, an effective anti-HCV vaccine is urgently needed.MethodsWe employed a highly complex combinatorial Myomedin-loop scaffold library to identify variants binding to paratopes of HCV E2-specific broadly neutralizing antibodies (bNAbs) HC-1AM and HC84.26.WH.5DL. The selected binders, named SHB and WIN, respectively, represent non-cognate mimotopes of the aforementioned bNAbs. These binders were subsequently used as immunogens in experimental mice to elicit serum antibodies capable of binding to HCV E2 and neutralize HCV pseudotyped viruses.Results and discussionThe non-cognate mimotopes SHB and WIN competed with the E2 glycoprotein for bNAbs binding and, after immunizing experimental mice, elicited E2- and HCV-pseudovirus-specific antibodies. WIN- and SHB-immunized mice exhibited neutralization against 15 HCV pseudoviruses with varying neutralization sensitivities. The most potent binders WIN028 and WIN047, were modified with a C-terminal His-tag, allowing the generation of WIN proteoliposome and subsequent use in experimental mice immunizations. Hyperimmune sera exhibited improved binding to HCV E2 and neutralized 60% of the tested HCV pseudoviruses. The broad neutralization of HCV pseudoviruses achieved by hypperimmune sera from SHB- and WIN-immunized mice highlights the potential of this approach in the HCV vaccine design. |
| format | Article |
| id | doaj-art-8cd5ef7e3b244a45af5b75aaa34ba30a |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-8cd5ef7e3b244a45af5b75aaa34ba30a2025-08-20T03:30:09ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.16242991624299Non-cognate ligands of hepatitis C virus envelope broadly neutralizing antibodies induce virus-neutralizing sera in miceStephen Ian Walimbwa0Stephen Ian Walimbwa1Shiv Bharadwaj2Petr Kosztyu3Lucie Vankova4Milan Kuchar5Eliska Kopecna6Roman Effenberg7Lukas Drasar8Leona Raskova Kafkova9Petr Maly10Milan Raska11Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, Olomouc, CzechiaInfectious Diseases Institute, Makerere University College of Health Sciences, Kampala, UgandaLaboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, CzechiaDepartment of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, Olomouc, CzechiaLaboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, CzechiaLaboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, CzechiaDepartment of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, Olomouc, CzechiaDepartment of Chemistry of Natural Compounds, University of Chemistry and Technology, Prague, CzechiaDepartment of Chemistry of Natural Compounds, University of Chemistry and Technology, Prague, CzechiaDepartment of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, Olomouc, CzechiaLaboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, CzechiaDepartment of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, Olomouc, CzechiaIntroductionThe persistent rise in new Hepatitis C virus (HCV) infections threatens WHO efforts to eliminate HCV infection by 2030. Although direct-acting antiviral (DAA) drugs are efficacious, access remains limited, reinfections occur, and perinatal infections continue to pose long-term complications. Therefore, an effective anti-HCV vaccine is urgently needed.MethodsWe employed a highly complex combinatorial Myomedin-loop scaffold library to identify variants binding to paratopes of HCV E2-specific broadly neutralizing antibodies (bNAbs) HC-1AM and HC84.26.WH.5DL. The selected binders, named SHB and WIN, respectively, represent non-cognate mimotopes of the aforementioned bNAbs. These binders were subsequently used as immunogens in experimental mice to elicit serum antibodies capable of binding to HCV E2 and neutralize HCV pseudotyped viruses.Results and discussionThe non-cognate mimotopes SHB and WIN competed with the E2 glycoprotein for bNAbs binding and, after immunizing experimental mice, elicited E2- and HCV-pseudovirus-specific antibodies. WIN- and SHB-immunized mice exhibited neutralization against 15 HCV pseudoviruses with varying neutralization sensitivities. The most potent binders WIN028 and WIN047, were modified with a C-terminal His-tag, allowing the generation of WIN proteoliposome and subsequent use in experimental mice immunizations. Hyperimmune sera exhibited improved binding to HCV E2 and neutralized 60% of the tested HCV pseudoviruses. The broad neutralization of HCV pseudoviruses achieved by hypperimmune sera from SHB- and WIN-immunized mice highlights the potential of this approach in the HCV vaccine design.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1624299/fullhepatitis Cvaccinemimotopebroadly neutralizing antibodiesmyomedinsprotein mimicry |
| spellingShingle | Stephen Ian Walimbwa Stephen Ian Walimbwa Shiv Bharadwaj Petr Kosztyu Lucie Vankova Milan Kuchar Eliska Kopecna Roman Effenberg Lukas Drasar Leona Raskova Kafkova Petr Maly Milan Raska Non-cognate ligands of hepatitis C virus envelope broadly neutralizing antibodies induce virus-neutralizing sera in mice Frontiers in Immunology hepatitis C vaccine mimotope broadly neutralizing antibodies myomedins protein mimicry |
| title | Non-cognate ligands of hepatitis C virus envelope broadly neutralizing antibodies induce virus-neutralizing sera in mice |
| title_full | Non-cognate ligands of hepatitis C virus envelope broadly neutralizing antibodies induce virus-neutralizing sera in mice |
| title_fullStr | Non-cognate ligands of hepatitis C virus envelope broadly neutralizing antibodies induce virus-neutralizing sera in mice |
| title_full_unstemmed | Non-cognate ligands of hepatitis C virus envelope broadly neutralizing antibodies induce virus-neutralizing sera in mice |
| title_short | Non-cognate ligands of hepatitis C virus envelope broadly neutralizing antibodies induce virus-neutralizing sera in mice |
| title_sort | non cognate ligands of hepatitis c virus envelope broadly neutralizing antibodies induce virus neutralizing sera in mice |
| topic | hepatitis C vaccine mimotope broadly neutralizing antibodies myomedins protein mimicry |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1624299/full |
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