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Epidemiology and Vaccinal Prevention

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Vol 20, No 4 (2021)
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PROBLEM-SOLVING ARTICLE

4-18 698
Abstract

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.

ORIGINAL ARTICLES

19-27 709
Abstract

Relevance. COVID-19 remains a serious problem for all countries of the world, affecting all areas of public life. The brunt of the problem falls on health care. The new coronavirus infection has raised many questions, in particular regarding its epidemiology

Aim. Determine the sequence of the global spread of COVID-19 at the beginning of the 2020 pandemic and the possible influence of seasonality on its distribution.

Materials and methods. Data on the countries of the Northern and Southern hemispheres of the sites «Our World in Data» from the section «Coronavirus (COVID-19) Cases». Стопкоронавирус.рф, Johns Hopkins University were used. The analysis of the spread of COVID-19 in the world was carried out based on data on the incidence and deaths from COVID-19 by climatogeographic zones.

Results and discussion. The sequence of the spatio-temporal spread of COVID-19 across countries and continents at the beginning of the pandemic in 2020 has been determined. The similarity of the global spread of COVID-19 and "seasonal" influenza A(H3N2) epidemics indicates the spread of these infections along the primary migration routes of the population. The global spread of the COVID-19 pandemic virus, as well as influenza A(H1N1), was sufficient for 1–1.5 months. The COVID-19 pandemic began in the Northern Hemisphere in the spring and summer, but atypical seasonality was often observed at the beginning of influenza pandemics. On the other hand, data on the influence of seasonality on the spread of COVID-19 were obtained: the highest incidence in the Northern Hemisphere countries was in the winter, and in the Southern Hemisphere countries, with reverse seasonality, a high incidence was observed already in the summer months. Therefore, it will be possible to make a final conclusion about the seasonality of this infection in the following years.

28-39 1663
Abstract

Background. Integrative epidemiological and etiological analysis of peculiarities of the development of the COVID-19 pandemic in different countries of the world is of significant scientific and practical interest in order to improve the preparedness of medical and social services during the upcoming pandemics. The purpose of the research. To determine the features of the epidemic process caused by a new coronavirus infection COVID-19, in all the diversity of its interaction with influenza viruses and other ARVI agents in the Russian Federation.

Materials and methods. The studies were performed in the system of routine influenza surveillance by the Federal Center for Influenza and ARI at the Smorodintsev Research Institute of Influenza and the Center for Ecology and Epidemiology of Influenza at the National Center for Epidemiology and Microbiology named after N.F. Gamaleya, in cooperation with Regional Collaborating Base Laboratories in accordance with the Order of the Federal Service for Consumer Rights Protection Surveillance and Human Well-being No. 373 of March 31, 2005. Information on morbidity and hospitalization was provided by the erritorial Departments of Rospotrebnadzor. Information on the results of PCR detection of influenza and ARVI viruses, including SARS-CoV-2, was received from the «enters for Hygiene and Epidemiology" and was entered on-line into the electronic database of the Smorodintsev Research Institute of Influenza of the Ministry of Health of Russia. «AmpliSens reagent kits produced by the Central Research Institute of Epidemiology were used for PCR detection and subtyping of influenza A and B viruses, to identify ARVI agents, for PCR diagnosis of COVID-19 the kits certified in the Russian Federation of various producers were used.

Results. It has been established that the annual epidemics of influenza, as well as the development of the second wave of the COVID- 19 pandemic in the season 2020–2021 was preceded pronounced increase of incidence rate (55.0 - 67.9 per 10,000), associated with rhinoviruses activity, starting from the week 38 to week 43. 2020, which reached on the peak 23–29.0% of patients examined. The increase of COVID-19 activity in the fall of 2020 began from week 41 with the peak (26.6–31.3%) of detection in the period from the week 47.2020 to week 4. 2021. The duration and severity of COVID-19 diseases, requiring hospitalization, distinguished the SARS-CoV-2 pandemic from influenza epidemics/pandemics. Significant changes in the nature of the epidemic process were found in the analysis of the age structure of morbidity and hospitalization – their distinct decrease in children's age groups against the background of pronounced growth among patients of the age group 15–64 yrs and, especially, in elderly people ≥ 65 yrs. The incidence growth curves coincided in time with an increase in SARS-CoV-2 activity against the background of a decrease in the detection frequency of other ARVI pathogens, including influenza and RSV viruses, as a result of pronounced interference between pathogens. Interestingly, as the frequency of SARS-CoV-2 detection decreased to 15–19%, the activity of rhinoviruses, seasonal coronaviruses and metapneumoviruses began to increase again from 0.7–3.0% to 5.6–6.6%, which indicated the existence of a quantitative relationship between the interference indicators of SARS-CoV-2 with other ARI agents. It was most clearly manifested in relation to influenza and RSV viruses, which detection in general for the season dropped to 0.04% and 0.3% respectively.

Conclusions. The phenomenon of interference of SARS-CoV-2 with other viral respiratory agents was established, based on the facts of a sharp suppression of the circulation of influenza viruses, respiratory syncytial virus and other ARVI pathogens during the period of active spread of the pandemic coronavirus. A distinctive feature of the SARS-CoV-2 pandemic, in comparison with influenza epidemics, was its long duration and the severity of the diseases caused by that virus. During the period of the pandemic, a clear decrease in the incidence and hospitalization among children was revealed, with their pronounced growth in adults and, especially, in older people ≥ 65 years old.

40-47 879
Abstract

Relevance. During the pandemic of the new coronavirus infection (COVID-19), the organized collectives of Moscow, living in public housing organizations (dormitories) with different planning arrangements, were one of the most vulnerable groups of the population prone to focal morbidity.

The purpose of the study. To conduct a comparative clinical and epidemiological assessment of the epidemic process of COVID-19 in dormitories, depending on the type of their planning device.

Materials and methods. In the period from 12.04 to 23.06.2020, a selective longitudinal prospective analytical study of the course of the epidemic process was conducted in the foci of COVID-19, formed dormitories of different types of planning devices with a total number of 3,228 patients. For statistical processing of the results, one-factor analysis of variance and correlation analysis using the Cheddock scale were used. We used the following programs: IBM SPSS Statistics V. 23. 0, Analysis ToolPak Excel.

Results and discussion. The planning arrangement of buildings for public accommodation was a fundamental factor influencing the course of the COVID-19 epidemic process in dormitories. The epidemic process in the dormitories of the reported type had an earlier development, the first foci of COVID-19 began to form already on 12.04.2020, which was 7 days ahead of the formation of foci in isolated dormitories. The average growth rate in the dormitories of the reported type was equal to 8.4%, which was 5.3 times higher than the corresponding indicator in the dormitories of the isolated type. The infection rate (Rt), indicating the intensity of the spread of the infectious process, was 1.5 times higher in the dormitories of the reported type. In the studied period of time from 12.04.2020 to 23.06.2020, the number of infected COVID-19 in the dormitories of the isolated type was significantly less than in the dormitories of the reported type: there were 4 cases of infection per 100 guests of the dormitories of the isolated type, while in the reported dormitories there were 10 cases of COVID-19 per 100 residents. The contagiousness of the virus in combination with a long course of focal morbidity led to the development of severe forms of COVID-19. The coefficient of occurrence of severe forms of COVID-19 on average in isolated dormitories was equal to 1.1%, while in dormitories of the reported type, the studied coefficient was 11 times higher and averaged 11.6%.

Conclusion. The type of planning arrangement of collective living organizations was a fundamental factor influencing the course of the COVID-19 epidemic process in hostels. The complex of necessary anti-epidemic measures aimed at localizing and eliminating the outbreak of COVID-19 directly depended on this factor.

48-56 851
Abstract

Relevance. Unencapsulated strains of meningococcus (NmNG) very rarely cause invasive meningococcal disease. A new ciprofloxacin-resistant strain NmNG ST-175 cc175, which has recently caused several cases of invasive meningococcal infection in Europe, has been discovered in the Russian Federation.

Aim. To compare the new Russian strains of NmNG ST-175 with the already characterized NmNG ST-175 and to analyze the genetic markers associated with antibiotic resistance.

Materials and methods. The nucleotide sequences of NmNG ST-175 strains of more than 2 million base pairs were exported from the PubMLST database. Comparison was carried out for 1605 core genome loci using the N. meningitidis cgMLST v1.0 ". Genetic relationships of 127 NmNG ST-175 strains, including 8 Russian carrier strains, were visualized using the SplitsTree software (version 4.16.2).

Results. Of the eight Russian strains, six found themselves in a cluster with German and Swedish isolates that caused invasive meningococcal infection. Two more Russian strains were closest to the isolates of the cluster, including carrier isolates from England. Seven strains showed resistance to ciprofloxacin and possessed the gyrA-187 and gyrA-152 alleles, which, based on the phylogenetic analysis of the alleles, belonged to the genetic branches of Neisseria cinerea and Nm.

Conclusion. Protein vaccines alone could potentially provide protection against ST-175 NmNG. It seems promising to study the antigenic characteristics of Russian Nm strains, including NmNG ST-175, to assess the potential vaccination coverage with existing protein vaccines, the possibility of their registration on the territory of the Russian Federation, as well as the development of domestic vaccines.

57-67 1454
Abstract

Relevance. Post-exposure prophylaxis (PEP) is the most effective method for reducing the morbidity and mortality of human rabies. Since 2000, in Russia, domestically produced cultural purified and concentrated rabies vaccine (COCAV) and equine immunoglobulin (AIG) are used as the main drugs for PEP.

Aims. To assess the epidemiological effectiveness of post-exposure rabies prophylaxis and possible causes of failure in the Russian Federation in 2001–2018.

Materials & methods. A comprehensive retrospective epidemiological study of 167 cases of rabies in humans and PEP statistics in the Russian Federation was carried out. To test the hypotheses about the relationship between PEP failures and risk factors, namely (gender, age, place of residence of the sick, nature of the injuries received, source of infection), two main comparison groups were formed: «vaccinated» (n = 28) and «not vaccinated» (n = 139). In addition, we compared the groups who received PEP correctly and those vaccinated with violations of instructions. The failure rate was assessed in relation to the total number of vaccinated and the number of vaccinated after contact with rabid animals.

Results. During the analyzed period, the incidence of human rabies decreased from 0.015 to 0.0013 per 100 thousand population. Of the patients, 83.2% did not receive PEP (did not apply, vaccinations were not prescribed, refused). In the group «vaccinated» in 53.6% (n = 15), the schemes of PEP prescribing and administering were violated, including in 35.7% (n = 10) of cases AIG was not administered. The rest 46.4% (n = 13), received vaccinations in accordance with the instructions. Before the end of the vaccination course, 85.7% (n = 24) fell ill; the rest fell ill with an incubation period of more than three months. Only one person received AIG and all 6 vaccine injections. The group «vaccinated» differed from the group «not vaccinated» by a higher frequency of category III injuries (χ2 = 9.99, p = 0.019) and injuries caused by wild animals, especially wolves (χ2 = 22.24, p < 0.001).

Conclusions. Among people who developed rabies in 2001–2018, 16.8% received PEP. The proportion of the number of cases and the total number of those who received PEP was 1: 240.0 thousand. The failure rate of PEP after contact with rabid animals was 0.03% (excluding the nature of the contact and the animal species). More than 70% of all failures are associated with wolf and fox bites, more than 85% with category III injuries.

68-72 559
Abstract

Relevance. The development of effective and safe vaccines for pertussis prevention remains an urgent public health challenge.

Aim. To study the protective activity and safety of acellular pertussis vaccine (AcPV) containing a complex of protective antigens from freshly isolated and vaccine strains of Bordetella pertussis.

Materials and methods. Freshly isolated (No. 287, and No. 317) and vaccine (No. 305 and No. 475) B. pertussis strains with «non-vaccine» and «vaccine» allelic variants of the pertussis toxin (PT) subunit A gene, the PT promoter gene, the pertactin gene, the fimbria 2 gene, and the fimbria 3 gene strains were used for the production of AcPV.

Results. All the studied variants of AcPV were harmless in the test of changes in the body weight of mice and sensitivity to histamine. The protective activity of AcPV3 (strains No. 287, No. 317 and No. 305) and AcPV1 (strains No. 287, No. 305 and No. 475) was higher than that of AcPV2 (strains No. 317, No. 305, and No. 475). IgG antibody titers to PT were also higher in mice immunized with AcPV1 and AcPV3.

Conclusion. The higher protective activity of AcPV3 and AcPV1 may be associated with the genotype of strain No. 287, which has a ptxP3 PT promoter and is characterized by an increased level of PT production and high virulence. The most promising for further preclinical and clinical studies is AcPV3, which contains 2/3 of the antigens of the dominant «non-vaccine» genotype and 1/3 of the «vaccine» genotype, corresponding to the genes of PT, pertactin and fimbria to the currently circulating B. pertussis strains.

PRACTICAL ASPECTS OF EPIDEMIOLOGY AND VACCINE PREVENTION

73-78 541
Abstract

Relevance The epidemiological disadvantage of measles in developed countries reflects the weakening of herd immunity and is caused, first of all, a change in society's attitude to vaccine prevention and the risks of infectious diseases, which requires a revision of the prevention strategy

Aim: assessment of measles immunity in employees of the regional multidisciplinary children's hospital.

Materials & Methods. 365 employees were examined at the same time in 2019 on the basis of the regional children's hospital. Investigation of the intensity of immunity to measles by ELISA using the VectoKor-IgG test system (Vector-Best, Russia). The surveyed were divided into 4 age groups (20–29, 30–39, 40–49 and 50 years and older). Statistical processing was carried out using the χ2 test and Spearman's rank correlation.

Results. 63% of the examined had a protective titer of antibodies. The least protected were medical workers under the age of 40, especially up to 30 years old, with a share of immune persons of 30%. In older age groups, the proportion of seropositive persons was 80.9%. The age of the employees and the levels of measles immunity were highly correlated (r = 0.72). There was no statistically significant effect on the state of measles immunity of professional status, the presence of documentary evidence of vaccination.

Conclusions. Thus, the results of the conducted study indicate a high epidemiological risk of measles in medical institutions and when applying to them. The worst indicators of protective immunity were found among young employees. It is advisable to continue serological monitoring in medical institutions, organized vaccination of seronegative individuals, as well as conduct cooperative research

79-88 1066
Abstract

Relevance. In the Kyrgyz Republic, the measles and rubella elimination program has been implemented in accordance with the strategy of the World Health Organization (WHO) for 20 years, which uses a two-fold immunization tactic against measles at the age of 12 months and 6 years, which is complemented by clean-up campaigns. Despite the high coverage of vaccinations with both the first and second doses, there are epidemic rises in infection, reaching in 2018 (15.9), 2019 (36.4) and 2020 (11.2) per one hundred thousand population. In the years of recent epidemic ups, a high incidence among young children revealed. The epidemiological situation with measles that has developed in recent years has made it necessary to study the state of specific measles immunity in different age groups, to determine the vulnerable population group and assess the quality of vaccination work.

The aim of the work: to assess the epidemic process of measles at the present stage and the state of specific immunity in the population of the Kyrgyz Republic to identify groups at high risk of infection.

Materials and methods. In the course of the work, descriptive-evaluative and analytical epidemiological research methods are used. The materials are statistical reporting data on the incidence of measles from 1987 to 2020 and 568 blood serum samples taken from residents of Bishkek and Jalal-Abat region in the following indicator age groups: 1-4 years old n = 122; 5-9 years old n = 108; 10-14 years old n = 114; 15-19 years old n = 77; 20-29 years old n = 103; 30 years and older n = 44. The level of anti-measles antibodies is determined by enzymelinked immunosorbent assay (ELISA) using the VectorMeasles-IgG test system manufactured by VEKTOR BEST, Russia. The method of retrospective analysis of the incidence of measles in the Kyrgyz Republic in long-term dynamics, by age groups, according to vaccination history is used. The method of retrospective analysis of the incidence of measles in the Kyrgyz Republic in longterm dynamics, by age groups, according to vaccination history is used. The data obtained statistically processed using the Excel program. The critical level of significance is p = 0.05. Descriptive statistics – mean and standard error of the mean (data are presented as M ± m) for quantitative variables, for qualitative variables – determination of proportion.

Results and Discussions. The introduction of specific prophylaxis of measles led to decrease the incidence of measles, 15 times on average, mortality also decreased, however, despite the effectiveness of vaccination, cyclical increases in infection persisted, seasonality in intra-annual dynamics, school-age children began to get sick more often. To change the situation, including in order eliminating primary postvaccination failures, in 1986 a second dose of vaccine introduced into the vaccination schedule for children 6 years old, which led to decrease the incidence to single case and in some years to the complete absence of measles cases. However, in 2018, the importation of measles from bordering countries led to an epidemic outbreak with the number of cases of 1004. The incidence rate increased from 0.1 in 2017 to 15.9 per 100 thousand population in 2018. At the subnational level, a clean-up campaign carried out among children aged two to five years. However, due to the lack of vaccine, the target group covered less than 50% and the increase in the incidence of measles in 2019 continued to 2377 people (36.4 per 100 thousand population). A slight decrease in the incidence of measles outlined in 2020, when 733 cases were registered. The highest percentage of cases is among children under one year old, 43.3% (2019) and 52.7% (2020), who are not vaccinated by age. In second place in importance is the age group of children from one to four years old, an extensive incidence rate is 29.5% (2019) and 39.3% (2020). The data of serological studies confirmed the formation of a high-risk group for measles infection among preschool children, where the proportion of seronegatives is 36%; this is probably due to not post-vaccination failures, but rather to a high proportion of children who are not vaccinated for various reasons. This hypothesis confirmed by the high percentage of unvaccinated children of this age in the structure of the sickindividuals. All this casts doubt on the official data on the coverage of children of this age with preventive vaccinations (95.7%) and indicates the accumulation of contingents susceptible to measles. The results of our research are consistent with the data obtained by other researchers.

Conclusion. The analysis showed the need for regular monitoring of the organization of the vaccination work to control the reliable accounting of the child contingent needed to immunization, based on the population census, as well as to identify the validity of medical withdrawals. To prevent the growth of refusals from vaccinations, it is advisable to expand the forms of work with the population to develop commitment to vaccination. We believe that in combination, this will increase the real coverage of measles vaccinations for children, reduce the number of sources of infection and indirectly reduce the risk of infection in children of the first year of life.

OVERVIEW

89-102 787
Abstract

Relevance. The COVID-19 pandemic is characterized by a long undulating course. One of the directions of the dynamic assessment of the incidence of this infection is, as is known, the characterization of the determinants of the epidemic process and the study of the actual effectiveness of various measures.

Aims. Were to study the features of the COVID-19 morbidity in the European, American and Asian regions of the world on the example of individual countries with an assessment of the possible impact of regime-restrictive measures on the daily increase in cases.

Materials & methods. A descriptive epidemiological study involved the use of the following data on COVID-19: daily increase in new infections in absolute numbers and relative indicators during 1 June 2020 till 30 November 2020 in five countries (France, Italy, USA, Brazil, India) , description and timing of various restrictive measures. Information obtained from open sources (situation reports from WHO, CDC, ECDC, national ministries of health, etc.). Time series characterized, defining sharply differing values, timing and duration of ups and downs, the rate of average daily growth (decline). Statistical analysis was carried out using the IBM SPSS Statistics 26.

Results. On average, for the analyzed period of time, 1303 were registered in Italy, 4897, France – 52799, Brazil – 31853, India –50507new cases. The average incidence rate in the compared countries ranged from 500.98 ± 417.06 per 100,000 in India to 4399.43 ± 2390.77 per 100,000 in the US. After the passage of the «first wave» of the incidence of COVID-19, regardless of the region of the world, there was an increase in the daily increase in new cases of SARS-CoV-2 in the summer-autumn period of 2020. Furthermore, with the differences in the morbidity rates in the different countries, there were also characteristics the formation of similar to the region. For the European region (Italy, France), there was a simultaneous beginning of an increase in the incidence in August-September 2020, a similar trend towards exponential growth and synchronous fluctuations in the daily increase in absolute cases of diseases. For the countries of the American region (USA and Brazil), a similar sinusoidal nature of the dynamics of the average daily increase in infection cases and its synchronicity until October 2020 was revealed. The Asian region, on the example of India, had significant differences in the dynamics of the analyzed indicators in comparison with the countries of the European and American regions. Differences in the formation of morbidity in the summerautumn period were more pronounced between the regions and related to the level of average daily growth, the incidence rate, the month of the maximum rise in the incidence in this period, and trend differences. Comparison of the ongoing isolation measures with the daily increase in cases revealed their discrepancy. This could create the preconditions for the activation of the epidemic process of infection and the ineffectiveness of measures.

Conclusions. We found that in the five countries examined, the situation developed according to a similar scenario. Nevertheless, in different regions of the world there was a specificity in the involvement of the territory in the epidemic process. A more in-depth study of the timeliness and completeness of regime-restrictive measures against SOCID-19 should include a comparison with the patterns of formation and manifestations of the epidemic process. In turn, this is important for scientifically based implementation and increasing their effectiveness.

103-113 618
Abstract

Relevance. Meningococcal vaccine refers to any of the vaccines used to prevent infection by Neisseria meningitidis. Therefore, there is a great scientific and practical interest in the existing and developed menicococcal vaccines.

Aims the review is to provide an analysis: literature data on the effectiveness of meningococcal vaccines of new generations - conjugated polysaccharide serogroups A, C, W and Y and protein serogroup B.

Conclusions. With regard to conjugated vaccines, there are a large number of reliable observations confirming the high immunological and epidemiological effectiveness of these vaccine preparations, including the prevention of bacterial carriage and the development of herd immunity. These vaccines are weakly reactogenic, and in many countries, they are introduced into national immunization programs and in some countries are used as mandatory (UK) or in connection with the existing epidemic indications. The protein «vesicle» vaccine based on serogroup B meningococcal outer membrane proteins, showed high efficacy only in those cases when the protein composition of the strain that caused the morbidity corresponded to the composition (mainly in terms of the PorA subtype antigen) of the vaccine. Genetic-engineered vaccines containing only a few serogroup B meningococcal protein antigens with or without the addition of «vesicle» proteins are difficult to evaluate due to the small number of observations associated with low serogroup В prevalence, but in Great Britain, such vaccine was also introduced as mandatory in the national immunization schedule for babies. At the same time, new vaccines of serogroup B induce immune protection against some strains of meningococcus of other serogroups C, W, and Y, and even against other species of Neisseria, in particular - gonococcus. This circumstance gives rise to hope for the development of protein meningococcal vaccines with a wider spectrum of specificity than the group, and even than the species.

114-122 731
Abstract

Relevance. Severe fever with thrombocytopenia syndrome is a viral disease characterized by acute fever, accompanied by progressive thrombocytopenia, leucopenia. The mortality is up to 30%. The disease was first identified in 2009 in rural areas of central China, Hubei and Henan. The causative agent of the disease is a new Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV). The SFTSV is mainly transmitted through tick bites, especially Haemaphysalis longicornis which is the dominant tick species in East Asia.

The aim of the review is to analyze relevant information about Severe Fever with Thrombocytopenia Syndrome, including the molecular genetics features of the pathogen, clinical manifestations, geographical distribution, epidemiological features, as well as the possibility of drift and spread of infection in the Russian Federation.

Conclusions. SFTS is a serious health threat as it relates to new and re-emerging infections. The further spread of SFTS in China may complicate the epidemiological situation in the country. SFTSV may have a much wider global distribution in Southeast Asia than is currently known. The risk of H. longicornis ticks spreading is predicted in the north-east United States, New Zealand, parts of Australia and several Pacific islands. The presence of the H. longicornis in the Primorsky Territory on the Far East indicates a possible risk of the natural focus formation in the event of the introduction of the pathogen.

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ISSN 2073-3046 (Print)
ISSN 2619-0494 (Online)