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Broadly Protective CD8+ T Cell Immunity to Highly Conserved Epitopes Elicited by Heat Shock Protein gp96-Adjuvanted Influenza Monovalent Split Vaccine.
J Virol. 2021 05 24; 95(12)JV

Abstract

Currently, immunization with inactivated influenza virus vaccines is the most prevalent method to prevent infections. However, licensed influenza vaccines provide only strain-specific protection and need to be updated and administered yearly; thus, new vaccines that provide broad protection against multiple influenza virus subtypes are required. In this study, we demonstrated that intradermal immunization with gp96-adjuvanted seasonal influenza monovalent H1N1 split vaccine could induce cross-protection against both group 1 and group 2 influenza A viruses in BALB/c mouse models. Vaccination in the presence of gp96 induced an apparently stronger antigen-specific T cell response than split vaccine alone. Immunization with the gp96-adjuvanted vaccine also elicited an apparent cross-reactive CD8+ T cell response that targeted the conserved epitopes across different influenza virus strains. These cross-reactive CD8+ T cells might be recalled from a pool of memory cells established after vaccination and recruited from extrapulmonary sites to facilitate viral clearance. Of note, six highly conserved CD8+ T epitopes from the viral structural proteins hemagglutinin (HA), M1, nucleoprotein (NP), and PB1 were identified to play a synergistic role in gp96-mediated cross-protection. Comparative analysis showed that most of conservative epitope-specific cytotoxic T lymphocytes (CTLs) apparently induced by heterologous virus infection were also activated by gp96-adjuvanted vaccine, thus resulting in broader protective CD8+ T cell responses. Our results demonstrated the advantage of adding gp96 to an existing seasonal influenza vaccine to improve its ability to provide better cross-protection.IMPORTANCE Owing to continuous mutations in hemagglutinin (HA) or neuraminidase (NA) or recombination of the gene segments between different strains, influenza viruses can escape the immune responses developed by vaccination. Thus, new strategies aimed to efficiently activate immune response that targets to conserved regions among different influenza viruses are urgently needed in designing broad-spectrum influenza vaccine. Heat shock protein gp96 is currently the only natural T cell adjuvant with special ability to cross-present coupled antigen to major histocompatibility complex class I (MHC-I) molecule and activate the downstream antigen-specific CTL response. In this study, we demonstrated the advantages of adding gp96 to monovalent split influenza virus vaccine to improve its ability to provide cross-protection in the BALB/c mouse model and proved that a gp96-activated cross-reactive CTL response is indispensable in our vaccine strategy. Due to its unique adjuvant properties, gp96 might be a promising adjuvant for designing new broad-spectrum influenza vaccines.

Authors+Show Affiliations

Key Laboratory of Pathogenic Microbiology and Immunology, Center for Biosafety Mega-Science, Chinese Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China.Key Laboratory of Pathogenic Microbiology and Immunology, Center for Biosafety Mega-Science, Chinese Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China.Key Laboratory of Pathogenic Microbiology and Immunology, Center for Biosafety Mega-Science, Chinese Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China.Key Laboratory of Pathogenic Microbiology and Immunology, Center for Biosafety Mega-Science, Chinese Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China.Key Laboratory of Pathogenic Microbiology and Immunology, Center for Biosafety Mega-Science, Chinese Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China.Key Laboratory of Pathogenic Microbiology and Immunology, Center for Biosafety Mega-Science, Chinese Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China.Key Laboratory of Pathogenic Microbiology and Immunology, Center for Biosafety Mega-Science, Chinese Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.Key Laboratory of Pathogenic Microbiology and Immunology, Center for Biosafety Mega-Science, Chinese Institute of Microbiology, Chinese Academy of Sciences, Beijing, China mengsd@im.ac.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33827939

Citation

Zhang, Han, et al. "Broadly Protective CD8+ T Cell Immunity to Highly Conserved Epitopes Elicited By Heat Shock Protein gp96-Adjuvanted Influenza Monovalent Split Vaccine." Journal of Virology, vol. 95, no. 12, 2021.
Zhang H, Zheng H, Guo P, et al. Broadly Protective CD8+ T Cell Immunity to Highly Conserved Epitopes Elicited by Heat Shock Protein gp96-Adjuvanted Influenza Monovalent Split Vaccine. J Virol. 2021;95(12).
Zhang, H., Zheng, H., Guo, P., Hu, L., Wang, Z., Wang, J., Ju, Y., & Meng, S. (2021). Broadly Protective CD8+ T Cell Immunity to Highly Conserved Epitopes Elicited by Heat Shock Protein gp96-Adjuvanted Influenza Monovalent Split Vaccine. Journal of Virology, 95(12). https://doi.org/10.1128/JVI.00507-21
Zhang H, et al. Broadly Protective CD8+ T Cell Immunity to Highly Conserved Epitopes Elicited By Heat Shock Protein gp96-Adjuvanted Influenza Monovalent Split Vaccine. J Virol. 2021 05 24;95(12) PubMed PMID: 33827939.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Broadly Protective CD8+ T Cell Immunity to Highly Conserved Epitopes Elicited by Heat Shock Protein gp96-Adjuvanted Influenza Monovalent Split Vaccine. AU - Zhang,Han, AU - Zheng,Huaguo, AU - Guo,Peng, AU - Hu,Liuyi, AU - Wang,Zihao, AU - Wang,Jiuru, AU - Ju,Ying, AU - Meng,Songdong, Y1 - 2021/05/24/ PY - 2021/03/24/received PY - 2021/03/28/accepted PY - 2021/11/24/pmc-release PY - 2021/4/9/pubmed PY - 2021/6/16/medline PY - 2021/4/8/entrez KW - CD8+ T cells KW - conserved epitopes KW - cross-protection KW - gp96 KW - influenza vaccine JF - Journal of virology JO - J Virol VL - 95 IS - 12 N2 - Currently, immunization with inactivated influenza virus vaccines is the most prevalent method to prevent infections. However, licensed influenza vaccines provide only strain-specific protection and need to be updated and administered yearly; thus, new vaccines that provide broad protection against multiple influenza virus subtypes are required. In this study, we demonstrated that intradermal immunization with gp96-adjuvanted seasonal influenza monovalent H1N1 split vaccine could induce cross-protection against both group 1 and group 2 influenza A viruses in BALB/c mouse models. Vaccination in the presence of gp96 induced an apparently stronger antigen-specific T cell response than split vaccine alone. Immunization with the gp96-adjuvanted vaccine also elicited an apparent cross-reactive CD8+ T cell response that targeted the conserved epitopes across different influenza virus strains. These cross-reactive CD8+ T cells might be recalled from a pool of memory cells established after vaccination and recruited from extrapulmonary sites to facilitate viral clearance. Of note, six highly conserved CD8+ T epitopes from the viral structural proteins hemagglutinin (HA), M1, nucleoprotein (NP), and PB1 were identified to play a synergistic role in gp96-mediated cross-protection. Comparative analysis showed that most of conservative epitope-specific cytotoxic T lymphocytes (CTLs) apparently induced by heterologous virus infection were also activated by gp96-adjuvanted vaccine, thus resulting in broader protective CD8+ T cell responses. Our results demonstrated the advantage of adding gp96 to an existing seasonal influenza vaccine to improve its ability to provide better cross-protection.IMPORTANCE Owing to continuous mutations in hemagglutinin (HA) or neuraminidase (NA) or recombination of the gene segments between different strains, influenza viruses can escape the immune responses developed by vaccination. Thus, new strategies aimed to efficiently activate immune response that targets to conserved regions among different influenza viruses are urgently needed in designing broad-spectrum influenza vaccine. Heat shock protein gp96 is currently the only natural T cell adjuvant with special ability to cross-present coupled antigen to major histocompatibility complex class I (MHC-I) molecule and activate the downstream antigen-specific CTL response. In this study, we demonstrated the advantages of adding gp96 to monovalent split influenza virus vaccine to improve its ability to provide cross-protection in the BALB/c mouse model and proved that a gp96-activated cross-reactive CTL response is indispensable in our vaccine strategy. Due to its unique adjuvant properties, gp96 might be a promising adjuvant for designing new broad-spectrum influenza vaccines. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/33827939/Broadly_Protective_CD8+_T_Cell_Immunity_to_Highly_Conserved_Epitopes_Elicited_by_Heat_Shock_Protein_gp96_Adjuvanted_Influenza_Monovalent_Split_Vaccine_ L2 - https://journals.asm.org/doi/10.1128/JVI.00507-21?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -