RESUMO
INTRODUCTION: The WHO regularly updates influenza vaccine recommendations to maximize their match with circulating strains. Nevertheless, the effectiveness of the influenza A vaccine, specifically its H3N2 component, has been low for several seasons. The aim of the study is to develop a mathematical model of cross-immunity based on the array of published WHO hemagglutination inhibition assay (HAI) data. MATERIALS AND METHODS: In this study, a mathematical model was proposed, based on finding, using regression analysis, the dependence of HAI titers on substitutions in antigenic sites of sequences. The computer program we developed can process data (GISAID, NCBI, etc.) and create real-time databases according to the set tasks. RESULTS: Based on our research, an additional antigenic site F was identified. The difference in 1.6 times the adjusted R2, on subsets of viruses grown in cell culture and grown in chicken embryos, demonstrates the validity of our decision to divide the original data array by passage histories. We have introduced the concept of a degree of homology between two arbitrary strains, which takes the value of a function depending on the Hamming distance, and it has been shown that the regression results significantly depend on the choice of function. The provided analysis showed that the most significant antigenic sites are A, B, and E. The obtained results on predicted HAI titers showed a good enough result, comparable to similar work by our colleagues. CONCLUSION: The proposed method could serve as a useful tool for future forecasts, with further study to confirm its sustainability.
Assuntos
Vacinas contra Influenza , Influenza Humana , Embrião de Galinha , Animais , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Vacinas contra Influenza/genética , Antígenos Virais/genética , Epitopos , Modelos Teóricos , Influenza Humana/epidemiologia , Influenza Humana/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Estações do AnoRESUMO
Mutations arising in influenza viruses that have undergone immune pressure may promote a successful spread of mutants in nature. In order to evaluate the variability of nonpathogenic influenza virus A/duck/Moscow/4182-C/2010(H5N3) and to determine the common epitopes between it and highly pathogenic H5N1 avian influenza viruses (HPAIV), a set of escape mutants was selected due to action of MABs specific against A/chicken/Pennsylvania/8125/83(H5N2), A/Vietnam/1203/04(H5N1) and A/duck/Novosibirsk/56/05(H5N1) viruses. The complete genomes of escape mutants were sequenced and amino acid point mutations were determined in HA, NA, PA, PB1, PB2, M1, M2, and NP proteins. Comprehensive analysis of the acquired mutations was performed using the Influenza Research Database (https://www.fludb.org) and revealed that all mutations were located inside short linear epitopes, in positions characterized by polymorphisms. Most of the mutations found were characterized as substitutions by predominant or alternative amino acids existing in nature. Antigenic changes depended only on substitutions at positions 126, 129, 131, 145 and 156 of HA (H3 numbering). The positions 126, 145 and 156 were common for HA/H5 of different phylogenetic lineages of H5N1 HPAIV (arisen from A/goose/Guangdong/1/96) and low pathogenic American and Eurasian viruses. Additionally, mutation S145P increased the temperature of HA heat inactivation, compared to wild-type, as was proved by reverse genetics. Moreover, nonpathogenic A/duck/Moscow/4182-C/2010(H5N3) and H5N1 HPAI viruses have the same structure of short linear epitopes in HA (145-157) and internal proteins (PB2: 186-200, 406-411; PB1: 135-143, 538-546; PA: 515-523; NP: 61-68; M1: 76-84; M2: 45-53). These facts may indicate that H5 wild duck nonpathogenic virus could be used as vaccine against H5N1 HPAIV. Keywords: avian influenza virus; H5 hemagglutinin; escape mutants; genetic analysis; phenotypic properties; site-specific mutagenesis.
Assuntos
Vírus da Influenza A/classificação , Vírus da Influenza A/imunologia , Neuraminidase/genética , Filogenia , Proteínas Virais/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/imunologia , Vírus da Influenza A Subtipo H5N2 , MutaçãoRESUMO
The influenza A virus remains one of the most common and dangerous human health concerns due to its rapid evolutionary dynamics. Since the evolutionary changes of influenza A viruses can be traced in real time, the last decade has seen a surge in research on influenza A viruses due to an increase in experimental data (selection of escape mutants followed by examination of their phenotypic characteristics and generation of viruses with desired mutations using reverse genetics). Moreover, the advances in our understanding are also attributable to the development of new computational methods based on a phylogenetic analysis of influenza virus strains and mathematical (integro-differential equations, statistical methods, probability-theory-based methods) and simulation modeling. Continuously evolving highly pathogenic influenza A viruses are a serious health concern which necessitates a coupling of theoretical and experimental approaches to predict the evolutionary trends of the influenza A virus, with a focus on the H5 subtype.
