Determinants of antibody persistence across doses and continents after single-dose rVSV-ZEBOV vaccination for Ebola virus disease: an observational cohort study.
Determinants of antibody persistence across doses and continents after single-dose rVSV-ZEBOV vaccination for Ebola virus disease: an observational cohort study.
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DOI：
10.1016/s1473-3099(18)30165-8
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发表时间：
2018-07
期刊：
影响因子：
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通讯作者：
VSV-EBOPLUS Consortia
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作者：
Huttner A;Agnandji ST;Combescure C;Fernandes JF;Bache EB;Kabwende L;Ndungu FM;Brosnahan J;Monath TP;Lemaître B;Grillet S;Botto M;Engler O;Portmann J;Siegrist D;Bejon P;Silvera P;Kremsner P;Siegrist CA;VEBCON;VSV-EBOVAC;VSV-EBOPLUS Consortia
表达扎伊尔埃博拉病毒（ZEBOV）糖蛋白的重组水泡性口炎病毒（rVSV）疫苗在单次注射后数周内有效，但免疫持续时间未知。我们的目的是评估在三个先前的试验中接受单剂量rVSV-ZEBOV的志愿者在1年和2年时的抗体持久性。在这项观察性队列研究中，我们前瞻性随访了来自非洲和欧洲1期rVSV-ZEBOV试验的参与者，他们在2014-15年接种了一次30万（低剂量）或1000 - 5000万（高剂量）空斑形成单位（pfu）的rVSV-ZEBOV疫苗，以评估ZEBOV糖蛋白（IgG）抗体持久性。主要结果是通过ELISA每年测量的ZEBOV糖蛋白特异性IgG几何平均浓度（GMC）与免疫后1个月（即28天）相比。根据多变量分析，我们报告了疫苗接种后2年（瑞士日内瓦，包括中和抗体长达6个月）和1年（加蓬Lambaréné;肯尼亚Kilifi）的GMC以及与6个月以上较高抗体持久性相关的因素。试验和观察性研究在ClinicalTrials.gov（日内瓦：NCT 02287480和NCT 02933931; Kilifi：NCT 02296983）和泛非临床试验登记处（Lambaréné PACTR 201411000919191）注册。在原始研究的217名接种者中（102名来自日内瓦研究，75名来自Lambaréné研究，40名来自Kilifi研究），197名在1年时返回并提供了样本（95名来自日内瓦研究，63名来自Lambaréné研究，39名来自Kilifi研究），90名在2年时返回并提供了样本（均来自日内瓦研究）。在日内瓦组中，44例（100%）接种高剂量（即1000 - 5000万pfu）疫苗且在第28天血清阳性的参与者在2年内保持血清阳性，而37例接种低剂量（即300 000 pfu）疫苗的参与者中有33例（89%）在2年内保持血清阳性（p= 0.042）。在接受高剂量的参与者中，ZEBOV糖蛋白IgG GMC在其峰值和峰值之间显著降低。在日内瓦接种后1-3个月和6个月（p<0·0001）和Lambaréné（p=0·0298）但在Kilifi中未发现（p=0·5833），随后在除日内瓦外的所有地点保持稳定，其中，在6个月至1年期间，给予高剂量疫苗的患者的GMC显著增加（p= 0.0264）。在接种低剂量疫苗的受试者中，1年和6个月时的抗体持久性相似，日内瓦研究参与者中，接种后2年的滴度低于接种后1年的滴度（GMC比率为0·61，95% CI为0·49-0·77; p<0·0001）。在多变量分析中，6个月后IgG GMC增加的预测因素包括高剂量与低剂量疫苗接种（日内瓦p= 0.0133; Lambaréné p= 0.008）和疫苗相关性关节炎（p= 0.0176），但不包括性别、年龄或基线血清阳性（均p> 0.05）。中和抗体似乎不太持久，日内瓦研究参与者的血清阳性率从28天的64-71%降至6个月的27-31%。对单剂量rVSV-ZEBOV疫苗接种的抗体应答在剂量范围和设置上是持续的，这是加强疫苗接种不切实际的国家的关键标准。Wellcome Trust和创新药物倡议2联合承诺。
The recombinant vesicular stomatitis virus (rVSV) vaccine expressing the Zaire Ebola virus (ZEBOV) glycoprotein is efficacious in the weeks following single-dose injection, but duration of immunity is unknown. We aimed to assess antibody persistence at 1 and 2 years in volunteers who received single-dose rVSV-ZEBOV in three previous trials. In this observational cohort study, we prospectively followed-up participants from the African and European phase 1 rVSV-ZEBOV trials, who were vaccinated once in 2014–15 with 300 000 (low dose) or 10–50 million (high dose) plaque-forming units (pfu) of rVSV-ZEBOV vaccine to assess ZEBOV glycoprotein (IgG) antibody persistence. The primary outcome was ZEBOV glycoprotein-specific IgG geometric mean concentrations (GMCs) measured yearly by ELISA compared with 1 month (ie, 28 days) after immunisation. We report GMCs up to 2 years (Geneva, Switzerland, including neutralising antibodies up to 6 months) and 1 year (Lambaréné, Gabon; Kilifi, Kenya) after vaccination and factors associated with higher antibody persistence beyond 6 months, according to multivariable analyses. Trials and the observational study were registered at ClinicalTrials.gov (Geneva: NCT02287480 and NCT02933931; Kilifi: NCT02296983) and the Pan-African Clinical Trials Registry (Lambaréné PACTR201411000919191). Of 217 vaccinees from the original studies (102 from the Geneva study, 75 from the Lambaréné study, and 40 from the Kilifi study), 197 returned and provided samples at 1 year (95 from the Geneva study, 63 from the Lambaréné, and 39 from the Kilifi study) and 90 at 2 years (all from the Geneva study). In the Geneva group, 44 (100%) of 44 participants who had been given a high dose (ie, 10–50 million pfu) of vaccine and who were seropositive at day 28 remained seropositive at 2 years, whereas 33 (89%) of 37 who had been given the low dose (ie, 300 000 pfu) remained seropositive for 2 years (p=0·042). In participants who had received a high dose, ZEBOV glycoprotein IgG GMCs decreased significantly between their peak (at 1–3 months) and month 6 after vaccination in Geneva (p<0·0001) and Lambaréné (p=0·0298) but not in Kilifi (p=0·5833) and subsequently remained stable at all sites apart from Geneva, where GMC in those given a high dose of vaccine increased significantly between 6 months and 1 year (p=0·0264). Antibody persistence was similar at 1 year and at 6 months in those who had received a low dose of vaccine, with lower titres among participants from the Geneva study at 2 years than at 1 year after vaccination (GMC ratio 0·61, 95% CI 0·49–0·77; p<0·0001). In multivariable analyses, predictors of increased IgG GMCs beyond 6 months included high-dose versus low-dose vaccination (Geneva p=0·0133; Lambaréné p=0·008) and vaccine-related arthritis (p=0·0176), but not sex, age, or baseline seropositivity (all p>0·05). Neutralising antibodies seem to be less durable, with seropositivity dropping from 64–71% at 28 days to 27–31% at 6 months in participants from the Geneva study. Antibody responses to single-dose rVSV-ZEBOV vaccination are sustained across dose ranges and settings, a key criterion in countries where booster vaccinations would be impractical. The Wellcome Trust and Innovative Medicines Initiative 2 Joint Undertaking.