提示: 手机请竖屏浏览!

接种H4:IC31疫苗或复种卡介苗预防结核分枝杆菌感染
Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination


Elisa Nemes ... 呼吸系统疾病 • 2018.07.12
相关阅读
• M72/AS01ᴇ疫苗预防结核病的2b期对照试验 • 纳米微粒可能改善结核分枝杆菌感染的诊断 • 潜伏性结核病的自我治疗 • 头孢他啶加阿维巴坦(avibactam):TB新疗法

摘要


背景

新近结核分枝杆菌感染使感染者易患结核病,结核病是全球传染病中的主要杀手。H4:IC31是一种候选亚单位疫苗,在临床前模型中显示出对结核病有防护作用,观察性研究表明,卡介苗(BCG)初次接种可以提供对感染的部分防护。

 

方法

在这项2期试验中,我们将990名接受过新生儿卡介苗接种的高危青少年随机分组,分别接受H4:IC31疫苗接种、卡介苗复种或安慰剂接种。所有参与者的结核分枝杆菌感染(通过QuantiFERON-TB Gold管内测定[QuantiFERON-TB Gold In-tube assay,QFT])和人类免疫缺陷病毒检测结果均为阴性。主要结局为安全性和获得结核分枝杆菌感染(定义为QFT初始转阳,在2年期间每6个月进行1次QFT检测)。次要结局为免疫原性和QFT持续转阳,并且在转阳后3个月和6个月时未转阴。疫苗效力的估计是基于Cox回归模型的风险比,并将每种疫苗与安慰剂进行比较。

 

结果

卡介苗和H4:IC31疫苗均具有免疫原性。H4:IC31组308例参与者中的44例(14.3%)、卡介苗组312例参与者中的41例(13.1%)和安慰剂组310例参与者中的49例(15.8%)发生了QFT转阳;在H4:IC31组、卡介苗组和安慰剂组中,持续转阳率分别为8.1%、6.7%和11.6%。H4:IC31疫苗和卡介苗均不能预防QFT初始转阳,效力的点估计值分别为9.4%(P=0.63)和20.1%(P=0.29)。然而,卡介苗降低了QFT持续转阳率,效力为45.4%(P=0.03);H4:IC31疫苗的效力为30.5%(P=0.16)。尽管在卡介苗复种组中轻至中度注射部位反应较常见,但在严重不良事件发生率方面,无临床上显著的组间差异。

 

结论

在这项试验中,在高传播风险背景下,疫苗接种降低了QFT持续转阳率,而QFT持续转阳可能反映结核分枝杆菌的持续感染。这一发现可能为临床开发新候选疫苗提供信息(由Aeras等资助;C-040-404在ClinicalTrials.gov注册号为NCT02075203)。





作者信息

Elisa Nemes, Ph.D., Hennie Geldenhuys, M.B., Ch.B., Virginie Rozot, Ph.D., Kathryn T. Rutkowski, M.Sc., Frances Ratangee, B.N., Nicole Bilek, Ph.D., Simbarashe Mabwe, M.Sc., Lebohang Makhethe, B.Sc., Mzwandile Erasmus, B.Sc., Asma Toefy, B.Sc., Humphrey Mulenga, M.P.H., Willem A. Hanekom, M.B., Ch.B., Steven G. Self, Ph.D., Linda-Gail Bekker, M.D., Ph.D., Robert Ryall, Ph.D., Sanjay Gurunathan, M.D., Carlos A. DiazGranados, M.D., Peter Andersen, D.V.M., D.M.Sc., Ingrid Kromann, B.Sc., Thomas Evans, M.D., Ruth D. Ellis, M.D., Bernard Landry, M.P.H., David A. Hokey, Ph.D., Robert Hopkins, M.D., Ann M. Ginsberg, M.D., Ph.D., Thomas J. Scriba, Ph.D., and Mark Hatherill, M.D. for the C-040-404 Study Team†
From the South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology (E.N., H.G., V.R., F.R., N.B., S.M., L.M., M.E., A.T., H.M., W.A.H., T.J.S., M.H.), and Desmond Tutu HIV Foundation (L.-G.B.), University of Cape Town, Cape Town, South Africa; Aeras, Rockville, MD (K.T.R., T.E., R.D.E., B.L., D.A.H., R.H., A.M.G.); Statistical Center for HIV Research, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle (S.G.S.); Sanofi Pasteur, Swiftwater, PA (R.R., S.G., C.A.D.); and Center for Vaccine Research, Statens Serum Institut, Copenhagen (P.A., I.K.). Address reprint requests to Dr. Hatherill at the Wernher Beit South Bldg., Health Sciences Faculty, University of Cape Town, Cape Town, South Africa, or at mark.hatherill@uct.ac.za. Dr. Ryall, Ph.D., is deceased. A list of investigators in the C-040-404 trial is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Global tuberculosis report 2017. Geneva: World Health Organization, 2017.

2. Knight GM, Griffiths UK, Sumner T, et al. Impact and cost-effectiveness of new tuberculosis vaccines in low- and middle-income countries. Proc Natl Acad Sci U S A 2014;111:15520-15525.

3. Pai M, Behr MA, Dowdy D, et al. Tuberculosis. Nat Rev Dis Primers 2016;2:16076-16076.

4. Pai M, Denkinger CM, Kik SV, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev 2014;27:3-20.

5. Nemes E, Rozot V, Geldenhuys H, et al. Optimization and interpretation of serial QuantiFERON testing to measure acquisition of Mycobacterium tuberculosis infection. Am J Respir Crit Care Med 2017;196:638-648.

6. Mahomed H, Hawkridge T, Verver S, et al. The tuberculin skin test versus QuantiFERON TB Gold in predicting tuberculosis disease in an adolescent cohort study in South Africa. PLoS One 2011;6(3):e17984-e17984.

7. Machingaidze S, Verver S, Mulenga H, et al. Predictive value of recent QuantiFERON conversion for tuberculosis disease in adolescents. Am J Respir Crit Care Med 2012;186:1051-1056.

8. Andrews JR, Hatherill M, Mahomed H, et al. The dynamics of QuantiFERON-TB Gold in-tube conversion and reversion in a cohort of South African adolescents. Am J Respir Crit Care Med 2015;191:584-591.

9. Hawn TR, Day TA, Scriba TJ, et al. Tuberculosis vaccines and prevention of infection. Microbiol Mol Biol Rev 2014;78:650-671.

10. Riley RL, Mills CC, Nyka W, et al. Aerial dissemination of pulmonary tuberculosis: a two-year study of contagion in a tuberculosis ward: 1959. Am J Epidemiol 1995;142:3-14.

11. Dahlstrom A. The instability of the tuberculin reaction: observations on dispensary patients with special reference to the existence of demonstrable tuberculous lesions and the degree of exposure to tubercle bacilli Am Rev Tuberc 1940;42:471-487.

12. Dharmadhikari AS, Basaraba RJ, Van Der Walt ML, et al. Natural infection of guinea pigs exposed to patients with highly drug-resistant tuberculosis. Tuberculosis (Edinb) 2011;91:329-338.

13. Soysal A, Millington KA, Bakir M, et al. Effect of BCG vaccination on risk of Mycobacterium tuberculosis infection in children with household tuberculosis contact: a prospective community-based study. Lancet 2005;366:1443-1451.

14. Eisenhut M, Paranjothy S, Abubakar I, et al. BCG vaccination reduces risk of infection with Mycobacterium tuberculosis as detected by gamma interferon release assay. Vaccine 2009;27:6116-6120.

15. Basu Roy R, Sotgiu G, Altet-Gómez N, et al. Identifying predictors of interferon-γ release assay results in pediatric latent tuberculosis: a protective role of bacillus Calmette-Guerin? A pTB-NET collaborative study. Am J Respir Crit Care Med 2012;186:378-384.

16. Roy A, Eisenhut M, Harris RJ, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ 2014;349:g4643-g4643.

17. Dye C. Making wider use of the world’s most widely used vaccine: Bacille Calmette-Guerin revaccination reconsidered. J R Soc Interface 2013;10:20130365-20130365.

18. Barreto ML, Pereira SM, Pilger D, et al. Evidence of an effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: second report of the BCG-REVAC cluster-randomised trial. Vaccine 2011;29:4875-4877.

19. Rodrigues LC, Pereira SM, Cunha SS, et al. Effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial. Lancet 2005;366:1290-1295.

20. Karonga Prevention Trial Group. Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. Lancet 1996;348:17-24.

21. Aagaard C, Hoang TT, Izzo A, et al. Protection and polyfunctional T cells induced by Ag85B-TB10.4/IC31 against Mycobacterium tuberculosis is highly dependent on the antigen dose. PLoS One 2009;4(6):e5930-e5930.

22. Elvang T, Christensen JP, Billeskov R, et al. CD4 and CD8 T cell responses to the M. tuberculosis Ag85B-TB10.4 promoted by adjuvanted subunit, adenovector or heterologous prime boost vaccination. PLoS One 2009;4(4):e5139-e5139.

23. Billeskov R, Elvang TT, Andersen PL, Dietrich J. The HyVac4 subunit vaccine efficiently boosts BCG-primed anti-mycobacterial protective immunity. PLoS One 2012;7(6):e39909-e39909.

24. Geldenhuys H, Mearns H, Miles DJ, et al. The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: a randomized controlled trial. Vaccine 2015;33:3592-3599.

25. Norrby M, Vesikari T, Lindqvist L, et al. Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: two phase I dose escalation trials. Vaccine 2017;35:1652-1661.

26. Joint review of HIV, TB and PMTCT programmes in South Africa: main report. Pretoria, South Africa: Department of Health, April 2014.

27. Graves AJ, Padilla MG, Hokey DA. OMIP-022: comprehensive assessment of antigen-specific human T-cell functionality and memory. Cytometry A 2014;85:576-579.

28. Andrews JR, Nemes E, Tameris M, et al. Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study. Lancet Respir Med 2017;5:282-290.

29. Hatherill M, Geldenhuys H, Pienaar B, et al. Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults. Vaccine 2014;32:3982-3988.

30. Winje BA, White R, Syre H, et al. Stratification by interferon-γ release assay level predicts risk of incident TB. Thorax 2018 April 5 (Epub ahead of print).

31. Andersen P, Doherty TM, Pai M, Weldingh K. The prognosis of latent tuberculosis: can disease be predicted? Trends Mol Med 2007;13:175-182.

32. Mangtani P, Abubakar I, Ariti C, et al. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin Infect Dis 2014;58:470-480.

33. Abubakar I, Pimpin L, Ariti C, et al. Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis. Health Technol Assess 2013;17:1-372.

34. Pönnighaus JM, Fine PE, Sterne JA, et al. Efficacy of BCG vaccine against leprosy and tuberculosis in northern Malawi. Lancet 1992;339:636-639.

35. Lin PL, Ford CB, Coleman MT, et al. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med 2014;20:75-79.

36. Cadena AM, Fortune SM, Flynn JL. Heterogeneity in tuberculosis. Nat Rev Immunol 2017;17:691-702.

37. Ellis RD, Hatherill M, Tait D, et al. Innovative clinical trial designs to rationalize TB vaccine development. Tuberculosis (Edinb) 2015;95:352-357.

服务条款 | 隐私政策 | 联系我们