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A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera
Next-generation COVID-19 vaccines are critical due to the ongoing evolution of SARS-CoV-2 virus and rapid waning duration of the neutralizing antibody response against current vaccines. The mRNA vaccines mRNA-1273 and BNT162b2 were developed using linear transcripts encoding the prefusion-stabilized...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier B.V.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9235288/ https://www.ncbi.nlm.nih.gov/pubmed/35772601 http://dx.doi.org/10.1016/j.antiviral.2022.105370 |
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author | Seephetdee, Chotiwat Bhukhai, Kanit Buasri, Nattawut Leelukkanaveera, Puttipatch Lerdwattanasombat, Pat Manopwisedjaroen, Suwimon Phueakphud, Nut Kuhaudomlarp, Sakonwan Olmedillas, Eduardo Saphire, Erica Ollmann Thitithanyanont, Arunee Hongeng, Suradej Wongtrakoongate, Patompon |
author_facet | Seephetdee, Chotiwat Bhukhai, Kanit Buasri, Nattawut Leelukkanaveera, Puttipatch Lerdwattanasombat, Pat Manopwisedjaroen, Suwimon Phueakphud, Nut Kuhaudomlarp, Sakonwan Olmedillas, Eduardo Saphire, Erica Ollmann Thitithanyanont, Arunee Hongeng, Suradej Wongtrakoongate, Patompon |
author_sort | Seephetdee, Chotiwat |
collection | PubMed |
description | Next-generation COVID-19 vaccines are critical due to the ongoing evolution of SARS-CoV-2 virus and rapid waning duration of the neutralizing antibody response against current vaccines. The mRNA vaccines mRNA-1273 and BNT162b2 were developed using linear transcripts encoding the prefusion-stabilized trimers (S-2P) of the wildtype spike, which have shown a reduced neutralizing activity against the variants of concern B.1.617.2 and B.1.1.529. Recently, a new version of spike trimer, termed VFLIP (five (V) prolines, Flexibly-Linked, Inter-Protomer disulfide) was developed. Based on the original amino acid sequence of the wildtype spike, VFLIP was genetically engineered by using five proline substitutions, a flexible cleavage site amino acid linker, and an inter-protomer disulfide bond. It has been suggested to possess native-like glycosylation, and greater pre-fusion trimeric stability as opposed to S-2P. Here, we report that the spike protein VFLIP-X, containing six rationally substituted amino acids to reflect emerging variants (K417N, L452R, T478K, E484K, N501Y and D614G), offers a promising candidate for a next-generation SARS-CoV-2 vaccine. Mice immunized by a circular mRNA (circRNA) vaccine prototype producing VFLIP-X had detectable neutralizing antibody titers for up to 7 weeks post-boost against SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs). In addition, a balance in T(H)1 and T(H)2 responses was achieved by immunization with VFLIP-X. Our results indicate that the VFLIP-X delivered by circRNA induces humoral and cellular immune responses, as well as broad neutralizing activity against SARS-CoV-2 variants. |
format | Online Article Text |
id | pubmed-9235288 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier B.V. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92352882022-06-28 A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera Seephetdee, Chotiwat Bhukhai, Kanit Buasri, Nattawut Leelukkanaveera, Puttipatch Lerdwattanasombat, Pat Manopwisedjaroen, Suwimon Phueakphud, Nut Kuhaudomlarp, Sakonwan Olmedillas, Eduardo Saphire, Erica Ollmann Thitithanyanont, Arunee Hongeng, Suradej Wongtrakoongate, Patompon Antiviral Res Article Next-generation COVID-19 vaccines are critical due to the ongoing evolution of SARS-CoV-2 virus and rapid waning duration of the neutralizing antibody response against current vaccines. The mRNA vaccines mRNA-1273 and BNT162b2 were developed using linear transcripts encoding the prefusion-stabilized trimers (S-2P) of the wildtype spike, which have shown a reduced neutralizing activity against the variants of concern B.1.617.2 and B.1.1.529. Recently, a new version of spike trimer, termed VFLIP (five (V) prolines, Flexibly-Linked, Inter-Protomer disulfide) was developed. Based on the original amino acid sequence of the wildtype spike, VFLIP was genetically engineered by using five proline substitutions, a flexible cleavage site amino acid linker, and an inter-protomer disulfide bond. It has been suggested to possess native-like glycosylation, and greater pre-fusion trimeric stability as opposed to S-2P. Here, we report that the spike protein VFLIP-X, containing six rationally substituted amino acids to reflect emerging variants (K417N, L452R, T478K, E484K, N501Y and D614G), offers a promising candidate for a next-generation SARS-CoV-2 vaccine. Mice immunized by a circular mRNA (circRNA) vaccine prototype producing VFLIP-X had detectable neutralizing antibody titers for up to 7 weeks post-boost against SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs). In addition, a balance in T(H)1 and T(H)2 responses was achieved by immunization with VFLIP-X. Our results indicate that the VFLIP-X delivered by circRNA induces humoral and cellular immune responses, as well as broad neutralizing activity against SARS-CoV-2 variants. Elsevier B.V. 2022-08 2022-06-27 /pmc/articles/PMC9235288/ /pubmed/35772601 http://dx.doi.org/10.1016/j.antiviral.2022.105370 Text en © 2022 Elsevier B.V. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Seephetdee, Chotiwat Bhukhai, Kanit Buasri, Nattawut Leelukkanaveera, Puttipatch Lerdwattanasombat, Pat Manopwisedjaroen, Suwimon Phueakphud, Nut Kuhaudomlarp, Sakonwan Olmedillas, Eduardo Saphire, Erica Ollmann Thitithanyanont, Arunee Hongeng, Suradej Wongtrakoongate, Patompon A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera |
title | A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera |
title_full | A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera |
title_fullStr | A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera |
title_full_unstemmed | A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera |
title_short | A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera |
title_sort | circular mrna vaccine prototype producing vflip-x spike confers a broad neutralization of sars-cov-2 variants by mouse sera |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9235288/ https://www.ncbi.nlm.nih.gov/pubmed/35772601 http://dx.doi.org/10.1016/j.antiviral.2022.105370 |
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