HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis.
HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis.
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DOI：
10.1016/s0140-6736(08)61592-5
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发表时间：
2008-11-29
期刊：
影响因子：
168.9
通讯作者：
Casimiro, Danilo R.
中科院分区：
文献类型：
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作者：
McElrath, M. Juliana;De Rosa, Stephen C.;Moodie, Zoe;Dubey, Sheri;Kierstead, Lisa;Janes, Holly;Defawe, Olivier D.;Carter, Donald K.;Hural, John;Akondy, Rama;Buchbinder, Susan P.;Robertson, Michael N.;Mehrotra, Devan V.;Self, Steven G.;Corey, Lawrence;Shiver, John W.;Casimiro, Danilo R.
在STEP研究中，MRKAd5 HIV-1 Gag/Poll/nef疫苗并不能降低感染后的血浆病毒血症，并且疫苗治疗组的HIV-1发病率高于安慰剂治疗的已有5型腺病毒(Ad5)免疫的男性。我们评估了疫苗诱导的免疫及其对感染风险的潜在贡献。为了评估免疫原性，采用病例队列设计，使用有效的干扰素-γELISpot和细胞内细胞因子染色(ICS)试验对HIV特异性T细胞进行了体外鉴定。为了确定疫苗和预先存在的Ad5免疫对感染风险的影响，流式细胞仪研究检测了Ad5特异性T细胞和表达CCR5的循环激活(Ki67+/Bcl2LO)CD4+T细胞。在77%(258/354)的接种者中，ELISpot在体外检测到分泌干扰素-γ的HIV特异性T细胞(范围163-686/106PBMC)，大多数人识别2-3个HIV蛋白。免疫印迹法检测到HIV特异性CD_4~+T细胞占41%，~85%表达IL-2，其中三分之二共表达干扰素-γ和/或肿瘤坏死因子-α。73%的患者可观察到HIV特异性CD8+T细胞(范围为0.4-1.0%)，主要表达干扰素-γ或与肿瘤坏死因子-α共同表达。接种疫苗的男性病例(感染前)与未接种病例相比，在疫苗诱导的艾滋病毒特异性免疫方面没有发现重大差异，包括应答率、应答率、应答幅度和细胞因子谱。有趣的是，在几个亚组分析中，病例组的Ad5特异性T细胞低于非病例组。病例组与非病例组的Ki67+Bcl2LO/CCR5+CD4+T细胞百分率无明显差异。与以前的试验一致，MRKAd5/HIV-1 Gag/Poll/nef疫苗在诱导HIV特异性CD8+T细胞方面具有高度的免疫原性。比较分析没有显示病例和非病例之间艾滋病毒特异性免疫反应的差异，这解释了疫苗效力的缺乏和潜在的感染增强。如果T细胞免疫在疫苗诱导的HIV保护中起关键作用，我们的发现表明，未来的候选疫苗必须引起与本试验中观察到的反应在幅度或广度和/或功能上不同的反应。美国国家卫生研究院国家过敏和传染病研究所；默克研究实验室
In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not lower post-infection plasma viremia, and HIV-1 incidence was higher in vaccine-treated than placebo-treated males with pre-existing adenovirus serotype 5 (Ad5) immunity. We evaluated vaccine-induced immunity and its potential contributions to infection risk. To assess immunogenicity, HIV-specific T-cells were characterized ex vivo using validated IFN-γ ELISpot and intracellular cytokine staining (ICS) assays, employing a case-cohort design. To determine effects of vaccine and pre-existing Ad5 immunity on infection risk, flow cytometric studies measured Ad5-specific T-cells and circulating activated (Ki67+/Bcl- 2lo) CD4+ T-cells expressing CCR5. IFN-γ-secreting HIV-specific T-cells (range, 163–686/106 PBMC) were detected ex vivo by ELISpot in 77% (258/354) of vaccinees; the majority recognized 2–3 HIV proteins. HIV- specific CD4+ T-cells were identified by ICS in 41%; ~85% expressed IL-2, and two-thirds of these co-expressed IFN-γ and/or TNF-α. HIV-specific CD8+ T-cells (range, 0.4–1.0%) were observed in 73%, expressing predominantly either IFN-γ alone or with TNF-α. No major differences were found in vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile comparing vaccinated male cases (pre-infection) with non-cases. Interestingly, Ad5-specific T-cells were lower in cases than non-cases in several subgroup analyses. The percent circulating Ki67+Bcl-2lo/CCR5+ CD4+ T-cells did not differ between cases and non-cases. Consistent with previous trials, the MrkAd5/HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T-cells. Comparative analyses did not reveal differences in HIV-specific immunologic responses between cases and non-cases that explain the lack of vaccine efficacy and potential infection enhancement. If T-cell immunity is critical in vaccine-induced HIV protection, our findings suggest that future candidate vaccines must elicit responses that either exceed in magnitude or differ in breadth and/or function from those observed in this trial. National Institute of Allergy and Infectious Diseases, U.S. National Institute of Health; Merck Research Laboratories