Brey Robert N, Mantis Nicholas J, Pincus Seth H, Vitetta Ellen S, Smith Leonard A, Roy Chad J
a Kinesis Vaccines, LLC , Chicago , IL , USA.
b Division of Infectious Disease , Wadsworth Center, New York State Department of Health, Albany, NY, USA Department of Biomedical Sciences, University of Albany School of Public Health , Albany , NY , USA.
Hum Vaccin Immunother. 2016 May 3;12(5):1196-201. doi: 10.1080/21645515.2015.1124202. Epub 2016 Jan 25.
Several promising subunit vaccines against ricin toxin (RT) have been developed during the last decade and are now being tested for safety and immunogenicity in humans and for efficacy in nonhuman primates. The incentive to develop a preventive vaccine as a countermeasure against RT use as a bioweapon is based on the high toxicity of RT after aerosol exposure, its environmental stability, abundance, and ease of purification. RT is the second most lethal biological toxin and is considered a "universal toxin" because it can kill all eukaryotic cells through binding to ubiquitous cell surface galactosyl residues. RT has two subunits conjoined by a single disulfide linkage: RTB, which binds galactosyl residues and RTA which enzymatically inactivates ribosomes intracellularly by cleavage ribosomal RNA. Attenuation of toxicity by elimination of the active site or introduction of other structural mutations of RTA has generated two similar clinical subunit vaccine candidates which induce antibodies in both humans and nonhuman primates. In rhesus macaques, inhaled RT causes rapid lung necrosis and fibrosis followed by death. After parenteral vaccination with RTA vaccine, macaques can be protected against aerosol RT exposure, suggesting that circulating antibodies can protect lung mucosa. Vaccination induces RT-neutralizing antibodies, the most likely correlate of protection. Macaques responded to conformational determinants in an RTA vaccine formulation, indicating preservation of RTA structure during initial manufacture. Comparative mapping studies have also demonstrated that macaques and humans recognize the same epitopes, significant in the study of macaques as a model during development of vaccines which cannot be tested for efficacy in humans.
在过去十年中，已经研发出几种有前景的抗蓖麻毒素（RT）亚单位疫苗，目前正在进行人体安全性和免疫原性测试以及非人类灵长类动物的有效性测试。研发预防性疫苗作为应对将RT用作生物武器的对策，其动机基于气溶胶暴露后RT的高毒性、环境稳定性、丰富性和易于纯化。RT是第二大致死性生物毒素，被认为是一种“通用毒素”，因为它可以通过与普遍存在的细胞表面半乳糖基残基结合来杀死所有真核细胞。RT有两个通过单个二硫键连接的亚基：RTB，它结合半乳糖基残基；RTA，它通过切割核糖体RNA在细胞内酶促使核糖体失活。通过消除活性位点或引入RTA的其他结构突变来减弱毒性，产生了两种类似的临床亚单位疫苗候选物，它们在人类和非人类灵长类动物中均能诱导产生抗体。在恒河猴中，吸入RT会导致肺部迅速坏死和纤维化，随后死亡。用RTA疫苗进行肠胃外接种后，恒河猴可以免受气溶胶RT暴露的影响，这表明循环抗体可以保护肺黏膜。接种疫苗可诱导产生RT中和抗体，这很可能是保护作用的相关因素。恒河猴对RTA疫苗制剂中的构象决定簇有反应，表明在初始生产过程中RTA结构得以保留。比较图谱研究还表明，恒河猴和人类识别相同的表位，这在将恒河猴作为疫苗研发过程中无法在人体进行有效性测试的模型的研究中具有重要意义。
