АДЪЮВАНТНЫЙ И ДРУГИЕ ЭФФЕКТЫ ВАКЦИНЫ БЦЖ И ЕЕ ВЛИЯНИЕ НА ЭПИДЕМИОЛОГИЮ НОВОЙ КОРОНАВИРУСНОЙ БОЛЕЗНИ COVID-19


Авторы

https://doi.org/10.32415/jscientia_2020_6_4_5-29

Ключевые слова:

адъювант, аутоиммунитет, вакцинация БЦЖ, острый респираторный дистресс-синдром, перекрестная антигенная специфичность, тренированный иммунитет, коронавирус, SARS-CoV-2, коронавирусная болезнь, COVID-19, цитокины
Финансирование
Работа выполнена в рамках реализации постановления Правительства Российской Федерации 220 и поддержана грантом Правительства РФ для государственной поддержки научных исследований, проводимых под руководством ведущих ученых, договор 14.W03.31.0009

Аннотация

Живая вакцина БЦЖ, вызывая комплексный ответ как врожденного, так и клеточного/гуморального адаптивного иммунитета, служит биологическим адъювантом. Она выступает триггером «тренированной» реакции иммунной системы, характеризующейся активацией моноцитов, макрофагов, естественных киллеров, а также лимфоидных клеток врожденных популяций. Это способствует скорейшей активации неантигенспецифических защитных программ организма в борьбе с рядом вирусных, грибковых, протозойных инфекций и неоплазией. Одной из таких инфекций может быть COVID-19. Патогенез развития острой интерстициальной пневмонии/респираторного дистресс-синдрома, вызванных COVID-19, характеризуется запуском избыточного системного действия медиаторов воспаления, в частности – цитокинов, при нарушении его фокальных барьеров. Гамма-интерферон, вырабатываемый лимфоцитами после вакцинации БЦЖ, модулирует активность ряда интерлейкинов, что, в свою очередь, может способствовать менее тяжелому течению COVID-19 за счет снижения активности ИЛ-12 и ИЛ-18-зависимых реакций. Между возбудителями микобактериозов и COVID-19 существует антигенный перекрест из-за гомологии белков. В отличие от многих адъювантов, неоднозначно влияние БЦЖ на разные аутоиммунные заболевания (провокация одних и протективное действие при других), как и на риск возникновения лимфом (БЦЖ его снижает, тогда как многие адъюванты повышают). Это, видимо, связано с назначением БЦЖ в очень ранний период, при незрелой иммунной системе и отражает симбионтный характер взаимодействия штамма БЦЖ и организма хозяина. Приведены по странам данные о связи исторической практики применения вакцинации БЦЖ и текущей заболеваемости новой коронавирусной инфекцией и смертности от нее. Рассмотрены в историческом ключе медико-социальные причины разной национальной политики органов здравоохранения в отношении применения вакцины БЦЖ.

Библиографические ссылки

Авцын А.П. Адаптация и дизадаптация с позиции патолога // Клин. мед. 1974. № 5. С. 3-15. [Avtsyn AP. Adaptation and desadaptation from the viewpoint of pathologist. Klin. med. 1974;5:3-15. (in Russ)].

Поземковска М., Чурилов Л.П. Илья Ильич Мечников и всемирное значение его наследия // Клин. патофизиол. 2016. Т. 22. № 3. С. 3-28. [Pozemkovska M, Churilov LP. Elie Metchnikoff and the global importance of his legacy. Clin. Pathophysiol. 2016;22(3):3-28. (in Russ)].

Рябкова В.А., Чурилов Л.П., Шенфельд И. Гиперстимуляция иммунной системы как причина аутоиммунных заболеваний // Вестник РАМН. 2020. Т. 75. № 3. С. 204-213. [Ryabkova VA, Churilov LP. Shoenfeld Y. Hyperstimulation of the immune system as a cause of autoimmune diseases. Annals of the Russian Academy of Medical Sciences. 2020;75(3):204-213. (in Russ)]. DOI: 10.15690/vramn1276.

Чурилов Л.П. Общая патофизиология с основами иммунопатологии. Изд-е 5-е, дополн., СПб.: ЭЛБИ-Спб, 2015. [Churilov LP. General Pathophysiology with the Fundamentals of Immunopathology. 5th ed., amended. ELBI-SPb Publisher: Saint Petersburg, 2015. (in Russ)].

Abate G, Hamzabegovic F, Eickhoff CS, et al. BCG Vaccination Induces M. avium and M. abscessus Cross-Protective Immunity. Front Immunol. 2019;10:234. DOI: 10.3389/fimmu.2019.00234.

Abbas AM, AbouBakr A, Bahaa N, et al. The effect of BCG vaccine in the era of COVID-19 pandemic. Scand J Immunol. 2020;e12947. DOI: 10.1111/sji.12947.

Ambrosch F, Krepler P, Wiedermann G. Zur Frage des Einflusses der BCG-Neugeborenen-Impfung auf die Leukämie-Häufigkeit. MMW Munch Med Wochenschr. 1978;120(8):243-246.

Angelidou A, Diray-Arce J, Conti MG, et al. BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny. Front Microbiol. 2020;11:332. DOI: 10.3389/fmicb.2020.00332.

Arts RJW, Moorlag SJCFM, Novakovic B, et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018;23(1):89-100.e5. DOI: 10.1016/j.chom.2017.12.010.

Asher R. The seven sins of medicine. Lancet. 1949;2(6574):358-360. DOI: 10.1016/s0140-6736(49)90090-2.

Ayoub BM. COVID-19 vaccination clinical trials should consider multiple doses of BCG. Pharmazie. 2020;75(4):159. DOI: 10.1691/ph.2020.0444.

Aziz AB, Dembinski JL, Jahan Y. Debate on Bacille Calmette-Guérin vaccination against COVID-19: Is it worth performing clinical trials? Biosaf Health. 2020;10.1016/j.bsheal.2020.07.001. DOI: 10.1016/j.bsheal.2020.07.001.

Bai JN, Bian YQ, Zhao BH. Construction of recombinant BCG bearing S1 glycoprotein of nephropathogenic IBV and study on its immunogenicity on chickens. Wei Sheng wu xue bao = Acta Microbiologica Sinica. 2007;47(2):324-328.

Barneoud P, Rivet JM, Vitiello S, et al. Brain norepinephrine levels after BCG stimulation of the immune system. Immunol Lett. 1988;18(3):201-4. DOI: 10.1016/0165-2478(88)90019-3. Erratum in: Immunol Lett 1988;19(4):351.

Berg MR, Yu QG, Salvador CE, et al. Mandated Bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19. Sci. Adv. 2020;6:eabc1463. DOI: 10.1126/sciadv.abc1463.

Berendsen ML, van Gijzel SW, Smits J, et al. BCG vaccination is associated with reduced malaria prevalence in children under the age of 5 years in sub-Saharan Africa. BMJ Glob. Health. 2019;4:e001862.

Calmette A, Guerin C, Weill-Halle B, et al. Essai d’immunisation contre l’infection tuberculeuse. Bull Acad Med. (Paris);1924;91:787-796.

Caminati M, Furci F, Senna G, et al. BCG vaccination and COVID-19: Much ado about nothing? Med Hypotheses. 2020;144:110109. DOI: 10.1016/j.mehy.2020.110109.

Carroll MV, Lack N, Sim E, et al. Multiple routes of complement activation by Mycobacterium bovis BCG. Mol Immunol. 2009;46(16):3367-3378. DOI: 10.1016/j.molimm.2009.07.015.

Charoenlap S, Piromsopa K, Charoenlap C. Potential role of Bacillus Calmette-Guérin (BCG) vaccination in COVID-19 pandemic mortality: Epidemiological and Immunological aspects. Asian Pac J Allergy Immunol. 2020;10.12932/AP-310520-0863. DOI: 10.12932/AP-310520-0863.

Checcucci E, Piramide F, Pecoraro A, et al. The vaccine journey for COVID-19: a comprehensive systematic review of current clinical trials in humans. Panminerva Med. 2020;10.23736/S0031-0808.20.03958-0. DOI: 10.23736/S0031-0808.20.03958-0.

Ciliberto G, Mancini R, Paggi MG. Drug repurposing against COVID-19: focus on anticancer agents. J Exp Clin Cancer Res. 2020;39(1):86. DOI: 10.1186/s13046-020-01590-2.

Chopra KK, Arora VK, Singh S. COVID 19 and tuberculosis. Indian J Tuberc. 2020;67(2):149-151. DOI: 10.1016/j.ijtb.2020.06.001.

Covián C, Retamal-Díaz A, Bueno SM, et al. Could BCG Vaccination Induce Protective Trained Immunity for SARS-CoV-2? Front Immunol. 2020;11:970. DOI: 10.3389/fimmu.2020.00970.

Curtis N, Sparrow A, Ghebreyesus TA, et al. Considering BCG vaccination to reduce the impact of COVID-19. Lancet. 2020;395(10236):1545-1546. DOI: 10.1016/S0140-6736(20)31025-4.

Das G, Mukherjee N, Ghosh S. Neurological Insights of COVID-19 Pandemic. ACS Chem Neurosci. 2020;11(9):1206-1209. DOI: 10.1021/acschemneuro.0c00201.

David P, Shoenfeld Y. Bacillus Calmette-Guerin (BCG) as a Protective Factor for COVID-19? Isr Med Assoc J. 2020;8(22):448-449.

Desouky E. BCG versus COVID-19: impact on urology. World J Urol. 2020;1-5. DOI: 10.1007/s00345-020-03251-7.

Ehrenfeld M, Tincani A, Andreoli L, et al. Covid-19 and autoimmunity. Autoimmun Rev. 2020;19(8):102597. DOI: 10.1016/j.autrev.2020.102597.

Faustman DL. Permanent reversal of diabetes in NOD mice. Science. 2007;317(5835):196. DOI: 10.1126/science.317.5835.196a.

Floc'h F, Werner GH. Increased resistance to virus infections of mice inoculated with BCG (Bacillus calmette-guérin). Ann Immunol (Paris). 1976;127(2):173-186.

Freund J, McDermott K. Sensitization to horse serum by means of adjuvants. Proc Soc Exp Biol Med. 1942;49(4):548-553. DOI: 10.3181/00379727-49-13625.

Gheorghiu M. BCG-induced mucosal immune responses. Int J Immunopharmacol. 1994;16(5-6):435-444. DOI: 10.1016/0192-0561(94)90033-7.

Greenwood M. Professor Calmette’s Statistical Study of BCG Vaccination. BMJ. 1928;1:793-795.

Gupta PK. New disease old vaccine: Is recombinant BCG vaccine an answer for COVID-19? Cell Immunol. 2020;356:104187. DOI: 10.1016/j.cellimm.2020.104187.

Jain VK, Iyengar K, Vaish A, et al. Differential mortality in COVID-19 patients from India and western countries. Diabetes Metab Syndr. 2020;14(5):1037-1041. DOI: 10.1016/j.dsx.2020.06.067.

Johnson S, Laloraya M. A cytokine super cyclone in COVID-19 patients with risk factors: the therapeutic potential of BCG immunization. Cytokine and Growth Factor Reviews, 2020;preprint. DOI: 10.1016/j.cytogfr.2020.06.014.

Hanekom WA. The immune response to BCG vaccination of newborns. Ann N Y Acad Sci. 2005;1062:69-78. DOI: 10.1196/annals.1358.010.

Harandi AM. Systemic analysis of human vaccine adjuvants. Semin Immunol. 2018;39:30-34.

Hauer J, Fischer U, Auer F, Borkhardt A. Regional BCG vaccination policy in former East- and West Germany may impact on both severity of SARS-CoV-2 and incidence of childhood leukemia. Leukemia. 2020;34:2217-2219. DOI: 10.1038/s41375-020-0871-4.

Hegarty PK, Sfakianos JP, Giannarini G, et al. COVID-19 and Bacillus Calmette-Guérin: What is the Link? Eur Urol Oncol. 2020;3(3):259-261. DOI: 10.1016/j.euo.2020.04.001.

Huszarik K, Wright B, Keller C, et al. Adjuvant immunotherapy increases beta cell regenerative factor Reg2 in the pancreas of diabetic mice. J Immunol. 2010;185(9):5120-5129. DOI: 10.4049/jimmunol.1001596.

Kantor IN. ¿BCG versus COVID-19? Medicina (B Aires). 2020;80(3):292-294.

Kinoshita M, Tanaka M. Impact of routine infant BCG vaccination in young generation on prevention of local COVID-19 spread in Japan. J Infect. 2020;S0163-4453(20)30547-8. DOI: 10.1016/j.jinf.2020.08.013.

Klein BY. Newborn BCG vaccination complemented by boosting correlates better with reduced juvenile diabetes in females, than vaccination alone. Vaccine. 2020;S0264-410X(20)31008-2. DOI: 10.1016/j.vaccine.2020.07.066.

Kleinnijenhuis J, Quintin J, Preijers P, et al. Netea, Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A. 2012;109:17537-17542.

Koti M, Morales A, Graham CH, et al. BCG vaccine and COVID-19: implications for infection prophylaxis and cancer immunotherapy. J Immunother Cancer. 2020;8(2):e001119. DOI: 10.1136/jitc-2020-001119.

Kowalewicz-Kulbat M, Locht C. BCG and protection against inflammatory and auto-immune diseases. Expert Rev Vaccines. 2017;16(7):1-10. DOI: 10.1080/14760584.2017.1333906.

Kumar J, Meena J. Demystifying BCG Vaccine and COVID-19 Relationship. Indian Pediatr. 2020;57(6):588-589. DOI: 10.1007/s13312-020-1872-0.

Lawton G. Trials of BCG vaccine will test for covid-19 protection. New Sci. 2020;246(3280):9. DOI: 10.1016/S0262-4079(20)30836-8.

Lee IF, van den Elzen P, Tan R, et al. NKT cells are required for complete Freund's adjuvant-mediated protection from autoimmune diabetes. J Immunol. 2011;187(6):2898-2904. DOI: 10.4049/jimmunol.1002551.

Lenfant L, Seisen T, Loriot Y, et al. Adjustments in the Use of Intravesical Instillations of Bacillus Calmette-Guérin for High-risk Non-muscle-invasive Bladder Cancer During the COVID-19 Pandemic. Eur Urol. 2020;78(1):1-3. DOI: 10.1016/j.eururo.2020.04.039.

Li X, Geng M, Peng Y, et al. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal. 2020;10(2):102-108. DOI: 10.1016/j.jpha.2020.03.001.

Luca S, Mihaescu T. History of BCG Vaccine. Maedica (Bucharest). 2013;8(1):53-58.

Lyu J, Miao T, Dong J, et al. Reflection on lower rates of COVID-19 in children: Does childhood immunizations offer unexpected protection? Med Hypotheses. 2020;143:109842. DOI: 10.1016/j.mehy.2020.109842.

Macedo A, Febra C. Relation between BCG coverage rate and COVID-19 infection worldwide. Med Hypotheses. 2020;142:109816. DOI: 10.1016/j.mehy.2020.109816.

Marimuthu Y, Nagappa B, Sharma N, et al. COVID-19 and tuberculosis: A mathematical model based forecasting in Delhi, India. Indian J Tuberc. 2020;67(2):177-181. DOI: 10.1016/j.ijtb.2020.05.006.

Mastaglio S, Ruggeri A, Risitano AM, et al. The first case of COVID-19 treated with the complement C3 inhibitor AMY-101. Clin Immunol. 2020;215:108450. DOI: 10.1016/j.clim.2020.108450.

Matsumoto M, Seya T, Kikkawa S, et al. Interferon gamma-producing ability in blood lymphocytes of patients with lung cancer through activation of the innate immune system by BCG cell wall skeleton. Int Immunopharmacol. 2001;1(8):1559-1569. DOI: 10.1016/s1567-5769(01)00071-6. Erratum in: Int Immunopharmacol 2002;2(5):731.

Miller A, Reandelar MJ, Fasciglione K, et al. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. MedRxiv. 2020;preprint. DOI: 10.1101/2020.03.24.20042937.

Miyasaka M. Is BCG vaccination causally related to reduced COVID-19 mortality? EMBO Mol Med. 2020;12(6):e12661. DOI: 10.15252/emmm.202012661.

Moorlag SJCFM, van Deuren RC, van Werkhoven CH, et al. Safety and COVID-19 Symptoms in Individuals Recently Vaccinated with BCG: a Retrospective Cohort Study. Cell Rep Med. 2020;1(5):100073. DOI: 10.1016/j.xcrm.2020.100073.

Morra ME, Kien ND, Elmaraezy A, et al. Early vaccination protects against childhood leukemia: a systematic review and meta-analysis. Sci Rep. 2017;7:15986.

Naserghandi A, Saffarpour R, Allameh SF. Exploring the causes of mild COVID-19 involvement in pediatric patients. New Microbes and New Infections. 2020;37:100741. DOI: 10.1016/j.nmni.2020.100741.

Netea MG, van Crevel R. BCG-induced protection: effects on innate immune memory. Semin Immunol. 2014;26(6):512-517. DOI: 10.1016/j.smim.2014.09.006.

Nuovo G, Tili E, Suster D, et al. Strong homology between SARS-CoV-2 envelope protein and a Mycobacterium sp. antigen allows rapid diagnosis of Mycobacterial infections and may provide specific anti-SARS-CoV-2 immunity via the BCG vaccine. Ann Diagn Pathol. 2020;48:151600. DOI: 10.1016/j.anndiagpath.2020.151600.

O'Connor E, Teh J, Kamat AM, et al. Bacillus Calmette Guérin (BCG) vaccination use in the fight against COVID-19 – what's old is new again? Future Oncol. 2020;16(19):1323-1325. DOI: 10.2217/fon-2020-0381.

O'Connor RA, Li X, Blumerman S, et al. Adjuvant immunotherapy of experimental autoimmune encephalomyelitis: immature myeloid cells expressing CXCL10 and CXCL16 attract CXCR3+CXCR6+ and myelin-specific T cells to the draining lymph nodes rather than the central nervous system. J Immunol. 2012;188(5):2093-2101. DOI: 10.4049/jimmunol.1101118.

O'Neill LAJ, Netea MG. BCG-induced trained immunity: can it offer protection against COVID-19? Nat Rev Immunol. 2020;20(6):335-337. DOI: 10.1038/s41577-020-0337-y.

Osama El-Gendy A, Saeed H, Ali AMA, et al. Bacillus Calmette-Guérin vaccine, antimalarial, age and gender relation to COVID-19 spread and mortality. Vaccine. 2020;38(35):5564-5568. DOI: 10.1016/j.vaccine.2020.06.083.

Őzdemir C, Kucuksezer UC, Tamay ZU. Is BCG vaccination affecting the spread and severity of COVID-19? Allergy. 2020;75(7):1824-1827. DOI: 10.1111/all.14344.

Pan D, Sze S, Minhas JS, et al. The impact of ethnicity on clinical outcomes in COVID-19: A systematic review. EClinicalMedicine. 2020;23:100404. DOI: 10.1016/j.eclinm.2020.100404.

Petroff SA, Branch A, Steenken W. A Study of Bacillus Calmette-Guerin (B.C.G.). Am Rev Tuberc. 1929;19: 9-46.

Raghab Mohapatra P, Mishra B, Behera B. BCG vaccination induced protection from COVID-19. Indian Journal of Tuberculosis. 2020;preprint. DOI: 10.1016/j.ijtb.2020.08.004.

Riccò M, Gualerzi G, Ranzieri S, Bragazzi NL. Stop playing with data: there is no sound evidence that Bacille Calmette-Guérin may avoid SARS-CoV-2 infection (for now). Acta Biomed. 2020;91(2):207-213. DOI: 10.23750/abm.v91i2.9700.

Rosenthal SR, Crispen RG, Thorne MG, et al. BCG vaccination and leukemia mortality. J Am Med Assoc. 1972;222:1543-1544.

Sehrawat S, Rouse BT. Does the hygiene hypothesis apply to COVID-19 susceptibility? Microbes Infect. 2020;S1286-4579(20)30127-1. DOI: 10.1016/j.micinf.2020.07.002.

Semple PL, Watkins M, Davids V, et al. Induction of granulysin and perforin cytolytic mediator expression in 10-week-old infants vaccinated with BCG at birth. Clin Dev Immunol. 2011;2011:438463. DOI: 10.1155/2011/438463.

Sharma AR, Batra G, Kumar M, et al. BCG as a game-changer to prevent the infection and severity of COVID-19 pandemic? Allergol Immunopathol (Madrid). 2020:S0301-0546(20)30106-3. DOI: 10.1016/j.aller.2020.05.002.

Shoenfeld Y. Corona (COVID-19) time musings: Our involvement in COVID-19 pathogenesis, diagnosis, treatment and vaccine planning. Autoimmun Rev. 2020;19(6):102538. DOI: 10.1016/j.autrev.2020.102538.

Shoenfeld Y, Aron-Maor A, Tanai A, Ehrenfeld M. BCG and autoimmunity: another two-edged sword. J Autoimmun. 2001;16(3):235-240. DOI: 10.1006/jaut.2000.0494.

Shoenfeld Y, Isenberg DA. Mycobacteria and autoimmunity. Immunol. Today. 1988;9(6):178-182. DOI: 10.1016/0167-5699(88)91294-7.

Spix C, Eletr D, Blettner M, Kaatsch P. Temporal trends in the incidence rate of childhood cancer in Germany 1987-2004. Int J Cancer. 2008;122:1859-1867.

Ten Doesschate T, et al. Correction to: Two Randomized Controlled Trials of Bacillus Calmette-Guerin Vaccination to reduce absenteeism among health care workers and hospital admission by elderly persons during the COVID-19 pandemic: A structured summary of the study protocols for two randomised controlled trials. Trials. 2020;21(1):555.

Van Rie A, Madhi SA, Heera JR, et al. Gamma interferon production in response to Mycobacterium bovis BCG and Mycobacterium tuberculosis antigens in infants born to human immunodeficiency virus-infected mothers. Clin Vaccine Immunol. 2006;13(2):246-252. DOI: 10.1128/CVI.13.2.246-252.2006

Wardhana A, Datau EA, Sultana A, et al. The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly. Acta Med. Indones. 2011;43:185-190.

Watad A, Quaresma M, Brown S, et al. Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld’s syndrome) – An update. Lupus, 2017;26(7):675-681. DOI: 10.1177/0961203316686406.

Watad A, Bragazzi NL, Shoenfeld Y. Immunologist's Little Dirty Secret Finger: A Case Report of Polyautoimmunity Following an Accidental Self-injection of Complete Freund's Adjuvant. Isr Med Assoc J. 2020;22(6):393-394.

Wu J, Li X, Song W, et al. The roles and applications of autoantibodies in progression, diagnosis, treatment and prognosis of human malignant tumours. Autoimmun Rev. 2017;16(12):1270-1281. DOI: 10.1016/j.autrev.2017.10.012.

Yamamoto N, Bauer G. Apparent difference in fatalities between Central Europe and East Asia due to SARS-COV-2 and COVID-19: Four hypotheses for possible explanation. Med Hypotheses. 2020;144:110160. DOI: 10.1016/j.mehy.2020.110160.

Yamazaki-Nakashimada MA, Unzueta A, Berenise Gámez-González L, et al. BCG: a vaccine with multiple faces. Hum Vaccin Immunother. 2020;29:1-10. DOI: 10.1080/21645515.2019.1706930.

Zhou G, Chen S, Chen Z. Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies. Front Med. 2020;14(2):117-125. DOI: 10.1007/s11684-020-0773-x.

Zwerling A, Behr MA, Verma A, et al. The BCG World Atlas: A Database of Global BCG Vaccination Policies and Practices. PLoS Med. 2011;8(3):e1001012. DOI: 10.1371/journal.pmed.1001012.

URL: https://www.worldometers.info/coronavirus

URL: https://en.wikipedia.org/wiki/BCG_vaccine#Europe

URL:https://apps.who.int/immunization_monitoring/globalsummary/countres?countrycriteria%5Bcountry%5D%5B%5D=TJK

URL: https://www.whonamedit.com/synd.cfm/2816.html

URL: https://www.nobelprize.org/nomination/archive

Portrait of Jean Marie Camille Guerin with Leon Charles Albert Calmette // Wellcome Library, London. Wellcome Images. http://catalogue.wellcomelibrary.org/record=b1349948

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30.08.2020

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Ивашкевич Я.В., Козачевская Л.Ю., Петяева А.В., Чурилов Л.П. АДЪЮВАНТНЫЙ И ДРУГИЕ ЭФФЕКТЫ ВАКЦИНЫ БЦЖ И ЕЕ ВЛИЯНИЕ НА ЭПИДЕМИОЛОГИЮ НОВОЙ КОРОНАВИРУСНОЙ БОЛЕЗНИ COVID-19 // Juvenis Scientia. 2020. т. 6, № 4. сс. 5-29. DOI: 10.32415/jscientia_2020_6_4_5-29.

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