Impact of untranslated mRNA sequences on immunogenicity of mRNA vaccines against M. tuberculosis in mice

Shepelkova GS1, Reshetnikov VV2,3, Avdienko VG1, Sheverev DV2, Yeremeev VV1, Ivanov RA2
About authors

1 Central Tuberculosis Research Institute, Moscow, Russia

2 Sirius University of Science and Technology, Sochi, Russia

3 Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia

Correspondence should be addressed: Galina S. Shepelkova
Jauzskaja alleja, 2, 107564, Moscow, Russia; ur.irtc@avoklepehs.g

About paper

Funding: the study was supported by the Ministry of Science and Higher Education of the Russian Federation (agreement No. 075-10-2021-113, project ID RF---193021X0001).

Acknowledgements: the authors express their gratitude to staff members of the Sirius University of Science and Technology: I.M. Terenin for in vitro transcription, O.V. Zaborova for mRNA formulation into lipid nanoparticles.

Author contribution: Shepelkova GS — planning the experiments and experimental procedure (in vivo and ex vivo), data analysis, manuscript writing; Reshetnikov VV — cloning, mRNA vaccine preparation, manuscript writing; Avdienko VG — experimental procedure (in vivo and ex vivo), data analysis; Sheverev DV — mRNA vaccine preparation, data analysis; Yeremeev VV — study design, data analysis, manuscript writing; Ivanov RA — study design, manuscript writing.

Compliance with ethical standards: the study was approved by the Ethics Committee of the Central Tuberculosis Research Institute (protocol № 3/2 dated 11 May 2023) and conducted in accordance with the Order of the Ministry of Health No. 755 and the Guidelines issued by the Office of Laboratory Animal Welfare (А5502-01).

Received: 2023-11-17 Accepted: 2023-12-19 Published online: 2023-12-31

Vaccination is among the most effective measures to reduce tuberculosis morbidity and mortality. In 1974, BCG vaccination was included in the Expanded Program on Immunization. Today, it covers 80% of all children around the globe. Unfortunately, BCG vaccine provides no protection against pulmonary tuberculosis, the most prevalent form of tuberculosis. It is necessary to urgently develop new vaccination strategies to stop large-scale dissemination of infection caused by the multidrugresistant pathogen. The study was aimed to compare the capabilities of three variants of mRNA vaccines encoding Esat6 epitopes of stimulating adaptive immune response formation in C57BL/6 mice (ELISpot, delayed hypersensitivity, IgG titers), as well as of protecting I/St mice against M. tuberculosis infection. Efficacy of mRNA vaccines comprising different untranslated regions packaged in lipid nanoparticles was compared with that of BCG vaccine. The 5'-TPL-Esat6-3'-Mod vaccine demonstrated the highest efficacy in our experimental model. Thus, the 5'-TPL-Esat6-3'-Mod mRNA vaccine can be considered as a candidate vaccine for further optimization, improving efficacy and subsequent use for prevention of tuberculosis.

Keywords: tuberculosis, BCG, mRNA vaccine, adaptive immune response