Email this article CROSS-PROTECTIVE PROPERTIES OF AN INFLUENZA VACCINE BASED ON HBC4M2E RECOMBINANT PROTEIN
- Authors: Tsybalova L.M.1, Stepanova L.A.1, Shuklina M.A.1, Petrov S.V.1, Kovaleva A.A.1, Potapchuk M.V.1, Shaldzhan A.A.1, Zabrodskaya Y.A.1, Egorov V.V.1
-
Affiliations:
- Research Institute of Influenza
- Issue: Vol 63, No 2 (2018)
- Pages: 68-76
- Section: ORIGINAL RESEARCH
- Submitted: 20.01.2020
- Published: 20.04.2018
- URL: https://virusjour.crie.ru/jour/article/view/188
- DOI: https://doi.org/10.18821/0507-4088-2018-63-2-68-76
- ID: 188
Cite item
Full Text
Abstract
One of the main problems in the area of influenza prophylaxis and pandemic prevention is the development of cross-reactive vaccines, i.e. vaccines directed against all subtypes of human influenza viruses. Such vaccines are being developed in many countries for more than 10 years. A number of vaccines are presently undergoing clinical trials. We created Uniflu candidate vaccine based on recombinant HBc4M2e protein consisting of 4 tandem-connected copies of the highly conserved ectodomain of M2 protein of the influenza A virus. These 4 copies were genetically fused to the carrier protein, namely hepatitis B core antigen. Commercially available Derinat was used as adjuvant in the candidate vaccine. Preclinical studies on laboratory animals (mice, ferrets) demonstrated that immunization with Uniflu leads to significantly higher level of specific immunoglobulins in the blood and bronchoalveolar lavages. Moreover, it produces immunoglobulins belonging to subtype IgG2a that is the most important mediator of antibody-dependent cytotoxicity. The vaccine under review stimulates the proliferation of T-lymphocytes, as well as the formation of CD4+ and CD8+ T-cells synthesizing ɣ-IFN. When infected with the lethal doses (5 LD50) of influenza A viruses of the subtypes H1N1, H2N2, H3N2, and H1N1pdm09, immunized animals typically developed mild form of illness. This kept them alive in 90-100% of cases, which demonstrated almost complete protection from death. Replication of the virus in the lungs of immunized mice was reduced by 1.8-4.8 log10. High immunogenicity of the vaccine, and reduced clinical symptoms following experimental infection, were demonstrated in ferrets as well. The developed recombinant vaccine Uniflu has high specific activity and cross-protection. Uniflu can be proposed as pre-pandemic vaccine, provided that it passes clinical trials.
About the authors
L. M. Tsybalova
Research Institute of Influenza
Author for correspondence.
Email: sovet@influenza.spb.ru
Russian Federation
L. A. Stepanova
Research Institute of Influenza
Email: noemail@neicon.ru
Russian Federation
M. A. Shuklina
Research Institute of Influenza
Email: noemail@neicon.ru
Russian Federation
S. V. Petrov
Research Institute of Influenza
Email: noemail@neicon.ru
Russian Federation
A. A. Kovaleva
Research Institute of Influenza
Email: noemail@neicon.ru
Russian Federation
M. V. Potapchuk
Research Institute of Influenza
Email: noemail@neicon.ru
Russian Federation
A. A. Shaldzhan
Research Institute of Influenza
Email: noemail@neicon.ru
Russian Federation
Y. A. Zabrodskaya
Research Institute of Influenza
Email: noemail@neicon.ru
Russian Federation
V. V. Egorov
Research Institute of Influenza
Email: noemail@neicon.ru
Russian Federation
References
- Wood J.M. Developing vaccines against pandemic influenza. Phil. Trans. R. Soc. Lond. B Biol. Sci. 2001; 356(1416): 1953-60.
- Neirynck S., Deroot I., Saelans X., Vanlandschoot P., Jou W., Fiers W. A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat. Med. 1999; 5(10): 1157-63.
- Fiers W., De Filette M., El Bakkouri K., Schepens B., Roose K., Schotsaert M., et al. M2e-based universal influenza A vaccine. Vaccine. 2009; 27(45): 6280-3.
- Steel J., Lowen A., Wang T.T., Yondola M., Gao Q., Haye K., et al. Influenza virus vaccine based on the conserved hemagglutinin stalk domain. MBio. 2010; 1(1): е00018-10.
- Hessel A., Savidis-Dacho H., Coulibaly S., Portsmouth D., Kreil T.R., Crowe B.A., et al. MVA vectors expressing conserved influenza proteins protect mice against lethal challenge with H5N1, H9N2 and H7N1 viruses. PLoS One. 2014; 9(2): e88340.
- Dehg L., Ibanes L.I., Van den Bossche V., Roose K., Youssef S.A., de Bruin A. et al. Protection against Influenza A Virus Challenge with M2e-Displaying Filamentous Escherichia coli Phages. PLoS One. 2015; 10(5): e0126650.
- WHO. Global Vaccine Action Plan. Available at: http://www.who.int/immunization/global_vaccine_action_plan/en/
- Jegerlehner A., Schmitz N., Storni T., Bachmann M.F. Influenza A vaccine based on the extracellular domain of M2: weak protection mediated via antibody-dependent NK cell activity. J. Immunol. 2004; 172(9): 5598-605.
- El Bakkouri K., Descamps F., De Fillete M., Smet A., Festjens E., Birkett A. et al. Universal vaccine based on ectodomain of matrix protein 2 of influenza A: Fc receptors and alveolar macrophages mediate protection. J. Immunol. 2011; 186(2): 1022-31.
- Andersson A.M., Hakansson K.O., Jensen B.A., Christensen D., Andersen P., Thomsen A. R., et al. Increased immunogenicity and protective efficacy of influenza M2e fused to a tetramerizing protein. PLoS One. 2012; 7(10): e46395.
- Kim M.C., Lee Y.N., Ko E.J. Supplementation of influenza split vaccines with conserved M2 ectodomains overcomes strain specificity and provides long-term cross protection. Mol. Ther. 2014; 22(7): 1364-74.
- Ravin N.V., Blokhina E.A., Kuprianov V.V., Stepanova L.A., Shaldjan A.A., Kovaleva A.A., et al. Development of a candidate influenza vaccine based on virus-like particles displaying influenza M2e peptide into the immunodominant loop region of hepatitis B core antigen: Insertion of multiple copies of M2e increases immunogenicity and protective efficiency. Vaccine. 2015; 33(29): 3392-7.
- Tsybalova L.M., Stepanova L.A., Kuprianov V.V., Blokhina E.A., Potapchuk M.V., Korotkov A.V., et al. Development of a candidate influenza vaccine based on virus-like particles displaying influenza M2e peptide into the immunodominant region of hepatitis B core antigen: Broad protective efficacy of particles carrying four copies of M2e. Vaccine. 2015; 33(29): 3398-406.
- Laemmli U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970; 227(5259): 680-5.
- Malen H., Berven F.S., Fladmark K.E., Wiker H.G. Comprehensive analysis of exported proteins from Mycobacterium tuberculosis H37Rv. Proteomics. 2007; 7(10): 1702-18.
- Stepanova L.A., Kotlyarov R.Y., Kovaleva A.A., Potapchuk M.V., Korotkov A.V., Sergeeva M.V., et al. Protection against multiple influenza A virus strains induced by candidate recombinant vaccine based on heterologous M2e peptides linked to flagellin. PLoS One. 2015; 10(3): e0119520.
- Филатов О.Ю., Кашаева О.В., Бугримов Д.Ю., Климович А.А. Морфофизиологические принципы иммунологического действия ДНК эукариот. Российский иммунологический журнал. 2013; 7(4): 385-90.
- Бугримов Д.Ю., Лядов Д.В., Красноруцкая О.Н., Климович А.А. Оценка уровня экспрессии TLR-9 рецепторов при введении препарата Деринат. Вестник новых медицинских технологий. 2012; 19(2): 288-9.
- De Filette M., Jou W.M., Birkett A., Lyons K., Schultz B., Tonkyro A., et al. Universal influenza A vaccine: optimization of M2-based constructs. Virology. 2005; 337(1): 149-61.
- Mozdzanovska K., Zharikova D., Cudic M., Otvos l., Gerhard W. Roles of adjuvantand route of vaccination in antibody response and protection engendered by a synthetic matrix protein 2-based influenza A virus vaccine in the mouse. Virol. J. 2007; 4: 118-29.
- Schmiz N., Beerli R., Bauer M., Jegerlehner A., Dietmeier K., Maudrich M., et al. Universal vaccine against influenza virus: linking TLR signaling to anti-viral protection. Eur. J. Immunol. 2012; 42(4): 863-9.
- Herzenberg L.A., Tokuhisa T., Park D.R. Epitope-specific regulation. II. A bistable, Igh-restricted regulatory mechanism central to immunologic memory. J. Exp. Med. 1982; 155(6): 1741-53.
- Spellberg В. Type 1/Type 2 Immunity in Infectious Diseases. Clin. Infect. Dis. 2000; 32(1): 76-102.
Supplementary files
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).