Progress towards a safe and effective chlamydial vaccine

安全有效的衣原体疫苗研究进展David Mabey

London School of Hygiene & Tropical Medicine

Why do we need a chlamydial vaccine?为何需要衣原体疫苗？

• Most infections cause no symptoms 大多数感染无症状

• Screening programmes are expensive and have had little or no impact 筛查项目昂贵且效果不大

• Reported number of cases continues to increase worldwide 世界范围内报告病例数持续增加

Why is there no chlamydial vaccine?为何尚无衣原体疫苗？

• Chlamydia are difficult to study and could not be genetically manipulated until recently 衣原体研究困难，尚不能基因操作

• Lack of good animal models: mice and guinea pigs are different from humans 缺少好的动物模型：小鼠和豚鼠不同于人类

• Non-human primates (monkeys) are expensive 非人类灵长类（猴）模型昂贵

• Concern that vaccines could cause immunopathology 对疫苗引起免疫病理损伤的担忧

Recent progress 新近进展• Good evidence that protective immunity follows natural infection in

humans 人体自然感染后发生保护性免疫的证据• Review of evidence from trachoma vaccine trials: some evidence of

efficacy, no evidence of harm 沙眼疫苗试验的证据：一些有效、无损伤的证据

• Better understanding of the immunological correlates of protective immunity in humans 对人体保护性免疫相关性的认识

• New adjuvants can elicit the required immune response 新的佐剂可引致所需要的免疫反应

• Identification of new target antigens through genomic and proteomic approaches 基因组和蛋白质组研究发现新的靶抗原

• Genetic transformation of Chlamydia trachomatis 沙眼衣原体基因转化• Encouraging results with a live attenuated vaccine in monkeys 在猴进行的

活的减毒疫苗的令人鼓舞的结果

Trachoma Follicles (TF) 沙眼滤泡

Trachoma Scarring (TS) 沙眼瘢痕形成

Trachoma Trichiasis (TT) 沙眼倒睫

Is there evidence of protective immunity following natural infection?

是否有自然感染后保护性免疫的证据？ • Reduced prevalence and intensity of ocular C.

trachomatis infection with increasing age 随着年龄增长沙眼衣原体眼感染率及严重程度下降Solomon AW et al. NEJM 2004; 351: 1962-71.

• Reduced duration and incidence of untreated ocular C. trachomatis infection with increasing age 随着年龄增长未经治疗的沙眼衣原体眼感染病程及发生率下降Grassly NC PLoS Negl Trop Dis 2008; 2: e341

Evidence of protective immunity following natural ocular Ct infection from Tanzania 来自坦桑尼亚的沙眼衣原体眼自然感染

后产生保护性免疫的证据 Solomon AW et al. N Eng J Med 2004; 351: 1962-71

Kahe Mpya village, population 978

Ocular swabs taken for detection and quantitation of C. trachomatis infection by PCR from whole population

从全人群取眼拭子标本进行沙眼衣原体 PCR 定量检测

Prevalence and intensity of infection declines with age

随年龄增长感染率及严重程度下降

Age (years)

0 25 50 75 100

Copies omp1 per

swab

n=956

91 positives

(9.5%)

491709 copies

0

Robin Bailey and colleaguesin Jali village, The Gambia冈比亚

Followed up children with trachoma and their household contacts with clinical exam and ocular swab for C. trachomatis infection every 2 weeks for 6 months对沙眼儿童及其家庭接触者每隔 2 周进行眼拭子及临床检查的随访，共 6 个月

Duration of trachoma infection and disease (with approximate 95% confidence intervals) by age group 不同年龄组沙眼疾病及感染的病程

Grassly NC, Ward ME, Ferris S, Mabey DC, et al. (2008) The Natural History of Trachoma Infection and Disease in a Gambian Cohort with Frequent Follow-Up. PLoS Negl Trop Dis 2(12): e341. doi:10.1371/journal.pntd.0000341http://www.plosntd.org/article/info:doi/10.1371/journal.pntd.0000341

Trachoma vaccine trials in The Gambia在冈比亚开展的沙眼疫苗试验 (1960s)

Trachoma vaccine trials in 1960s1960 年代沙眼疫苗试验

• Taiwan: formalin inactivated local strain (s) – No impact on incidence of clinical trachoma

• 台湾：福尔马林灭活地方株– 对临床沙眼发病率无影响Woolridge RL et al. Am J Ophthalmol 1967; 63 (supp 5): 1645-50

• Saudi Arabia: killed bivalent vaccine– No impact on incidence of active trachoma or Ct infection– Lower bacterial load in vaccinated children

• 沙特阿拉伯：灭活二价疫苗– 对活动性沙眼或沙眼衣原体感染发病率无影响– 被免疫儿童细菌载量下降Nichols RL et al. Am J Trop Med Hyg 1969; 18: 723-30

Trachoma vaccine trials in 1960s 1960 年代沙眼疫苗试验

• India: killed bivalent vaccine 印度：灭活二价疫苗– Reduced prevalence of active trachoma in vaccinated arm

at 12 months: 接种组 12 个月时活动性沙眼感染率下降： – 26/182 (14%) vs 33/87 (37%), P<0.01Dhir SP et al. Am J Ophthalmol 1967; 63 (supp 5); 1639-44

• The Gambia: Live vaccines 冈比亚：活疫苗– Reduced prevalence of scarring at 24 months in vaccinated

group 接种组 24 个月时瘢痕形成比例下降：– 9/55 (16%) vs 18/47 (38%), p=0.034Sowa S et al. J Hyg (London) 1969; 67: 699-717

Conclusions from trachoma vaccine trials in monkeys and humans

猴和人沙眼疫苗试验总结• Some evidence of short lived, serotype specific

protection against infection and active disease 针对感染和活动性疾病的短期存在、血清型特异性保护作用

• Some evidence that vaccination may reduce scarring 接种疫苗可减少瘢痕形成的某些证据

• Some evidence that, in monkeys, vaccination led to more severe disease on subsequent ocular challenge with live chlamydia 在猴中的某些证据表明，接种后再给予活的衣原体可导致更为严重的疾病

• No evidence for this in humans 在人体尚无类似证据

Immunological correlates of protective immunity and pathology in humans

人体保护性免疫和病理的免疫学因素Mabey D et al. Vaccine 2014; 32: 1572-8

• Strong T-helper 1 responses to chlamydial antigens associated with protection from scarring sequelae 对瘢痕形成的保护作用与针对衣原体抗原的较强的 Th 1 免疫反应有关

• Increased levels of TNFα, IL-10, and pro-inflammatory markers such as IL-17A, S100A7, CXCL5, IL-1β and matrix metalloproteinases (MMPs) associated with increased inflammation and scarring 炎症与瘢痕形成的减少与 TNFα, IL-10 及前炎症因子如 IL-17A, S100A7, CXCL5, IL-1β和基质金属蛋白酶水平增加有关

New target antigens 新的靶抗原• Immuno-proteomic screening has identified new B and

T cell antigens which stimulate immune responses in mice and humans 免疫蛋白质组学研究发现了可刺激小鼠和人体免疫反应的新的 B 和 T 细胞抗原Finco O et al. PNAS 2011; 108: 9969-74

• Genome-wide profiling has identified antibody responses to target antigens associated with protection from scarring sequelae in humans 基因组学研究发现与人瘢痕形成起保护作用相关的针对靶抗原的抗体反应性Lu C et al. Invest Ophthalmol Vis Sci 2012;

Genetic manipulation of Chlamydia trachomatis

沙眼衣原体的基因操作• Will enable identification of virulence factors in

C. trachomatis, and the development of live attenuated vaccines 有助于鉴定沙眼衣原体毒力因子及研发减毒活疫苗

Wang Y et al. Development of a transformation system for Chlamydia trachomatis: restoration of glycogen biosynthesis by acquisition of a plasmid shuttle vector. PLoS Pathogens 2011; 7: e1002258

A live-attenuated chlamydial vaccine protects against trachoma in nonhuman primates

一种可保护非人灵长类沙眼的衣原体减毒活疫苗• Plasmid-cured ocular Tanzanian strain (serovar A) 质粒处理的坦

桑尼亚眼株（血清型 A ）• Inoculated into the eyes of 6 cynomolgus macaques 接种于 6只猕猴

的眼内• Led to a productive infection but minimal pathology 引起有效的感

染但极轻微的病理改变 • On subsequent challenge with the same strain containing plasmid

(wild type), 3 monkeys were completely protected, and 3 had reduced pathology and shedding随后以同样含质粒菌株（野生型）感染， 3只猴完全保护， 3只猴病理损伤和细菌排出减少Kari L, et al. J Exp Med. 2011;208:2217-23.

The C. trachomatis plasmid-cured trachoma strain A2497P− is highly attenuated for the monkey eye. 沙眼衣原体质粒处理沙眼株A2497P− 对猴眼高度减毒

Monkeys vaccinated with the attenuated A2497P− strain are protected against a challenge infection with virulent A2497 organisms以减毒 A2497P− 接种的猴对随后的毒性 A2497 感染有部分作用

Conclusions 小结• Recent progress could lead to the development

of a chlamydial vaccine in the near future 新的进展可望在不远的将来研发出衣原体疫苗

• Careful thought will need to be given to how the safety, efficacy and cost-effectiveness of a chlamydial vaccine would be best evaluated 需要认真考虑如何评估衣原体疫苗的安全性、有效性和成本 - 效益比