New conjugates based on N4-hydroxycytidine with more potent antiviral efficacy in vitro than EIDD-2801 against SARS-CoV-2 and other human coronaviruses

Siniavin, Andrei E.; Gushchin, Vladimir A.; Shastina, Natal'ya S.; Darnotuk, Elizaveta S.; Luyksaar, Sergey I.; Russu, Leonid I.; Inshakova, Anna M.; Shidlovskaya, Elena V.; Vasina, Daria V.; Kuznetsova, Nadezhda A.; Savina, Daria M.; Zorkov, Ilya D.; Dolzhikova, Inna V.; Sheremet, Anna B.; Logunov, Denis Y.; Zigangirova, Nailya A.; Gintsburg, Alexander L.

doi:10.1016/j.antiviral.2024.105871

Antiviral Research

2024

DOI: 10.1016/j.antiviral.2024.105871

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New conjugates based on N4-hydroxycytidine with more potent antiviral efficacy in vitro than EIDD-2801 against SARS-CoV-2 and other human coronaviruses

Andrei E. Siniavin,

Vladimir A. Gushchin,

Natal'ya S. Shastina

et al.

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2024

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Cited by 2 publications

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The Antigen‐Specific Response of NK Cells to SARS‐CoV‐2 Correlates With KIR2DS4 Expression

Ustiuzhanina,

Boyko,

Vavilova

et al. 2024

Journal of Medical Virology

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Natural killer (NK) cells play a pivotal role in the immune response against viral infections, including SARS‐CoV‐2. However, our understanding of memory NK cell responses in the context of SARS‐CoV‐2 remains limited. To address this, we investigated the memory‐like response of NK cells to SARS‐CoV‐2 peptides, presented by autologous cells. Blood samples from 45 donors underwent analysis for SARS‐CoV‐2 IgG antibodies, categorizing them into four groups based on the antibody kind and level. NK cells from SARS‐CoV‐2‐experienced donors demonstrated enhanced degranulation and activation levels, IFNγ production and proliferative potential in response to SARS‐CoV‐2 peptides. Investigation of highly proliferating NK cells demonstrated the formation of distinct clusters depending on the SARS‐CoV‐2 peptide supplementation and the donor group. RNA sequencing revealed differential gene expression patterns, highlighting metabolism, protein transport, and immune response genes. Notably, KIR2DS4 expression correlated with enhanced IFNγ production, degranulation and proliferation levels, suggesting a role in SARS‐CoV‐2 recognition. Collectively, these findings provide detailed insights into antigen‐specific NK cell responses to SARS‐CoV‐2 peptides, indicating potential mechanisms underlying NK cell activation in antiviral immunity.

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The Antigen‐Specific Response of NK Cells to SARS‐CoV‐2 Correlates With KIR2DS4 Expression

Ustiuzhanina,

Boyko,

Vavilova

et al. 2024

Journal of Medical Virology

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Immunogenicity and Efficacy of Combined mRNA Vaccine Against Influenza and SARS-CoV-2 in Mice Animal Models

Mazunina,

Gushchin,

Bykonia

et al. 2024

Vaccines

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Background. The combined or multivalent vaccines are actively used in pediatric practice and offer a series of advantages, including a reduced number of injections and visits to the doctor, simplicity of the vaccination schedule and minimization of side effects, easier vaccine monitoring and storage, and lower vaccination costs. The practice of widespread use of the combined vaccines has shown the potential to increase vaccination coverage against single infections. The mRNA platform has been shown to be effective against the COVID-19 pandemic and enables the development of combined vaccines. There are currently no mRNA-based combined vaccines approved for use in humans. Some studies have shown that different mRNA components in a vaccine can interact to increase or decrease the immunogenicity and efficacy of the combined vaccine. Objectives. In the present study, we investigated the possibility of combining the mRNA vaccines, encoding seasonal influenza and SARS-CoV-2 antigens. In our previous works, both vaccine candidates have shown excellent immunogenicity and efficacy profiles in mice. Methods. The mRNA-LNPs were prepared by microfluidic mixing, immunogenicity in mice was assessed by hemagglutination inhibition assay, enzyme-linked immunoassay and virus neutralization assay. Immunological efficacy was assessed in a mouse viral challenge model. Results. In this work, we demonstrated that the individual mRNA components of the combined vaccine did not affect the immunogenicity level of each other. The combined vaccine demonstrated excellent protective efficacy, providing a 100% survival rate when mice were infected with the H1N1 influenza virus and reducing the viral load in the lungs. Four days after the challenge with SARS-CoV-2 EG.5.1.1., no viable virus and low levels of detectable viral RNA were observed in the lungs of vaccinated mice. Conclusions. The combination does not lead to mutual interference between the individual vaccines. We believe that such a combined mRNA-based vaccine could be a good alternative to separated human vaccinations for the prevention of COVID-19 and influenza.

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New conjugates based on N4-hydroxycytidine with more potent antiviral efficacy in vitro than EIDD-2801 against SARS-CoV-2 and other human coronaviruses

Cited by 2 publications

References 72 publications

The Antigen‐Specific Response of NK Cells to SARS‐CoV‐2 Correlates With KIR2DS4 Expression

The Antigen‐Specific Response of NK Cells to SARS‐CoV‐2 Correlates With KIR2DS4 Expression

Immunogenicity and Efficacy of Combined mRNA Vaccine Against Influenza and SARS-CoV-2 in Mice Animal Models

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