A step forward for HIV vaccines.
A step forward for HIV vaccines.
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DOI：
10.1016/s2352-3018(18)30095-x
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Barouch DH
中科院分区：
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作者：
Barouch DH
开发一种安全有效的艾滋病毒疫苗可能是持久结束艾滋病毒流行的关键。然而，在HIV流行的35年历史中，只有四种HIV疫苗方案的临床疗效得到了评估。2.艾滋病毒疫苗开发面临的主要挑战是科学性的，在疫苗学历史上是前所未有的，包括需要防止全球不同的病毒株和不清楚的免疫保护相关性。Linda-Gail Bekker及其同事在《柳叶刀HIV》中报道了寻求开发HIV疫苗的重要下一章。3 2009年，RV 144试验显示了艾滋病毒疫苗在人体中的有效性试验的第一个也是迄今为止唯一的阳性结果。4该疫苗包括用金丝雀痘ALVAC载体初免和用明矾佐剂包膜（env）gp 120蛋白加强，在泰国的低风险人群中提供了31%的效力。尽管这些数据还不足以获得许可证，但它们激发了人们对了解保护的免疫相关性并试图改进这种疫苗的热情。免疫相关性分析的结果表明，针对env可变环1和2（V1 V2）的抗体与感染风险呈负相关，5筛选分析同样显示了疫苗诱导的对env V1 V2的免疫压力。6这些数据导致了一种假设，即疫苗引起的针对V1 V2的结合抗体可能解释了在RV 144中观察到的保护作用。RV 144产生的保护作用的其他潜在相关性包括IgG 3应答和CD 4 + T细胞应答。一种有效的和预测性的免疫保护相关性将是HIV疫苗领域的一个重大进展。因此，一个关键的优先事项是在另一项研究中前瞻性地测试这种潜在的V1 V2免疫相关性。Bekker及其同事的目标是使RV 144疫苗方案适应南非的C分支流行病。制备新的ALVAC载体（vCP 2438，表达进化枝C env gp 120和进化枝B env gp 41/gag/pro）和二价进化枝C env gp 120蛋白（TV 1/1086），并且使用更有效的基于角鲨烯的佐剂MF 59代替RV 144中使用的明矾佐剂。Bekker及其同事在HIV疫苗试验网络（HVTN）100试验3中评估了这种新疫苗的安全性和免疫原性-这是南非的一项安慰剂对照，随机，双盲，1/2期试验。在第12个月时将晚期加强添加到RV 144疫苗时间表中，在第0、1、3、6和12个月施用疫苗。因此，RV 144和HVTN 100试验在许多变量上存在差异。与RV 144相比，HVTN 100中的结合抗体反应幅度更高，细胞免疫反应频率更高，但HVTN 100中的V1 V2特异性抗体反应低于RV 144。这些差异的原因尚不完全清楚，但可能与选择用于疫苗的特定env菌株和HVTN 100中使用的更有效的佐剂有关。HVTN 100的发现很重要，因为达到了预先规定的免疫学go/no-go标准，包括IgG抗体结合和CD 4 + T细胞应答，这导致启动了2b/3期疗效试验（HVTN 702），以确定该疫苗在南非预防HIV感染的能力（NCT 02968849）。HVTN 702还将前瞻性地测试疫苗引发的V1 V2结合抗体是否与保护相关。这种免疫相关性的验证将是有用的，因为它可以用作替代生物标志物，这将大大加速HIV疫苗的开发。作为艾滋病领域...
Development of a safe and effective HIV vaccine will probably be essential to achieve a durable end to the HIV pandemic. 1, 2 However, only four HIV vaccine regimens have been assessed for clinical efficacy in the 35-year history of the HIV epidemic. 2 The main challenges facing the development of an HIV vaccine are scientific and are unprecedented in the history of vaccinology, including the need to protect against globally diverse virus strains and unclear immune correlates of protection. In The Lancet HIV, Linda-Gail Bekker and colleagues report an important next chapter in the quest to develop an HIV vaccine. 3 In 2009, the RV144 trial showed the first, and to date only, positive results from an HIV vaccine efficacy trial in human beings. 4 This vaccine included priming with canarypox ALVAC vectors and boosting with alum-adjuvanted envelope (env) gp120 proteins, and it provided 31% efficacy in a low-risk population in Thailand. Although not sufficient for licensure, these data catalysed a wave of enthusiasm to understand the immune correlates of protection and to try to improve this vaccine. Findings from an immune correlates analysis indicated that antibodies against env variable loops 1 and 2 (V1V2) correlated inversely with infection risk, 5 and a sieve analysis similarly showed vaccine-induced immune pressure on env V1V2. 6 These data led to a hypothesis that vaccine-elicited binding antibodies against V1V2 might have accounted for the protection observed in RV144. Additional potential correlates of protection that emerged from RV144 included IgG3 responses and CD4+ T-cell responses. A validated and predictive immune correlate of protection would be a major advance for the HIV vaccine field. Thus, a key priority has been to test this potential V1V2 immune correlate prospectively in another study. Bekker and colleagues aimed to adapt the RV144 vaccine regimen to the clade C epidemic in South Africa. New ALVAC vectors (vCP2438, expressing clade C env gp120 and clade B env gp41/gag/pro) and bivalent clade C env gp120 proteins (TV1/1086) were manufactured, and instead of the alum adjuvant used in RV144, the more potent squalene-based adjuvant MF59 was used. Bekker and colleagues assessed the safety and immunogenicity of this new vaccine in the HIV Vaccine Trials Network (HVTN) 100 trial3—a placebo-controlled, randomised, double-blind, phase 1/2 trial in South Africa. A late boost was added to the RV144 vaccine schedule at 12 months, with vaccine administered at months 0, 1, 3, 6, and 12. Thus, the RV144 and HVTN 100 trials differed by many variables. Binding antibody responses were of a higher magnitude and cellular immune responses were of a higher frequency in HVTN 100 compared with RV144, but V1V2-specific antibody responses were lower in HVTN 100 than in RV144. The reasons for these differences are not entirely clear but could be related to the specific env strains selected for the vaccines and the more potent adjuvant used in HVTN 100. The findings of HVTN 100 are important because prespecified immunological go/no-go criteria were achieved, including IgG antibody binding and CD4+ T-cell responses, which led to initiation of a phase 2b/3 efficacy trial (HVTN 702) to ascertain the capacity of this vaccine to protect against HIV acquisition in South Africa (NCT02968849). HVTN 702 will also test prospectively whether vaccine-elicited V1V2-binding antibodies correlate with protection. Validation of this immune correlate would be useful because it could then be used as a surrogate biomarker that would greatly accelerate HIV vaccine development moving forward. As the area of HIV …