Construction of the vaccine strain of the influenza B virus with chimeric hemagglutinin to induce a cross-protective immune response

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Abstract

BACKGROUND: Influenza viruses cause worldwide epidemics, and the most effective method to prevent influenza disease is regular vaccinations. The development of new generation vaccines is aimed primarily at the formation of an immune response against a wide range of influenza viruses. One of the promising approaches is sequential vaccination with chimeric influenza viruses with identical stem domains of the hemagglutinin surface protein.

AIM: The development of an experimental vaccine strain of influenza B virus with chimeric hemagglutinin consisting of head and stem domains of influenza B viruses belonging to different genetic lineages.

MATERIALS AND METHODS: A chimeric influenza hemagglutinin gene was obtained by genetic engineering from the genetic material of B/Victoria and B/Yamagata influenza strains. The gene was inserted into the vector for the reverse genetics of the influenza virus. The influenza B virus strain with chimeric hemagglutinin was obtained by transfection of Vero cells using an 8-plasmid system. The rest of the genes were obtained from the attenuated influenza B virus with cold-adapted and temperature-sensitive phenotypes. The biological properties of the obtained recombinant strain, its infectious titer in developing chicken embryos and MDCK cell culture were evaluated.

RESULTS: A recombinant vaccine strain has been successfully rescued. The head domain of the hemagglutinin of the virus is inherited from the B/Victoria influenza virus, and the stem domain from the B/Yamagata virus. The virus actively replicated in eggs and MDCK cells, with temperature-sensitive and cold-adapted phenotypes identical to classical live attenuated influenza vaccine viruses. The thermal stability of the chimeric hemagglutinin did not differ significantly from the thermal stability of the hemagglutinins of the donor viruses.

CONCLUSIONS: The results obtained indicate the possibility of creating a strain with chimeric hemagglutinin, fragments of which are inherited from different genetic lineages. The growth characteristics and biological properties of the strain make it a promising candidate for the experimental evaluation of the possibility of inducing a cross-protective immune response by sequential vaccination with vaccine strains with identical stem hemagglutinin domains.

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About the authors

Konstantin V. Baranov

Institute of Experimental Medicine; Peter the Great St. Petersburg Polytechnic University

Email: mrk2185@gmail.com
ORCID iD: 0000-0002-8476-1469

student

Russian Federation, Saint Petersburg

Pei-Fong Wong

Institute of Experimental Medicine

Email: po333222@gmail.com
ORCID iD: 0000-0002-7939-6313

Postgraduate student

Russian Federation, Saint Petersburg

Ekaterina A. Stepanova

Institute of Experimental Medicine

Author for correspondence.
Email: fedorova.iem@gmail.com
ORCID iD: 0000-0002-8670-8645
SPIN-code: 8010-3047

Cand. Sci. (Biol.), Senior Researcher

Russian Federation, Saint Petersburg

Ekaterina A. Bazhenova

Institute of Experimental Medicine

Email: bazhea@mail.ru
ORCID iD: 0000-0003-3280-556X

Cand. Sci. (Biol.), Senior Researcher

Russian Federation, Saint Petersburg

Elena V. Krutikova

Institute of Experimental Medicine

Email: krutev@mail.ru
ORCID iD: 0000-0002-0383-2625
SPIN-code: 6330-6128

Cand. Sci. (Biol.), Researcher

Russian Federation, Saint Petersburg

Irina N. Isakova-Sivak

Institute of Experimental Medicine

Email: isakova.sivak@iemspb.ru
ORCID iD: 0000-0002-2801-1508
SPIN-code: 3469-3600

Dr. Sci. (Biol.), Head of Laboratory

Russian Federation, Saint Petersburg

Larisa G. Rudenko

Institute of Experimental Medicine

Email: vaccine@mail.ru
ORCID iD: 0000-0002-0107-9959
SPIN-code: 4181-1372

Dr. Sci. (Biol.), Professor, Honored Scientist of the Russian Federation

Russian Federation, Saint Petersburg

References

  1. Up to 650 000 people die of respiratory diseases linked to seasonal flu each year [Internet]. WHO. Available from: https://www.who.int/news/item/13-12-2017-up-to-650-000-people-die-of-respiratory-diseases-linked-to-seasonal-flu-each-year.Accessed: 17.08.2021.
  2. Wang Q, Cheng F, Lu M, et al. Crystal structure of unliganded influenza B virus hemagglutinin. J Virol. 2008;82(6):3011–3020. doi: 10.1128/JVI.02477-07
  3. Chen CJ, Ermler ME, Tan GS, et al. Influenza A viruses expressing intra- or intergroup chimeric hemagglutinins. J Virol. 2016;90(7):3789–3793. doi: 10.1128/JVI.03060-15
  4. Nachbagauer R, Feser J, Naficy A, et al. A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial. Nat Med. 2021;27(1):106–114. doi: 10.1038/s41591-020-1118-7
  5. Ermler ME, Kirkpatrick E, Sun W, et al. Chimeric hemagglutinin constructs induce broad protection against influenza B virus challenge in the mouse model. J Virol. 2017;91(12):e00286–00317. doi: 10.1128/JVI.00286-17
  6. Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints. American Journal of Epidemiology. 1938;27(3):493–497. doi: 10.1093/oxfordjournals.aje.a118408
  7. Isakova-Sivak I, Matyushenko V, Kotomina T, et al. Sequential immunization with universal live attenuated influenza vaccine candidates protects ferrets against a high-dose heterologous virus challenge. Vaccines (Basel). 2019;7(3):61. doi: 10.3390/vaccines7030061

Supplementary files

Supplementary Files
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1. Figure. The scheme of the chimeric hemagglutinin gene of the rescued strain. The head domain inherited from the B/Victoria lineage virus, other gene fragments – from the B/Yamagata lineage virus. НТР — untranslated region, СП — signal peptide, Стебл-1 and -2 — regions coding the hemagglutinin stem domain, Голов — region coding the hemagglutinin head domain, ТМД — transmembrane domain, ЦПД — cytosol domain. The numbers indicate the length (in nucleotide base pairs) of each fragment, as well as nucleotide positions of flanking regions. Index numbers correspond to the segments of original viruses

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Copyright (c) 2021 Baranov K.V., Wong P., Stepanova E.A., Bazhenova E.A., Krutikova E.V., Isakova-Sivak I.N., Rudenko L.G.

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