Walker David H, Mendell Nicole L
Department of Pathology, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX, 77555, USA.
NPJ Vaccines. 2023 Feb 9;8(1):11. doi: 10.1038/s41541-023-00605-1.
Scrub typhus caused by the obligately intracellular bacterium, Orientia tsutsugamushi, is a major cause of life-threatening acute undifferentiated febrile illness in eastern Asia and the islands of the Western Pacific and Indian oceans. Since the estimation of an incidence of 1 million cases annually two decades ago, the number of cases has increased substantially in endemic regions, reappeared where the disease was forgotten, and spread northward. Trombiculid mites are both reservoir and vector. Despite 80 years of efforts to develop a vaccine, there is none. Protective immunity is mediated by antibodies and CD8 and CD4 T cells. Previous efforts have failed because of gaps in understanding immunity to O. tsutsugamushi, particularly the requirements for vaccine-induced immunity, lack of knowledge regarding immune memory in scrub typhus, and lack of attention to addressing the issue of cross-protection between strains. There are numerous strains of O. tsutsugamushi, and modestly durable immunity is strain-specific. Antibodies to the strain that caused infection are protective against challenges with the homologous strain but, despite reactivity with other immunodominant antigens, the immune serum does not protect against heterologous strains. Among the antigens detected by western immunoblot in immune sera (22-, 47-, 56-, 58-, and 110 kDa proteins), only the 56 kDa protein stimulates strong protection. This protein contains four hypervariable regions which are likely, on the basis of limited data, to be the targets of neutralizing antibodies. However, a method that definitively detects neutralizing antibody has yet to be developed. Only one study has used genomic data to pursue the discovery of protective antigens. Three conserved autotransporters were identified, and only immunization with ScaA provided protection against the homologous strain, but only 40% of animals were protected against challenge with a heterologous strain. A multiplex vaccine containing conformational antigens of the hypervariable regions of the 56 kDa protein of the strains of the greatest clinical and epidemiological importance, as well as conserved regions of the 56 kDa protein, ScaA, and other protective antigens identified by future genomic and bioinformatics methods should be developed and tested.
由专性细胞内细菌恙虫东方体引起的恙虫病，是东亚以及西太平洋和印度洋岛屿上危及生命的急性未分化发热性疾病的主要病因。自二十年前估计每年发病100万例以来，流行地区的病例数大幅增加，在曾被遗忘该疾病的地区再度出现，并向北传播。恙螨既是储存宿主又是传播媒介。尽管经过80年努力研发疫苗，但仍无可用疫苗。保护性免疫由抗体以及CD8和CD4 T细胞介导。此前的努力均告失败，原因在于对恙虫东方体免疫的理解存在差距，尤其是疫苗诱导免疫的要求、对恙虫病免疫记忆缺乏了解，以及未关注解决菌株间交叉保护问题。恙虫东方体有众多菌株，适度持久的免疫具有菌株特异性。针对引起感染的菌株产生的抗体可抵御同源菌株的攻击，但尽管与其他免疫显性抗原发生反应，免疫血清却无法抵御异源菌株。在免疫血清中通过蛋白质免疫印迹法检测到的抗原（22 kDa、47 kDa、56 kDa、58 kDa和110 kDa蛋白）中，只有56 kDa蛋白能激发强大的保护作用。该蛋白包含四个高变区，基于有限数据，这些高变区可能是中和抗体的靶点。然而，尚未开发出能明确检测中和抗体的方法。仅有一项研究利用基因组数据探寻保护性抗原。鉴定出了三种保守的自转运蛋白，只有用ScaA免疫能提供针对同源菌株的保护，但只有40%的动物能抵御异源菌株的攻击。应研发并测试一种多价疫苗，该疫苗包含具有最大临床和流行病学重要性的菌株的56 kDa蛋白高变区的构象抗原，以及56 kDa蛋白的保守区、ScaA和未来通过基因组学和生物信息学方法鉴定出的其他保护性抗原。
