Publications by authors named "Alla Mironenko"

9 Publications

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Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial.

medRxiv 2021 Jan 12. Epub 2021 Jan 12.

Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called Coronavirus Disease 2019 (COVID-19). Control of SARS-CoV-2 spread will depend on vaccine-induced or naturally acquired protective herd immunity. Until then, antiviral strategies are needed to manage COVID-19, but approved antiviral treatments, such as remdesivir, can only be delivered intravenously. Enisamium (laboratory code FAV00A, trade name Amizon®) is an orally active inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. Here we show that enisamium can inhibit SARS-CoV-2 infections in NHBE and Caco-2 cells. , the previously identified enisamium metabolite VR17-04 directly inhibits the activity of the SARS-CoV-2 RNA polymerase. Docking and molecular dynamics simulations suggest that VR17-04 prevents GTP and UTP incorporation. To confirm enisamium's antiviral properties, we conducted a double-blind, randomized, placebo-controlled trial in adult, hospitalized COVID-19 patients, which needed medical care either with or without supplementary oxygen. Patients received either enisamium (500 mg per dose) or placebo for 7 days. A pre-planned interim analysis showed in the subgroup of patients needing supplementary oxygen (n = 77) in the enisamium group a mean recovery time of 11.1 days, compared to 13.9 days for the placebo group (log-rank test; p=0.0259). No significant difference was found for all patients (n = 373) or those only needing medical care (n = 296). These results thus suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis and that enisamium treatment shortens the time to recovery for COVID-19 patients needing oxygen.

Significance Statement: SARS-CoV-2 is the causative agent of COVID-19. Although vaccines are now becoming available to prevent SARS-CoV-2 spread, the development of antivirals remains necessary for treating current COVID-19 patients and combating future coronavirus outbreaks. Here, we report that enisamium, which can be administered orally, can prevent SARS-CoV-2 replication and that its metabolite VR17-04 can inhibit the SARS-CoV-2 RNA polymerase . Moreover, we find that COVID-19 patients requiring supplementary oxygen, recover more quickly than patients treated with a placebo. Enisamium may therefore be an accessible treatment for COVID-19 patients.
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http://dx.doi.org/10.1101/2021.01.05.21249237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814846PMC
January 2021

Antigenic Site Variation in the Hemagglutinin of Pandemic Influenza A(H1N1)pdm09 Viruses between 2009-2017 in Ukraine.

Pathogens 2019 Oct 18;8(4). Epub 2019 Oct 18.

"Gromashevsky L.V. Institute of epidemiology and infectious diseases, National Academy of Medical Sciences of Ukraine" 03680 Kyiv, Ukraine.

The hemagglutinin (HA) is a major influenza virus antigen, which, once recognized by antibodies and substitutions in HA genes, helps virus in escaping the human immune response. It is therefore critical to perform genetic and phylogenetic analysis of HA in circulating influenza viruses. We performed phylogenetic and genetic analysis of isolates from Ukraine, the vaccine strain and reference strains were used to phylogenetically identify trends in mutation locations and substitutions. Ukrainian isolates were collected between 2009-2017 and clustered in the influenza genetic groups 2, 6, 7, and 8. Genetic changes were observed in each of the antigenic sites: Sa - S162T, K163Q, K163I; Sb - S185T, A186T, S190G, S190R; Ca1 - S203T, R205K, E235V, E235D, S236P; Ca2 - P137H, H138R, A141T, D222G, D222N; Cb - A73S, S74R, S74N. In spite of detected mutations in antigenic sites, Ukrainian isolates retained similarity to the vaccine strain A/California/07/09 circulated during 2009-2017. However, WHO recommended a new vaccine strain A/Michigan/45/2015 for the Southern Hemisphere after the emergence of the new genetic groups 6B.1 and 6B.2. Our study demonstrated genetic variability of HA protein of A(H1N1)pdm09 viruses isolated in 2009-2017 in Ukraine. Influenza surveillance is very important for understanding epidemiological situations.
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http://dx.doi.org/10.3390/pathogens8040194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963832PMC
October 2019

The epidemiological signature of influenza B virus and its B/Victoria and B/Yamagata lineages in the 21st century.

PLoS One 2019 12;14(9):e0222381. Epub 2019 Sep 12.

Netherlands Institute for Health Services Research (Nivel), Utrecht, The Netherlands.

We describe the epidemiological characteristics, pattern of circulation, and geographical distribution of influenza B viruses and its lineages using data from the Global Influenza B Study. We included over 1.8 million influenza cases occurred in thirty-one countries during 2000-2018. We calculated the proportion of cases caused by influenza B and its lineages; determined the timing of influenza A and B epidemics; compared the age distribution of B/Victoria and B/Yamagata cases; and evaluated the frequency of lineage-level mismatch for the trivalent vaccine. The median proportion of influenza cases caused by influenza B virus was 23.4%, with a tendency (borderline statistical significance, p = 0.060) to be higher in tropical vs. temperate countries. Influenza B was the dominant virus type in about one every seven seasons. In temperate countries, influenza B epidemics occurred on average three weeks later than influenza A epidemics; no consistent pattern emerged in the tropics. The two B lineages caused a comparable proportion of influenza B cases globally, however the B/Yamagata was more frequent in temperate countries, and the B/Victoria in the tropics (p = 0.048). B/Yamagata patients were significantly older than B/Victoria patients in almost all countries. A lineage-level vaccine mismatch was observed in over 40% of seasons in temperate countries and in 30% of seasons in the tropics. The type B virus caused a substantial proportion of influenza infections globally in the 21st century, and its two virus lineages differed in terms of age and geographical distribution of patients. These findings will help inform health policy decisions aiming to reduce disease burden associated with seasonal influenza.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222381PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742362PMC
March 2020

Distribution of influenza virus types by age using case-based global surveillance data from twenty-nine countries, 1999-2014.

BMC Infect Dis 2018 06 8;18(1):269. Epub 2018 Jun 8.

Netherlands Institute for Health Services Research (NIVEL), Otterstraat 118-124, 3513, CR, Utrecht, The Netherlands.

Background: Influenza disease burden varies by age and this has important public health implications. We compared the proportional distribution of different influenza virus types within age strata using surveillance data from twenty-nine countries during 1999-2014 (N=358,796 influenza cases).

Methods: For each virus, we calculated a Relative Illness Ratio (defined as the ratio of the percentage of cases in an age group to the percentage of the country population in the same age group) for young children (0-4 years), older children (5-17 years), young adults (18-39 years), older adults (40-64 years), and the elderly (65+ years). We used random-effects meta-analysis models to obtain summary relative illness ratios (sRIRs), and conducted meta-regression and sub-group analyses to explore causes of between-estimates heterogeneity.

Results: The influenza virus with highest sRIR was A(H1N1) for young children, B for older children, A(H1N1)pdm2009 for adults, and (A(H3N2) for the elderly. As expected, considering the diverse nature of the national surveillance datasets included in our analysis, between-estimates heterogeneity was high (I>90%) for most sRIRs. The variations of countries' geographic, demographic and economic characteristics and the proportion of outpatients among reported influenza cases explained only part of the heterogeneity, suggesting that multiple factors were at play.

Conclusions: These results highlight the importance of presenting burden of disease estimates by age group and virus (sub)type.
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http://dx.doi.org/10.1186/s12879-018-3181-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994061PMC
June 2018

Rapid risk assessment during the early weeks of the 2015-2016 influenza season in Ukraine.

Influenza Other Respir Viruses 2018 03 15;12(2):241-249. Epub 2018 Jan 15.

Ukrainian Centre for Disease Control and Monitoring of the Ministry of Health of Ukraine, Kyiv, Ukraine.

Background: Several eastern European countries reported a severe influenza season to the World Health Organization (WHO) during late 2015. A country-specific rapid risk assessment for Ukraine was conducted to assess the season's severity and inform public health action.

Methods: The exposure and hazard were assessed using acute respiratory infection (ARI), severe acute respiratory infection (SARI), laboratory surveillance, virological and vaccine data from weeks 40/2015 to 7/2016 with comparison to 4 previous seasons to describe the influenza season start (5-week consecutive increase in ARI or SARI), predominant virus types, geographical spread and affected age groups.

Results: The exposure was characterised by an earlier and steeper increase in SARI (week 1/2016) and ARI (week 2/2016) compared to the previous 4 seasons. Transmission was across Ukraine with an increase in ARI and SARI cases aged 30-64 years compared to 2014/15. Laboratory-confirmed deaths increased from 11 in 2014/2015 to 342 in 2015/2016; the majority were 30-64 years old and unvaccinated; and 63.5% had underlying conditions. Total population vaccination coverage was 0.3%. The hazard assessment found influenza virus A(H1N1)pdm09 accounted for >95% of viruses detected. Ukrainian virus strains (n = 62) were antigenically similar to vaccine strains and susceptible to neuraminidase inhibitors.

Conclusions: The first weeks of the 2015/16 influenza season were more severe than previous seasons, with an earlier and steeper increase in severe cases and deaths, particularly in younger adults. Influenza A(H1N1)pdm09 was the predominant strain and was closely related to the seasonal vaccine strain with no evidence of resistance to antiviral drugs.
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http://dx.doi.org/10.1111/irv.12526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820420PMC
March 2018

Temporal Patterns of Influenza A and B in Tropical and Temperate Countries: What Are the Lessons for Influenza Vaccination?

PLoS One 2016 31;11(3):e0152310. Epub 2016 Mar 31.

Netherlands Institute for Health Services Research (NIVEL), Utrecht, The Netherlands.

Introduction: Determining the optimal time to vaccinate is important for influenza vaccination programmes. Here, we assessed the temporal characteristics of influenza epidemics in the Northern and Southern hemispheres and in the tropics, and discuss their implications for vaccination programmes.

Methods: This was a retrospective analysis of surveillance data between 2000 and 2014 from the Global Influenza B Study database. The seasonal peak of influenza was defined as the week with the most reported cases (overall, A, and B) in the season. The duration of seasonal activity was assessed using the maximum proportion of influenza cases during three consecutive months and the minimum number of months with ≥80% of cases in the season. We also assessed whether co-circulation of A and B virus types affected the duration of influenza epidemics.

Results: 212 influenza seasons and 571,907 cases were included from 30 countries. In tropical countries, the seasonal influenza activity lasted longer and the peaks of influenza A and B coincided less frequently than in temperate countries. Temporal characteristics of influenza epidemics were heterogeneous in the tropics, with distinct seasonal epidemics observed only in some countries. Seasons with co-circulation of influenza A and B were longer than influenza A seasons, especially in the tropics.

Discussion: Our findings show that influenza seasonality is less well defined in the tropics than in temperate regions. This has important implications for vaccination programmes in these countries. High-quality influenza surveillance systems are needed in the tropics to enable decisions about when to vaccinate.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152310PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816507PMC
August 2016

Cerium dioxide nanoparticles increase immunogenicity of the influenza vaccine.

Antiviral Res 2016 Mar 6;127:1-9. Epub 2016 Jan 6.

Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences, Moscow 119991, Russia; National Research Tomsk State University, Tomsk 634050, Russia. Electronic address:

We have demonstrated the influence of cerium dioxide nanoparticles on the immunogenicity of the influenza vaccine on an example of liquid split inactivated Vaxigrip vaccine. Antibody titers were analyzed using the hemagglutination inhibition (HI) assay. Seroprotection, seroconversion, the geometric mean titers (GMTs) and the factor increase (FI) in the GMTs were calculated. The effect of nano-ceria surface stabilizer on the enhancement of immunogenicity was shown. The vaccine modified by citrate-stabilized nano-ceria, in contrast to a non-modified Vaxigrip vaccine, did not provide an adequate level of seroprotection, and seroconversion after vaccination was 66.7% on days 49-63 for virus strain А(H1N1) and 100% on day 49 for virus strain B/Yamagata. For the low immunogenic influenza B virus, the rise in antibody titers (GMT/IF) was 24.38/3.28 after the first injection and 50.40/6.79 on day 49. For the vaccine modified by non-stabilized nano-ceria, for all virus strains under study, on day 63, upon immunization notable levels of seroprotection, seroconversion and GMT/IF were registered (higher than for the non-modified Vaxigrip vaccine). The successful attempt to modify the influenza vaccine demonstrates the possible ways of increasing the specific activity of vaccines using nano-ceria.
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http://dx.doi.org/10.1016/j.antiviral.2015.12.013DOI Listing
March 2016

Epidemiological and virological characteristics of influenza B: results of the Global Influenza B Study.

Influenza Other Respir Viruses 2015 Aug;9 Suppl 1:3-12

Netherlands Institute for Health Services Research (NIVEL), Utrecht, The Netherlands.

Introduction: Literature on influenza focuses on influenza A, despite influenza B having a large public health impact. The Global Influenza B Study aims to collect information on global epidemiology and burden of disease of influenza B since 2000.

Methods: Twenty-six countries in the Southern (n = 5) and Northern (n = 7) hemispheres and intertropical belt (n = 14) provided virological and epidemiological data. We calculated the proportion of influenza cases due to type B and Victoria and Yamagata lineages in each country and season; tested the correlation between proportion of influenza B and maximum weekly influenza-like illness (ILI) rate during the same season; determined the frequency of vaccine mismatches; and described the age distribution of cases by virus type.

Results: The database included 935 673 influenza cases (2000-2013). Overall median proportion of influenza B was 22·6%, with no statistically significant differences across seasons. During seasons where influenza B was dominant or co-circulated (>20% of total detections), Victoria and Yamagata lineages predominated during 64% and 36% of seasons, respectively, and a vaccine mismatch was observed in ≈25% of seasons. Proportion of influenza B was inversely correlated with maximum ILI rate in the same season in the Northern and (with borderline significance) Southern hemispheres. Patients infected with influenza B were usually younger (5-17 years) than patients infected with influenza A.

Conclusion: Influenza B is a common disease with some epidemiological differences from influenza A. This should be considered when optimizing control/prevention strategies in different regions and reducing the global burden of disease due to influenza.
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http://dx.doi.org/10.1111/irv.12319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549097PMC
August 2015

Strengthening the influenza vaccine virus selection and development process: Report of the 3rd WHO Informal Consultation for Improving Influenza Vaccine Virus Selection held at WHO headquarters, Geneva, Switzerland, 1-3 April 2014.

Vaccine 2015 Aug 3;33(36):4368-82. Epub 2015 Jul 3.

National Influenza Center, Helsinki, Finland.

Despite long-recognized challenges and constraints associated with their updating and manufacture, influenza vaccines remain at the heart of public health preparedness and response efforts against both seasonal and potentially pandemic influenza viruses. Globally coordinated virological and epidemiological surveillance is the foundation of the influenza vaccine virus selection and development process. Although national influenza surveillance and reporting capabilities are being strengthened and expanded, sustaining and building upon recent gains has become a major challenge. Strengthening the vaccine virus selection process additionally requires the continuation of initiatives to improve the timeliness and representativeness of influenza viruses shared by countries for detailed analysis by the WHO Global Influenza Surveillance and Response System (GISRS). Efforts are also continuing at the national, regional, and global levels to better understand the dynamics of influenza transmission in both temperate and tropical regions. Improved understanding of the degree of influenza seasonality in tropical countries of the world should allow for the strengthening of national vaccination policies and use of the most appropriate available vaccines. There remain a number of limitations and difficulties associated with the use of HAI assays for the antigenic characterization and selection of influenza vaccine viruses by WHOCCs. Current approaches to improving the situation include the more-optimal use of HAI and other assays; improved understanding of the data produced by neutralization assays; and increased standardization of serological testing methods. A number of new technologies and associated tools have the potential to revolutionize influenza surveillance and response activities. These include the increasingly routine use of whole genome next-generation sequencing and other high-throughput approaches. Such approaches could not only become key elements in outbreak investigations but could drive a new surveillance paradigm. However, despite the advances made, significant challenges will need to be addressed before next-generation technologies become routine, particularly in low-resource settings. Emerging approaches and techniques such as synthetic genomics, systems genetics, systems biology and mathematical modelling are capable of generating potentially huge volumes of highly complex and diverse datasets. Harnessing the currently theoretical benefits of such bioinformatics ("big data") concepts for the influenza vaccine virus selection and development process will depend upon further advances in data generation, integration, analysis and dissemination. Over the last decade, growing awareness of influenza as an important global public health issue has been coupled to ever-increasing demands from the global community for more-equitable access to effective and affordable influenza vaccines. The current influenza vaccine landscape continues to be dominated by egg-based inactivated and live attenuated vaccines, with a small number of cell-based and recombinant vaccines. Successfully completing each step in the annual influenza vaccine manufacturing cycle will continue to rely upon timely and regular communication between the WHO GISRS, manufacturers and regulatory authorities. While the pipeline of influenza vaccines appears to be moving towards a variety of niche products in the near term, it is apparent that the ultimate aim remains the development of effective "universal" influenza vaccines that offer longer-lasting immunity against a broad range of influenza A subtypes.
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http://dx.doi.org/10.1016/j.vaccine.2015.06.090DOI Listing
August 2015