EPIDEMIC INFLUENZA VIRUS NUCLEOPROTEIN GENE INCORPORATED INTO VACCINE INFLUENZA VIRUS STRAIN GENOME TO OPTIMIZE SYSTEMIC AND LOCAL T-CELL IMMUNE RESPONSE AGAINST LIVE ATTENUATED INFLUENZA VACCINE



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Introduction: Optimization of the vaccine-induced T-cell repertoire is one of the strategies to expand the spectrum of protective potential for live attenuated influenza vaccine (LAIV). LAIV cross-protective properties can be improved by introducing the nucleoprotein (NP) gene derived from epidemic parental virus into vaccine strain genome, i.e. by replacing the classical 6:2 genome formula with 5:3. The main objective of the present study was to detail evaluation for virus-specific systemic and tissue-resident memory T-cells subsets in mice immunized with seasonal H1N1 LAIV of the genome formula 6:2 and 5:3. Materials and Methods: Two H1N1 LAIV strains with varying NP genes (LAIV 6:2 and LAIV 5:3) were generated using reverse genetics techniques. C57BL/6J mice were immunized intranasally with the vaccine candidates, twice, 3 weeks apart. Cells from the spleen and lung tissues were isolated 7 days after booster immunization to be stimulated with whole H1N1 influenza virus for assessing cytokine-producing memory CD44+CD62L- T-cells as well as expression of CD69 and CD103 surface markers using flow cytometry. Humoral murine serum immunity against H1N1 virus was assessed by ELISA. Results: The LAIV 5:3 vs. classical 6:2 vaccine strain carrying the epidemic parental NP gene induced significantly more pronounced humoral immune response against recent influenza virus. The group of mice immunized with LAIV 5:3 demonstrated higher levels of virus-specific CD4+ and CD8+ effector memory T cells (TEM) in the spleen, including a subset of polyfunctional (IFNγ+TNFα+IL-2+) CD4+ TEM, compared to LAIV 6:2 group. Virus-specific memory T cell levels in lung tissues after immunization with LAIV 5:3 vs. LAIV 6:2 also tended to increase, but no significant difference in stimulated tissue-resident CD69+CD103- and CD69+CD103+ T cells between the groups were found. Conclusion: Modification of the seasonal LAIV strain genome for updating its epitope composition allowed to enhance the virus-specific T-cell immune response both at systemic level and in lung tissues, thereby shoeing that the effectiveness of the vaccine against circulating influenza viruses can be potentially increased.

About the authors

Polina I. Prokopenko

Department of Virology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

Email: pi.prokopenko@gmail.com

junior researcher, Department of Virology

Russian Federation

Ekaterina A. Stepanova

Department of Virology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

Email: stepanova.ea@iemspb.ru

PhD, leading researcher

Russian Federation

Victoria A. Matyushenko

Department of Virology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

Email: matyshenko@iemspb.ru

researcher

Russian Federation

Anna K. Chistyakova

Department of Virology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

Email: anna.k.chistiakova@gmail.com

research assistant

Russian Federation

Arina D. Kostromitina

Department of Virology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

Email: arina8goshina@gmail.com

research assistant, PhD student

Russian Federation

Tatiana S. Kotomina

Department of Virology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

Email: kotomina@iemspb.ru

researcher

Russian Federation

Alexandra Y. Rak

Department of Virology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

Email: rak.ay@iemspb.ru

PhD, senior researcher

Russian Federation

Artem A. Rubinstein

Department of Immunology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

Email: arrubin6@mail.ru

junior researcher

Russian Federation

Igor V. Kudryavtsev

Department of Immunology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

Email: kudryavtsev.iv@iemspb.ru

assistant professor, head of the laboratory of cellular immunology

Russian Federation

Vlada V. Novitskaya

Department of Virology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

Email: novitskaya.vv@iemspb.ru

research assistant, PhD student

Russian Federation

Larisa G. Rudenko

Department of Virology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

Email: rudenko.lg@iemspb.ru

Doctor of Medical Sciences, professor, head of the virology department

Russian Federation

Irina N. Isakova-Sivak

Отдел вирусологии им. А.А. Смородинцева ФГБНУ «ИЭМ», Санкт-Петербург, ул. Акад. Павлова, д.12.

Author for correspondence.
Email: isakova.sivak@iemspb.ru

Doctor of Biological Sciences, corresponding member of the Russian Academy of Sciences, head of the laboratory of immunology and prevention of viral infections

Russian Federation, Department of Virology, Institute of Experimental Medicine, Saint-Petersburg 12, Acad. Pavlov Street.

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Copyright (c) Prokopenko P.I., Stepanova E.A., Matyushenko V.A., Chistyakova A.K., Kostromitina A.D., Kotomina T.S., Rak A.Y., Rubinstein A.A., Kudryavtsev I.V., Novitskaya V.V., Rudenko L.G., Isakova-Sivak I.N.

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