基于新城疫病毒载体的H7N9亚型禽流感疫苗诱导的补体应答解析

doi:10.1016/j.jia.2023.11.007

Journal of Integrative Agriculture ›› 2024, Vol. 23 ›› Issue (6): 2052-2064.DOI: 10.1016/j.jia.2023.11.007

基于新城疫病毒载体的H7N9亚型禽流感疫苗诱导的补体应答解析

收稿日期:2023-07-04 接受日期:2023-10-14 出版日期:2024-06-20 发布日期:2024-05-30

Antibodies elicited by Newcastle disease virus-vectored H7N9 avian influenza vaccine are functional in activating the complement system

Zenglei Hu^{1, 2, 3*}, Ya Huang^{2, 3*}, Jiao Hu^{2, 3}, Xiaoquan Wang^{2, 3}, Shunlin Hu^{2, 3}, Xiufan Liu^{1, 2,
3#}

¹Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
² Animal Infectious Disease Laboratory, School of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
³Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China

Received:2023-07-04 Accepted:2023-10-14 Online:2024-06-20 Published:2024-05-30
About author:Zenglei Hu, E-mail: zengleihu@163.com; #Correspondence Xiufan Liu, Tel: +86-514-87991416, E-mail: xfliu@yzu.edu.cn * These authors contributed equally to this study.
Supported by:
This work was supported by the earmarked fund for China Agriculture Research System (CARS-40), the Key Research and Development Project of Yangzhou (Modern Agriculture), China (YZ2022052), and the ‘‘High-end Talent Support Program’’ of Yangzhou University, China.

摘要/Abstract

摘要：

【背景】H7N9亚型禽流感病毒（Avian influenza virus, AIV）是家禽养殖业的重大威胁。基于新城疫病毒载体的H7N9亚型禽流感疫苗（NDV_vecH7N9）的保护效力高，且可通过群体免疫方式（如喷雾、饮水等）进行投放，为提高H7N9亚型禽流感的防控效率提供了有效措施。NDV_vecH7N9疫苗不能诱导鸡产生H7N9特异性的血凝抑制（Hemagglutination-inhibition, HI）抗体，却可以诱导高水平的IgG抗体。但是，NDV_vecH7N9疫苗抗体应答的分子基础和抗体保护机制尚不清楚。【目的】解析NDV_vecH7N9疫苗抗体免疫的分子基础与抗体的免疫保护机制。【方法】制备NDV_vecH7N9疫苗免疫鸡血清并测定血清的HI、病毒中和（Virus neutralization, VN）与IgG抗体滴度；基于被动免疫模型评价NDV_vecH7N9免疫血清对H7N9亚型AIV的保护力；利用竞争酶联免疫吸附试验鉴定NDV_vecH7N9免疫血清识别的优势抗原表位；基于建立的抗体依赖的补体介导的细胞毒试验与补体介导的病毒中和试验，评价NDV_vecH7N9免疫血清诱导的补体应答。【结果】NDV_vecH7N9疫苗诱导鸡产生较低的HI、VN抗体与较高的血凝素（Hemagglutinin, HA）特异性IgG抗体。经被动免疫方式接种NDV_vecH7N9免疫血清可对鸡提供针对H7N9病毒攻击的完全保护。位于HA蛋白抗原位点A区的S150、G151与S152位点是NDV_vecH7N9免疫血清识别的优势抗原表位。此外，NDV_vecH7N9免疫血清能够介导表达HA蛋白的细胞或H7N9病毒感染细胞的裂解，并显著抑制H7N9病毒的感染性。加热灭活或补体抑制剂处理显著降低血清介导的细胞裂解与病毒中和效应，说明补体发挥了重要作用。将HA蛋白S150、G151与S152位点突变后，NDV_vecH7N9免疫血清介导突变病毒感染细胞的裂解与对突变病毒的中和活性均显著下降，说明血清抗体与抗原的结合对于补体活性是必须的。【结论】NDV_vecH7N9疫苗诱导的抗体能够激活补体系统，介导对H7N9病毒感染细胞的细胞毒作用，以及对H7N9亚型AIV的中和作用。【创新性】研究结果揭示了补体系统激活是NDV_vecH7N9疫苗抗体免疫的重要机制，提示激活补体系统对H7N9亚型禽流感疫苗的设计具有潜在意义。

Abstract:

H7N9 subtype avian influenza virus poses a great challenge for poultry industry. Newcastle disease virus (NDV)-vectored H7N9 avian influenza vaccines (NDV_vecH7N9) are effective in disease control because they are protective and allow mass administration. Of note, these vaccines elicit undetectable H7N9-specific hemagglutination-inhibition (HI) but high IgG antibodies in chickens. However, the molecular basis and protective mechanism underlying this particular antibody immunity remain unclear. Herein, immunization with an NDV_vecH7N9 induced low anti-H7N9 HI and virus neutralization titers but high levels of hemagglutinin (HA)-binding IgG antibodies in chickens. Three residues (S150, G151 andS152) in HA of H7N9 virus were identified as the dominant epitopes recognized by the NDV_vecH7N9 immune serum. Passively transferred NDV_vecH7N9 immune serum conferred complete protection against H7N9 virus infection in chickens. The NDV_vecH7N9 immune serum can mediate a potent lysis of HA-expressing and H7N9 virus-infected cells and significantly suppress H7N9 virus infectivity. These activities of the serum were significantly impaired after heat-inactivation or treatment with complement inhibitor, suggesting the engagement of the complement system. Moreover, mutations in the 150-SGS-152 sites in HA resulted in significant reductions in cell lysis and virus neutralization mediated by the NDV_vecH7N9 immune serum, indicating the requirement of antibody-antigen binding for complement activity. Therefore, antibodies induced by the NDV_vecH7N9 can activate antibody-dependent complement-mediated lysis of H7N9 virus-infected cells and complement-mediated neutralization of H7N9 virus. Our findings unveiled a novel role of the complement in protection conferred by the NDV_vecH7N9, highlighting a potential benefit of engaging the complement system in H7N9 vaccine design.

Key words: H7N9 subtype , avian influenza virus , NDV vector , vaccine , antibody immunity , complement , protection

. 基于新城疫病毒载体的H7N9亚型禽流感疫苗诱导的补体应答解析[J]. Journal of Integrative Agriculture, 2024, 23(6): 2052-2064.

Zenglei Hu, Ya Huang, Jiao Hu, Xiaoquan Wang, Shunlin Hu, Xiufan Liu.

Antibodies elicited by Newcastle disease virus-vectored H7N9 avian influenza vaccine are functional in activating the complement system [J]. Journal of Integrative Agriculture, 2024, 23(6): 2052-2064.

参考文献

Bart S A, Hohenboken M, Della Cioppa G, Narasimhan V, Dormitzer P R, Kanesa-Thasan N. 2014. A cell culture-derived MF59-adjuvanted pandemic A/H7N9 vaccine is immunogenic in adults. Science Translational Medicine, 6, 234ra255.

Cao Y Z, Deng J, Huang Y, Bo Z Y, Hu Z L. 2023. Generation and application of 293T cell line stably expressing the haemugglutinin of H7N9 subtype avian influenza virus. China Poultry, 45, 59–64. (in Chinese)

Chang P, Lukosaityte D, Sealy J E, Rijal P, Sadeyen J R, Bhat S, Crossley S, Daines R, Huang K A, Townsend A R, Iqbal M. 2023a. Antigenic characterization of human monoclonal antibodies for therapeutic use against H7N9 avian influenza virus. Journal of Virology, 97, e0143122.

Chang P, Sadeyen J R, Bhat S, Daines R, Hussain A, Yilmaz H, Iqbal M. 2023b. Risk assessment of the newly emerged H7N9 avian influenza viruses. Emerging Microbes Infections, 12, 2172965.

Coudeville L, Bailleux F, Riche B, Megas F, Andre P, Ecochard R. 2010. Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: Development and application of a bayesian random-effects model. BMC Medical Research Methodology, 10, 18.

Dunand C J H, Leon P E, Huang M, Choi A, Chromikova V, Ho I Y, Tan G S, Cruz J, Hirsh A, Zheng N Y, Mullarkey C E, Ennis F A, Terajima M, Treanor J J, Topham D J, Subbarao K, Palese P, Krammer F, Wilson P C. 2016. Both neutralizing and non-neutralizing human H7N9 influenza vaccine-induced monoclonal antibodies confer protection. Cell Host Microbe, 19, 800–813.

Fox J M, Roy V, Gunn B M, Huang L, Edeling M A, Mack M, Fremont D H, Doranz B J, Johnson S, Alter G, Diamond M S. 2019. Optimal therapeutic activity of monoclonal antibodies against chikungunya virus requires Fc-FcγR interaction on monocytes. Science Immunology, 4, eaav5062.

Gao R B, Cao B, Hu Y W, Feng Z J, Wang D Y, Hu W F, Chen J, Jie Z J, Qiu H B, Xu K, Xu X W, Lu H Z, Zhu W F, Gao Z C, Xiang N J, Shen Y Z, He Z B, Gu Y, Zhang Z Y, Yang Y, et al. 2013. Human infection with a novel avian-origin influenza A (H7N9) virus. New England Journal of Medicine, 368, 1888–1897.

Ge J Y, Deng G H, Wen Z Y, Tian G B, Wang Y, Shi J Z, Wang X J, Li Y B, Hu S, Jiang Y P, Yang C L, Yu K Z, Bu Z G, Chen H L. 2007. Newcastle disease virus-based live attenuated vaccine completely protects chickens and mice from lethal challenge of homologous and heterologous H5N1 avian influenza viruses. Journal of Virology, 81, 150–158.

Gunn B M, Yu W H, Karim M M, Brannan J M, Herbert A S, Wec A Z, Halfmann P J, Fusco M L, Schendel S L, Gangavarapu K, Krause T, Qiu X, He S, Das J, Suscovich T J, Lai J, Chandran K, Zeitlin L, Crowe Jr J E, Lauffenburger D, et al. 2018. A role for Fc function in therapeutic monoclonal antibody-mediated protection against ebola virus. Cell Host Microbe, 24, 221–233.

Hoffmann E, Krauss S, Perez D, Webby R, Webster R G. 2002. Eight-plasmid system for rapid generation of influenza virus vaccines. Vaccine, 20, 3165–3170.

Hu Z L, Hu S L, Meng C C, Wang X Q, Zhu J, Liu X F. 2011. Generation of a genotype VII Newcastle disease virus vaccine candidate with high yield in embryonated chicken eggs. Avian Diseases, 55, 391–397.

Hu Z L, Liu X F, Jiao X A. 2017. Newcastle disease virus (NDV) recombinant expressing the hemagglutinin of H7N9 avian influenza virus protects chickens against NDV and highly pathogenic avian influenza A (H7N9) virus challenges. Vaccine, 35, 6585–6590.

Hu Z L, Zhao J Y, Shi L, Hu J, Hu S L, Liu X F. 2021. Identification of the dominant non-neutralizing epitope in the haemagglutinin of H7N9 avian influenza virus. Virus Research, 298, 198409.

Hu Z L, Zhao J Y, Zhao Y H, Fan X L, Hu J, Shi L, Wang X Q, Liu X W, Hu S L, Gu M, Cao Y Z, Liu X F. 2019. Hemagglutinin-specific non-neutralizing antibody is essential for protection provided by inactivated and viral-vectored H7N9 avian influenza vaccines in chickens. Frontiers in Veterinary Science, 6, 482.

Ito M, Yamayoshi S, Murakami K, Saito K, Motojima A, Nakaishi K, Kawaoka Y. 2019. Characterization of mouse monoclonal antibodies against the HA of A(H7N9) influenza virus. Viruses, 11, 149.

Jackson L A, Campbell J D, Frey S E, Edwards K M, Keitel W A, Kotloff K L, Berry A A, Graham I, Atmar R L, Creech C B, Thomsen I P, Patel S M, Gutierrez A F, Anderson E L, El Sahly H M, Hill H, Noah D L, Bellamy A R. 2015. Effect of varying doses of a monovalent H7N9 influenza vaccine with and without AS03 and MF59 adjuvants on immune response: A randomized clinical trial. JAMA, 314, 237–246.

Kamal R P, Blanchfield K, Belser J A, Music N, Tzeng W P, Holiday C, Burroughs A, Sun X, Maines T R, Levine M Z, York I A. 2017. Inactivated H7 influenza virus vaccines protect mice despite low levels of neutralizing antibodies. Journal of Virology, 91, e01202–e01219.

Krammer F. 2019. The human antibody response to influenza A virus infection and vaccination. Nature Reviews. Immunology, 19, 383–397.

Lam A K, Roshan R, Miley W, Labo N, Zhen J, Kurland A P, Cheng C, Huang H, Teng P L, Harelson C, Gong D, Tam Y K, Radu C G, Epeldegui M, Johnson J R, Zhou Z H, Whitby D, Wu T T. 2023. Immunization of mice with virus-like vesicles of Kaposi Sarcoma-associated herpesvirus reveals a role for antibodies targeting ORF4 in activating complement-mediated neutralization. Journal of Virology, 97, e0160022.

Li J X, Yang Y, Wang M, Ren X H, Yang Z, Liu L Y, Zhang G Z, Chen Q, Yang W, Chen Y H, Wan X C. 2019. Rapid isolation of a potent human antibody against H7N9 influenza virus from an infected patient. Antiviral Research, 170, 104564.

Li M X, Chen L, Wang Q G, Hao M C, Zhang X Q, Liu L L, Yu X, Yang C P, Xu J Q, Chen J J, Gong R. 2019. A cross-reactive human monoclonal antibody targets the conserved H7 antigenic site A from fifth wave H7N9-infected humans. Antiviral Research, 170, 104556.

Liu D, Zhang Z J, He L H, Gao Z, Li J, Gu M, Hu J, Wang X Q, Liu X F. 2018. Characteristics of the emerging chicken-origin highly pathogenic H7N9 viruses: A new threat to public health and poultry industry. Journal of Infection, 76, 217–220.

Liu Q, Mena I, Ma J, Bawa B, Krammer F, Lyoo Y S, Lang Y, Morozov I, Mahardika G N, Ma W, Garcia-Sastre A, Richt J A. 2015. Newcastle disease virus-vectored H7 and H5 live vaccines protect chickens from challenge with H7N9 or H5N1 avian influenza viruses. Journal of Virology, 89, 7401–7408.

Miller-Novak L K, Das J, Musich T A, Demberg T, Weiner J A, Venzon D J, Mohanram V, Vargas-Inchaustegui D A, Tuero I, Ackerman M E, Alter G, Robert-Guroff M. 2018. Analysis of complement-mediated lysis of simian immunodeficiency virus (SIV) and SIV-infected cells reveals sex differences in vaccine-induced immune responses in rhesus macaques. Journal of Virology, 92, e00721–e00739.

Nagy A, Lee J, Mena I, Henningson J, Li Y, Ma J, Duff M, Lang Y, Yang J, Abdallah F, Richt J, Ali A, Garcia-Sastre A, Ma W. 2016. Recombinant Newcastle disease virus expressing H9 HA protects chickens against heterologous avian influenza H9N2 virus challenge. Vaccine, 34, 2537–2545.

Schmeisser F, Vasudevan A, Verma S, Wang W, Alvarado E, Weiss C, Atukorale V, Meseda C, Weir J P. 2015. Antibodies to antigenic site A of influenza H7 hemagglutinin provide protection against H7N9 challenge. PLoS ONE, 10, e0117108.

Shi J Z, Deng G H, Ma S J, Zeng X Y, Yin X, Li M, Zhang B, Cui P F, Chen Y, Yang H L, Wan X P, Liu L L, Chen P C, Jiang Y P, Guan Y T, Liu J X, Gu W L, Han S Y, Song Y M, Liang L B, et al. 2018. Rapid evolution of H7N9 highly pathogenic viruses that emerged in China in 2017. Cell Host Microbe, 24, 558–568.

Shi L, Hu Z L, Hu J, Liu D, He L H, Liu J, Gu H, Gan J J, Wang X Q, Liu X F. 2018. Single immunization with Newcastle disease virus-vectored H7N9 vaccine confers a complete protection against challenge with highly pathogenic avian influenza H7N9 virus. Avian Diseases, 63, 61–67.

Sicca F, Neppelenbroek S, Huckriede A. 2018. Effector mechanisms of influenza-specific antibodies: Neutralization and beyond. Expert Review of Vaccines, 17, 785–795.

Stadlbauer D, Rajabhathor A, Amanat F, Kaplan D, Masud A, Treanor J J, Izikson R, Cox M M, Nachbagauer R, Krammer F. 2017. Vaccination with a recombinant H7 hemagglutinin-based influenza virus vaccine induces broadly reactive antibodies in humans. mSphere, 2, e00502–e00519.

Sun S H, Zhao G Y, Liu C F, Fan W, Zhou X J, Zeng L, Guo Y, Kou Z H, Yu H, Li J F, Wang R X, Li Y, Schneider C, Habel M, Riedemann N C, Du L Y, Jiang S B, Guo R F, Zhou Y S. 2015. Treatment with anti-C5a antibody improves the outcome of H7N9 virus infection in African green monkeys. Clinical Infectious Diseases, 60, 586–595.

Tan G S, Leon P E, Albrecht R A, Margine I, Hirsh A, Bahl J, Krammer F. 2016. Broadly-reactive neutralizing and non-neutralizing antibodies directed against the H7 influenza virus hemagglutinin reveal divergent mechanisms of protection. PLoS Pathogens, 12, e1005578.

Wang X L, Jiang H, Wu P, Uyeki T M, Feng L Z, Lai S J, Wang L L, Huo X, Xu K, Chen E F, Wang X X, He J F, Kang M, Zhang R L, Zhang J, Wu J B, Hu S X, Zhang H J, Liu X Q, Fu W J, et al. 2017. Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013–17: An epidemiological study of laboratory-confirmed case series. Lancet Infectious Diseases, 17, 822–832.

Wibroe P P, Helvig S Y, Moein Moghimi S. 2014. The role of complement in antibody therapy for infectious diseases. Microbiology Spectrum, 2, AID-0015–2014.

Yang F, Xiao Y X, Lu R F, Chen B, Liu F M, Wang L Y, Yao H P, Wu N P, Wu H B. 2020. Generation of neutralizing and non-neutralizing monoclonal antibodies against H7N9 influenza virus. Emerging Microbes Infections, 9, 664–675.

Yin X, Deng G H, Zeng X Y, Cui P F, Hou Y J, Liu Y J, Fang J Z, Pan S X, Wang D X, Chen X H, Zhang Y P, Wang X R, Tian G B, Li Y B, Chen Y, Liu L L, Suzuki Y, Guan Y T, Li C J, Shi J Z, et al. 2021. Genetic and biological properties of H7N9 avian influenza viruses detected after application of the H7N9 poultry vaccine in China. PLoS Pathogens, 17, e1009561.

Yu F, Song H, Wu Y L, Chang S Y, Wang L L, Li W, Hong B B, Xia S, Wang C Y, Khurana S, Feng Y, Wang Y P, Sun Z W, He B A, Hou D N, Manischewitz J, King L R, Song Y L, Min J Y, Golding H, et al. 2017. A potent germline-like human monoclonal antibody targets a pH-sensitive epitope on H7N9 influenza hemagglutinin. Cell Host Microbe, 22, 471–483.

Zeng X Y, He X W, Meng F, Ma Q, Wang Y, Bao H M, Liu Y J, Deng G H, Shi J Z, Li Y B, Tian G B, Chen H L. 2022. Protective efficacy of an H5/H7 trivalent inactivated vaccine (H5-Re13, H5-Re14, and H7-Re4 strains) in chickens, ducks, and geese against newly detected H5N1, H5N6, H5N8, and H7N9 viruses. Journal of Integrative Agriculture, 21, 2086–2094.

基于新城疫病毒载体的H7N9亚型禽流感疫苗诱导的补体应答解析

Antibodies elicited by Newcastle disease virus-vectored H7N9 avian influenza vaccine are functional in activating the complement system

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