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Эпидемиология и Вакцинопрофилактика

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На путях к индивидуализации вакцинации: значение возраста и пола

https://doi.org/10.31631/2073-3046-2021-20-6-88-99

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Аннотация

Актуальность. Высокая вариабельность защиты от инфекций, контролируемых вакцинацией, включая COVID-19, является одной из актуальных проблем инфектологии. Цель. На основе анализа результатов научных публикаций и отчетов проанализирована роль факторов возраста и пола, их взаимодействия и основных механизмов в иммунном ответе на вакцины, в совершенствовании вакцин и схем вакцинации. Заключение. Показано, что вакцинопрофилактика всегда развивалась в направлении индивидуализации, проходя этапы определения целевых групп и разработки схем иммунизации различных групп. Проанализированы полученные в последние десятилетия важные данные о значении генетических и внешних факторов, в частности, возраста и пола, в вариабельности ответа на вакцины. Анализ роли таких факторов выполнен также для коронавирусных вакцин. Обсуждены необходимость и возможности очередных действий, которые могут обеспечить оптимальные ответы различных людей на вакцинацию.

Об авторе

Б. В. Каральник
Общественное Объединение «Научно-медицинское общество»; Научный центр гигиены и эпидемиологии им. Х. Жуматова, филиал Национального Центра общественного здравоохранения
Казахстан

Борис Вольфович Каральник  – д. м. н. (микробиология), профессор (иммунология), главный научный сотрудник, Общественное Объединение «Научно-медицинское общество»

Республика Казахстан
Тел. +7 27 303 10 89, +7 (705) 302-86-78



Список литературы

1. Jenner E An Inquiry Into the Causes and Effects of the Variolae Vaccinae, A Disease Discovered in Some of the Western Countries of England, Particularly Gloucestershire, and Known by the Name of the Cow Pox - London.1798

2. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin. Inf. Dis. 2014;59(1):144. https:doi.org/10.1093/cid/cit816

3. Каральник Б. В, Рамазанова Б. А. Защита от инфекций групп риска вакцинацией. На чем основаны правила вакцинации групп риска? Методические рекомендации. Алматы. Научное издание. 2018. 44 с.

4. Poland GA, Kennedy RB, McKinney BA, et al. Vaccinomics, adversomics, and the immune response network theory: Individualized vaccinology in the 21st century Seminars in Immunology 2013;25(2):89–103 https:doi.0rg/10.1016/j.smim.2013.04.007

5. Qin L, Li X, Shi J, et al. Gendered effects on inflammation reaction and outcome of COVID-19 patients in Wuhan. Med. Virol.2020;92(11):2684–2692. https:doi.org/10.1002/jmv.26137

6. Wtinberger B, Heinder-Brandstetter D, Schwanninger A, et al. Biology of immune responses to vaccines in elderly persons. Clin. Infect. Dis.2008;46(7):1078–84

7. Chen WH, Kozlovsky BF, Effros RB, et al. Vaccination in the elderly: an immunological perspective Trends Immunol. 2009;30(7):351–9.

8. Williamson EJ, Walker AJ, Goldacre B, et al. Factors associated with COVID-19-related death using Open SAFELY. Nature.2020;584:430–436.

9. Senden Th.F Response to intradermal hepatitis B vaccination: differences between males and females? Vaccine. 1990;8(6):612–613. https:doi.org/10.1016/0264-410X(90)90037-m

10. Kiecolt-Glaser JK, Glaser R, Gravenstein S, et al. Chronic stress alters the immune response to influenza virus vaccine in older adults. PNAS 1996;93(7):3043–3047. https:doi.0rg/10.1073/pnas.937.3043

11. Giefing-Kroll C, Berger P, Lepperdinger G, et al. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell.2015;14:309–321. doi:10.1111/acel.12326.

12. Edelman R, Deming ME, Toapanta FR, et al. The SENIEUR protocol and the efficacy of hepatitis B vaccination in healthy elderly persons by age, gender, and vaccine route. Immunity and Ageing,2020;17::9. doi:10.1186/s12979-020-00179

13. Marquez EJ, Chung Ch-h, Marches R, et al. Sexual-dimorphism in human immune system aging. Nature Communications. 2020;11(1):751. doi:10.1038/s41467-020-14396-9.

14. Piasecka B, Duffy D, Urrutia A, et al. Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges PNAS.2018;115(3):E488–E497. https:doi.org/10.1073/pnas.1714765115

15. Gensous N, Franceschi C, Blombtug BB, et al. Responders and non-responders to influenza vaccination: a DNA methylation approach on blood cells. Exp.Gerontology. 2018;105:94–100.

16. Paul WE. Bridging innate and adaptivei mmunity Cell. 2011:147(6):1212–1215 doi:101016/j.cell.2011.11.036

17. Seyda M, Elkhal A, Quante M, et al. T cells going innate. Trends Immunol.2016;37(8):546–556. doi:10.1016/j.it.2016.06.004

18. Pereira BI, Akbar AN. Convergence of innate and adaptive immunity during human aging. Front. Immunol. 2016; Nov 4;7:445. https:doi.org/10.3389/fimmu.2016.00445.

19. Deshpande S. Effect of biological sex and age on universal influenza vaccine induced immunity in mice. Available at: https:jscholarship.library.jhu.edu/handle/1774.2/62647

20. Beeslaar J, Peyrani P, Absalon J, et al. Sex, age, and race effects on immunogenicity of MenB-FHbp, a bivalent meningococcal B vaccine: pooled evaluation of clinical trial data. Inf. Dis. and Therapy.2020;9:625–639. https:doi.org/10.1007/s40121-020-00322-5

21. Ursin RL, Liu H, Powell HR, et al. Differential antibody recognition of H3N2 vaccine and seasonal influenza virus strains based on age, vaccine status, and sex in the 2017–2018 season. J. Inf. Dis.2020;222(8):1371–1382. https://doi.org/10.1093/infdis/jiaa289

22. Morton SU, Brodsky D. Fetal physiology and the transition to extrauterine life Clin Perinato.2016;43:395–407. doi:10.1016/j.clp.2016.04.001

23. Tsafaras GP, Ntontsi P, Xanthou G. Advantages and limitations of neonatal immune system. Front. Pediatr. 2020. Jan 28;8:5.. https:doi.org/10.3389/fped.2020.00005

24. Chiara F, Bartolucci GB, Mongillo M, et al. Hepatitis B vaccination at three months of age. A successful strategy? Vaccine. 2013;31(13):1696–1700. https:doi.org/10.1016/j.vaccine.2013.01.046

25. Verso MG, Lo Cascio N, Noto Laddeca E, et al. Predictors of hepatitis B surface antigen titres two decades after vaccination in a cohort of students and post-graduets of the Medical School at the University of Palermo, Italy Ann. Agric Environ. Med. 2017;24:303–306. https:doi.org/10.26444/aaem/74716

26. Trevisan A, Giuliani A, Scapellato ML, et al. Sex disparity in response to hepatitis B vaccine related to the age of vaccinationю. Int. J. Environ. Res. 2020;17(1):327. https:doi.org/10.3390/jerph17010327

27. Morris MC, Surendran N. Neonatal vaccination: Challenges and intervention strategies. Neonatology. 2016;109:161–169. https:doi.org/10.1159/000442460

28. Прививки. Вакцины и взрослые. Здоровье на всю жизнь. (перевод 3-го издания). Vaccinations. Vaccines and adults. Health for Life. Philadelphia. 2013:47.

29. Fischer J, Ung N, Robinson N, et al. Sex differences in immune responses to infectious diseases. Infection. 2015;43(4):399–403. https:doi.org/10.1007/s15010-015-0791-9

30. Cook IF. Sexual dimorphism of humoral immunity with human vaccines. Vaccines. 2008;26:3551–3555. https:doi.org/10.1016/j.vaccine.2008.04.054

31. Stanberry LR, Spruance SL, Cunningham AL, et al. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N. Engl. J. Med. 2002;347(21):1652–1661. DOI:10.1056/NEJMoa011915

32. Klein SL, Jedlicka A, Pekosz A. The Xs and Y of immune responses to viral vaccines. Lancet inf dis 2010;10(5):338–349. https:doi.org/10.1016/S1473-3099(10)70049-9;

33. Robert-Guroff M. Immunologic correlates of sexual dimorphism in human and simian immunodeficiency virus vaccine efficacy. Future virology. 2018;13(12):editorial. https:doi.org/10.2217/fvl-2018-0179

34. Klein S, Morgan R. The impact of sex and gender on immunotherapy outcomes Biology of sex differences 2020;11:24. https:doi.org/10.1186s13293-029-00301-y

35. Voysey M, Barker ChIS, Snape MD, et al. Sex-dependent immune responses to infant vaccination: an individual participant data meta-analysis of antibody and memory B cells Vaccine 2016;34:1657–1664. https:doi.org/10.1016/j.vaccine.2016.02.036

36. Furman D, Hejblum BP, Simon N, et al. Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination PNAS. 2013;111(2):869–874. https:doi.org/10.1073/pnas.1321060111

37. Wagenvoort GHJ, Sanders EAM, Vlaminckx BJ, et al. Sex differences in invasive pneumococcal diseases and the impact of pneumococcal conjugate vaccination in the Netherlands. 2004 to 2015. Euro Surveillance. 2017;22(10):30481. https:doi.org/10.2807/1560-7917.ES.2017.22.10.30481

38. Flanagan KL, Fink AL, Plebanski M, et al. Sex and gender differences in the outcomes of vaccination over the life course. Ann. Rev. Cell Dev. Biol.2017;33:577–599. https:doi.org/10.1146/annurev-cellbio-100616-060718

39. Klein SL, Flanagan KL. Sex differences in immune responses. Nat. Rev. Immunol. 2016;16(10):626–638. https:doi.org/10.1038/nri.2016.90

40. Ruggieri A, Malorni W, Ricciardi W. Gender disparity in response to anti-viral vaccines: new clues toward personalized vaccinology. Ital J Gender Med. 2016;2(3):93–98. http:dx.doi.org/10.1723/2625.26991

41. Kadel S, Kovats S. Sex hormones regulate innate immune cells and promote sex differences in respiratory virus infection. Front Immunol. 2018; Jul 20;9:1653. https: doi.org/10.3389/fimmu.2018.01653

42. Douling DK, Mancell E. Toll-like receptors: the swiss army knife of immunity and vaccine development. Clinical and translation immunology. 2016 May 20;5(5):e85. https: doi.org/10.1038/cti.2016.22

43. Aaby P, Benn CS, Flanagan KL, et al. The non-specific and sex-differential effects of vaccines. Nature Reviews Immunology. 2020;20:464–470. https: doi.org/10.1038/s41577-020-0338-x

44. Rechtien A, Altfeld M. Sexual dimorphism in HIV-1 infection. Semin. Immunopathol. 2018. doi:10.1007/s00281-018-0704-y

45. Trigunaite AR, Dimo J, Jǿrgensen TN, et al. Suppressive effects of androgens on the immune system. Cell. Immunology 2015;294(2):87–94. https:doi.org/10.1016/j.cellimm.2015.02.004

46. Waller LA, McGregor AJ. Sex and gender specific observations and implications for COVID-19. West J Emerg Med.2020;21;507–509, https:dx.doi.org/10.5811/westjem.2020.4.47536

47. Taneja V. Sex hormones determine immune response. Front Immunol.2018;9:1931. https:doi.org/10.3389/fimmu.2018.01.1931

48. Beadley KW, Gockel CM Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS Immunol. Med. Microbiol. 2003;38:13–22. https:doi.org/10.1016/S0928-8244(03)00202-5

49. Voigt EA, Ovsyannikova IG, Schaid DJ, et al. Sex differences in older adults immune responses to seasonal influenza vaccination. Frontiers in immunology. Vaccines and molecular therapeutics. https:doi.org/10.3389/fimmu.2019.00180

50. Sankaran-Walters S, Macal M, Grishina I, et al. Sex differences matter in the gut: effect on mucosal immune activation and inflammation. Biol. Sex Differ. 2013;4(1):1–12. https:doi.org/10.1186/2042-6410-4-10

51. Fragiadakis GK, Bjornson-Hooper ZB, Madhireddy D, et al. Variation of immune cell responses in humans reveals sex-specific coordinated signaling across cell types. https:doi.org/10.1101/567784

52. Grgelak L, Velay A, Madek Y, et al. Sex differences in the decline in the neutralizing antibodies to SARS-CoV-2. medRXiv BMJ Yale. https:doi.org/10.1101/2020.11.12.20230466

53. Engler RJ, Nelson MR, Klote MM, et al. Half-vs full dose trivalent inactivated influenza vaccine (2004–2005): age, dose, and sex effects on immune responses. Arch Intern Med. 2008;168(22):2405–2414. doi:10.1001/archinternmed.2008.513

54. Gebhard C, Regitz-Zagrosek V, Neuhauser HK, et al. Impact of sex and gender on COVID-19 outcomes in Europe. Biol Sex Differ. 2020;11:29. https: doi.org/10.1186/s13293-020-00304-09

55. Fathi A, Addo MM, Dahlke Ch. Sex differences in immunity: implications for the development of novel vaccines against emerging pathogens. Front Immunol. 2020;11:601170. doi:10.3389/fimmu.2020.601170

56. Bunders MJ, Altfeld M. Implications of sex differences in immunity for SARS-CoV-2 pathogenesis and design of therapeutic interventions. J.Immun. 2020;53(3):487–495. https:doi.org/10.1016/j.immuni.2020.08.003

57. Duffy D. Milieu interieur: Defining the boundaries of a healthy immune response for improved vaccination strategies. Human vaccines & immunotherapeutics. 2018;14(9):2217–2221. https:doi.org/10.1080/21645515.2018.1466764

58. Klein SL, Schiebinger L, Stefanick ML, et al. Opinion: Sex inclusion in basic research drives discovery. PNAS 2015;112(17):5257–5258. https:doi.org/10.1073/pnas.1502843112

59. Brotman RM, Ravel J, Bavoil PM, et al. Microbiome, sex hormones, and immune responses in the reproductive tract. Challenges for vaccine development against sexually transmitted infections. Vaccine. 2014;32:1543–1552. https:doi.org/10.1016/j.vaccine.2013.10.010

60. Kozlowski PA, Williams SB, Lynch RM, et al. Differential induction of mucosal and systemic antibody responses in woman after nasal, rectal, vaginal immunization influence of the menstrual cycle. J. Immunol. 2002;169:566–574. https:doi.org/10.4049/jimmunol.169.1.566

61. Lorenz TK, Demas GE, Heiman Jr. Interaction of menstrual cycle phase and sexual activity predicts mucosal and systemic humoral immunity in healthy women. Physiology & Behavior 2015;152:92–98. https:doi.org/10.1016/j.physbeh.2015.09.018

62. Giefing-Kröll C, Berger P, Lepperdinger G, et al. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell, 2015;14(3):309–321. https:doi.org/10.1111/acel.12326

63. Scully EP, Haverfield J, Ursin RL, et al. Considering how biological sex impacts immune responses and COVID-19 outcomes. Nature Reviews Immunology. 2020;20:442–447. https:doi.org/10.1038/s41577-020-0348-8

64. Logunov DY, Dolzhikova IV, Shcheblyakov DV, et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 2021;397(10275):671–681. https:doi.org/10.1016/S0140-6736(21)00234-8

65. Jones I, Roy P Sputnik V COVID-19 vaccine candidate appears safe and effective. Lancet 2021;397(10275):642–643. https:doi.org/10.1016/S0140-6736(21)00191-4

66. Yelin I, Katz R, Herzel E, et al. Associations of the BNT162b2 COVID-19 vaccine effectiveness with patient age and comorbidities. https:doi.org/10.1101/2021.03.16.21253686

67. Li AJ, Li X, Sex-dependent immune response and lethality of COVID-19 Stem Cell Res. 2021;50:102116. https: doi.10.1016/j.scr.2020.102116 PMCID: PMC7837330 PMID:33352531

68. Jabal KA, Ben-Amram H, Beiruti K, et al. Impact of age, ethnicity, sex and prior infection on immunogenicity following a single dose of the BNT162b2 mRNA COVID-19 vaccine: real-world evidence from healthcare workers, Israel, December 2020 to January 2021. Euro surveillance 2021;26(6). https:doi.org/10.2807/1560-7917.ES.2021.26.6.2100096

69. Lumley SF, Wei J, O’Donnell D, et al. The duration, dynamics and determinants of SARS-CoV-2 antibody responses in individual healthcare workers. Clin Infect Dis. 2021Aug 2;73(3):e699-e709. https:doi.org/10.1093/cid/ciab004

70. Hall V, Foulkes S, Charlett A, et al. Do antibody positive healthcare workers have lower SARS-CoV-2 2 infection rates than antibody negative healthcare workers? Large multicentre prospective cohort study (the SIREN study), England: 4 June to November 2020. medRxi BMJ Yale. https:doi.org/10.1101/2021.01.13.21249642

71. Roeker LE, Knor DA, Thompson MC, et al. Efficacy of the Vaccine in Patients with Chronic Lymphocytic Leukemia. Leukemia.2021;5808.Accesses54. https:doi.org/10.1182/blood.2021011568

72. Herishanu Y, Avivi I, Aharon, A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood. 2021;137(23):3165–3173. https:doi.org/10.1182/blood.2021011568

73. Rubin LG, Levin MJ, Ljungman P, et al. IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host. C58lin infect dis. 2014;58(3):309–318. https:doi.org/10.1093/cid/cit816

74. Monin IL, Laing AG, Muñoz MM, et al. Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study. Lancet Oncology 2021;22(22):765–778. https:doi.org/10.1016/S1470-2045(21)00213-8

75. Rahimi G, Rahimi B, Panahi M, et al. An overview of Betacoronaviruses-associated severe respiratory syndromes, focusing on sex-type-specific immune responses International Immunopharmacology. 2021;92:107365. https:doi.org/10.1016/j.intimp.2021.107365

76. ECDC scientific advice on seasonal influenza vaccination of children and pregnant women. ECGC Technical report European Centre for Disease Prevention and Control. Stockholm. ECDC.2012;68.

77. Черданцев А. П, Костинов М. П, Кусельман А. И. Вакцинация беременных против гриппа и других инфекционных заболеваний. Руководство для врачей.3-е издание. Москва. «Группа МДВ» «Карнавал Стайл».2018. 143 С.

78. Klein SL,Creisher PS, Burd I. COVID-19 vaccine testing in pregnant females is necessary. J. Clin. Invest. 2021;131(5):e147553. https:doi.org/10.1172/JCI147553

79. Sadarangani M, Raya BA, Conway JM, et al. Importance of COVID-19 vaccine efficacy in older age groups. Vaccine.2021;39(15):2020–2023. https:doi.org/10.1016/j.vaccine.2021.03.020

80. Salvagno GL, Henry BM, Piazza G, et al. Anti-SARS-CoV-2 Receptor-Binding Domain Total Antibodies Response in Seropositive and Seronegative Healthcare Workers Undergoing COVID-19 mRNA BNT162b2. Vaccination.2021 May 4;11(5):832. doi:10.3390/diagnostics11050832.

81. Pellini R, Venuti A, Pimpinelli F, et al. Obesity may hamper SARS-CoV-2 vaccine immunogenicity. https:doi.org/10.1101/2021.02.24.21251664

82. Bubar KM, Reinholt K, Kissler SM, et al. Model-informed COVID-19 vaccine prioritization strategies by age and serostatus. Science 2021;371(6532):916–921 doi:10.1126/science.abe6959

83. Bajaj V, Gadi N, Spihlman AP, et al. Aging, Immunity, and COVID-19: How Age Influences the Host Immune Response to Coronavirus Infections? Front. Physiol.2021;11:571416. Publ: 12 Jan 2021 https:doi:10.3389/fphys.2020.571416

84. Lundberg L, Bygdell M, GS, et al. Recent MMR vaccination in health care workers and Covid-19: A test negative case-control study. Vaccine Available online 22 June 2021. in press. https:doi.org/10.1016/j.vaccine.2021.06.045

85. Aaby P, Benn CS. Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies. Clin Microbiol Infect. 2019;25(12):1459–1467.

86. Zimmermann P, Curtis N Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections BMG Arch Dis Childhood 2020;106(5):5–10. http:dx.doi.org/10.1136/archdischild-2020-320338

87. Каральник БВ, Алимбекова БИ, Ералиева Л. Т. Коронавирусная инфекция и BCG вакцинация: факты и возможности. Эпидемиология и Вакцинопрофилактика. Москва. 2020;19(5):18–24. https:doi.org/10.31631/2073-046-2020-19-5-18-24

88. Poland GA, Ovsyannikova IG, Kennedy RB. Personalized vaccinology: a review. Vaccine. 2017. https:doi.org/10.1016/j.vaccine.2017.07.062

89. Медуницын НВ, Яковлева ТВ. Совершенствование подходов к вакцинопрофилактике. Эпидемиология и Вакцинопрофилактика.2012;3:66–78.

90. Vaccines for older adults: current practices and future opportunities. Ed. Weinberger B. In: Interdisciplinary Topics in Gerontology and Geriatrics Vol. 43 Ed. T. Fulop 2020;X+ 254. https:www.karger.com/Article/Pdf/511782

91. Перфильева ЮВ, Каральник БВ, Остапчук ЕО, и др. Возрастное снижение эффективности вакцинации: потенциальная роль миелоидных супрессорных клеток. Успехи геронтологии. Санкт-Петербург. 2020;33(4):785–795.

92. Gross PA, Hermogenes AW, Sacks HS, et al. The efficacy of influenza vaccine in elderly persons. Ann Intern Med.1995;123:518–527. https:doi.org/10.7326/0003-4819-123-7-199510010-00008

93. Grubeck-Loebenstein B. Fading immune protection in old age: vaccination in the elderly. J. Comp. Pathol. 2010;142(Suppl 1):S116–S119. https:doi.org/10.1016/j.jcpa.2009.10.002

94. Long JE, Drayson MI, Taylor AE, et al. Morning vaccination enhances antibody response over afternoon vaccination: A cluster-randomized trial. Vaccine. 2016;34:2679–2685. https:dx.doi.org10.1016/j.vaccine.2016.04.032

95. Curtis AM, Fagundes CT, Yang G, et al. Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1. PNAS 2015;112(23):7231–7236. https:doi.org/10.1073/pnas.1501327112

96. Ruiz FS, Rosa DS, Zimberg IZ, et al. Night shift work and immune response to the meningococcal conjugate vaccine in healthy workers: a proof of concept study. Sleep Medicine. 2020:263–275. https:doi.org/10.1016/j.sleep.2020.05.032

97. Dhakal S, Klein SL, Coyne CB Host factors impact vaccine efficacy: implications for seasonal and universal Influenza vaccine programs. J. Virol. 2019 Oct 15;93(21):e00797–19. https:doi.org/10.1128/JVI.00797-19


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Каральник Б.В. На путях к индивидуализации вакцинации: значение возраста и пола. Эпидемиология и Вакцинопрофилактика. 2021;20(6):88-99. https://doi.org/10.31631/2073-3046-2021-20-6-88-99

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Karalnik B.V. On the Road to Individualization of Vaccination: the Significance of Age and Sex. Epidemiology and Vaccinal Prevention. 2021;20(6):88-99. (In Russ.) https://doi.org/10.31631/2073-3046-2021-20-6-88-99

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