TO THE DEVELOPMENT OF THE COMPLEX DIPHTERIА VACCINE WITH BACTERIAL ADJUVANT

Yeliseyeva I. V., Babich E. M., Zhdamarova L. A., Belozersky V. I., Kolpak S. A.

MICROBIOLOGY

Scentific article

The lessons of the great diphtheria epidemic in Eastern Europe in the 1990s and the increasing trend of diphtheria in the world over the past few years have forced the medical community not to forget about the threat of a diphtheria outbreak. Sporadic cases of disease in Ukraine over the last 10 years are just the tip of the iceberg, as the transmission of infection through bacterial carriers and latent forms of diphtheria unrestrained continues. An analysis of the number of cases of diphtheria registered in Ukraine since the late 1980s and the corresponding rates of vaccination coverage against diphtheria reveals a paradoxical phenomenon: a significant increase in the incidence since 1990 was accompanied by an annual increase in the percentage of population coverage of DTP3. The maximum number of diphtheria cases in 1994-1996 was accompanied by the highest – almost 100 % – rates of vaccination. Thus, the epidemic has not been stopped by increasing the number of vaccinated persons. For a number of years, in our laboratory are conducted the research on the development of a complex diphtheria vaccine with a bacterial component. The vaccine has not only a protective effect against diphtheria disease, but is also directed against the colonization of the respiratory tract by the pathogen and the sanation of C. diphtheriae bacterial carriers. The development of bacterial adjuvant is carried out using ultrasonic disintegration of bacteria in line with two modern vaccine design strategies, namely: an anti-adhesive strategy that developes drugs that prevent colonization by the pathogen of the mucous membranes of the macroorganism and its subsequent invasion, as well as strategies for potentiation of the trained innate immunity, and to promote the elimination of the pathogen from the body in immunodeficiency states, which are associated with prolonged bacterial activity, and to enhance the immune protection of the body after vaccination. The development of bacterial adjuvant is in line with two modern vaccine design strategies, namely: (1) anti-adhesive strategy that implements drugs that prevent the pathogen colonization of the mucous membranes of the macroorganism and its subsequent invasion; (2) strategies for potentiation of trained innate immunity, which can protect against infection and promote the elimination of the pathogen in immunodeficiency states that are associated with prolonged bacterial activity, as well as the treatment of inverse immunotolerant states to enhance immune response. The experimental candidate vaccine has been preclinically tested in an enterprise setting. However, the study of the effect of experimental antigenic preparations on cellmediated immunity is being continued and the technological process of manufacturing the experimental candidate vaccine is being worked out. It was established that the tested samples of C. diphtheriae antigenic preparations increased the adhesiveness of the C. diphtheriae test strain at previous exposure with formalinized human red blood cells, and also demonstrated phagocytosis-stimulating effect (t> 2; p = 0.05). The decrease in the indeces of adhesion and phagocytosis of the test strain at pH=5.5, apparently indicates that even a weakly acidic environment damages the molecular structures – PAMS of erythrocytes and adhesines of corynebacteria, respectively – which partially lose their specificity and ability to stimulate mechanisms of innate immunity. The obtained data indicate the importance of determining the optimum pH value in the technological process of obtaining a bacterial antigenic preparation in the design of combined diphtheria vaccines.

diphtheria vaccine, bacterial adjuvant, adhesion, phagocytosis.

1. Open database: Data provided by Member States through WHO-UNICEF Joint Reporting Form and WHO Regional offices. WHO vaccinepreventable disease monitoring system, 2019 global summary. Available from: https://www.who.int/immunization/monitoring_surveillance/ data/gs_gloprofile.pdf?ua=1
2. Open database: Incidence time series for Ukraine (UKR). Last updated 15-July-2019 (data as of 1-July-2019). Available from: WHO vaccine-preventable diseases: monitoring system. 2019 global summary. Available from: http://apps.who.int/immunization_monitoring/ globalsummary/incidences?c=UKR
3. Open database: Coverage time series for Ukraine (UKR). Last updated 15-July-2019 (data as of 1-July-2019). Available from: WHO vaccine-preventable diseases: monitoring system. 2019 global summary. Available from: http://apps.who.int/immunization_monitoring/ globalsummary/coverages?c=UKR
4. Open database: The immunological basis for immunization series: module 2: diphtheria. WHO Press. 2009. Available from: WHO Library Cataloguing-in-Publication Data. Available from: https://apps.who.int/iris/bitstream/handle/10665/44094/9789241597869_eng. pdf?sequence=1
5. Chudnaia LM, Oksyiuk VH, Krasiuk LS, Moroz LV, Brуzhata SY, Skuratovskaia YM, et al. Epydemyolohycheskaia sytuatsyia po dyfteryy v Ukrayne. Epydemyolohyia y ynfektsyonnye bolezny. 1999;1:10-2. [in Russiаn].
6. Popkova SM, Shmeleva EA, Leshchuk SY. Ymmunytet y еkolohycheskye aspektу bakteryonosytelstva pry dyfteryy. Biulleten VSNTs SO RAMN. 2005;1(39):134-40. [in Russiаn].
7. Yelyseyeva I, Babych Eu, Kivva F. New approaches to development of diphtheria vaccine. Anti-colonization strategy for the development of a combined diphtheria vaccine with bacterial antigen component. Publishing House: LAP LAMBERT Academic Publishing; 2018.
8. Yelyseieva IV, Babych YeM, Bilozerskyi VI, Zhdamarova LA, Kolpak SA. Doslidzhennia nespetsyfichnoi zakhysnoi dii antyhennykh preparativ C.diphtheriae ta B.pertussis, oderzhanykh za dopomohoiu fizychnykh faktoriv dezintehratsii. Materialy mizhnar. nauk.-prakt. konf. «Okhorona ta zakhyst zdorovia liudyny v umovakh sohodennia»; 2018 2-3 Lyst.; Kyiv, Ukraina. Kyiv; 2018. s. 50-4. [in Ukrainian].
9. Yelyseieva IV, Babych YeM, Bilozerskyi VI, Zhdamarova LA, Kolpak SA. Poverkhnevi antyheny zbudnyka dyfterii, oderzhani za dopomohoiu fizychnykh chynnykiv, yak biolohichna platforma dlia rozrobky kombinovanoi dyfteriinoi kandydat-vaktsyny. Visnyk problem biolohii i medytsyny. 2018;3(145):251-6. [in Ukrainian].
10. Babych YeM, Yelyseieva IV, Bilozerskyi VI, Zhdamarova LA, Isaienko OIu, Bobyrieva IV, Horbach TV, vynakhidnyky; Derzhavna ustanova «Instytut mikrobiolohii ta imunolohii im. I. I. Mechnykova NAMN Ukrainy», pravonastupnyk. Sposib otrymannia dyfteriinoho bakterialnoho antyhenu: patent Ukrainy UA 86891. 2014 Sich. 10. [in Ukrainian].
11. van der Meer JW, Joosten LA, Riksen N, Netea MG. Trained immunity: A smart way to enhance innate immune defence. Mol Immunol. 2015 Nov;68(1):40-4. DOI: 10.1016/j.molimm.2015.06.019
12. Rappuoli R, Santoni A, Mantovani A. Vaccines: An achievement of civilization, a human right, our health insurance for the future. J Exp Med. 2019 Jan 7;216(1):7-9. DOI: 10.1084/jem.20182160
13. Seregina NV, Chestnova TV, Zherebczova VA, Khromushin VA. Obzor biofizicheskikh osobennostej mikrobnoj adgezii. Vestnik novi`kh mediczinskikh tekhnologij. 2008;ХV(3):175-7. [in Russiаn].
14. Hasty DL, Ofek I, Courtney HS, Doyle RJ. Multiple adhesins of streptococci. Infect Immun. 1992;60:2147-52.
15. Scott JR, Barnett TC. Surface proteins of gram‐positive bacteria and how they get there. Annu Rev Microbiol. 2006;60:397-423.
16. Tauch A, Burkovski A. Molecular armory or niche factors: virulence determinants of Corynebacterium species. FEMS Microbiol Lett. 2015 Dec;362(23):fnv185.
17. Ott L. Adhesion properties of toxigenic corynebacteria. AIMS Microbiol. 2018;4(1):85-103. Published online 2018 Feb 9. DOI: 10.3934/ microbiol.2018.1.85
18. Zemledelie [Іnternet]. Dostupno: http://racechrono.ru/pochva-i-mikroorganizmy/3677-zavisimost-adgezii-ot-sostava-sredy-chast-2.html [in Russiаn].
19. Brylys VY, Brylyne TA, Lentsner KhP, Lentsner AA. Metodyka yzuchenyia adhezyvnoho protsessa mykroorhanyzmov. Laboratornoe delo. 1986;4:210-2. [in Russiаn].
20. Yelyseieva IV, Babych YeM, Bilozerskyi VI, Zhdamarova LA, Kolpak SA. Vplyv eksperymentalnykh bakterialnykh antyhennykh preparativ zbudnyka dyfterii, oderzhanykh za dopomohoiu fizychnykh chynnykiv, na adheziiu test-shtamiv C.diphtheriae. Visnyk problem biolohii i medytsyny. 2016;4,1(133):264-8. [in Ukrainian].
21. Mykroskopycheskaia tekhnyka [Іnternet]. Metodу yssledovanyia fahotsytoza in vitro. Dostupno: http://labx.narod.ru/documents/issledovanie_fagocitoza.html [in Russiаn].
22. Zajczev VM, Liflyandskij VG, Marinkin VI. Prikladnaya mediczinskaya statistika: uchebnoe posobie. Sankt-Peterburg: OOO «Izdatel`stvo Foliant»; 2003. 428 s. [in Russiаn].

«Bulletin of problems biology and medicine» Issue 3 (152), 2019 year, 264-268 pages, index UDK 579.871.1 : 651.371-025

10.29254/2077-4214-2019-3-152-264-268