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M72/AS01ᴇ疫苗预防结核病的2b期对照试验
Phase 2b Controlled Trial of M72/AS01ᴇ Vaccine to Prevent Tuberculosis


Olivier Van Der Meeren ... 呼吸系统疾病 • 2018.10.25
相关阅读
• 接种H4:IC31疫苗或复种卡介苗预防结核分枝杆菌感染 • 潜伏性结核分枝杆菌感染的治疗建议更新

疫苗降低了潜伏结核感染人群的结核发病率

 

王宾†,Douglas B. Lowrie‡*

†复旦大学上海基础医学院;‡复旦大学上海市公共卫生临床中心

*通讯作者

 

中国是世界上结核病最多的国家之一1,2016年统计有895,000个新发病例。虽然结核病的年发病率和死亡率正在下降,但随着人类免疫缺陷病毒的传播2和多重耐药结核病(MDR-TB)的增加,中国结核病的传染仍在恶化。

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摘要


背景

我们需要通过疫苗来阻断结核病的传播。

 

方法

我们在肯尼亚、南非和赞比亚进行了一项M72/AS01E结核病疫苗的随机、双盲、安慰剂对照的2b期试验。人类免疫缺陷病毒(HlV)阴性的18~50岁潜伏性结核分枝杆菌感染(通过γ干扰素释放试验确定)成人被随机分组(按1∶1的比例),分别接受两剂M72/AS01E慰剂肌内注射,间隔时间1个月。大多数参与者先前接种过卡介苗。我们评估了M72/AS01E的安全性,以及阻止感染者进展至细菌学证实的活动性肺结核的效果。通过痰液聚合酶链反应试验、分枝杆菌培养或两者结合来证实临床结核病疑似患者。

 

结果

我们在本文中报告此项尚在进行中的试验的主要分析(平均随访2.3年后进行)结果。共有1,786例参与者接受了M72/AS01E疫苗,1,787例参与者接受了安慰剂,两组中分别有1,623例和1,660例参与者被纳入符合方案效果观察队列。M72/AS01E组共有10例参与者合原发病例定义(细菌学证实的活动性肺结核,在治疗前证实),安慰剂组为22例(发病率,0.3例/100人-年vs. 0.6例/100人-年)。疫苗效果为54.0%(90%置信区间[CI],13.9~75.4;95% CI,2.9~78.2;P=0.04)。总体接种疫苗效果队列的结果相似(疫苗效果,57.0%;90% CI,19.9~76.9;95% CI,9.7~79.5;P=0.03)。在注射后30日内,M72/AS01E组(67.4%)参与者主动提供的不事件报告比安慰剂组(45.4%)多,差异主要归因于注射部位反应和流感样症状。两组中严重不良事件、潜在免疫介导疾病和死亡的发生率相似。

 

结论

M72/AS01E为结核分枝杆菌感染的成人提供54.0%的保护作用,免于患活动性肺结核,没有明显的安全问题(由GlaxoSmithKline Biologicals和Aeras资助;在ClinicalTrials.gov注册号为NCT01755598)。





作者信息

Olivier Van Der Meeren, M.D., Mark Hatherill, M.D., Videlis Nduba, M.B., Ch.B., M.P.H., Robert J. Wilkinson, F.Med.Sci., Monde Muyoyeta, M.B., Ch.B., Ph.D., Elana Van Brakel, M.B., Ch.B., Helen M. Ayles, M.B., B.S., Ph.D., German Henostroza, M.D., Friedrich Thienemann, M.D., Thomas J. Scriba, Ph.D., Andreas Diacon, M.D., Ph.D., Gretta L. Blatner, M.S., M.P.H., Marie-Ange Demoitié, M.Sc., Michele Tameris, M.B., Ch.B., Mookho Malahleha, M.D., M.P.H., James C. Innes, M.B., Ch.B., Elizabeth Hellström, M.B., Ch.B., Neil Martinson, M.B., Ch.B., M.P.H., Tina Singh, M.D., Elaine J. Akite, M.Sc., Aisha Khatoon Azam, M.B., B.S., Anne Bollaerts, M.Sc., Ann M. Ginsberg, M.D., Ph.D., Thomas G. Evans, M.D., Paul Gillard, M.D., and Dereck R. Tait, M.B., Ch.B.
From GlaxoSmithKline, Wavre, Belgium (O.V.D.M., M.-A.D., T.S., E.J.A., A.K.A., A.B., P.G.); South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology (M.H., T.J.S., M.T.), and Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (R.J.W., F.T.), University of Cape Town, Task Applied Science (E.V.B., A.D.), Stellenbosch University (A.D.), and Aeras Global TB Vaccine Foundation (D.R.T.) Cape Town, Setshaba Research Centre, Pretoria (M. Malahleha), the Aurum Institute, Klerksdorp and Tembisa Research Centres (J.C.I.), and the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, South African Medical Research Council Collaborating Centre for HIV/AIDS and TB, and National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, University of the Witwatersrand (N.M.), Johannesburg, and Be Part Yoluntu Centre, Paarl (E.H.) — all in South Africa; Kenya Medical Research Institute, Nairobi (V.N.); Francis Crick Institute (R.J.W.), the Department of Medicine, Imperial College London (R.J.W.), and the London School of Hygiene and Tropical Medicine (H.M.A.) — all in London; Centre for Infectious Disease Research in Zambia (M. Muyoyeta, G.H.) and Zambart, University of Zambia (H.M.A.) — both in Lusaka, Zambia; the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and Aeras, Rockville (G.L.B., A.M.G., T.G.E.), and Johns Hopkins University Center for Tuberculosis Research, Baltimore (N.M.) — both in Maryland. Address reprint requests to Dr. Van Der Meeren at GlaxoSmithKline, 20 Fleming Ave., 1300 Wavre, Belgium, or at olivier.x.van-der-meeren@gsk.com.

 

参考文献

1. Houben RM, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med 2016;13(10):e1002152-e1002152.

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

3. Dheda K, Gumbo T, Maartens G, et al. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med 2017 March 15 (Epub ahead of print).

4. Harris RC, Sumner T, Knight GM, White RG. Systematic review of mathematical models exploring the epidemiological impact of future TB vaccines. Hum Vaccin Immunother 2016;12:2813-2832.

5. 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.

6. Al-Attiyah R, Mustafa AS, Abal AT, El-Shamy AS, Dalemans W, Skeiky YA. In vitro cellular immune responses to complex and newly defined recombinant antigens of Mycobacterium tuberculosis. Clin Exp Immunol 2004;138:139-144.

7. Skeiky YA, Lodes MJ, Guderian JA, et al. Cloning, expression, and immunological evaluation of two putative secreted serine protease antigens of Mycobacterium tuberculosis. Infect Immun 1999;67:3998-4007.

8. Dillon DC, Alderson MR, Day CH, et al. Molecular characterization and human T-cell responses to a member of a novel Mycobacterium tuberculosis mtb39 gene family. Infect Immun 1999;67:2941-2950.

9. Day CL, Tameris M, Mansoor N, et al. Induction and regulation of T-cell immunity by the novel tuberculosis vaccine M72/AS01 in South African adults. Am J Respir Crit Care Med 2013;188:492-502.

10. Gillard P, Yang PC, Danilovits M, et al. Safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in adults with tuberculosis: a phase II randomised study. Tuberculosis (Edinb) 2016;100:118-127.

11. Idoko OT, Owolabi OA, Owiafe PK, et al. Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine when given as a booster to BCG in Gambian infants: an open-label randomized controlled trial. Tuberculosis (Edinb) 2014;94:564-578.

12. Kumarasamy N, Poongulali S, Bollaerts A, et al. A randomized, controlled safety, and immunogenicity trial of the M72/AS01 candidate tuberculosis vaccine in HIV-positive Indian adults. Medicine (Baltimore) 2016;95(3):e2459-e2459.

13. Leroux-Roels I, Forgus S, De Boever F, et al. Improved CD4⁺ T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: a randomized trial. Vaccine 2013;31:2196-2206.

14. Montoya J, Solon JA, Cunanan SR, et al. A randomized, controlled dose-finding phase II study of the M72/AS01 candidate tuberculosis vaccine in healthy PPD-positive adults. J Clin Immunol 2013;33:1360-1375.

15. Penn-Nicholson A, Geldenhuys H, Burny W, et al. Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in a TB endemic setting. Vaccine 2015;33:4025-4034.

16. Thacher EG, Cavassini M, Audran R, et al. Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine in HIV-infected adults on combination antiretroviral therapy: a phase I/II, randomized trial. AIDS 2014;28:1769-1781.

17. Williams A, Orme IM. Animal models of tuberculosis: an overview. Microbiol Spectr 2016;4(4).

18. Skeiky YA, Alderson MR, Ovendale PJ, et al. Differential immune responses and protective efficacy induced by components of a tuberculosis polyprotein vaccine, Mtb72F, delivered as naked DNA or recombinant protein. J Immunol 2004;172:7618-7628.

19. Brandt L, Skeiky YA, Alderson MR, et al. The protective effect of the Mycobacterium bovis BCG vaccine is increased by coadministration with the Mycobacterium tuberculosis 72-kilodalton fusion polyprotein Mtb72F in M. tuberculosis-infected guinea pigs. Infect Immun 2004;72:6622-6632.

20. Tsenova L, Harbacheuski R, Moreira AL, et al. Evaluation of the Mtb72F polyprotein vaccine in a rabbit model of tuberculous meningitis. Infect Immun 2006;74:2392-2401.

21. Irwin SM, Izzo AA, Dow SW, et al. Tracking antigen-specific CD8 T lymphocytes in the lungs of mice vaccinated with the Mtb72F polyprotein. Infect Immun 2005;73:5809-5816.

22. Lewinsohn DA, Lines RA, Lewinsohn DM. Human dendritic cells presenting adenovirally expressed antigen elicit Mycobacterium tuberculosis–specific CD8+ T cells. Am J Respir Crit Care Med 2002;166:843-848.

23. 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.

24. Tameris MD, Hatherill M, Landry BS, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 2013;381:1021-1028.

25. von Reyn CF, Mtei L, Arbeit RD, et al. Prevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine. AIDS 2010;24:675-685.

26. Nemes E, Geldenhuys H, Rozot V, et al. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N Engl J Med 2018;379:138-149.

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

28. Behr MA, Warren SA, Salamon H, et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 1999;353:444-449.

29. 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.

30. 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.

31. Lau E, Tucker Rutkowski K, van Brakel E, et al. Prevalence of latent TB infection among adults in endemic regions screened for a phase IIb, double-blind, randomized, placebo-controlled study to evaluate GSK candidate vaccine M72/AS01E. Presented at the 21st International AIDS Conference, Durban, South Africa, July 16, 2016 (poster).

32. Mahomed H, Hawkridge T, Verver S, et al. Predictive factors for latent tuberculosis infection among adolescents in a high-burden area in South Africa. Int J Tuberc Lung Dis 2011;15:331-336.

33. Mahomed H, Hughes EJ, Hawkridge T, et al. Comparison of mantoux skin test with three generations of a whole blood IFN-gamma assay for tuberculosis infection. Int J Tuberc Lung Dis 2006;10:310-316.

34. Wood R, Liang H, Wu H, et al. Changing prevalence of tuberculosis infection with increasing age in high-burden townships in South Africa. Int J Tuberc Lung Dis 2010;14:406-412.

35. Benator D, Bhattacharya M, Bozeman L, et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 2002;360:528-534.

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