A Randomized Placebo-Controlled Efficacy Study of a Prime Boost Therapeutic Vaccination Strategy in HIV-1-Infected Individuals: VRI02 ANRS 149 LIGHT Phase II Trial.
A Randomized Placebo-Controlled Efficacy Study of a Prime Boost Therapeutic Vaccination Strategy in HIV-1-Infected Individuals: VRI02 ANRS 149 LIGHT Phase II Trial.
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DOI：
10.1128/jvi.02165-20
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发表时间：
2021-04-12
影响因子：
5.4
通讯作者：
Thiébaut R
中科院分区：
文献类型：
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作者：
Lévy Y;Lacabaratz C;Lhomme E;Wiedemann A;Bauduin C;Fenwick C;Foucat E;Surenaud M;Guillaumat L;Boilet V;Rieux V;Bouchaud O;Girard PM;Molina JM;Morlat P;Hocqueloux L;Richert L;Pantaleo G;Lelièvre JD;Thiébaut R
在这项安慰剂对照的II期随机临床试验中，我们评估了在接受联合抗逆转录病毒治疗的hiv感染患者中，使用重组DNA疫苗（GTU-MultiHIV B分支），然后使用脂肽疫苗（hiv - lipo5）加强疫苗的治疗性初始-增强疫苗策略的安全性和免疫原性。我们在这里表明，这种主要加强策略具有良好的耐受性，与先前在hiv -1感染个体和健康志愿者中单独接种每种疫苗成分的研究一致。在这项安慰剂对照的II期随机临床试验中，103名接受cART（联合抗逆转录病毒治疗）的人类免疫缺陷病毒1型（HIV-1）感染患者被随机分为2:1，分别在第0周（W0）、W4和W12周接受3剂DNA GTU-MultiHIV B（编码Rev、Nef、Tat、Gag和gp160），然后在W20和W24周接受2剂含有Gag、Pol和Nef长肽的lipo5疫苗或安慰剂。在W36至W48之间进行分析性治疗中断（ATI）。在W28时，接种者经历了功能性CD4+ T细胞反应的增加（与W0相比，每种细胞因子的P < 0.001），主要针对Gag和Pol/Env， hiv特异性CD8+ T细胞产生白细胞介素2 （IL-2）和肿瘤坏死因子α (TNF-α)的增加（P分别= 0.001和0.013），主要针对Pol/Env和Nef。然而，对T细胞亚群的大规模细胞计数分析显示，与安慰剂组相比，疫苗接种者中共表达衰竭和衰老标志物如PD-1/TIGIT （P = 0.004）和CD27/CD57 （P = 0.044）的记忆性CD8+ T细胞的W28/W0比增加。在ATI期间，所有患者均出现病毒反弹，观察到的最大HIV RNA水平为W42（中位数，4.63 log10拷贝[cp]/ml；四分位数范围[IQR]， 4.00至5.09），各组间无差异。无患者因CD4细胞计数下降而恢复cART。从全球来看，疫苗战略是安全的。然而，在ATI期间观察到二次艾滋病毒传播。这些数据表明，DNA和LIPO-5疫苗的促发组合引发了广泛和多功能的T细胞。免疫反应的质量与缺乏有效的病毒控制之间的对比强调了联合免疫调节策略的必要性。(本研究已在ClinicalTrials.gov注册，注册号为：NCT01492985)。在这项安慰剂对照的II期随机临床试验中，我们评估了在接受联合抗逆转录病毒治疗的hiv感染患者中，使用重组DNA疫苗（GTU-MultiHIV B分支），然后使用脂肽疫苗（hiv - lipo5）进行加强接种的治疗性初始-强化疫苗策略的安全性和免疫原性。我们在这里表明，这种主要加强策略具有良好的耐受性，与先前在hiv -1感染个体和健康志愿者中单独接种每种疫苗成分的研究一致。与安慰剂组相比，接种疫苗者引发了强烈和多功能的hiv特异性CD4+和CD8+ t细胞反应。然而，这些免疫反应存在一些定性缺陷，无法控制抗逆转录病毒治疗中断后的病毒血症，因为在疫苗组和安慰剂组中没有观察到HIV病毒反弹的差异。从这些结果中吸取了一些教训，指出迫切需要将疫苗战略与其他基于免疫的干预措施结合起来。
In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually. In this placebo-controlled phase II randomized clinical trial, 103 human immunodeficiency virus type 1 (HIV-1)-infected patients under cART (combined antiretroviral treatment) were randomized 2:1 to receive either 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, and gp160) at week 0 (W0), W4, and W12, followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or placebo. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4+ T-cell responses (P < 0.001 for each cytokine compared to W0) measured, predominantly against Gag and Pol/Env, and an increase in HIV-specific CD8+ T cells producing interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α) (P = 0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T-cell subsets by mass cytometry in a subpopulation showed an increase in the W28/W0 ratio for memory CD8+ T cells coexpressing exhaustion and senescence markers such as PD-1/TIGIT (P = 0.004) and CD27/CD57 (P = 0.044) in vaccinees compared to the placebo group. During ATI, all patients experienced viral rebound, with the maximum observed HIV RNA level at W42 (median, 4.63 log10 copies [cp]/ml; interquartile range [IQR], 4.00 to 5.09), without any difference between arms. No patient resumed cART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed. These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need for combined immunomodulatory strategies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01492985.) IMPORTANCE In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually. Compared to the placebo group, vaccinees elicited strong and polyfunctional HIV-specific CD4+ and CD8+ T-cell responses. However, these immune responses presented some qualitative defects and were not able to control viremia following antiretroviral treatment interruption, as no difference in HIV viral rebound was observed in the vaccine and placebo groups. Several lessons were learned from these results, pointing out the urgent need to combine vaccine strategies with other immune-based interventions.