biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2026-26-2-230-240biopreparat-737Research ArticleСТАНДАРТИЗАЦИЯ И КОНТРОЛЬ КАЧЕСТВАQUALITY CONTROL AND STANDARDISATIONЛипоолигосахарид в цельноклеточных коклюшных вакцинах: корреляция его содержания с параметрами специфической безопасности у мышейLipooligosaccharide in whole-cell pertussis vaccines: Correlation of its content with specific safety parameters in micehttps://orcid.org/0000-0001-5586-2933АлексееваИ. А.AlekseevaI. A.

Алексеева Ирина Андреевна, д-р мед. наук

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

Irina A. Alekseeva, Dr. Sci. (Med.)

8/2 Petrovsky Blvd., Moscow 127051

alekseevai@expmed.ruhttps://orcid.org/0000-0003-0305-7769ШаповаловаО. В.ShapovalovaO. V.

Шаповалова Ольга Владимировна, канд. фарм. наук

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

Olga V. Shapovalova, Cand. Sci. (Pharm.)

8/2 Petrovsky Blvd., Moscow 127051

shapovalova@expmed.ruhttps://orcid.org/0000-0003-0379-5980СапожниковаГ. А.SapozhnikovaG. A.

Сапожникова Галина Алексеевна

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

Galina A. Sapozhnikova

8/2 Petrovsky Blvd., Moscow 127051

sapozhnikova@expmed.ruhttps://orcid.org/0000-0001-8615-952XНеугодоваН. П.NeugodovaN. P.

Неугодова Наталия Петровна, канд. биол. наук

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

Nataliia P. Neugodova, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd., Moscow 127051

neugodova@expmed.ruhttps://orcid.org/0009-0003-4061-8892ЛепиховаД. Н.LepikhovaD. N.

Лепихова Дарья Николаевна

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

Darya N. Lepikhova

8/2 Petrovsky Blvd., Moscow 127051

lepihova@expmed.ruhttps://orcid.org/0009-0001-8002-2407ИбрагимхалиловаИ. В.IbragimkhalilovaI. V.

Ибрагимхалилова Ильхамья Вейсаловна, канд. биол. наук

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

Ilkhamya V. Ibragimkhalilova, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd., Moscow 127051

ibragimhalilova@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202604072026262230240Copyright © Алексеева И.А., Шаповалова О.В., Сапожникова Г.А., Неугодова Н.П., Лепихова Д.Н., Ибрагимхалилова И.В., 20262026Алексеева И.А., Шаповалова О.В., Сапожникова Г.А., Неугодова Н.П., Лепихова Д.Н., Ибрагимхалилова И.В.Alekseeva I.A., Shapovalova O.V., Sapozhnikova G.A., Neugodova N.P., Lepikhova D.N., Ibragimkhalilova I.V.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/737 

 

ВВЕДЕНИЕ

ВВЕДЕНИЕ. Реактогенность цельноклеточных коклюшных вакцин (ЦКВ) в основном обусловлена присутствием липоолигосахарида (ЛОС) – бактериального эндотоксина (БЭ) наружной мембраны Bordetella pertussis. Оценка содержания ЛОС в ЦКВ и его корреляции со специфической безопасностью позволит определить приемлемый уровень ЛОС, не усиливающий реактогенность.

ЦЕЛЬ

ЦЕЛЬ. Определение содержания липоолигосахарида в цельноклеточных коклюшных вакцинах и установление корреляции с параметрами специфической безопасности у мышей (изменением массы тела и показателем специфической безопасности).

МАТЕРИАЛЫ И МЕТОДЫ

МАТЕРИАЛЫ И МЕТОДЫ. Исследовали экспериментальные серии ЦКВ из производственных (38, 475, 703) и циркулирующих штаммов B. рertussis (1-20, 2-20, 16-16, 25-16, 28(1)-18, 30-18, 33-18), выделенных от больных коклюшем детей. Содержание БЭ определяли гель- тромб тестом и турбидиметрическим методом. Параметры специфической безопасности оценивали через 24 ч и 7 сут после введения препарата по изменению массы тела аутбредных мышей обоего пола, а также по значению показателя специфической безопасности (%).

РЕЗУЛЬТАТЫ

РЕЗУЛЬТАТЫ. Определено содержание БЭ на протяжении следующих сроков хранения: 1 год после изготовления ЦКВ (до сведения ЦКВ с другими компонентами АКДС-вакцины); от 1 до 2,5 года (срок годности ЦКВ в составе АКДС-вакцины); от 2,5 до 6 лет (после истечения срока годности). Средние значения содержания БЭ в ЦКВ из циркулирующих штаммов при хранении 1 год и 1–2,5 года составили 41872,9–70576,0 ЕЭ/мл; в ЦКВ из производственного штамма при хранении 1–2,5 года – 43980,6 ЕЭ/мл. В вакцинах с продолжительностью хранения 2,5–6 лет средние значения БЭ составляли 1353,8–26655,0 ЕЭ/мл. Установлен широкий диапазон значений содержания БЭ в изготовленных сериях: от <1000–1270 ЕЭ/мл (штамм 30-18) до 36430–94270 ЕЭ/мл (штамм 703). Показатели специфической безопас­ности образцов, кроме свежеизготовленных 16-16 и 33-18, составили >60%. Установлена обратная корреляционная связь умеренной силы между содержанием БЭ и изменением массы тела мышей и показателем специфической безопасности.

ВЫВОДЫ

ВЫВОДЫ. Содержание БЭ в образцах ЦКВ с продолжительностью хранения 1 год и 1–2,5 года статистически не различалось. Показатели специфической безопасности образцов (>60%) свидетельствуют о соответствии уровня БЭ требованиям безопасности. Обратная корреляция между содержанием БЭ (in vitro) и показателем специфической безопасности (in vivo) подтверждает роль ЛОС в специфической токсичности препарата, что обосновывает актуальность дальнейшего изучения его уровня в штаммах B. pertussis и влияния на безопасность ЦКВ.

 

 

INTRODUCTION

INTRODUCTION. The reactogenicity of whole-cell pertussis vaccines (wPV) is largely attributable to the presence of lipooligosaccharide (LOS), a bacterial endotoxin (BE) from the outer membrane of Bordetella pertussis. Assessing the LOS content in wPV and its correlation with specific safety parameters would help establish an acceptable LOS level that does not increase reactogenicity.

AIM

AIM. This study aimed to determine the lipooligosaccharide content in whole-cell pertussis vaccines and establish its correlation with specific safety parameters in mice (body weight change and specific safety index).

MATERIALS AND METHODS

MATERIALS AND METHODS. Experimental batches of wPV manufactured from production strains (38, 475, 703) and from B. pertussis circulating strains (1-20, 2-20, 16-16, 25-16, 28(1)-18, 30-18, 33-18), isolated from children with pertussis, were studied. BE content was measured using the gel-clot test and the turbidimetric method. Specific safety parameters were assessed 24 hours and 7 days after administration by monitoring body weight changes in outbred mice of both sexes and by calculating the specific safety index (%).

RESULTS

RESULTS. BE content was determined at three time intervals: within 1 year after wPV manufacture (prior to combining with other diphtheria, tetanus, and pertussis (DTP) vaccine com­ponents); from 1 to 2.5 years (shelf life of wPV as part of the DTP vaccine); and from 2.5 to 6 years (after expiry). Mean BE content in wPV from circulating strains stored for 1 year and for 1–2.5 years ranged from 41,872.9 to 70,576.0 EU/mL; in wPV from the production strain stored for 1–2.5 years, it was 43,980.6 EU/mL. Vaccines stored for 2.5–6 years showed mean BE values ranging from 1353.8 to 26,655.0 EU/mL. A wide range of BE content was observed across manufactured batches, varying from <1000–1270 EU/mL (strain 30-18) to 36,430–94,270 EU/mL (strain 703). Specific safety index values for all samples, except for the freshly prepared 16-16 and 33-18, were >60%. A moderate inverse correlation was found between BE content and both mouse body weight change and the specific safety index.

CONCLUSIONS

CONCLUSIONS. BE content did not differ statistically between wPV samples stored for 1 year and those stored for 1–2.5 years. The specific safety index values (>60%) indicate that the BE levels comply with safety requirements. The inverse correlation between BE content (in vitro) and the specific safety index (in vivo) confirms the role of LOS in the specific toxicity of the vaccine, supporting further investigation into its levels in B. pertussis strains and its impact on wPV safety.

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