Different configurations of SARS-CoV-2 spike protein delivered by integrase-defective lentiviral vectors induce persistent functional immune responses, characterized by distinct immunogenicity profiles
Several COVID-19 vaccine strategies utilizing new formulations for the induction of neutralizing antibodies (nAbs) and T cell immunity are still under evaluation in preclinical and clinical studies. Here we used Simian Immunodeficiency Virus (SIV)-based integrase defective lentiviral vector (IDLV) d...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1147953/full |
| _version_ | 1797852216092000256 |
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| author | Martina Borghi Alessandra Gallinaro Maria Franca Pirillo Andrea Canitano Zuleika Michelini Maria Laura De Angelis Serena Cecchetti Antonella Tinari Chiara Falce Sabrina Mariotti Antonio Capocefalo Maria Vincenza Chiantore Angelo Iacobino Antonio Di Virgilio Marit J. van Gils Rogier W. Sanders Alessandra Lo Presti Roberto Nisini Donatella Negri Andrea Cara |
| author_facet | Martina Borghi Alessandra Gallinaro Maria Franca Pirillo Andrea Canitano Zuleika Michelini Maria Laura De Angelis Serena Cecchetti Antonella Tinari Chiara Falce Sabrina Mariotti Antonio Capocefalo Maria Vincenza Chiantore Angelo Iacobino Antonio Di Virgilio Marit J. van Gils Rogier W. Sanders Alessandra Lo Presti Roberto Nisini Donatella Negri Andrea Cara |
| author_sort | Martina Borghi |
| collection | DOAJ |
| description | Several COVID-19 vaccine strategies utilizing new formulations for the induction of neutralizing antibodies (nAbs) and T cell immunity are still under evaluation in preclinical and clinical studies. Here we used Simian Immunodeficiency Virus (SIV)-based integrase defective lentiviral vector (IDLV) delivering different conformations of membrane-tethered Spike protein in the mouse immunogenicity model, with the aim of inducing persistent nAbs against multiple SARS-CoV-2 variants of concern (VoC). Spike modifications included prefusion-stabilizing double proline (2P) substitutions, mutations at the furin cleavage site (FCS), D614G mutation and truncation of the cytoplasmic tail (delta21) of ancestral and Beta (B.1.351) Spike, the latter mutation to markedly improve IDLV membrane-tethering. BALB/c mice were injected once with IDLV delivering the different forms of Spike or the recombinant trimeric Spike protein with 2P substitutions and FCS mutations in association with a squalene-based adjuvant. Anti-receptor binding domain (RBD) binding Abs, nAbs and T cell responses were detected up to six months from a single immunization with escalating doses of vaccines in all mice, but with different levels and kinetics. Results indicated that IDLV delivering the Spike protein with all the combined modifications, outperformed the other candidates in terms of T cell immunity and level of both binding Abs and nAbs soon after the single immunization and persistence over time, showing the best capacity to neutralize all formerly circulating VoC Alpha, Beta, Gamma and Delta. Although present, the lowest response was detected against Omicron variants (BA.1, BA.2 and BA.4/5), suggesting that the magnitude of immune evasion may be related to the higher genetic distance of Omicron as indicated by increased number of amino acid substitutions in Spike acquired during virus evolution. |
| first_indexed | 2024-04-09T19:30:24Z |
| format | Article |
| id | doaj.art-d6a90457e0554050aaece8683c609075 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-09T19:30:24Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-d6a90457e0554050aaece8683c6090752023-04-05T04:25:47ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-04-011410.3389/fimmu.2023.11479531147953Different configurations of SARS-CoV-2 spike protein delivered by integrase-defective lentiviral vectors induce persistent functional immune responses, characterized by distinct immunogenicity profilesMartina Borghi0Alessandra Gallinaro1Maria Franca Pirillo2Andrea Canitano3Zuleika Michelini4Maria Laura De Angelis5Serena Cecchetti6Antonella Tinari7Chiara Falce8Sabrina Mariotti9Antonio Capocefalo10Maria Vincenza Chiantore11Angelo Iacobino12Antonio Di Virgilio13Marit J. van Gils14Rogier W. Sanders15Alessandra Lo Presti16Roberto Nisini17Donatella Negri18Andrea Cara19Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, ItalyNational Center for Global Health, Istituto Superiore di Sanità, Rome, ItalyNational Center for Global Health, Istituto Superiore di Sanità, Rome, ItalyNational Center for Global Health, Istituto Superiore di Sanità, Rome, ItalyNational Center for Global Health, Istituto Superiore di Sanità, Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, ItalyConfocal Microscopy Unit, Core Facilities, Istituto Superiore di Sanità, Rome, ItalyCenter for Gender Medicine, Istituto Superiore di Sanità, Rome, ItalyNational Center for Global Health, Istituto Superiore di Sanità, Rome, ItalyDepartment of Infectious Diseases, Istituto Superiore di Sanità, Rome, ItalyDepartment of Veterinary Public Health & Food Safety, Istituto Superiore di Sanità, Rome, ItalyDepartment of Infectious Diseases, Istituto Superiore di Sanità, Rome, ItalyDepartment of Infectious Diseases, Istituto Superiore di Sanità, Rome, ItalyCenter for Animal Research and Welfare, Istituto Superiore di Sanità, Rome, ItalyDepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam, NetherlandsDepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam, NetherlandsDepartment of Infectious Diseases, Istituto Superiore di Sanità, Rome, ItalyDepartment of Infectious Diseases, Istituto Superiore di Sanità, Rome, ItalyDepartment of Infectious Diseases, Istituto Superiore di Sanità, Rome, ItalyNational Center for Global Health, Istituto Superiore di Sanità, Rome, ItalySeveral COVID-19 vaccine strategies utilizing new formulations for the induction of neutralizing antibodies (nAbs) and T cell immunity are still under evaluation in preclinical and clinical studies. Here we used Simian Immunodeficiency Virus (SIV)-based integrase defective lentiviral vector (IDLV) delivering different conformations of membrane-tethered Spike protein in the mouse immunogenicity model, with the aim of inducing persistent nAbs against multiple SARS-CoV-2 variants of concern (VoC). Spike modifications included prefusion-stabilizing double proline (2P) substitutions, mutations at the furin cleavage site (FCS), D614G mutation and truncation of the cytoplasmic tail (delta21) of ancestral and Beta (B.1.351) Spike, the latter mutation to markedly improve IDLV membrane-tethering. BALB/c mice were injected once with IDLV delivering the different forms of Spike or the recombinant trimeric Spike protein with 2P substitutions and FCS mutations in association with a squalene-based adjuvant. Anti-receptor binding domain (RBD) binding Abs, nAbs and T cell responses were detected up to six months from a single immunization with escalating doses of vaccines in all mice, but with different levels and kinetics. Results indicated that IDLV delivering the Spike protein with all the combined modifications, outperformed the other candidates in terms of T cell immunity and level of both binding Abs and nAbs soon after the single immunization and persistence over time, showing the best capacity to neutralize all formerly circulating VoC Alpha, Beta, Gamma and Delta. Although present, the lowest response was detected against Omicron variants (BA.1, BA.2 and BA.4/5), suggesting that the magnitude of immune evasion may be related to the higher genetic distance of Omicron as indicated by increased number of amino acid substitutions in Spike acquired during virus evolution.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1147953/fulllentiviral vector (LV)IDLVvaccineSARS-CoV-2neutralizing Abs |
| spellingShingle | Martina Borghi Alessandra Gallinaro Maria Franca Pirillo Andrea Canitano Zuleika Michelini Maria Laura De Angelis Serena Cecchetti Antonella Tinari Chiara Falce Sabrina Mariotti Antonio Capocefalo Maria Vincenza Chiantore Angelo Iacobino Antonio Di Virgilio Marit J. van Gils Rogier W. Sanders Alessandra Lo Presti Roberto Nisini Donatella Negri Andrea Cara Different configurations of SARS-CoV-2 spike protein delivered by integrase-defective lentiviral vectors induce persistent functional immune responses, characterized by distinct immunogenicity profiles Frontiers in Immunology lentiviral vector (LV) IDLV vaccine SARS-CoV-2 neutralizing Abs |
| title | Different configurations of SARS-CoV-2 spike protein delivered by integrase-defective lentiviral vectors induce persistent functional immune responses, characterized by distinct immunogenicity profiles |
| title_full | Different configurations of SARS-CoV-2 spike protein delivered by integrase-defective lentiviral vectors induce persistent functional immune responses, characterized by distinct immunogenicity profiles |
| title_fullStr | Different configurations of SARS-CoV-2 spike protein delivered by integrase-defective lentiviral vectors induce persistent functional immune responses, characterized by distinct immunogenicity profiles |
| title_full_unstemmed | Different configurations of SARS-CoV-2 spike protein delivered by integrase-defective lentiviral vectors induce persistent functional immune responses, characterized by distinct immunogenicity profiles |
| title_short | Different configurations of SARS-CoV-2 spike protein delivered by integrase-defective lentiviral vectors induce persistent functional immune responses, characterized by distinct immunogenicity profiles |
| title_sort | different configurations of sars cov 2 spike protein delivered by integrase defective lentiviral vectors induce persistent functional immune responses characterized by distinct immunogenicity profiles |
| topic | lentiviral vector (LV) IDLV vaccine SARS-CoV-2 neutralizing Abs |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1147953/full |
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