Enhanced Broad-Spectrum Efficacy of an L2-Based mRNA Vaccine Targeting HPV Types 6, 11, 16, 18, with Cross-Protection Against Multiple Additional High-Risk Types
Background: Current L1-based human papillomavirus (HPV) vaccines provide type-specific protection but offer limited cross-protection against non-vaccine HPV types. Therefore, developing a broad-spectrum HPV vaccine is highly desirable. Methods: In this study, we optimized mRNA constructs and develop...
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2024-10-01
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| author | Kosuke Tsukamoto Akio Yamashita Masatoshi Maeki Manabu Tokeshi Hirotatsu Imai Akira Fukao Toshinobu Fujiwara Koji Okudera Nobuhisa Mizuki Kenji Okuda Masaru Shimada |
| author_facet | Kosuke Tsukamoto Akio Yamashita Masatoshi Maeki Manabu Tokeshi Hirotatsu Imai Akira Fukao Toshinobu Fujiwara Koji Okudera Nobuhisa Mizuki Kenji Okuda Masaru Shimada |
| author_sort | Kosuke Tsukamoto |
| collection | DOAJ |
| description | Background: Current L1-based human papillomavirus (HPV) vaccines provide type-specific protection but offer limited cross-protection against non-vaccine HPV types. Therefore, developing a broad-spectrum HPV vaccine is highly desirable. Methods: In this study, we optimized mRNA constructs and developed a multivalent L2-based mRNA vaccine encoding L2 aa 2-130, which includes all known neutralizing epitopes from four prevalent HPV types (HPV-6, -11, -16, and -18). We evaluated its immunogenicity in a mouse model and compared the efficacy of a commercially available mRNA delivery reagent with a custom-synthesized lipid nanoparticle (LNP) formulation. Results: We identified that a construct containing E01 (a 5′-untranslated region) and SL2.7 (a poly(A) polymerase recruitment sequence) significantly increased protein expression. The L2-based mRNA vaccine induced robust and long-lasting humoral immune responses, with significant titers of cross-reactive serum IgG antibodies against L2 epitopes. Notably, the vaccine elicited cross-neutralizing antibodies and conferred cross-protective immunity not only against vaccine-targeted HPV types but also against non-vaccine HPV types, following intravaginal challenge in mice. We also found that LNP delivered mRNA more effectively in vivo. Conclusions: The L2-based mRNA vaccine developed in this study shows significant potential for broad-spectrum protection against multiple HPV types. This approach offers a promising strategy for reducing the global burden of HPV-associated cancers. |
| format | Article |
| id | doaj-art-57415faddeaa4098a275206bb23ba405 |
| institution | OA Journals |
| issn | 2076-393X |
| language | English |
| publishDate | 2024-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj-art-57415faddeaa4098a275206bb23ba4052025-08-20T02:04:41ZengMDPI AGVaccines2076-393X2024-10-011211123910.3390/vaccines12111239Enhanced Broad-Spectrum Efficacy of an L2-Based mRNA Vaccine Targeting HPV Types 6, 11, 16, 18, with Cross-Protection Against Multiple Additional High-Risk TypesKosuke Tsukamoto0Akio Yamashita1Masatoshi Maeki2Manabu Tokeshi3Hirotatsu Imai4Akira Fukao5Toshinobu Fujiwara6Koji Okudera7Nobuhisa Mizuki8Kenji Okuda9Masaru Shimada10Department of Ophthalmology and Visual Science, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, JapanDepartment of Investigative Medicine, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishiharacho 903-0215, JapanDivision of Applied Chemistry, Faculty of Engineering, Hokkaido University, Kita 13 Nishi 8, Kita-ku, Sapporo 060-8628, JapanDivision of Applied Chemistry, Faculty of Engineering, Hokkaido University, Kita 13 Nishi 8, Kita-ku, Sapporo 060-8628, JapanDepartment of Investigative Medicine, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishiharacho 903-0215, JapanDepartment of Biochemistry, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka 577-8502, JapanDepartment of Biochemistry, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka 577-8502, JapanDepartment of Pathology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, JapanDepartment of Ophthalmology and Visual Science, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, JapanDepartment of Molecular Biodefense Research, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, JapanDepartment of Molecular Biodefense Research, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, JapanBackground: Current L1-based human papillomavirus (HPV) vaccines provide type-specific protection but offer limited cross-protection against non-vaccine HPV types. Therefore, developing a broad-spectrum HPV vaccine is highly desirable. Methods: In this study, we optimized mRNA constructs and developed a multivalent L2-based mRNA vaccine encoding L2 aa 2-130, which includes all known neutralizing epitopes from four prevalent HPV types (HPV-6, -11, -16, and -18). We evaluated its immunogenicity in a mouse model and compared the efficacy of a commercially available mRNA delivery reagent with a custom-synthesized lipid nanoparticle (LNP) formulation. Results: We identified that a construct containing E01 (a 5′-untranslated region) and SL2.7 (a poly(A) polymerase recruitment sequence) significantly increased protein expression. The L2-based mRNA vaccine induced robust and long-lasting humoral immune responses, with significant titers of cross-reactive serum IgG antibodies against L2 epitopes. Notably, the vaccine elicited cross-neutralizing antibodies and conferred cross-protective immunity not only against vaccine-targeted HPV types but also against non-vaccine HPV types, following intravaginal challenge in mice. We also found that LNP delivered mRNA more effectively in vivo. Conclusions: The L2-based mRNA vaccine developed in this study shows significant potential for broad-spectrum protection against multiple HPV types. This approach offers a promising strategy for reducing the global burden of HPV-associated cancers.https://www.mdpi.com/2076-393X/12/11/1239human papillomavirus vaccineL2mRNAchallenge studyanimal model |
| spellingShingle | Kosuke Tsukamoto Akio Yamashita Masatoshi Maeki Manabu Tokeshi Hirotatsu Imai Akira Fukao Toshinobu Fujiwara Koji Okudera Nobuhisa Mizuki Kenji Okuda Masaru Shimada Enhanced Broad-Spectrum Efficacy of an L2-Based mRNA Vaccine Targeting HPV Types 6, 11, 16, 18, with Cross-Protection Against Multiple Additional High-Risk Types Vaccines human papillomavirus vaccine L2 mRNA challenge study animal model |
| title | Enhanced Broad-Spectrum Efficacy of an L2-Based mRNA Vaccine Targeting HPV Types 6, 11, 16, 18, with Cross-Protection Against Multiple Additional High-Risk Types |
| title_full | Enhanced Broad-Spectrum Efficacy of an L2-Based mRNA Vaccine Targeting HPV Types 6, 11, 16, 18, with Cross-Protection Against Multiple Additional High-Risk Types |
| title_fullStr | Enhanced Broad-Spectrum Efficacy of an L2-Based mRNA Vaccine Targeting HPV Types 6, 11, 16, 18, with Cross-Protection Against Multiple Additional High-Risk Types |
| title_full_unstemmed | Enhanced Broad-Spectrum Efficacy of an L2-Based mRNA Vaccine Targeting HPV Types 6, 11, 16, 18, with Cross-Protection Against Multiple Additional High-Risk Types |
| title_short | Enhanced Broad-Spectrum Efficacy of an L2-Based mRNA Vaccine Targeting HPV Types 6, 11, 16, 18, with Cross-Protection Against Multiple Additional High-Risk Types |
| title_sort | enhanced broad spectrum efficacy of an l2 based mrna vaccine targeting hpv types 6 11 16 18 with cross protection against multiple additional high risk types |
| topic | human papillomavirus vaccine L2 mRNA challenge study animal model |
| url | https://www.mdpi.com/2076-393X/12/11/1239 |
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