M72/AS01候选结核病疫苗在接受联合抗逆转录病毒治疗的HIV感染成人中的安全性和免疫原性：一项I/II期随机试验。
Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine in HIV-infected adults on combination antiretroviral therapy: a phase I/II, randomized trial.
作者信息
Thacher Eleonora G, Cavassini Matthias, Audran Régine, Thierry Anne-Christine, Bollaerts Anne, Cohen Joe, Demoitié Marie-Ange, Ejigu Dawit, Mettens Pascal, Moris Philippe, Ofori-Anyinam Opokua, Spertini François
机构信息
aDivision of Immunology and Allergy bService of Infectious Diseases, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland cGlaxoSmithKline Vaccines, Rixensart, Belgium. *The authors Eleonora G. Thacher and Matthias Cavassini contributed equally to the writing of this article. †Opokua Ofori-Anyinam and François Spertini are equal senior authors.
出版信息
AIDS. 2014 Jul 31;28(12):1769-81. doi: 10.1097/QAD.0000000000000343.
OBJECTIVE
Tuberculosis (TB) is highly prevalent among HIV-infected people, including those receiving combination antiretroviral therapy (cART), necessitating a well tolerated and efficacious TB vaccine for these populations. We evaluated the safety and immunogenicity of the candidate TB vaccine M72/AS01 in adults with well controlled HIV infection on cART.
DESIGN
A randomized, observer-blind, controlled trial (NCT00707967).
METHODS
HIV-infected adults on cART in Switzerland were randomized 3 : 1 : 1 to receive two doses, 1 month apart, of M72/AS01, AS01 or 0.9% physiological saline (N = 22, N = 8 and N = 7, respectively) and were followed up to 6 months postdose 2 (D210). Individuals with CD4⁺ cell counts below 200 cells/μl were excluded. Adverse events (AEs) including HIV-specific and laboratory safety parameters were recorded. Cell-mediated (ICS) and humoral (ELISA) responses were evaluated before vaccination, 1 month after each dose (D30, D60) and D210.
RESULTS
Thirty-seven individuals [interquartile range (IQR) CD4⁺ cell counts at screening: 438-872 cells/μl; undetectable HIV-1 viremia] were enrolled; 73% of individuals reported previous BCG vaccination, 97.3% tested negative for the QuantiFERON-TB assay. For M72/AS01 recipients, no vaccine-related serious AEs or cART-regimen adjustments were recorded, and there were no clinically relevant effects on laboratory safety parameters, HIV-1 viral loads or CD4⁺ cell counts. M72/AS01 was immunogenic, inducing persistent and polyfunctional M72-specific CD4⁺ T-cell responses [medians 0.70% (IQR 0.37-1.07) at D60] and 0.42% (0.24-0.61) at D210, predominantly CD40L⁺IL-2⁺TNF-α⁺, CD40L⁺IL-2⁺ and CD40L⁺IL-2⁺TNF-α⁺IFN-γ⁺]. All M72/AS01 vaccines were seropositive for anti-M72 IgG after second vaccination until study end.
CONCLUSION
M72/AS01 was clinically well tolerated and immunogenic in this population, supporting further clinical evaluation in HIV-infected individuals in TB-endemic settings.
目的
结核病（TB）在HIV感染者中高度流行，包括那些接受抗逆转录病毒联合疗法（cART）的患者，因此需要为这些人群研发一种耐受性良好且有效的TB疫苗。我们评估了候选TB疫苗M72/AS01在接受cART且HIV感染得到良好控制的成人中的安全性和免疫原性。
设计
一项随机、观察者盲法、对照试验（NCT00707967）。
方法
瑞士接受cART的HIV感染成人按3∶1∶1随机分组，分别接受间隔1个月的两剂M72/AS01、AS01或0.9%生理盐水（分别为N = 22、N = 8和N = 7），并随访至第2剂接种后6个月（D210）。排除CD4⁺细胞计数低于200个/μl的个体。记录不良事件（AE），包括HIV特异性和实验室安全参数。在接种疫苗前、每次接种后1个月（D30、D60）和D210评估细胞介导（ICS）和体液（ELISA）反应。
结果
纳入37名个体[筛查时CD4⁺细胞计数的四分位间距（IQR）：438 - 872个/μl；HIV - 1病毒血症检测不到]；73%的个体报告既往接种过卡介苗，97.3%的个体QuantiFERON - TB检测为阴性。对于接受M72/AS01的个体，未记录到与疫苗相关的严重AE或cART方案调整，且对实验室安全参数、HIV - 1病毒载量或CD4⁺细胞计数无临床相关影响。M72/AS01具有免疫原性，可诱导持续且多功能的M72特异性CD4⁺T细胞反应[D60时中位数为0.70%（IQR 0.37 - 1.07）]，D210时为0.42%（0.24 - 0.61），主要为CD40L⁺IL - 2⁺TNF - α⁺、CD40L⁺IL - 2⁺和CD40L⁺IL - 2⁺TNF - α⁺IFN - γ⁺]。所有接受M72/AS01疫苗接种的个体在第二次接种后至研究结束时抗M72 IgG均为血清阳性。
结论
M72/AS01在该人群中临床耐受性良好且具有免疫原性，支持在结核病流行地区的HIV感染个体中进行进一步的临床评估。
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