武汉云克隆科技股份有限公司

Abstract:

Background:

Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1.

Methods:

Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate.

Findings:

174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23,100 copies per mL Vacc-4x vs 71,800 copies per mL placebo; p=0·025) and week 52 (median 19,550 copies per mL vs 51,000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations.

Interpretation：

The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies.

摘要：

背景：

目前仅依赖联合抗逆转录病毒疗法(CART)并不能治愈艾滋病毒，还需终生的药物辅助治疗。我们正在考虑将HIV治疗疫苗的潜在作用作为治疗的一部分。Vacc-4x是一种针对p24(Gag)上保守结构域的肽基HIV-1治疗疫苗。研究目的是评估HIV-1成人患者接种vacc-4x的有效性、安全性和免疫原性。

方法：

从2008年7月至2010年6月，我们做了一个多国双盲随机第二阶段安慰剂对照试验。参与者为年龄在18-55岁之间感染HIV-1的成人，其HIV-1病毒被cART疗法抑制（病毒载量<50/mL），CD4细胞计数为400×106/L及以上。该试验在德国、意大利、西班牙、英国和美国的18个地点进行。参与者按2：1比例随机分配到Vacc-4x组和安慰剂组，参与者和调查员都对分组无所知晓。对参与者进行四次初次免疫，每四周一次，在佐剂给药后进行皮内注射含有Vacc-4x（或安慰剂）的药物。第16周和第18周给予增强免疫。从第28周，cART治疗被中断长达24周。在治疗中断期间，检测终点指标是cART恢复和CD4细胞数的变化。通过修改治疗意向进行分析：所有接受一次干预的参与者。此外还评估了安全性、病毒载量和免疫原性（用ELISPOT和细胞增殖法）。52周的跟进期于2011年6月结束。最后采用Logistic回归模型对符合cART恢复标准的参与者比例进行了分析，并把国家作为协变量在模型中对治疗效果进行了评估。

结果：

由于招募缓慢，计划参与者为345人，实际参与者为136人，其中93人被随机分配到Vacc-4x组，43人分配到安慰剂组。第28周停止了cART治疗的两组在第一疗效终点无差异。在恢复CART的参与者中，Vacc-4x组30人（34%），安慰剂组11人（29%），CD4计数的百分比变化不显著(平均治疗差异-5·71，95% CI -13·01 to 1·59)。然而，Vacc-4x组在48周时病毒载量有显著差异（23100次/mL vacc-4x：71800次/mL安慰剂；p=0.025）和52周（19 550份/mL vacc-4x：51 000份/mL安慰剂；p=0·041）。据报道，多发性硬化症的恶化可能与该项研究治疗有关。VACC-4x具有免疫原性，可诱导CD4和CD8的T细胞增殖。

结论：

试验结束前恢复cART的参与者比例和CD4计数的变化表明在治疗期间中断接种疫苗没有任何好处。Vacc-4x具有安全、良好耐受性、免疫原性的特点，似乎有助于CART中断后降低病毒载量，可能成为未来的艾滋病的治疗策略。

使用试剂原文信息：Interleukin 6 measurements (eBioscience, San Diego,CA, USA) and detection of antibodies to recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF; USCN Life, Wuhan, China) were done by Bionor Laboratories (Skien, Norway).