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The article discusses the limitations of the protective potential of the immune system associated with the peculiarities of the evolutionary mechanisms of the emergence of protein diversity and the late emergence in the evolution of the adaptive immune system, as well as problems associated with the formation of immunity to viral infections and immune collisions during vaccination. Using the example of hemagglutinin of the H1N1 influenza virus and S protein of the SARS-Cov-2 coronavirus, the features of the amino acid composition of their immunodominant (NA1 and S1) and subdominant (NA2 and S2) subunits are illustrated and the possibility of creating a universal vaccine against influenza viruses is analyzed. The principle of a new method for detecting linear peptide immunoepitopes recognized by MHC I and II and biomarkers of long-term immunity in surface viral proteins used as vaccines is described. The model of proteolysis of vaccine proteins in immunoprotesomes and lysosomes, features of the amino acid composition of surface proteins of viruses to which vaccines cause long-term immunity, and viruses to which vaccines have not yet been developed, as well as possible collisions with mRNA vaccines are examined. Possible collisions with mRNA vaccines are also being considered in connection with the identification of gene encoding limitations.

The article discusses the residual effects of survivors of COVID-19, referred to as long-term covid, a short list of their manifestations, their possible causes and difficulties of recognition. Changes in the primary structure of emerging coronaviruses from the Wuhan strain to new omicron strains are analyzed. Among the features of their evolution, there is an increase in the content of arginine and lysine, especially in the S1 subunit, and a decrease in the proportion of aspartic and glutamic amino acids. The receptorbinding domain of omicrons is characterized by a tendency to decrease the content of threonine, serine and glutamine. Mutations in the S protein are characterized by asymmetry in relation to both substitutable and substitutive amino acids. Isoleucine and cysteine are not replaced. Certain trends and limitations in the mutations of their S protein and especially the unusual ratio transversion: transitions in them argue for the version of the artificial origin of the SARS-Cov-2 variants. At the level of the S protein genes, there are prohibitions regarding the use of certain codons. To assess the effectiveness of vaccines and the sensitivity of coronaviruses to them during a pandemic, it is useful to divide pandemic coronaviruses into two groups: omicrons and pre-omicrons. This division is justified by the fact that these groups differ sharply in the number of mutations and changes in the composition of immune epitopes, especially in the receptor-binding domain. The specific tendency of changes in its amino acid composition, apparently, is associated with a consistent decrease in pathogenicity in BA.1, BA.2, BA.4 and BA.5 variants. Taking into account these features makes it possible to predict the sensitivity of coronavirus strains to the vaccines used and rationally design vaccines with a wide range of specificity.

The article discusses the properties of the pandemic strain XBB.1.5 S protein in comparison with the 1918 and 2009 pandemic strains hemagglutinin H1. The S-protein XBB.1.5 already contains more than 40 mutations realized by substituting different amino acids through single and dinucleotide substitutions, deletions and the use of predominantly transversions. The variability of H1N1 influenza virus hemagglutinin is associated with single nucleotide substitutions at a constant length. Conditional extrapolation of influenza virus hemagglutinin variability data on coronavirus S-protein sizes suggests that new pandemic strains will emerge in the next 2-3 years, avoiding the immune defense formed by vaccination against the strains preceding them. The inability to create through the adaptive immune system a long-term immunity to pandemic coronaviruses, as well as to other respiratory viruses with a short incubation cycle, puts on the agenda the need to find new vaccine designs that provide a combination of long-term adaptive and trained immunity. The problem in the search for such vaccines is associated with the regulation of the activity of the innate immune system and ensuring the stability of trained immunity.

Relevance of searching for computer methods with high efficiency of immunoepitopes recognition and predicting the longevity of the immunity they induce is determined primarily by the need to quickly create vaccines against newly emerging infections, especially during pandemic periods. Aim. To develop a new immunoinformation method for recognizing immunoepitopes, to identify in the viral proteins possible potential markers to induce long-term immunity and to evaluate by them the vaccines against Covid-19. Materials and methods. For computer analysis, an Internet-accessible databases of immunoep topes 15 and 9 amino acids long, restricted respectively by MHC I and MHC II, and peptides not binding to MHC, as well as human and virus proteins, were used. The algorithm for discriminating immunoepitopes was based on positional distinction of specific short peptides in their primary structures. Results. The «inventory» in the training samples of di- and tripeptides or pentapeptides of immunoepitopes and nonimmunoepitopes makes it possible to accurately recognize in the control samples up to 93–97% of immunoepitopes restricted by MHC I and MHC II. Comparison of the amino acid composition of proteins of subunit vaccines causing long-term immunity revealed dominance of amino acids (especially proline), which form the basis of internally disorganized regions, and proline-containing dipeptides, that allowed them to be considered as biomarkers of the potential of a viral protein to form a long-term immune memory.In the S-protein of coronavirus SARS-CoV-2 two candidates for immunospressive domains are present and the dominance of proline and dipeptides containing it is absent. Conclusion. The immunoepitope recognition method and the biomarker for inducing longterm immune memory can be used as immunoinformative tools of computational vaccinology. Providing long-term immunity by vaccines based on the coronavirus SARS-CoV-2 protein S is unlikely.

Relevance. Coronaviruses and influenza viruses induce pandemics taking away many human lives and seeding social-economic chaos. Possibility to prognose pandemic features on characteristics of surface proteins of their pathogens is not investigated.Aim is to characterize the common features of the pandemic coronavirus S-protein and the pandemic virus influenza hemagglutinin in connection with the features of a coronavirus pandemic and influenza pandemics.Materials and method. For the bioinformatic analysis the protein sequences of pandemic coronavirus strains and pandemic influenza virus strains, influenza virus strains of 2017–2018 season and also influenza virus type B strains were used. In proteins an amino acid content, the sums of the charged amino acids and the.Results. It was found out that the increase of amount of the amino acids forming intrinsically disordered regions in the coronavirus S-protein S1 subunit and influenza virus H1 hemagglutinin HA1 subunit is characteristic of the pandemics with high morbidity and the increase of arginine and lysine with comparison with aspartic and glutamic acids in those proteins is peculiar to viruses inducing the pandemics with lower lethality.Conclusion. The features (morbidity and lethality) of the coronavirus pandemic and influenza virus pandemic are associated with the quantitative amino acids content of pandemic virus surface proteins.

Relevance. Vaccines are regarded as an effective means for control of the Covid-19 pandemic spreading and their search, analysis, and comparison of their features are important for elucidating the most safe and effective one. Aim. At the end of 2020 two types of vaccines (viral based vaccines and mRNA vaccines) have been licensed to vaccinate. The aim is to compare their features for objective substantiation of their application. Conclusions. As both vaccine types have high effectiveness in inducing antibodies to SARS-Cov-2 (in more 90% recipients) the utility of each vaccine type in blocking the Covid-19 pandemic spreading is beyond doubt. In both vaccine types eventually S protein is the antigen source, and they have limitations for vaccination. In comparison with the vector vaccines mRNA vaccines may induce serious complications, have the least potential to induce trained immunity and can be included into the recipient’s genome. The low frequency of influenza cases in the current epidemic season serves as an of interference between SARS-Cov-2 and influenza viruses. In epidemic seasons after the Covid-19 pandemic coronaviruses may dominate amongst viruses inducing acute respiratory viruses diseases. It is likely that the decline of the Covid-19 case count (in December-January) in Russia is determined by the heterologous collective immunity formed earlier.

Relevance. The vaccine against the SARS-Cov-2 coronavirus is considered as the most promising approach to curb (tame) a current pandemic and prevent new one. Three vaccines (AstraZeneca’s СhAdOx1 nCov-19, CanSino’s vaccine and Russia’s Sputnik V one) are in Phase III clinical trials and have the S protein as immunogen but different adenovirus vectors. It is known adverse neurological events associated with the СhAdOx1 nCov-19 vacсine.Aim is to investigate the distribution of homologous sequences of adenovirus proteins in human nervous and immune systems proteins, estimate potential risks of using adenovirus vectors in vaccines and discuss possible mechanisms inducing immune damage in the nervous system.Materials and methods. For the computer analysis of peptide (immune epitope) relationship between adenovirus structural proteins and human proteins, the search of homologous sequences was made. All protein sequences were used from databases available on the INTERNET.Results. Among adenoviruses (НАд5, НАд26 , ChАдY25, and SAd3) ChАдY25 has the highest content of sequences homologous to human nervous system proteins that may be the cause of autoimmune complications in vaccination.Conclusion: In AstraZeneca’s СhAdOx1 nCov-19 vaccine there are a large number of peptide sequences homologous to human nervous system proteins and it allows to predict the possible risks with this vaccine.

Relevance. The vaccine against the SARS-Cov-2 coronavirus is considered as the most promising approach to curb (tame) a current pandemic and prevent new one. Among difficulties in vaccine creating is a right choice of immunodominant antigens providing the effectiveness and safety of vaccines. Aim is to show the usefulness of application of the global immune epitope continuum protein relationship concept in the search of vaccines against SARS-Cov-2 and discuss the possible nature of future pandemics. Materials and method. For the computer analysis of peptide (immune epitope) relationship amongst the SARS-Cov-2 structural proteins, human proteins and proteins of other viruses, the search of homologous sequences was made. All protein sequences sequences were used from databases available on the INTERNET. Results. In the SARS-Cov-2 structural proteins, especially in S-protein, there are a large number of peptide sequences homologous to human and viral proteins that may be the cause of autoimmune complications and/or heterologous immunity. Conclusion: The concept of the global immune epitope continuum of protein relationship is of value in the search of immune epitopes for the vaccines against SARS-Cov-2 and allows us to predict the possible risks in vaccines. The coronavirus breaks and pandemics may be more often than the influenza pandemics.

Relevance. Of the different subtypes, H3N2 influenza virus subtype has the highest variability and pathogenicity, often dominates in epidemiological seasons and induces high mortality exceeding its rate in pandemic. Aim is to identify some features of H3N2 molecular characteristics which could determine its high variability and domination over other subtypes in epidemiological seasons and discuss possible nature of the future influenza pandemic.Materials and method. For the computer analysis, the database of the hemagglutinin (HA) and nucleoprotein primary structures of the H3N2, H1N1, В\Yamagata and В\Victoria strains isolated in the influenza epidemiological seasons 2009-2019 were used from the Internet. From the primary structure of their genes it were defined their translational codes. To trace the H3N2 subtype evolution in the last decade we compared the H3 dominant sequences of adjacent seasons to establish their changes.Results. It has been indicated that H3, in comparison with H1 and В\Yamagata and В\Victoria hemagglutinins, contains more cysteine and the H3N2 strain very similar to the Hong Kong influenza virus continues to circulate in birds.The H3 gene translation code contains the least number of prohibitions. During last decade the H3 dominant sequence evolves faster than H1 one. The nucleoprotein of H3N2 strains is characterized by more content of lysine and less content of arginine.Conclusion: H3N2, H1N1, В\Yamagata and В\Victoria strains one may conclude that least of all the nature restricts H3N2 to evolve and adapt to new hosts. It is likely that the following influenza pandemic will be generated by H1N1 subtype but H3N2 one and also be more mild than the 2019 pandemic.

Relevance. The genetic recombination between viruses and men is known long ago. It can be divided on relict and ontogenic ones. For the host the recombination may display different consequences the nature of which is not exposed explicitly.Aim is to analyze (on the base of computer comparison of the primary structure of viral and human proteins ) the occurrence of twodirectional recombination by small genome fragments between viruses and men and describe its possible after-effects.Materials and methods. For this computer study human and virus protein sequences were used from data bases available in INTERNET.Results. It was indicated that recombination (cryptical and explicit) by small genome fragments between viruses and men occurred many times in the past and many viruses pathogenic for men were involved in it.Conclusion. The bioinformatics approach allows to look at the past of viruses and men and find the traces of genetic information changes between them that may predetermine the effects of vaccines and diagnostic immune tests.

Relevance.Upon the unquestionable utility of regular season vaccination influenza vaccine effectiveness varies depending on how vaccinal strains to be in accord with seasonal circulating influenza strains, i.e. the influenza vaccines are virtually strain-spesific and not able to elicit broad, protective immune responses. Aim is widening the scope of bioinformatics applications to show the possibility to construct H1 and H3 hemagglutinin structures that contain long identical invariant (conservative) sequences from various strains and can accordingly be used as a universal influenza vaccine at the level of strain subtypes for the future seasons and also to discuss possibilities and limitations in the search for the universal influenza vaccine. Materials and methods. For the computer analysis, the database of the hemagglutinin (HA) primary structures of the H1N1 and H3N2 strains isolated in the influenza epidemiological season 2009/2010–2018/2019 were used from the Internet. For every epidemical season dominant and invariant H1 sequences (presenting the generalized HA images of circulating strains) are constructed and used for the comparison of seasons. The dominant sequence of the seasonal dominant sequences and the invariant sequences of the seasonal dominant sequences are used as the HA characteristics for ten year period. Results. The seasonal dominant HA sequences of the last ten year period contain a few changes, i.e. their structures are robust and each structure contains practically all identical conservative sequences of the HA of the following seasons. During the last ten years the bird and swine HA H1 and H3, in contrast to human HA H1 and H3, have requiredsignificant changes. Conclusion. The vacccines using the H1 and H3 dominant sequences for preceding epidemical seasons could be effective against the various strain subtypes in the future seasons.

Relevance. The influenza vaccine can reduce the incidence and mortality from influenza if that are antigenically the same or related to the viruses. There are at least 3 levels of prediction: vaccine strains for the upcoming epidemic season; the trend of influenza viruses for 2–3 years ahead, the emergence of pre-pandemic virus strains. The aim of the work was to analyze the potential of bioinformatics to implement prediction at these 3 levels for subtypes H1N1 and H3N2. Materials and methods. For the computer analysis, the database of the hemagglutinin (HA) primary structures of the H1N1 and H3N2 strains isolated in the influenza epidemiological season 2016–2017 – 2018–2019 was used from the Internet. At the first prediction level, an adapted hidden Markov model was used, at the second, invariants were searched for НА H1N1 and its antigenic sites, and at the third level, prediction was based on identifying invariants in structural proteins of pandemic strains. Results. The circulation of several dominant strains in the epidemiological season 2018–2019 was predicted, the existence of invariants in НА Н1 and its antigenic sites НА H1N1 was shown, and it was concluded that the threat of an influenza pandemic caused by avian influenza viruses was unlikely. Conclusion The bioinformatics approach can be considered as a valuable tool in predicting, at different levels of circulation, certain strains of the influenza virus in the epidemic season.

Relevance. Vaccination is still the most effective way to reduce the incidence and mortality from influenza and the complications it causes. WHO recommends the composition of the vaccine strain for each influenza season. Unfortunately, the relevance of vaccines and strains of influenza virus circulating during the epidemic season cannot always coincide. The cause is flu variability.Aim is to develop a new computational method for predicting an optimal hemagglutinin (HA) structure in H1N1 and H3N2 human influenza vaccine strains for coming epidemic seasons and to compare its results with WHO recommendations.Materials and method. For this study HA sequences were used from data bases available in INTERNET and the modified hidden Markov model was used to construct the HA primary structures.Results. It was indicated that the new bioinformatics approach allowed to construct an optimal structure of HA for vaccine strains. It was at most close to HA of circulating virus strains in coming epidemic seasons, spreaded over them and was superior to WHO recommendations. Conclusion: HA sequences should be considered as reliable background for predicting vaccine strains to decrease risks of not optimal and even mistakable choices. Bioinformatics approach allows to continually monitor HA changes after epidemics and to estimate adequacy of manufacturing vaccines to the future epidemic season.

The purpose of the study was to compare molecular characteristics of genes and proteins of pandemic influenza strains and find features of the 1918 Spanish influenza virus. Computer analysis has shown that the genes of the Spanish influenza virus in contrast to other pandemic strains contain optimal quantity of long complementary sequences that allow to obtain a supramolecular assembly of 8 virus RNA in according to a model ensuring selective packing of one copy of each virus RNA by the only possible scheme and high transmission to induce infection by single virions. Other pandemic strains contain redundant or insufficient quantity of complementary sequences that allow an assembly of its genome by means of some models including a stochastic one and occurrence of virions with incomplete genome, that is influenza virusts can exist primarily as a swarm of complementation-dependent semi-infectious virions. Analysis of an HA gene of the Spanish influenza virus found out exclusion from its translation code four triplets (CGG, CGA, CGC и CGU) coding arginine. This exclusion is observed in all the HlNl strains isolated during 100 years. Coding arginine in an HA gene of HlNl strains is provided by only triplets AGG and AGA. A NP gene of the Spanish influenza virus in contrast to other pandemics strains is avian-like and its NP protein is characterized by elevated quantity of arginine and decreased quantity of lysine that is considered as viral adaptation to avian body temperature. Prevalence of arginine provides more high positive charge for the Spanish influenza NP protein and its more powerful interaction with RNA and consequently more high thermal stability of the its RNP in comparison with the RNP of other pandemic strains. Potential consequence of existence of the avian-like NP in the Spanish influenza virus could be its high pathogenicity as infection fever creates optimal temperature for virus replication. These new data obtained by computer analysis of genomes in the Spanish influenza virus and other pandemic strains (altogether information about its proteins) can potentially be used to track pre-pandemic strains among circulating influenza A viruses and detect the formation of a possible trajectory of pandemic alert.

The article briefly considers physiological aspects of the human gut microbiota, associations between dysbiosis and colorectal cancer (CRC), disturbance of immune system in CRC, mechanisms of avoidance of immune surveillance by tumors, genetic instability in CRC, collisions and perspective of immunotherapy of CRC.

With computer analysis occurrence of small homologous and complementary fragments (21 nucleotides in length) has been studied in genomes of 14 human viruses causing most dangerous infections. The sample includes viruses with (+) and (–) single stranded RNA and DNA-containing hepatitis A virus. Analysis of occurrence of homologous sequences has shown the existence two extreme situations. On the one hand, the same virus contains homologous sequences to almost all other viruses (for example, Ebola virus, severe acute respiratory syndrome-related coronavirus, and mumps virus), and numerous homologous sequences to the same other virus (especially in severe acute respiratory syndrome-related coronavirus to Dengue virus and in Ebola virus to poliovirus). On the other hand, there are rare occurrence and not numerous homologous sequences in genomes of other viruses (rubella virus, hepatitis A virus, and hepatitis B virus). Similar situation exists for occurrence of complementary sequences. Rubella virus, the genome of which has the high content of guanine and cytosine, has no complementary sequences to almost all other viruses. Most viruses have moderate level of occurrence for homologous and complementary sequences. Autocomplementary sequences are numerous in most viruses and one may suggest that the genome of single stranded RNA viruses has branched secondary structure. In addition to possible role in recombination among strains autocomplementary sequences could be regulators of translation rate of virus proteins and determine its optimal proportion in virion assembly with genome and mRNA folding. Occurrence of small homologous and complementary sequences in RNA- and DNA-containing viruses may be the result of multiple recombinations in the past and the present and determine their adaptation and variability. Recombination may take place in coinfection of human and/or common hosts. Inclusion of homologous and complementary sequences into genome could not only renew viruses but also serve as memory of existence of a competitor for host and means of counteraction against a competitor in coinfection being an analogy of the bacterial CRISPR/Cas system.

Objectives: To identify homologous segments of human hemostatic and viral proteins and to assess the role of human hemostatic proteins in viral replication. Materials and Methods: The following viruses were chosen for comparison: influenza B (B/Astrakhan/2/2017), coronaviruses (Hcov229E and SARS-Co), type 1 adenovirus (adenoid 71), measles (ICHINOSE-BA) and rubella (Therien). The primary structures of viral proteins and 41 human hemostatic proteins were obtained from open–access www.ncbi.nlm.nih. gov and www.nextprot.org databases, respectively. Sequence homology was determined by comparing 12-amino-acid segments. Those sequences identical in ≥ 8 positions were considered homologous. Results: The analysis shows that viral proteins contain segments which mimic a number of human hemostatic proteins. Most of these segments, except those of adenovirus proteins, are homologous with coagulation factors. The increase in viral virulence, as in case of SARS-Co, correlates with an increased number of segments homologous with hemostatic proteins. Conclusion: Hemostasis plays an important role in viral replication and pathogenesis. The conclusion is consistent with the literature data about the relationship of hemostasis and inflammatory response to viral infections.

Antibodies (Ab), especially natural, display multiple specificity not only due to intrinsic conformational dynamics. With computational analysis the distribution of identical and homologous peptides has been studied in surface proteins from RNA and DNA viruses of widely distributed infections. It was established that each virus protein shared the fragments homologous to other virus proteins that allowed to propose the existence of the peptide continuum of the protein relationship (PCPR). Possible manifestations of PCPR are multiple reactivity and autoreactivity in Ab and therefore it is not possible to consider the immune methods of virus identification as high reliable because of crossing interactions. The PCPR excludes the existence of 100% specificity in immune tests for virus identification. Immunodiagnostic collisions may occur either in identification of virus itself or identification of Ab to viruses. Also PCPR may be responsible for heterologous immunity and consequently the infection associated with severe pathology. The comparative analysis of peptide relationship of H1N1 influenza virus nucleoprotein and human proteins found out, beyond early described its common motif with human hypocretin receptor 2, peptides homologous to those in melanotonin and glutamate receptors and three ion channels. It allows to propose that the sleep disorder narcolepsy associated with Pandemrix vaccination (an adjuvanted, influenza pandemic vaccine) and also with infection by influenza virus during the 2009 A(H1N1) influenza pandemic may be determined not only by Ab to the peptide motif common to influenza nucleoprotein and hypocretin receptor but also Ab to melanotonin and glutamate receptors and ion channels. Decreasing and even avoiding risks of complications from vaccination may be feasible by means of a computer analysis of vaccine proteins for the occurrence of epitopes homologous to the human protein those and particularly by an analysis of Ab profiles induced by vaccine using microarrays with the large number of human protein antigens.

The purpose of the study was to find molecular recognition characteristics of pandemic strains of influenza A viruses and to find out whether avian strains are the probable cause of a new influenza pandemic. Computer analysis of the internal proteins (nucleoprotein, matrix protein M1 and M2 proteins polymerase complex PB1, PB2 and PA, non-structural protein NS2; because of the variability of the length the non-structural NS1 protein was excluded from the analysis) of influenza A virus pandemics in 1918 (H1N1), 1957 (H2N2), 1968 (H3N2), 1977 (H1N1) and 2009 (H1N1) strains was used for search of the invariant pattern primary structure. It was revealed that internal proteins of pandemic strains are characterized by the constancy of the number and positions of certain amino acids and the presence of extended invariant fragments. On the basis of these identified patterns of invariances in internal proteins it was possible to accurately identify pandemic strains in the control sample. Pandemic strains, divided by decades in their emergence and different composition of subtypes of hemagglutinin and neuraminidase (H1, H2, H3 and N1, N2), have strong relationship for their internal proteins, forming a special subset. This suggests that emergence of influenza A virus pandemic strains is related to convergence of their internal proteins to the detected pandemic invariants. To identify pandemic invariant patterns is enough to have the training set including strains of four pandemics (1918, 1957, 1968, 1977). Therefore the 2009–2010 pandemic influenza strain could be predicted at the earliest stage according to its genome and proteome sequencing. According to a comparative analysis, the internal proteins of avian strains H5N1 and H7N9, particularly their nucleoproteins, are not close to those of pandemic strains. This suggests that the threat of a new influenza pandemic, provoked by current circulating avian strains, is unlikely. Invariant patterns of pandemic strains can potentially be used to track pre-pandemic strains among circulating influenza A viruses and detect the formation of a possible trajectory of pandemic alert.

Computer analysis of primary structure for >3300 proteins has shown an opportunity for existence of global immune epitope continuum of protein relationships (IECPR) for eukaryotes, prokaryotes, and viruses. On the basis of IECPR, one may provide new interpretations for immune events, and in particular, to consider them as an additional factor determining poly- and autoreactivity of antibodies, and, respectively, extend the concept of regulatory functions of natural antibodies. For medical practice, the IECPR would be especially useful in cases of search for novel vaccines and immune diagnostic preparations.

Abstract. Relations of immune tolerance between mother and fetus are considered in view of a common regulatory continuum which is formed under the influence of a growing fetus. To explain such an immune tolerance, a notion of immune system plasticity is introduced, as an analogue to the nervous system plasticity, which develops in response to a continuum of changes occurring in fetal and maternal organisms during the nine months of pregnancy. The immune system plasticity in females is supposed to be among possible factors causing collisions upon conception and in the course of pregnancy. (Med. Immunol., 2011, vol. 13, N 2-3, pp 121-132)