Evaluation of the epidemiological significance of molecular genetic factors in relation to the intensity of post-vaccination immunity against hepatitis B

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Abstract

Introduction. Hepatitis B retains the status of socially significant infection and remains a major health problem worldwide, including the Russian Federation. The improvement of the effectiveness of the current complex of preventive measures, especially vaccination, is an important task for public health. Although vaccination against hepatitis B is highly successful, 5% to 10% of individuals do not experience a response to vaccine with an adequate level of antibodies to hepatitis B surface antigen (anti-HBs). One of the key factors determining the absence or insufficiency of post-vaccination immunity against hepatitis B may be the single-nucleotide polymorphisms (SNPs) that change gene sequences, including those that determine the mechanism of immunogenesis. Such genetic changes may affect the signaling pathways and result in significant decrease in antibody response to hepatitis B vaccine. Assessment of epidemiological significance of such SNPs is an important task, considering its possible associations with failure to respond adequately to vaccination.

The aim of the study was to determine the effect of SNPs of IL1B (rs1143634, rs1143627), IL1RN (rs4251961, rs419598), IL6 (rs1800795), IL10 (rs1800896), TULP1 (rs9380516), TLR4 (rs4986790), MERTK (rs4374383) genes on the formation of post-vaccination immunity against hepatitis B.

Materials and methods. Healthcare workers (n = 271) of the Treatment and Rehabilitation Center of the Ministry of Health of the Russian Federation with known vaccination history, data on age, work experience and department of the medical institution were included in this research. The presence and levels of anti-HBs and anti-HBcore IgG antibodies were determined by the ELISA method using the DS-ELISA-ANTI-HBs and DS-ELISA-ANTI-HBc kits, according to the manufacturer’s instructions. Genotyping was performed by real time polymerase chain reaction. Statistical analysis of data was carried out using the "Statistica 6.0" software.

Results. Statistically significant differences in the frequencies of CC (rs9380516) genotypes (p = 0.034; OR 0.497; 95% CI 0.261–0.949) and CT (p = 0.044; OR 1.967; 95% CI 1.015–3.812) of the TULP1 gene in the group of individuals with anti-HBs concentrations of 10–100 IU/l were found in association with the intensity of the post-vaccination response against hepatitis B. Also, for this group, differences were found in the structure of the TT/CT genotype pair of IL-10/TULP1 genes (rs1800896/rs9380516) (p = 0.003; OR = 5.39; 95% CI 1.7–17.4) and for the combination of AA/TT SNP MERTK/IL1RN genotypes (rs4374383/rs4251961) (p = 0.003; OR = 7.96; 95% CI 1.7–37.6).

Conclusion. Our study revealed that above variants of genotypes could play a role in predicting an increased risk of low (or absence) post-vaccination immune response against hepatitis B. It seems appropriate to use the relationship between the gene polymorphisms and a low concentration of post-vaccination anti-HBs antibodies in assessing scenarios for the development of the epidemic process of hepatitis B, since the identified associations allow to quantify the risks of poor herd immunity against this infection.

Full Text

Introduction

Hepatitis B (HB) is an infection controllable through specific preventive measures; the implementation of the country-wide national program of preventive vaccination is the principal and the most effective epidemic control strategy in the system of epidemiological surveillance. Through vaccination programs, Russia has achieved steady and significant improvement in the HB epidemiological situation. Meanwhile, the findings of multiple studies focusing on the analysis of patterns and mechanisms of vaccine-induced immunity against HB demonstrate that 5–10% of the vaccinees who completed the vaccination (a three-dose series on a 0, 1, and 6-month schedule) are defined as non-responders, i.e. they do not develop antibodies or their levels of antibodies are equal to or below the protective level of 10 IU/L [1–3].

Immediate attention should be given to studying the causes of insufficient immune responses in vaccinated people, considering that HB vaccination programs have been adopted by most of the countries. There is no common opinion about the factors causing the problem and about the ways it can be resolved, as antigen presentation and subsequent interactions involved in building both humoral and cell-mediated immunity constitute a complex, multistep process.

As assumed by Abebe et al., the partial or complete failure to produce anti-HBs following a complete immunization series can be caused by dysregulated differentiation of naive B cells into specific antibody-secreting cells and plasmablasts [4]. Kardar et al. attribute low seroconversion rates to diminished production of interleukin-2 (IL-2), interferon-γ , and IL-10 cytokines after HB vaccination [5]. The study conducted by Korber et al. showed that non-responders typically had suppressed IL-10 expression in regulatory B cells [6]. As expected, the administration of a vaccine booster dose resulted in a slight increase in the levels of anti- HBs, which was significantly different from the levels recorded in the control group of individuals with the normal IL-10 expression. Garner-Spitzer et al. have also concluded that absent immune responses to HBsAg- containing vaccines are associated not only with the administered vaccine, but also with genetic characteristics of vaccinated individuals [7].

Immunogenesis is a fairly complex mechanism including a cascade of successive interactions (signaling pathways) inducing immune responses to host-invading antigens. Obviously, by creating new variants of nucleotide sequences, single nucleotide polymorphisms (SNPs) can cause changes both in the subsequent function of non-coding regions of genes and in the amino acid composition of translated polypeptides participating in signaling pathways. Multiple studies address the SNP association, contributing to the extensive experience in studying the impact of human genetic variants in association with different pathological conditions of non-infectious [8–10] and infectious [11] etiology.

The aim of the study was to assess the impact of IL-1B (rs1143634, rs1143627), IL1RN (rs4251961, rs419598), IL6 (rs1800795), IL-10 (rs1800896), TULP1 (rs9380516), TLR4 (rs4986790), and MERTK (rs4374383) SNPs on vaccine-induced immunity against HB.

Materials and methods

The study was conducted in the laboratory of viral hepatitis at the Central Research Institute of Epidemiology (CRIE). The study group was composed of healthcare workers from the Treatment and Rehabilitation Center of the Ministry of Health of Russia (n = 271; men/women — 56/215; mean age 45 ± 10 years), with confirmed vaccination history and employment at the healthcare facility. All the participants signed their informed consent; the study was approved by the CRIE Local Ethics Committee (Minutes No. 114 dated 22/4/2021).

Serological tests for identifying anti-HBs and anti- HBc IgG antibody levels were performed using the enzyme immunoassay (EIA) and DS-EIA-ANTI-HBS and DS-EIA-ANTI-HBc reagent kits (Diagnostic Systems) in accordance with the manufacturer’s instructions.

In the study group, the tests for detection of SNPs were performed for the following genes: IL-1B (rs1143634, rs1143627), IL1RN (rs4251961, rs419598), IL6 (rs1800795), IL-10 (rs1800896), TULP1 (rs9380516), TLR4 (rs4986790), and MERTK (rs4374383). For DNA extraction, we used a Gemolitik reagent and a Ribo-PREP reagent kit (AmpliSens). SNP-containing gene fragments were amplified in a Rotor-Gene Q 6plex thermal cycler (Qiagen). The method of polymorphism detection is based on detection of SNP alleles using allele-specific locked nucleic acid (LNA) probes detectable in 2 or 4 channels of fluorescence detection and designed by the CRIE Research Group for New Methods of Genetic Polymorphism Detection. The obtained results were verified through Sanger sequencing and pyrosequencing [12]. The sample representativeness was assessed statistically using the Pearson chi-square (χ 2) test for estimating differences between the allele frequencies detected in this study and those reported in the international dbSNP (NCBI) database for group Caucasians (CEU)1.

The Pearson χ2 test was based on the standard fourfold table to check whether there is an association between SNPs and levels of post-vaccination anti-HBs. The variables were deemed as statistically significant at p < 0.05 when comparing frequencies of individual polymorphisms and at p < 0.005 when comparing frequencies of SNP pairwise combinations.

Results

During the first stage of the study, the entire cohort (n = 271) was examined for the presence of anti-HBc antibodies using the EIA method to exclude individuals with infection-induced immunity from the further study. Anti-HBc antibodies were detected in 48 (17.7%) participants (95% CI, 13.4–22.8%). In this group of healthcare workers, the mean age was 44 ± 10 years, and the length of occupational employment was 18 ± 11 years. The HB vaccination was reported by 47 participants (25 participants completed full-series immunization more than 5 years ago and 22 participants had full-series immunization less than 5 years ago). Anti-HBs antibodies were detected in 36 (76.6%) participants; in 12 participants, their levels were within a 10 ± 100 IU/L range, and 19 participants had anti-HBs levels higher than 100 IU/L. In 12 healthcare workers, anti-HBs antibodies either were not detected or their levels were below the protective level (10 IU/L).

The division of the healthcare workers into groups of individuals with infection-induced and vaccine-induced immunity against HB was essential for valid assessment of the effectiveness of the preventive measures. 15–20 years ago, the healthcare workers having an occupational exposure to HB and the length of employment over 10 years accounted for 45–50% [13]. At present, the risks for acquiring infection through occupational exposure of healthcare workers have significantly decreased, though not completely eliminated and still requiring close attention.

The study group comprised 223 healthcare workers, who, based on the serological tests, had never been infected with the HB virus (HBV). The mean age in the group was 45 ± 10 years; the length of occupational employment — 20 ± 11 years. Based on the quantitative measurement of anti-HBs antibodies and depending on the anti-HBs antibody levels, the study group was divided into three subgroups: 55 (24.7%; 95% CI, 19.2–30.9%) participants with levels below 10 IU/L; 69 (30.9%; 95% CI, 24.9–37.5%) participants with levels within a 10–100 IU/L range; 99 (42.4%; 95% CI, 37.8–51.2%) participants with levels above 100 IU/L. It should be noted that in the third sub-group, 13 participants had anti-HBs levels higher than 15,000 IU/L, regardless of their vaccination timeframe. Here, we can speak about the pattern when the average levels of post-vaccination anti-HBs antibodies tend to decrease along with the increasing mean age of the participants in the study group. The mean age in the subgroups was as follows: 41 ± 8 years in the group > 100 IU/L; 45 ± 10 years — in the group 10–100 IU/L and 51 ± 8 years — in the group with HB levels < 10 IU/L. The gender factor had no effect on vaccine-induced immunity against the HBV (Table 1).

Table 1. Intensity of post-vaccination immunity against hepatitis B depending on gender, % (95% CI)

To assess the sample representativeness in the reference-group represented by the group of healthcare workers having post-vaccination anti-HBs antibody levels > 100 IU/L (n = 99), we performed a comparative analysis of allele frequency distributions for the studied polymorphisms, using the international dbSNP database (NCBI) (Table 2).

Table 2. Comparison of allele frequencies of the reference group of healthcare workers with the database "DbSNP" (NCBI)

The distribution of genotype frequencies for the studied polymorphisms conforms to the Hardy-Weinberg equilibrium and is consistent with the data available for the European (CEU) population in the dbSNP database (NCBI). Therefore, the reference-group data can be used as reference data, against which the results obtained from other study groups can be compared.

The analysis of the identified presence or absence of an association between the levels of post-vaccination antibodies to HBsAg and the studied SNPs showed statistically significant differences between the frequencies of CC (rs9380516) (p = 0.034; OR 0.497; 95% CI, 0.261–0.949) and CT (p = 0.044; OR 1.967; 95% CI, 1.015–3.812) genotypes of the TULP1 gene in the group of healthcare workers with anti-HBs antibody levels ranging from 10 to 100 IU/L (Table 3). The same group also demonstrated differences for TT/CT genotypes of IL-10/TULP1 genes (rs1800896/rs9380516) (p = 0.003; OR = 5.39; 95% CI, 1.7–17.4).

Тable 3. Significant associations regarding the intensity of post-vaccination immunity against hepatitis B

Note. Significant associations are highlighted in bold.

In addition to the above pair of SNPs, significant differences were found for AA/TT genotypes of SNPs in MERTK/IL1RN (rs4374383/rs4251961) (p = 0.003; OR = 7.96; 95% CI, 1.7–37.6). The comparison of frequency distributions for individual genotypes of MERTK (rs4374383) and IL1RN (rs4251961) genes did not show any statistically significant differences.

The combinations of genes with detected associations do not form any linkage groups; they are inherited independently and the gene linkage disequilibrium is 0.0663 for rs1800896/rs9380516 of the IL-10/TULP1 genes and 0.0294 — for rs4374383/rs4251961 of MERTK/IL1RN.

As opposed to the group of healthcare workers having levels of specific antibodies within a 10–100 IU/L range, the group with low levels of anti-HBs antibodies (< 10 IU/L) did not show any significant differences in polymorphism allele and genotype frequencies.

Discussion

Summarizing data of multiple studies, a number of authors noted that approximately among 10% of the population, the standard HB vaccination schedule (0–1–6 months) does not result in producing antibodies to HBsAg, which would reach the protective level ( > 10 IU/L). It has been found that the vaccination failure rate is associated with the older age, existing comorbid pathology [14][15], obesity, harmful habits [16], and depends on the type of vaccines [17] and on several other factors causing immunosuppression. In addition, the importance of host immunogenetic characteristics cannot be neglected, as the major histocompatibility complex plays a key role in the genetic control of immune responses in normal and pathological conditions.

As the problem is becoming increasingly urgent worldwide, there have been multiple studies addressing the effect of SNPs on vaccine-induced immunity against HB and having resulted in identification of several significant polymorphisms. Researchers tend to focus their attention on the human leukocyte antigen (HLA) system, as it is believed that non-responders have disrupted primary antigen presentation. It is known that lower levels of anti-HBs antibodies (< 10 IU/L) are more frequently detected in combination with HLA-DRB1*0301, DQB1*1302, DRB1*0701 and DRB1*0401 variants. In their turn, DRB1*1301, DRB1*0101 and DRB1*1501 [18] have been more frequently detected in groups of individuals with pronounced post-vaccination response. In their genome-wide association study (GWAS) backed up by multiple verification, Pan et al. detected significant SNP associations located in non-coding regions of HLA class II genes [19], including rs477515, rs28366298 and rs13204672 (HLA-DRB1), rs3763316 (BTNL2).

The findings reported by Silvestri et al. are of significant interest. Based on 14 family cases, the researchers proved the fact of hereditary transmission of the HLA class III C4AQ0 allele associated with suppression of post-vaccination immunity after the full-series vaccination [20].

As demonstrated by several studies, the weak serological response to immunization against HB can also be associated with SNPs not belonging to the major histocompatibility complex. Davila et al. found associations for a number of polymorphisms such as rs6789153 located close to the FOXP1 transcription factor gene; rs1654668 in the LILRB4 gene encoding leukocyte immunoglobulin-like receptors; rs1978270 and rs7029078 belonging to the C5 complement component, as well as rs854692 and rs854625 in the CCL15 gene encoding the C-C motif chemokine ligand 15 [21]. Pan et al. found the association between the rs12133337 SNP in the CD3Z gene encoding the T-cell surface glycoprotein CD3 zeta chain and the weak vaccine-induced immunity against HB [22]. The rs2243250 and rs2227284 polymorphisms in the IL-4 gene were also found to be associated with diminished immune responses [23]. The summarized data on the SNP effect on vaccine-induced immunity against HB are presented in Table 4.

Table 4. SNPs affecting the mechanisms of formation of post-vaccination immunity against hepatitis B (literature data)

Note. #The study was conducted on a group with high levels of anti-HBs (> 100 IU/liter), therefore, in this case, the odds ratio (OR) value should be interpreted in reverse order relative to the group with a reduced post-vaccination effect.

It should be noted that in Russia, the impact of SNPs on vaccine-induced immunity against HB has received no attention until recently, thus making it impossible to compare our results. We detected differences in the distribution of genotype frequencies for the combination of two polymorphic loci in IL-10/TULP1 (rs1800896/rs9380516) between the group of healthcare workers with anti-HBs antibody levels of 10-100 IU/L and the reference group. The rs9380516 SNP is also significant by itself as the marker indicating the increased risk of weak vaccine-induced immunity. At the moment, there is no clear understanding of the mechanism involved in the identified associations, as the role of the TULP1 gene and nearby polymorphisms, has been insufficiently studied. There are publications reporting the association of rs9380516 SNP with some pathological conditions in humans. For example, Salmaninejad et al. [24] and Souzeau et al. [25] have reported the association between rs9380516 and retinal dystrophies, which is consistent with the findings obtained by Hollander et al. who have reported the association between the above SNP and several inherited retinal diseases [26]. The rs9380516 SPN has an easily identifiable association with epithelial cancer of the bladder [27]. Kutalik et al. [28] and Rueger et al. [29] have found that the above SNP is associated with the progression rate of fibrosis and cirrhotic changes in the liver, which are caused by hepatitis C. The literature data and the results of this study, which demonstrate the variability of immune responses in people vaccinated against infectious diseases, give all grounds to believe that further studies will help identify new associations of rs9380516 in the TULP1 gene.

The newly identified association between the combination of polymorphisms (rs4374383/rs4251961) in MERTK/IL1RN genes and the insufficient production of post-vaccination anti-HBs antibodies comes obviously from the functional impairment of these genes. The rs4374383 polymorphism is located in the MERTK gene encoding proto-oncogene tyrosine-protein kinase MER, which belongs to the TAM (tumor-associated macrophages) family. This enzyme performs a lot of functions, including inhibition of signaling pathways triggered by cytokines and TLR ligands as well as participation in apoptotic cell clearance. Today, researchers have identified the association of the G-allele of rs4374383 with highly intensive development of liver fibrosis in patients with hepatitis C [29][30]. It has also been found that the AA genotype (rs4374383) is associated with the reduced expression of the MERTK gene, which, consequently, can be seen as a marker of protective effect on nonalcoholic fatty liver disease [31].

Rs4251961 is located in the promoter region of the IL1RN gene encoding the interleukin-1 receptor antagonist (IL-1RA). Its main function is to block the pro-inflammatory cascade of responses. It has been found that the C allele of rs4251961 (IL1RN) is associated with elevated levels of several markers of systemic inflammatory process, such as C-reactive protein, fibrinogen, and IL-6 [32]. Our data on the association of the above pair of polymorphisms indirectly correlate with the findings of foreign studies, as the rs4374383 AA genotype and the rs4251961 TT genotype are apparently typical of individuals with lower activity of the inflammatory profile of immune responses, thus resulting in relatively reduced immunogenicity of vaccines.

This study is the first one in Russia to identify associations between SNPs in some genes participating in regulation of different functions of the human immune system and the patterns of the humoral constituent of the vaccine-induced immunity against HB. It has been found that in the group of healthcare workers, lower levels of post-vaccination anti-HBs antibodies consistently correlate with two paired SNPs in MERTK/IL-1RN genes (rs4374383/rs4251961) and IL-10/TULP1 genes (rs1800896/rs9380516) as well as with the single rs9380516 SNP of the TULP1 gene. Note that the above associations were detected only in individuals with lower levels of specific antibodies to HBsAg (10– 100 IU/L) and did not apply to the other groups. The results obtained by foreign researchers and the outcome of our study resulting in 3 identified associations out of 9 SNPs give every reason to assume that the impact of SNPs on vaccine-induced immunity is much more versatile and that it needs further research.

The obtained results are significant not only in the context of individual specific characteristics in building the adequate immune response to vaccination, but also for the assessment of post-vaccination herd immunity. The above data can be interpreted from the epidemiological perspective, as they offer quantitative assessment of risks associated with weak protection of the population against HB. Identification of factors, including molecular and genetic factors, which can have an adverse impact on the vaccination, is highly important, especially taking into account the Health National Project launched in Russia in 2006 and the subsequent mass HB vaccination program, the main strategic objective of which is to reach the highest possible level of herd immunity. The more thorough and fuller understanding in this field, including other aspects of the HB-related problem, can significantly contribute to improvement of the epidemiological surveillance system. Today, HB prevention and control measures need priority attention, as the general epidemiological situation, though demonstrating positive trends, is far from being satisfactory.

Conclusion

The obtained results lead to the following conclusions:

  1. In the recent years, the risk of occupational infection with HBV among healthcare workers has significantly decreased, as demonstrated by the anti-HBc antibody detection rates in the study groups of healthcare workers — 17.7% (95% CI, 13.4–22.8%).
  2. Post-vaccination anti-HBs antibodies at protective levels ( > 10 IU/L) were detected in 75.3% of healthcare workers, and high levels of anti-HBs antibodies ( > 100 IU/L) were detected in 42.4% of them.
  3. Some of the studied SNPs are associated with lower levels of post-vaccination anti-HBs antibodies (10–100 IU/L): MERTK/IL1RN SNP combinations (rs4374383/rs4251961) and IL-10/TULP1 SNP combinations (rs1800896/rs9380516) as well as the rs9380516 SNP of the TULP1 gene.
  4. The obtained data can be used in preparing scenarios for predicting the development of the HB epidemic process, as the identified associations of SNPs are the core component in quantitative assessment of insufficiently strong vaccine-induced immunity.

1. Database of Single Nucleotide Polymorphisms (dbSNP). Available at: https://www.ncbi.nlm.nih.gov/snp37.8

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About the authors

N. V. Vlasenko

Central Research Institute for Epidemiology

Author for correspondence.
Email: vlasenko@cmd.su
ORCID iD: 0000-0002-2388-1483

Natalia V. Vlasenko — researcher, Laboratory of viral hepatitis,
Central Research Institute for Epidemiology

Moscow

Russian Federation

N. S. Churilova

Central Research Institute for Epidemiology

Email: fake@neicon.ru
ORCID iD: 0000-0001-5344-5829

Nadezhda S. Churilova — junior researcher, Laboratory of viral hepatitis, Central Research Institute for Epidemiology

Moscow

Russian Federation

T. A. Loskutova

Central Research Institute for Epidemiology

Email: fake@neicon.ru
ORCID iD: 0000-0003-1478-665X

Tatiana A. Loskutova — assistant, Laboratory of viral hepatitis, Central Research Institute for Epidemiology

Moscow

Russian Federation

K. O. Mironov

Central Research Institute for Epidemiology

Email: fake@neicon.ru
ORCID iD: 0000-0001-8207-9215

Konstantin O. Mironov — Head, Scientific group for development of new methods of genetic polymorphisms detection, Central Research Institute for Epidemiology

Moscow

Russian Federation

A. S. Esman

Central Research Institute for Epidemiology

Email: fake@neicon.ru
ORCID iD: 0000-0002-5456-7649

Anna S. Esman — researcher, Scientific group for development of
new methods of genetic polymorphisms detection, Central Research Institute for Epidemiology

Moscow

Russian Federation

E. A. Dunaeva

Central Research Institute for Epidemiology

Email: fake@neicon.ru
ORCID iD: 0000-0002-4477-8506

Еlena A. Dunaeva — researcher, Scientific group for development of
new methods of genetic polymorphisms detection, Central Research Institute for Epidemiology

Moscow

Russian Federation

T. A. Semenenko

N.F. Gamaleya National Research Centre for Epidemiology and Microbiology

Email: fake@neicon.ru
ORCID iD: 0000-0002-6686-9011

Tatiana A. Semenenko — D. Sci. (Med.), Professor, Head, Epidemiology department, N.F. Gamaleya National Research Centre for Epidemiology and Microbiology

Moscow

Russian Federation

Z. S. Rodionova

Central Research Institute for Epidemiology

Email: fake@neicon.ru
ORCID iD: 0000-0003-0401-279X

Zinaida S. Rodionova — consultant, Organizational and methodological department, Central Research Institute for Epidemiology

Moscow

Russian Federation

I. G. Nikitin

National Medical Research Center "Treatment and Rehabilitation Center"

Email: fake@neicon.ru
ORCID iD: 0000-0003-1699-0881

Igor G. Nikitin — Director, National Medical Research Center "Treatment and Rehabilitation Center"

Moscow

Russian Federation

A. V. Tutelian

Central Research Institute for Epidemiology

Email: fake@neicon.ru
ORCID iD: 0000-0002-2706-6689

Alexei V. Tutelian — D. Sci. (Med.), Professor, Corresponding Member of the Russian Academy of Sciences; Head, Laboratory of infections associated with the provision of medical care, Central Research Institute for Epidemiology

Moscow

Russian Federation

S. N. Kuzin

Central Research Institute for Epidemiology

Email: fake@neicon.ru
ORCID iD: 0000-0002-0616-9777

Stanislav N. Kuzin — D. Sci. (Med.), Professor, Head, Laboratory of
viral hepatitis, Central Research Institute for Epidemiology

Moscow

Russian Federation

V. G. Akimkin

Central Research Institute for Epidemiology

Email: fake@neicon.ru
ORCID iD: 0000-0003-4228-9044

Vasily G. Akimkin — D. Sci. (Med.), Professor, Full Member of the
Russian Academy of Sciences, Director, Central Research Institute
for Epidemiology

Moscow

Russian Federation

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Copyright (c) 2022 Vlasenko N.V., Churilova N.S., Loskutova T.A., Mironov K.O., Esman A.S., Dunaeva E.A., Semenenko T.A., Rodionova Z.S., Nikitin I.G., Tutelian A.V., Kuzin S.N., Akimkin V.G.

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