biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2026-26-2-208-219biopreparat-722Research ArticleСТАНДАРТИЗАЦИЯ И КОНТРОЛЬ КАЧЕСТВАQUALITY CONTROL AND STANDARDISATIONОценка полноты сорбции адсорбированных вакцин для профилактики дифтерии и столбнякаEvaluation of the degree of adsorption of vaccine components in diphtheria and tetanus vaccines adsorbedhttps://orcid.org/0000-0002-9035-6072КомаровскаяЕ. И.KomarovskayaE. I.

Комаровская Елена Игоревна

Петровский б-р, д. 8, стр. 2, Москва, 127051

Elena I. Komarovskaya

8/2 Petrovsky Blvd, Moscow 127051

Komarovskaya@expmed.ruhttps://orcid.org/0009-0000-4276-4744ЛыскоК. А.LyskoK. A.

Лыско Ксения Андреевна, канд. техн. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Ksenia A. Lysko, Cand. Sci. (Techn.)

8/2 Petrovsky Blvd, Moscow 127051

Федеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202604072026262208219Copyright © Комаровская Е.И., Лыско К.А., 20262026Комаровская Е.И., Лыско К.А.Komarovskaya E.I., Lysko K.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/722ВВЕДЕНИЕ

ВВЕДЕНИЕ. Степень адсорбции компонентов вакцины на адъюванте определяет эффективность вакцины. Требования к показателю степени адсорбции антигенов в готовом продукте не установлены ВОЗ, тогда как в Государственной фармакопее Российской Федерации регламентированы. Разница в требованиях налагает ограничения для равнозначной оценки качества АКДС-вакцин различных производителей, а отсутствие международных требований вызывает сложности в адекватной оценке качества большого разнообразия вакцин.

ЦЕЛЬ

ЦЕЛЬ. Анализ данных литературы и требований нормативных документов к определению полноты сорбции дифтерийного и столбнячного анатоксинов в составе комбинированных вакцин для совершенствования системы контроля качества и гармонизации национальных требований с мировыми стандартами качества.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. В настоящее время отсутствуют международные требования к качеству геля алюминия гидроксида, используемого для адсорбции, и к величине степени адсорбции компонентов АКДС-вакцины. В ведущих фармакопеях мира установлены стандарты качества для геля алюминия гидроксида, тогда как в Российской Федерации требования не разработаны. Требования к степени адсорбции антигенов производители самостоятельно устанавливают для каждого продукта и определяют эту величину как минимум на стадии получения адсорбированного антигена. В спецификации на готовый препарат этот показатель качества может отсутствовать. Существуют три основных метода оценки степени адсорбции, которые определяют количество несвязанного антигена в супернатанте, при этом чувствительность и стоимость методов отличаются. Содержание антигенов выражают в общепринятых единицах флокуляции — Lf (limit of flocculation). Российские вакцины отличаются от зарубежных методами определения степени адсорбции антигенов и единицами выражения количественного содержания столбнячного анатоксина. Из-за разницы подходов и единиц выражения степени адсорбции отечественные вакцины уступают зарубежным, что, тем не менее, не указывает на низкую эффективность вакцин на основе АКДС.

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. Стандартизация требований к качеству геля алюминия гидроксида для адсорбции, методов контроля степени адсорбции антигенов и единиц выражения количественного содержания антигенов в настоящее время имеет решающее значение для гармонизации фармакопейных требований. Внедрение актуальных требований к адъюванту и современных методов контроля качества степени адсорбции антигенов позволит упрос­тить нормативное регулирование вакцин на основе АКДС.

INTRODUCTION

INTRODUCTION. The degree of adsorption of vaccine components on the adjuvant determines vaccine efficacy. Requirements for the degree of adsorption of antigen in the finished product have not been established by the WHO, whereas they are regulated in the Russian State pharmacopoeia. These differences in requirements limit the comparable quality assessment of DTP vaccines from different manufacturers, and the lack of international standards complicates adequately assessing the quality of a wide variety of vaccines.

AIM

AIM. To analyze regulatory requirements and literature data for determining the completeness of adsorption of diphtheria and tetanus toxoids in combined vaccines in order to improve quality control systems and harmonize national requirements with global quality standards.

DISCUSSION

DISCUSSION. Currently, there are no international requirements for the quality of aluminum hydroxide gel for adsorption or for the degree of adsorption of components of DTP vaccine. Leading global pharmacopoeias establish quality standards for aluminum hydroxide gel used for adsorption; however, no requirements have been developed in the Russian Federation. Manufacturers independently establish requirements for the degree of adsorption of antigen for each product, determining this value at least at the stage of obtaining the adsorbed antigen. This quality indicator may not be included in the specifications for the finished product. There are three main methods for assessing the degree of adsorption. They determine the amount of unbound antigen in the supernatant; their sensitivity and cost vary. Antigen content is expressed in generally accepted flocculation units — Lf (Limit of Flocculation). Domestic vaccines differ from foreign ones in the methods for determining the degree of antigen adsorption and the units used to express the quantitative content of tetanus toxoid. Due to the differences in approaches and units for expressing the degree of adsorption, domestic vaccines are inferior to foreign ones. However, this fact does not indicate the low efficacy of domestic DTP-based vaccines.

CONCLUSIONS

CONCLUSIONS. Standardizing aluminum hydroxide gel quality requirements for adsorption, antigen adsorption monitoring methods, and units for expressing quantitative antigen content is crucial for harmonizing pharmacopoeial requirements. Implementing current adjuvant requirements and current antigen adsorption quality control methods will simplify regulatory frameworks for DTP-based vaccines.

полнота сорбциистепень адсорбцииадъюванталюминия гидроксидАКДС-вакцинаметодыin vivoin vitroконтроль качествафармакопейные требованияdegree of adsorptionadjuvantaluminum hydroxideDPT vaccinein vivo methodsin vitro methodsquality controlpharmacopoeial requirementsРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00061-26-00 на проведение прикладных научных исследований (номер государственного учета НИР 124022200103-5)This study was conducted at the Scientific Centre for Expert Evaluation of Medicinal Products as part of the applied research funded under State Assignment No. 056-00061-26-00 (R&D state registration No. 124022200103-5)ReferencesRaponi A, Brewer JM, Garside P, Laera D. Nanoalum adjuvanted vaccines: Small details make a big difference. Semin Immunol. 2021;56:101544. https://doi.org/10.1016/j.smim.2021.101544Raponi A, Brewer JM, Garside P, Laera D. Nanoalum adjuvanted vaccines: Small details make a big difference. Semin Immunol. 2021;56:101544. https://doi.org/10.1016/j.smim.2021.101544Amini Y, Moradi B, Fasihi-Ramandi M. Aluminum hydroxide nanoparticles show strong activity to stimulate Th-1 immune response against tuberculosis. Artif. Cells Nanomed. Biotechnol. 2017;45:1331–5. https://doi.org/10.1080/21691401.2016.1233111Amini Y, Moradi B, Fasihi-Ramandi M. Aluminum hydroxide nanoparticles show strong activity to stimulate Th-1 immune response against tuberculosis. Artif. Cells Nanomed. Biotechnol. 2017;45:1331–5. https://doi.org/10.1080/21691401.2016.1233111Oyewumi MO, Kumar A, Cui Z. Nano-microparticles as immune adjuvants: Correlating particle sizes and the resultant immune responses. Expert Rev Vaccines. 2010;9(9):1095–107. https://doi.org/10.1586/erv.10.89Oyewumi MO, Kumar A, Cui Z. Nano-microparticles as immune adjuvants: Correlating particle sizes and the resultant immune responses. Expert Rev Vaccines. 2010;9(9):1095–107. https://doi.org/10.1586/erv.10.89O’Hagan DT, Fox CB. Are we entering a new age for human vaccine adjuvants? Expert Review of Vaccines. 2015;14(7):909–11. https://doi.org/10.1586/14760584.2015.1043273O’Hagan DT, Fox CB. Are we entering a new age for human vaccine adjuvants? Expert Review of Vaccines. 2015;14(7):909–11. https://doi.org/10.1586/14760584.2015.1043273Lan J, Feng D, He X, et al. Basic properties and development status of aluminum adjuvants used for vaccines. Vaccines. 2024;12:1187. https://doi.org/10.3390/vaccines12101187Lan J, Feng D, He X, et al. Basic properties and development status of aluminum adjuvants used for vaccines. Vaccines. 2024;12:1187. https://doi.org/10.3390/vaccines12101187Facciolà A, Visalli G, Laganà A, Di Pietro A. An overview of vaccine adjuvants: Current evidence and future perspectives. Vaccines (Basel). 2022;10(5):819. https://doi.org/10.3390/vaccines10050819Facciolà A, Visalli G, Laganà A, Di Pietro A. An overview of vaccine adjuvants: Current evidence and future perspectives. Vaccines (Basel). 2022;10(5):819. https://doi.org/10.3390/vaccines10050819He X, Pu Y, Li Z, et al. The global regulatory landscape for combined vaccines: A comparative case study of registration strategies for diphtheria-tetanus-pertussis-containing vaccines. Vaccine. 2025;54:127017. https://doi.org/10.1016/j.vaccine.2025.127017He X, Pu Y, Li Z, et al. The global regulatory landscape for combined vaccines: A comparative case study of registration strategies for diphtheria-tetanus-pertussis-containing vaccines. Vaccine. 2025;54:127017. https://doi.org/10.1016/j.vaccine.2025.127017Fatima M, Hong KJ. Innovations, challenges, and future prospects for combination vaccines against human infections. Vaccines (Basel). 2025;13(4):335. https://doi.org/10.3390/vaccines13040335Fatima M, Hong KJ. Innovations, challenges, and future prospects for combination vaccines against human infections. Vaccines (Basel). 2025;13(4):335. https://doi.org/10.3390/vaccines13040335Marshall GS, Petigara T, Liu Z, et al. Timing of monovalent vaccine administration in infants receiving DTaP-based combination vaccines in the United States. Pediatr Infect Dis J. 2022;41(9):775–81. https://doi.org/10.1097/INF.0000000000003609Marshall GS, Petigara T, Liu Z, et al. Timing of monovalent vaccine administration in infants receiving DTaP-based combination vaccines in the United States. Pediatr Infect Dis J. 2022;41(9):775–81. https://doi.org/10.1097/INF.0000000000003609Morefield GL, Sokolovska A, Jiang D, et al. Role of aluminum-containing adjuvants in antigen internalization by dendritic cells in vitro. Vaccine. 2005;23(13):1588–95. https://doi.org/10.1016/j.vaccine.2004.07.050Morefield GL, Sokolovska A, Jiang D, et al. Role of aluminum-containing adjuvants in antigen internalization by dendritic cells in vitro. Vaccine. 2005;23(13):1588–95. https://doi.org/10.1016/j.vaccine.2004.07.050He P, Zou Y, Hu Z. Advances in aluminum hydroxide-based adjuvant research and its mechanism. Hum Vaccin Immunother. 2015;11(2):477–88. https://doi.org/10.1080/21645515.2014.1004026He P, Zou Y, Hu Z. Advances in aluminum hydroxide-based adjuvant research and its mechanism. Hum Vaccin Immunother. 2015;11(2):477–88. https://doi.org/10.1080/21645515.2014.1004026Tritto E, Mosca F, De Gregorio E. Mechanism of action of licensed vaccine adjuvants. Vaccine. 2009;27(25–26):3331–4. https://doi.org/10.1016/j.vaccine.2009.01.084Tritto E, Mosca F, De Gregorio E. Mechanism of action of licensed vaccine adjuvants. Vaccine. 2009;27(25–26):3331–4. https://doi.org/10.1016/j.vaccine.2009.01.084Lu F, Hogenesch H. Kinetics of the inflammatory response following intramuscular injection of aluminum adjuvant. Vaccine. 2013;31(37):3979–86. https://doi.org/10.1016/j.vaccine.2013.05.107Lu F, Hogenesch H. Kinetics of the inflammatory response following intramuscular injection of aluminum adjuvant. Vaccine. 2013;31(37):3979–86. https://doi.org/10.1016/j.vaccine.2013.05.107McKee AS, Munks MW, MacLeod MK, et al. Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J Immunol. 2009;183(7):4403–14. https://doi.org/10.4049/jimmunol.0900164McKee AS, Munks MW, MacLeod MK, et al. Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J Immunol. 2009;183(7):4403–14. https://doi.org/10.4049/jimmunol.0900164Munks MW, McKee AS, MacLeod MK, et al. Aluminum adjuvants elicit fibrin-dependent extracellular traps in vivo. Blood. 2010;116(24):5191–9. https://doi.org/10.1182/blood-2010-03-275529Munks MW, McKee AS, MacLeod MK, et al. Aluminum adjuvants elicit fibrin-dependent extracellular traps in vivo. Blood. 2010;116(24):5191–9. https://doi.org/10.1182/blood-2010-03-275529Laera D, HogenEsch H, O'Hagan DT. Aluminum adjuvants-back to the future. Pharmaceutics. 2023;15(7):1884. https://doi.org/10.3390/pharmaceutics15071884Laera D, HogenEsch H, O'Hagan DT. Aluminum adjuvants-back to the future. Pharmaceutics. 2023;15(7):1884. https://doi.org/10.3390/pharmaceutics15071884Алпатова НА, Авдеева ЖИ, Лысикова СЛ и др. Общая характеристика адъювантов и механизм их действия (часть 1). БИОпрепараты. Профилактика, диагностика, лечение. 2020;20(4):245–56. https://doi.org/10.30895/2221-996X-2020-20-4-245-256Alpatova NА, Avdeeva ZhI, Lysikova SL, et al. General characteristics of adjuvants and their mechanism of action (part 1). BIOpreparations. Prevention, Diagnosis, Treatment. 2020;20(4):245–56 (In Russ.). https://doi.org/10.30895/2221-996X-2020-20-4-245-256Ho NI, Huis in 't Veld LGM, Raaijmakers TK, Adema GJ. Adjuvants enhancing cross-presentation by dendritic cells: The key to more effective vaccines? Front Immunol. 2018;9:2874. https://doi.org/10.3389/fimmu.2018.02874Ho NI, Huis in 't Veld LGM, Raaijmakers TK, Adema GJ. Adjuvants enhancing cross-presentation by dendritic cells: The key to more effective vaccines? Front Immunol. 2018;9:2874. https://doi.org/10.3389/fimmu.2018.02874Aradottir Pind AA, Dubik M, Thorsdottir S, et al. Adjuvants enhance the induction of germinal center and antibody secreting cells in spleen and their persistence in bone marrow of neonatal mice. Front Immunol. 2019;10:2214. https://doi.org/10.3389/fimmu.2019.02214Aradottir Pind AA, Dubik M, Thorsdottir S, et al. Adjuvants enhance the induction of germinal center and antibody secreting cells in spleen and their persistence in bone marrow of neonatal mice. Front Immunol. 2019;10:2214. https://doi.org/10.3389/fimmu.2019.02214Awate S, Babiuk LA, Mutwiri G. Mechanisms of action of adjuvants. Front Immunol. 2013;4:114. https://doi.org/10.3389/fimmu.2013.00114Awate S, Babiuk LA, Mutwiri G. Mechanisms of action of adjuvants. Front Immunol. 2013;4:114. https://doi.org/10.3389/fimmu.2013.00114Cerofolini L, Giuntini S, Ravera E, et al. Structural characterization of a protein adsorbed on aluminum hydroxide adjuvant in vaccine formulation. NPJ Vaccines. 2019;4:20. https://doi.org/10.1038/s41541-019-0115-7Cerofolini L, Giuntini S, Ravera E, et al. Structural characterization of a protein adsorbed on aluminum hydroxide adjuvant in vaccine formulation. NPJ Vaccines. 2019;4:20. https://doi.org/10.1038/s41541-019-0115-7Clapp T, Siebert P, Chen D, Jones Braun L. Vaccines with aluminum-containing adjuvants: Optimizing vaccine efficacy and thermal stability. J Pharm Sci. 2011;100(2):388–401. https://doi.org/10.1002/jps.22284Clapp T, Siebert P, Chen D, Jones Braun L. Vaccines with aluminum-containing adjuvants: Optimizing vaccine efficacy and thermal stability. J Pharm Sci. 2011;100(2):388–401. https://doi.org/10.1002/jps.22284Laera D, Scarpellini C, Tavarini S, et al. Maturation of aluminium adsorbed antigens contributes to the creation of homogeneous vaccine formulations. Vaccines (Basel). 2023;11(1):155. https://doi.org/10.3390/vaccines11010155Laera D, Scarpellini C, Tavarini S, et al. Maturation of aluminium adsorbed antigens contributes to the creation of homogeneous vaccine formulations. Vaccines (Basel). 2023;11(1):155. https://doi.org/10.3390/vaccines11010155Matheis W, Zott A, Schwanig M. The role of the adsorption process for production and control combined adsorbed vaccines. Vaccine. 2001;20(1–2):67–73. https://doi.org/10.1016/s0264-410x(01)00317-6Matheis W, Zott A, Schwanig M. The role of the adsorption process for production and control combined adsorbed vaccines. Vaccine. 2001;20(1–2):67–73. https://doi.org/10.1016/s0264-410x(01)00317-6Gupta RK, Siber GR. Adjuvants for human vaccines — current status, problems and future prospects. Vaccine. 1995;13(14):1263–76. https://doi.org/10.1016/0264-410x(95)00011-oGupta RK, Siber GR. Adjuvants for human vaccines — current status, problems and future prospects. Vaccine. 1995;13(14):1263–76. https://doi.org/10.1016/0264-410x(95)00011-oHogenEsch H, O’Hagan DT, Fox CB. Optimizing the utilization of aluminum adjuvants in vaccines: You might just get what you want. NPJ Vaccines. 2018;3:51. https://doi.org/10.1038/s41541-018-0089-xHogenEsch H, O’Hagan DT, Fox CB. Optimizing the utilization of aluminum adjuvants in vaccines: You might just get what you want. NPJ Vaccines. 2018;3:51. https://doi.org/10.1038/s41541-018-0089-xMbhele Z, Thwala L, Khoza T, Ramagoma F. Evaluation of aluminium hydroxide nanoparticles as an efficient adjuvant to potentiate the immune response against Clostridium botulinum serotypes C and D toxoid vaccines. Vaccines (Basel). 2023;11(9):1473. https://doi.org/10.3390/vaccines11091473Mbhele Z, Thwala L, Khoza T, Ramagoma F. Evaluation of aluminium hydroxide nanoparticles as an efficient adjuvant to potentiate the immune response against Clostridium botulinum serotypes C and D toxoid vaccines. Vaccines (Basel). 2023;11(9):1473. https://doi.org/10.3390/vaccines11091473Hem SL, White JL. Structure and properties of aluminum-containing adjuvants. Pharm Biotechnol. 1995;6:249–76. https://doi.org/10.1007/978-1-4615-1823-5_9Hem SL, White JL. Structure and properties of aluminum-containing adjuvants. Pharm Biotechnol. 1995;6:249–76. https://doi.org/10.1007/978-1-4615-1823-5_9Степанова ЕВ, Шарыгин ДЕ, Швалев ЮБ. Влияние условий осаждения на физико-химические характеристики геля гидроксида алюминия. Известия Томского политехнического университета. 2004;307(1):99–101. EDN: HTLMKFStepanova EV, Sharygin DE, Shvalev YuB. Effect of precipitation conditions on the physicochemical characteristics of aluminum hydroxide gel. News of Tomsk Polytechnic University. 2004;307(1):99–101 (In Russ.). EDN: HTLMKFСтась НФ. Зависимость свойств гидроксида алюминия от способа его получения, Современные проблемы науки и образования. 2012;(3):121. EDN: PAAEKFStas NF. Dependence of aluminum hydroxide properties from the method of its synthesis. Modern Problems of Science and Education. 2012;(3):121 (In Russ.). EDN: PAAEKFКадничанский ЭГ, Бадаев СВ, Храмов ВГ. Адсорбент и способ его получения. Патент Российской Федерации № 2293744 C1; 2005. EDN: FCCITTKadnichanskij EG, Badaev SV, Hramov VG. Adsorbent and a method for preparation thereof. Patent of the Russian Federation No. 2293744 C1; 2005 (In Russ.). EDN: FCCITTБыстрицкий ЛД, Долженко НН, Ставицкая НХ и др. Способ получения геля алюминия гидроксида для производства медицинских иммунобиологических препаратов. Патент Российской Федерации № 2171678 C1; 2000. EDN: GCTIEDBystrickij LD, Dolzhenko NN, Stavitkaja NKh, et al. Method of preparing aluminium hydroxide gel for production of medicinal immunobiological preparations. Patent of the Russian Federation No. RU2171678 C1; 2000 (In Russ.). EDN: GCTIEDChang M, Shi Y, Nail SL, et al. Degree of antigen adsorption in the vaccine or interstitial fluid and its effect on the antibody response in rabbits. Vaccine. 2001;19(20–22):2884–9. https://doi.org/10.1016/s0264-410x(00)00559-4Chang M, Shi Y, Nail SL, et al. Degree of antigen adsorption in the vaccine or interstitial fluid and its effect on the antibody response in rabbits. Vaccine. 2001;19(20–22):2884–9. https://doi.org/10.1016/s0264-410x(00)00559-4Hansen B, Belfast M, Soung G, et al. Effect of the strength of adsorption of hepatitis B surface antigen to aluminum hydroxide adjuvant on the immune response. Vaccine. 2009;27(6):888–92. https://doi.org/10.1016/j.vaccine.2008.11.078Hansen B, Belfast M, Soung G, et al. Effect of the strength of adsorption of hepatitis B surface antigen to aluminum hydroxide adjuvant on the immune response. Vaccine. 2009;27(6):888–92. https://doi.org/10.1016/j.vaccine.2008.11.078

The authors declare that there are no conflicts of interest present.