Diemert David J, Freire Janaína, Valente Vanderson, Fraga Carlo Geraldo, Talles Frederico, Grahek Shannon, Campbell Doreen, Jariwala Amar, Periago Maria Victoria, Enk Martin, Gazzinelli Maria Flávia, Bottazzi Maria Elena, Hamilton Robert, Brelsford Jill, Yakovleva Anna, Li Guangzhao, Peng Jin, Correa-Oliveira Rodrigo, Hotez Peter, Bethony Jeffrey
Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington DC, United States of America.
Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
PLoS Negl Trop Dis. 2017 May 2;11(5):e0005574. doi: 10.1371/journal.pntd.0005574. eCollection 2017 May.
Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) plays a role in the digestion of host hemoglobin by adult N. americanus hookworms. Vaccination of laboratory animals with recombinant Na-GST-1 is associated with significant protection from challenge infection. Recombinant Na-GST-1 was expressed in Pichia pastoris and adsorbed to aluminum hydroxide adjuvant (Alhydrogel) according to current Good Manufacturing Practice. Two Phase 1 trials were conducted in 142 healthy adult volunteers in the United States and Brazil, first in hookworm-naïve individuals and then in residents of a N. americanus endemic area in Brazil. Volunteers received one of three doses of recombinant Na-GST-1 (10, 30, or 100 μg) adjuvanted with Alhydrogel, adjuvanted with Alhydrogel and co-administered with an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF), or the hepatitis B vaccine. Vaccinations were administered via intramuscular injection on days 0, 56, and 112. Na-GST-1/Alhydrogel was well tolerated in both hookworm-naïve and hookworm-exposed adults, with the most common adverse events being mild to moderate injection site pain and tenderness, and mild headache and nausea; no vaccine-related severe or serious adverse events were observed. Antigen-specific IgG antibodies were induced in a dose-dependent fashion, with increasing levels observed after each vaccination in both trials. The addition of GLA-AF to Na-GST-1/Alhydrogel did not result in significant increases in specific IgG responses. In both the US and Brazil studies, the predominant IgG subclass induced against Na-GST-1 was IgG1, with lesser amounts of IgG3. Vaccination of both hookworm-naïve and hookworm-exposed adults with recombinant Na-GST-1 was safe, well tolerated, and resulted in significant antigen-specific IgG responses. Based on these results, this vaccine will be advanced into clinical trials in children and eventual efficacy studies.
ClinicalTrials.gov (NCT01261130 for the Brazil trial and NCT01385189 for the US trial).
美洲板口线虫谷胱甘肽 - S - 转移酶 - 1（Na - GST - 1）在美洲板口线虫成虫消化宿主血红蛋白过程中发挥作用。用重组Na - GST - 1对实验动物进行疫苗接种可显著保护其免受攻击感染。重组Na - GST - 1在毕赤酵母中表达，并按照现行药品生产质量管理规范吸附于氢氧化铝佐剂（Alhydrogel）上。在美国和巴西对142名健康成年志愿者进行了两项1期试验，首先是在未感染钩虫的个体中进行，然后是在巴西一个美洲板口线虫流行地区的居民中进行。志愿者接受三种剂量的重组Na - GST - 1（10、30或100μg）之一，这些重组Na - GST - 1分别与Alhydrogel佐剂、与Alhydrogel佐剂并用并与吡喃葡萄糖基脂质A（GLA - AF）的水性制剂共同给药，或接种乙肝疫苗。在第0、56和112天通过肌肉注射进行疫苗接种。Na - GST - 1/Alhydrogel在未感染钩虫和已接触钩虫的成年人中耐受性良好，最常见的不良事件为轻度至中度注射部位疼痛和压痛，以及轻度头痛和恶心；未观察到与疫苗相关的严重或重大不良事件。抗原特异性IgG抗体呈剂量依赖性诱导产生，在两项试验中每次接种后水平均有所升高。在Na - GST - 1/Alhydrogel中添加GLA - AF并未导致特异性IgG反应显著增加。在美国和巴西的研究中，针对Na - GST - 1诱导产生的主要IgG亚类均为IgG1，IgG3的量较少。用重组Na - GST - 1对未感染钩虫和已接触钩虫的成年人进行疫苗接种是安全的，耐受性良好，并产生了显著的抗原特异性IgG反应。基于这些结果，该疫苗将推进到儿童临床试验及最终的疗效研究中。
ClinicalTrials.gov（巴西试验注册号为NCT01261130，美国试验注册号为NCT01385189）。
