A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, MVA, and Env gp140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes.
A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, MVA, and Env gp140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes.
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DOI：
10.3389/fimmu.2017.00149
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发表时间：
2017
影响因子：
7.3
通讯作者：
Weber J
中科院分区：
文献类型：
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作者：
Joseph S;Quinn K;Greenwood A;Cope AV;McKay PF;Hayes PJ;Kopycinski JT;Gilmour J;Miller AN;Geldmacher C;Nadai Y;Ahmed MI;Montefiori DC;Dally L;Bouliotis G;Lewis DJ;Tatoud R;Wagner R;Esteban M;Shattock RJ;McCormack S;Weber J
仍然迫切需要预防性艾滋病毒疫苗。我们比较了DNA引发后组合MVA和佐剂化gp 140与顺序MVA/gp 140。我们预期在DNA和MVA引发后Env特异性CD 4 + T细胞，以及在用gp 140加强后100%的个体中Env结合抗体，并且组合疫苗不会损害安全性并且可能增加免疫原性。40名志愿者在0、4和8周时用编码（CN 54）env和（ZM 96）gag-pol-nef的DNA质粒致敏三次，然后用MVA-C（CN 54 env和gag-pol-nef）和以CN 54 gp 140为佐剂的吡喃葡萄糖基脂质澄清剂-水性制剂（GLA-AF）加强。他们被随机分配在第16周和第20周的同一次访视时接受联合治疗（加速），或在第16周和第20周依次接受MVA-C治疗，在第24周和第28周接受GLA-AF/gp 140治疗（标准）。所有疫苗均为肌肉注射。主要结局包括≥ 3级安全性事件和CN 54 gp 140特异性结合IgG滴度。其他结果包括中和、结合抗体特异性和T细胞应答。两名参与者发生了无症状的≥ 3级转氨酶升高，导致疫苗接种停止，三名参与者发生了3级征集性局部或全身反应。总共100%制备的抗CN 54 gp 140 IgG和联合疫苗未显著改变应答;几何平均滴度为6424（加速）和6578（标准）;标准组中MW965.2 1级假病毒的中和作用上级（82 vs 45%应答者，p = 0.04）。T细胞ELISpot反应以CD 4+和Env为主;加速组和标准组的反应率分别为85%和82%。疫苗诱导的IgG应答靶向gp 120内的多个区域，其中V3区域最具免疫显性，未检测到组间差异。MVA和gp 140疫苗的组合未导致不良事件增加，并且未显著影响Env特异性结合抗体的滴度，这在100%个体中观察到。然而，该方法确实影响了其他免疫应答;当疫苗组合时，仅对第1层假病毒观察到的中和抗体应答较差，并且虽然在两组中>80%的个体中观察到T细胞应答，并且类似地，CD 4和Env占优势，但当疫苗组合时，其宽度/多功能性倾向于较低，表明免疫原性减弱，并警告不要使用这种加速方案。
There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The approach did however affect other immune responses; neutralizing antibody responses, seen only to Tier 1 pseudoviruses, were poorer when the vaccines were combined and while T-cell responses were seen in >80% individuals in both groups and similarly CD4 and Env dominant, their breadth/polyfunctionality tended to be lower when the vaccines were combined, suggesting attenuation of immunogenicity and cautioning against this accelerated regimen.