Huttner Angela, Combescure Christophe, Grillet Stéphane, Haks Mariëlle C, Quinten Edwin, Modoux Christine, Agnandji Selidji Todagbe, Brosnahan Jessica, Dayer Julie-Anne, Harandi Ali M, Kaiser Laurent, Medaglini Donata, Monath Tom, Roux-Lombard Pascale, Kremsner Peter G, Ottenhoff Tom H M, Siegrist Claire-Anne
Infection Control Program, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
Sci Transl Med. 2017 Apr 12;9(385). doi: 10.1126/scitranslmed.aaj1701.
The 2014-2015 Ebola epidemic affected several African countries, claiming more than 11,000 lives and leaving thousands with ongoing sequelae. Safe and effective vaccines could prevent or limit future outbreaks. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSV-ZEBOV) vaccine has shown marked immunogenicity and efficacy in humans but is reactogenic at higher doses. To understand its effects, we examined plasma samples from 115 healthy volunteers from Geneva who received low-dose (LD) or high-dose (HD) vaccine or placebo. Fifteen plasma chemokines/cytokines were assessed at baseline and on days 1, 2 to 3, and 7 after injection. Significant increases in monocyte-mediated MCP-1/CCL2, MIP-1β/CCL4, IL-6, TNF-α, IL-1Ra, and IL-10 occurred on day 1. A signature explaining 68% of cytokine/chemokine vaccine-response variability was identified. Its score was higher in HD versus LD vaccinees and was associated positively with vaccine viremia and negatively with cytopenia. It was higher in vaccinees with injection-site pain, fever, myalgia, chills, and headache; higher scores reflected increasing severity. In contrast, HD vaccinees who subsequently developed arthritis had lower day 1 scores than other HD vaccinees. Vaccine dose did not influence the signature despite its influence on specific outcomes. The Geneva-derived signature associated strongly (ρ = 0.97) with that of a cohort of 75 vaccinees from a parallel trial in Lambaréné, Gabon. Its score in Geneva HD vaccinees with subsequent arthritis was significantly lower than that in Lambaréné HD vaccinees, none of whom experienced arthritis. This signature, which reveals monocytes' critical role in rVSV-ZEBOV immunogenicity and safety across doses and continents, should prove useful in assessments of other vaccines.
2014 - 2015年埃博拉疫情影响了多个非洲国家，夺走了11000多人的生命，并使数千人留下持续的后遗症。安全有效的疫苗可以预防或限制未来的疫情爆发。重组水疱性口炎病毒载体扎伊尔埃博拉（rVSV - ZEBOV）疫苗在人体中已显示出显著的免疫原性和疗效，但在高剂量时具有反应原性。为了解其效果，我们检测了来自日内瓦的115名健康志愿者的血浆样本，这些志愿者接受了低剂量（LD）或高剂量（HD）疫苗或安慰剂。在基线以及注射后第1天、第2至3天和第7天评估了15种血浆趋化因子/细胞因子。第1天单核细胞介导的MCP - 1/CCL2、MIP - 1β/CCL4、IL - 6、TNF - α、IL - 1Ra和IL - 10显著增加。确定了一个解释细胞因子/趋化因子疫苗反应变异性68%的特征。其分数在高剂量疫苗接种者中高于低剂量疫苗接种者，并且与疫苗病毒血症呈正相关，与血细胞减少呈负相关。在有注射部位疼痛、发热、肌痛、寒战和头痛的疫苗接种者中分数更高；分数越高反映严重程度越高。相比之下，随后发生关节炎的高剂量疫苗接种者第1天的分数低于其他高剂量疫苗接种者。尽管疫苗剂量对特定结果有影响，但并未影响该特征。来自日内瓦的特征与加蓬兰巴雷内一项平行试验中75名疫苗接种者的特征高度相关（ρ = 0.97）。在随后发生关节炎的日内瓦高剂量疫苗接种者中，其分数显著低于兰巴雷内高剂量疫苗接种者，后者均未发生关节炎。这一特征揭示了单核细胞在rVSV - ZEBOV跨剂量和各大洲的免疫原性和安全性中的关键作用，应证明对评估其他疫苗有用。
