Universal Protection Against Influenza Viruses by Multi-subtype Neuraminidase and M2 Ectodomain Virus-like Particle

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2022 Aug 25

PMID 36006890

Authors

Ki-Hye Kim

Zhuo Li

Noopur Bhatnagar

Jeeva Subbiah

Bo Ryoung Park

Chong Hyun Shin

Peter Pushko

Bao-Zhong Wang

Sang-Moo Kang

Affiliations

Soon will be listed here.

Abstract

Annual influenza vaccination is recommended to update the variable hemagglutinin antigens. Here, we first designed a virus-like particle (VLP) displaying consensus multi-neuraminidase (NA) subtypes (cN1, cN2, B cNA) and M2 ectodomain (M2e) tandem repeat (m-cNA-M2e VLP). Vaccination of mice with m-cNA-M2e VLP induced broad NA inhibition (NAI), and M2e antibodies as well as interferon-gamma secreting T cell responses. Mice vaccinated with m-cNA-M2e VLP were protected against influenza A (H1N1, H5N1, H3N2, H9N2, H7N9) and influenza B (Yamagata and Victoria lineage) viruses containing substantial antigenic variations. Protective immune contributors include cellular and humoral immunity as well as antibody-dependent cellular cytotoxicity. Furthermore, comparable cross protection by m-cNA-M2e VLP vaccination was induced in aged mice. This study supports a novel strategy of developing a universal vaccine against influenza A and B viruses potentially in both young and aged populations by inducing multi-NA subtype and M2e immunity with a single VLP entity.

Citing Articles

A Model H5N2 Vaccine Strain for Dual Protection Against H5N1 and H9N2 Avian Influenza Viruses.

Song J, Son S, Kim H, An S, Lee C, Kwon H Vaccines (Basel). 2025; 13(1).

PMID: 39852801 PMC: 11768808. DOI: 10.3390/vaccines13010022.

Delivery of dendritic cells targeting 3M2e-HA2 nanoparticles with a CpG adjuvant via lysosomal escape of Salmonella enhances protection against H9N2 avian influenza virus.

Jia F, Wang W, Tian Y, Zahra A, He Y, Ge C Poult Sci. 2024; 104(1):104616.

PMID: 39631272 PMC: 11665339. DOI: 10.1016/j.psj.2024.104616.

Prokaryote- and Eukaryote-Based Expression Systems: Advances in Post-Pandemic Viral Antigen Production for Vaccines.

Khudainazarova N, Granovskiy D, Kondakova O, Ryabchevskaya E, Kovalenko A, Evtushenko E Int J Mol Sci. 2024; 25(22).

PMID: 39596049 PMC: 11594041. DOI: 10.3390/ijms252211979.

CircRNA based multivalent neuraminidase vaccine induces broad protection against influenza viruses in mice.

Yue X, Zhong C, Cao R, Liu S, Qin Z, Liu L NPJ Vaccines. 2024; 9(1):170.

PMID: 39285168 PMC: 11405689. DOI: 10.1038/s41541-024-00963-4.

Capsid virus-like particle display improves recombinant influenza neuraminidase antigen stability and immunogenicity in mice.

Kang H, Martinez M, Aves K, Okholm A, Wan H, Chabot S iScience. 2024; 27(6):110038.

PMID: 38883830 PMC: 11179578. DOI: 10.1016/j.isci.2024.110038.

References

Johansson B, Pokorny B, Tiso V . Supplementation of conventional trivalent influenza vaccine with purified viral N1 and N2 neuraminidases induces a balanced immune response without antigenic competition. Vaccine. 2002; 20(11-12):1670-4. DOI: 10.1016/s0264-410x(01)00490-x. View

Getie-Kebtie M, Sultana I, Eichelberger M, Alterman M . Label-free mass spectrometry-based quantification of hemagglutinin and neuraminidase in influenza virus preparations and vaccines. Influenza Other Respir Viruses. 2012; 7(4):521-30. PMC: 5781000. DOI: 10.1111/irv.12001. View

Wohlbold T, Podolsky K, Chromikova V, Kirkpatrick E, Falconieri V, Meade P . Broadly protective murine monoclonal antibodies against influenza B virus target highly conserved neuraminidase epitopes. Nat Microbiol. 2017; 2(10):1415-1424. PMC: 5819343. DOI: 10.1038/s41564-017-0011-8. View

Johansson B, KILBOURNE E . Dissociation of influenza virus hemagglutinin and neuraminidase eliminates their intravirionic antigenic competition. J Virol. 1993; 67(10):5721-3. PMC: 237988. DOI: 10.1128/JVI.67.10.5721-5723.1993. View

Chen Y, Wohlbold T, Zheng N, Huang M, Huang Y, Neu K . Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies. Cell. 2018; 173(2):417-429.e10. PMC: 5890936. DOI: 10.1016/j.cell.2018.03.030. View

Hackett C, Horowitz D, Wysocka M, Eisenlohr L . Immunogenic peptides of influenza virus subtype N1 neuraminidase identify a T-cell determinant used in class II major histocompatibility complex-restricted responses to infectious virus. J Virol. 1991; 65(2):672-6. PMC: 239806. DOI: 10.1128/JVI.65.2.672-676.1991. View

Tretyakova I, Hidajat R, Hamilton G, Horn N, Nickols B, Prather R . Preparation of quadri-subtype influenza virus-like particles using bovine immunodeficiency virus gag protein. Virology. 2015; 487:163-71. PMC: 4679414. DOI: 10.1016/j.virol.2015.10.007. View

Kolpe A, Schepens B, Fiers W, Saelens X . M2-based influenza vaccines: recent advances and clinical potential. Expert Rev Vaccines. 2016; 16(2):123-136. DOI: 10.1080/14760584.2017.1240041. View

Lee Y, Kim M, Lee Y, Kim Y, Kang S . Mechanisms of Cross-protection by Influenza Virus M2-based Vaccines. Immune Netw. 2015; 15(5):213-21. PMC: 4637342. DOI: 10.4110/in.2015.15.5.213. View

10.

KILBOURNE E, Johansson B, Grajower B . Independent and disparate evolution in nature of influenza A virus hemagglutinin and neuraminidase glycoproteins. Proc Natl Acad Sci U S A. 1990; 87(2):786-90. PMC: 53351. DOI: 10.1073/pnas.87.2.786. View

11.

Kim Y, Ko E, Kim M, Lee Y, Kim K, Jung Y . Roles of antibodies to influenza A virus hemagglutinin, neuraminidase, and M2e in conferring cross protection. Biochem Biophys Res Commun. 2017; 493(1):393-398. PMC: 5636684. DOI: 10.1016/j.bbrc.2017.09.011. View

12.

Johansson B . Immunization with influenza A virus hemagglutinin and neuraminidase produced in recombinant baculovirus results in a balanced and broadened immune response superior to conventional vaccine. Vaccine. 1999; 17(15-16):2073-80. DOI: 10.1016/s0264-410x(98)00413-7. View

13.

Jegaskanda S, Co M, Cruz J, Subbarao K, Ennis F, Terajima M . Induction of H7N9-Cross-Reactive Antibody-Dependent Cellular Cytotoxicity Antibodies by Human Seasonal Influenza A Viruses that are Directed Toward the Nucleoprotein. J Infect Dis. 2016; 215(5):818-823. PMC: 5853654. DOI: 10.1093/infdis/jiw629. View

14.

Kim K, Lee Y, Park S, Jung Y, Lee Y, Ko E . Neuraminidase expressing virus-like particle vaccine provides effective cross protection against influenza virus. Virology. 2019; 535:179-188. PMC: 6946909. DOI: 10.1016/j.virol.2019.07.008. View

15.

McMahon M, Kirkpatrick E, Stadlbauer D, Strohmeier S, Bouvier N, Krammer F . Mucosal Immunity against Neuraminidase Prevents Influenza B Virus Transmission in Guinea Pigs. mBio. 2019; 10(3). PMC: 6529633. DOI: 10.1128/mBio.00560-19. View

16.

Monto A, Petrie J, Cross R, Johnson E, Liu M, Zhong W . Antibody to Influenza Virus Neuraminidase: An Independent Correlate of Protection. J Infect Dis. 2015; 212(8):1191-9. DOI: 10.1093/infdis/jiv195. View

17.

Van den Hoecke S, Ehrhardt K, Kolpe A, Bakkouri K, Deng L, Grootaert H . Hierarchical and Redundant Roles of Activating FcγRs in Protection against Influenza Disease by M2e-Specific IgG1 and IgG2a Antibodies. J Virol. 2017; 91(7). PMC: 5355615. DOI: 10.1128/JVI.02500-16. View

18.

Schepens B, De Vlieger D, Saelens X . Vaccine options for influenza: thinking small. Curr Opin Immunol. 2018; 53:22-29. DOI: 10.1016/j.coi.2018.03.024. View

19.

Bosch B, Bodewes R, de Vries R, Kreijtz J, Bartelink W, van Amerongen G . Recombinant soluble, multimeric HA and NA exhibit distinctive types of protection against pandemic swine-origin 2009 A(H1N1) influenza virus infection in ferrets. J Virol. 2010; 84(19):10366-74. PMC: 2937797. DOI: 10.1128/JVI.01035-10. View

20.

Deng L, Cho K, Fiers W, Saelens X . M2e-Based Universal Influenza A Vaccines. Vaccines (Basel). 2015; 3(1):105-36. PMC: 4494237. DOI: 10.3390/vaccines3010105. View