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. 2023 May 10;18(5):e0284823.
doi: 10.1371/journal.pone.0284823. eCollection 2023.

Development and characterization of chimera of yellow fever virus vaccine strain and Tick-Borne encephalitis virus

Nadezhda Kuznetsova  1 , Andrei Siniavin  1   2 , Alexander Butenko  1 , Victor Larichev  1 , Alina Kozlova  1 , Evgeny Usachev  1 , Maria Nikiforova  1 , Olga Usacheva  1 , Alexey Shchetinin  1 , Andrei Pochtovyi  1   3 , Elena Shidlovskaya  1 , Alina Odintsova  1 , Elizaveta Belyaeva  1 , Aleksander Voskoboinikov  1 , Arina Bessonova  1 , Lyudmila Vasilchenko  1 , Galina Karganova  4   5 , Vladimir Zlobin  1 , Denis Logunov  1 , Vladimir Gushchin  1   3 , Alexander Gintsburg  1   6
Affiliations

Development and characterization of chimera of yellow fever virus vaccine strain and Tick-Borne encephalitis virus

Nadezhda Kuznetsova et al. PLoS One. .

Abstract

Tick-borne encephalitis virus (TBEV) is one of the most threatening pathogens which affects the human central nervous system (CNS). TBEV circulates widely in Northern Eurasia. According to ECDC, the number of TBE cases increase annually. There is no specific treatment for the TBEV infection, thus vaccination is the main preventive measure. Despite the existence of several inactivated vaccines currently being licensed, the development of new TBEV vaccines remains a leading priority in countries endemic to this pathogen. Here we report new recombinant virus made by infectious subgenomic amplicon (ISA) approach using TBEV and yellow fever virus vaccine strain (YF17DD-UN) as a genetic backbone. The recombinant virus is capable of effective replication in mammalian cells and induce TBEV-neutralizing antibodies in mice. Unlike the original vector based on the yellow fever vaccine strain, chimeric virus became neuroinvasive in doses of 107-106 PFU and can be used as a model of flavivirus neuroinvasiveness, neurotropism and neurovirulence. These properties of hybrid structures are the main factors limiting their practical use as vaccines platforms.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Construction of YFV 17DD-UN.
(a) The layout of the regulatory region, structural and non-structural genes of YF 17DD in 3 pBADmini plasmids. The arrows show the sites of oligonucleotides for amplification of fragments of the YF genome before ISA full genome assembly protocol. (b) Control of VeroE6 cells without virus. (c) A virus-induced CPE of VeroE6 cells infected with the YF 17DD-UN.
Fig 2
Fig 2. Construction of chimeric YFV 17DD-UN/TBEV.
(a) Scheme for generation chimeric YFV 17DD-UN/TBEV. (b) Replication kinetics of parental and chimeric viruses. (c) Plaque assay of YFV 17DD-UN/TBEV, TBEV and YFV 17DD-UN.
Fig 3
Fig 3. Assessment the pathogenicity and residual neuroinvasiveness of the chimeric virus YFV 17DD-UN/TBEV.
Mice received YFV 17DD-UN/TBEV, EnceVir, YFV 17DD-UN, TBEV or Placebo (each group, n = 10) at the indicated doses. The mortality of animals was observed for 28 days. The statistical significance of differences among the survival curves between groups was determined using the log-rank test in GraphPad Prism 8.0.1.
Fig 4
Fig 4. Assessment protectivity of the chimeric virus YFV 17DD-UN/TBEV.
Mice received YFV 17DD-UN/TBEV, EnceVir or Placebo at the indicated doses (each group, n = 10). The mortality of animals was observed for 28 days. (a) Kaplan-Meier survival analysis immunised mice, TBEV Absettarov strain challenge by 2 LD50. (b) Kaplan-Meier survival analysis immunised mice, TBEV Absettarov strain challenge by 400 LD50.
See this image and copyright information in PMC

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