Herpes simplex type 2
Sexually Transmitted Diseases
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[url=http://www.who.int/vaccine_research/diseases/soa_std/en/index3.html#disease burden]Disease Burden[/url]
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[url=http://www.who.int/vaccine_research/diseases/soa_std/en/index3.html#virology]Virology[/url] Disease BurdenHerpes simplex virus type 2 (HSV-2) is the cause of genital herpes. The hallmark of herpesvirus infections is the establishment of a lifelong, latent infection that can reactivate to cause one or more rounds of disease. Latent HSV-2 infection occurs primarily in neurons found in the sacral root ganglia. The clinical spectrum of HSV-2 includes primary infection, characterized by the appearance of vesicles on the vulva or the penis that soon break to leave shallow, painful ulcerating lesions. The ulcers heal in 2–3 weeks, although healing may be very slow in immunocompromised patients. Primary infection is then followed by recurrent episodes of clinical disease (4–5 per year). The proportion of symptomatic infections is estimated to be between 13% and 37%, and probably higher in HIV positive individuals. Subclinical infection may be associated with infectious viral shedding. The virus is transmitted in genital secretions. Transmission of HSV-2 to newborns at the time of delivery may lead to devastating systemic infection with encephalitis. The risk of neonatal herpes fortunately is low among HIV-negative pregnant women living in industrialized countries (less than 3%), but few data are available on neonatal herpes in developing countries.
Genital herpes is one of the most common ulcerating diseases of the genital mucosa. It is estimated that in the USA, for example, from 40 to 60 million people are HSV-2-infected, with an incidence of 1–2 million infections and 600 000–800 000 clinical cases per year. Prevalence in the 30–40 year-old population is about 30%. Overall prevalence is higher in women compared with men, especially among the young. The same independent factors of HSV-2 infection were identified in both genders: older age, higher lifetime number of sexual partners, positive HIV serology and positive syphilis serology. Prevalence in developing countries can vary from 2–74% according to the country, age, gender, or urban versus rural areas. Rates up to 40% have been reported among women 15–19 years of age in rural Costa Rica, Kenya (Kisumu) and Mexico (Mexico-City). A study conducted on truck drivers in Bangladesh showed a high prevalence of HSV-2 (25.8%), compared to syphilis (5.7%), gonorrhoea (2.1%), and chlamydia (0.8%).
There is now ample evidence that HSV-2 infection is a major cofactor of HIV infection. In developed countries, where acquisition of HSV-1 in childhood has decreased, HSV-2 seroprevalence has increased, suggesting a possible protective effect of HSV-1 against HSV-2 acquisition. Although HSV-1 does not actually seem to modify the risk of HSV-2 acquisition, it appears to increase the proportion of asymptomatic seroconverters.
VirologyHSV-2, together with HSV-1 and the varicella-zoster virus (chickenpox), belongs to the subfamily Alphaherpesvirinae in the family Herpesviridae. These are large, complex enveloped viruses with an outer lipid envelope studded with at least 10 viral glycoproteins, an intermediate tegument layer comprising at least 15 viral proteins, and an icosahedral nucleocapsid containing the double-stranded DNA genome. The genome is organized into a 126-kb long and a 26-kb short region of double-stranded DNA bracketed by inverted repeat sequences that readily allow isomerization or recombination of the two regions. The genome comprises some 84 open reading frames. These have been divided into immediate-early genes, whose transcription depends on a virally-encoded activating protein, VP16, and which encode the viral α proteins; the early genes, which are turned on by the α proteins and whose products (β proteins) are involved in DNA replication; and the late genes, the products of which (γ proteins) are virion structural proteins and proteins needed for virus particle assembly and egress. Some of the viral envelope glycoproteins (gD) are antigenically related to those of HSV-1, whereas most are type-specific (particularly gG1 and gG2). Numerous viral gene products, which are dispensable for virus growth in vitro, can be considered as virulence genes that are involved in preventing apoptosis in the infected host cell, blocking the induction of interferons, or downregulating the presentation of viral antigens in the context of class I histocompatibility antigens (HLAs).
When the latent state is established in the neural ganglia, transcription is severely restricted such that a single transcript is produced from the latency-associated transcript (LAT) promoter, and only a few viral proteins are made. At intervals, changes in neuronal physiology induced by trauma, hormones, stress or immune suppression, render the neurones permissive to virus replication, resulting in full transcription of the genome and a burst of progeny virions. 5.3.3. Vaccines The prospect for developing a vaccine against HSV-2 that could provide sterilizing immunity is thought to be unrealistic. The goals of the vaccines under development are rather to prevent the establishment of latent infection by blocking access of the virus to sensory ganglia, to reduce the severity of the symptoms, and/or to reduce the frequency of recurrences. The correlates of protective immunity against HSV-2 are not entirely understood. Passive maternal antibody seems important in preventing infection of the newborn and CD4+ Th1 T-cells appear to be crucial to the immune response. IFN-γ secretion and CD8+ CTL may also play a major role, particularly in the prevention of recurrences.
HSV-2 subunit vaccines were developed based on the use of viral envelope glycoproteins.
- A two-component gB2 and gD2 recombinant glycoproteins subunit vaccine formulated in MF59 adjuvant was developed by Chiron. The 2-component vaccine induced high antibody titres and showed 26% efficacy in women for a period of six months but protection did not persist and male volunteers were not protected.
- GSK developed a single component gD2 vaccine formulated in AS04 adjuvant (alum + monophosphoryl lipid A). The gD2 vaccine induced good Th1 immunity in mice, including high IFN-γ secretion, and provided good protection against vaginal HSV-2 challenge in female guinea pigs. The vaccine was tested in two large, double-blind, controlled Phase III trials on volunteers with a partner with genital herpes disease. In the first study, 847 subjects were selected as seronegative for both HSV-1 and HSV-2, whereas in the second study the 2491 selected subjects were selected only on the basis of HSV-2 seronegativity. The vaccine was 73% efficacious against genital herpes disease in doubly seronegative women. Trends towards protection against infection were also observed, but the figures were not statistically significant (less than 48% efficacy). Most unexpectedly, however, the vaccine was not effective in women previously seropositive for HSV-1 and in men, regardless of their HSV seropositivity status. This suggests that HSV-1 immunity is protective against HSV-2, but no satisfactory explanation is available of why subunit vaccines seem to provide only gender-specific protection. Further Phase III efficacy trials of the gD2 vaccine (Herpevac) are in progress in collaboration with the NIH, involving about 7500 persons from 18 to 30 years of age, double HSV-1/HSV-2 seronegative women. A vaccine that protects women could be expected to decrease the rate of neonatal HSV infection and have an impact on the epidemic spread of genital herpes. Lack of efficacy of vaccines in HSV-1 infected individuals would however render the vaccine of little use in developing countries, where HSV-1 infection is ubiquitous.
- A novel, live attenuated HSV-2 candidate vaccine has been developed by Xenova/GSK using a replication-impaired virus mutant that lack the gene of the essential glycoprotein gH (ICP8 gene mutation) as a disabled infectious single cycle (DISC) virus vaccine. The vaccine was tested in Phase II trials in the USA as a therapeutic vaccine in HSV-2 seropositive symptomatic patients. It was well tolerated and induced neutralizing antibodies and CTL in 83% of the vaccinees, but no difference in time to recurrence and no difference in virus shedding were observed as compared with controls. The development of the DISC vaccine has been refocused towards its use as a prophylactic vaccine.
- Another live, replication-impaired vaccine is currently under development by Avant Immunotherapeutics. Other viral mutants that are defective for replication and impaired for establishment of latency, such as mutant dl5–29, are at a preclinical stage of development.
- A live attenuated vaccine based on a replication-competent ICP10 mutant of HSV-2 developed by AuRix is in Phase II clinical study.
DNA vaccine formulations have shown incomplete efficacy in animal models. Similarly, whole inactivated virus vaccines did not show efficacy and their development has been stopped.
疱疹单工通信制类型2
由性交传染的疾病
介绍
披衣菌trachomatis
淋病
疱疹单工通信制类型2
HIV/AIDS
- 疾病负担
- 病毒学
疾病负担
疱疹单工通信制病毒类型2 (HSV-2) 是生殖疱疹的起因。herpesvirus 传染标记是可能恢复活动导致疾病一个或更多圆终身, 潜在传染的创立。潜在HSV-2 传染发生主要在神经元里被发现在sacral 根神经节。很快打破留下浅, 痛苦的ulcerating 的损害的临床范围HSV-2 包括主要传染, 为泡出现描绘在vulva 或阴茎。溃疡愈合在2–3 个星期, 虽然愈合也许是非常慢的immunocompromised 患者。主要传染被周期性情节临床疾病然后跟随(4–5 每年) 。根据症状的传染的比例估计是在13% 和37% 之间, 和大概高在HIV 正面个体。临床症状不显的传染也许同感染病毒流出联系在一起。病毒被传送在生殖分泌物。HSV-2 传输对新出生在交付之时也许导致毁灭的系统传染以脑炎。出生疱疹风险幸运地是降低在HIV 消极孕妇之中居住在工业化国家(少于3%), 但少量数据是可利用的在出生疱疹在发展中国家。
生殖疱疹是生殖mucosa 的最共同的ulcerating 的疾病的当中一个。它估计, 在美国, 例如, 从40 到60 百万人民HSV 2 被传染, 以发生的1–2 百万传染和600 000–800 000 个临床案件每年。流行在30–40 岁人口是大约30% 。整体流行是高的在妇女比较人, 特别是在年轻人之中。HSV-2 传染同样独立因素被辨认了在两个性别: 更旧的年龄、性伙伴的更高的终身数字, 正面HIV 血清学和正面梅毒血清学。流行在发展中国家可能变化从2–74% 根据国家、年龄, 性别, 或都市对乡区。率由40% 决定被报告了在妇女15 之中–19 年纪在农村格斯达里加、肯尼亚(Kisumu) 并且墨西哥(墨西哥城市) 。研究进行在卡车司机在孟加拉国显示了HSV-2 (25.8% 的) 大流行, 与梅毒(5.7% 比较), 淋病(2.1%), 和披衣菌(0.8%) 。
有现在充足的证据, HSV-2 传染是艾滋病病毒感染一个主要辅助因素。在发达国家, HSV-1 承购在童年减少了, HSV-2 seroprevalence 增加了, 建议HSV-1 的一个可能的防护作用反对HSV-2 承购。虽然HSV-1 实际上不似乎修改HSV-2 承购风险, 看起来增加无症状seroconverters 的比例。
病毒学
HSV-2, 与HSV-1 和水痘zoster 病毒(水痘一起), 属于subfamily Alphaherpesvirinae 在家庭Herpesviridae 。这些是大, 复杂被包围的病毒与一个外面油脂信封散布与至少10 病毒糖蛋白, 中间tegument 层数包括至少15 病毒蛋白质, 和一icosahedral nucleocapsid 包含double-stranded DNA 染色体。染色体被组织入一126 kb 长和double-stranded DNA 的26 kb 短小区域由欣然允许二个地区的异构化或再结合的被倒置的重覆序列托。染色体包括大约84 个开放读书框架。这些被划分了成直接及早基因, 副本依靠virally 编码激活的蛋白质, VP16, 并且输入病毒 α 蛋白质; 早期的基因, 由打开 α 和产品的蛋白质(β 蛋白质) 被介入在DNA 复制; 并且晚基因, 产品(γ 蛋白质) 是virion 结构蛋白质和蛋白质需要为病毒微粒汇编和外出。一些病毒信封糖蛋白(gD) 抗原与那些HSV-1 有关, 但是多数是类型具体的(特殊gG1 和gG2) 。众多的病毒基因产品, 是可有可无的为病毒成长在试管内, 可能被考虑当被介入在防止apoptosis 在被传染的寄主细胞的剧毒基因, 阻拦干扰素的归纳, 或downregulating 病毒抗原的介绍就类I 组织相容性抗原(HLAs) 状况。
当潜在状态建立在神经系统的神经节, 副本严厉地被制约这样, 一本唯一抄本由潜在因素伴生的抄本(拉特银币) 促进者被生产, 并且唯一几病毒蛋白质被制作。在间隔时间, 变化在神经细胞的生理上被精神创伤导致, 激素、重音或免疫镇压, 使神经元许可对病毒复制, 造成染色体的充分的副本和后裔virions 爆炸。5.3.3 。疫苗开发疫苗的远景反对能提供消炎的免疫的HSV-2 认为是不切实际的。疫苗的目标在发展中是宁可防止潜在传染的创立由阻拦病毒的通入对知觉神经节, 减少症状的严肃, 并且/或者减少再现频率。防护免疫correlates 反对HSV-2 不整个地被了解。被动母亲抗体似乎重要在防止传染新出生并且CD4+ Th1 T 细胞看来是关键的对免疫反应。IFN-γ 分泌物和CD8+ CTL 也许并且充当一个主要角色, 特别在再现的预防。
HSV-2 亚单位疫苗被开发了根据了对病毒信封糖蛋白的用途。
二组分gB2 和gD2 再组合糖蛋白亚单位疫苗被公式化在MF59 辅药由Chiron 开发了。2 组分疫苗导致的高抗体滴定量和被显示的26% 效力在妇女六个月而是保护的期间没有坚持并且男性志愿者未被保护。
GSK 开发了唯一组分gD2 疫苗被公式化在AS04 辅药(白矾+ monophosphoryl 油脂A) 。gD2 疫苗导致好Th1 免疫在老鼠, 包括高的IFN-γ 分泌物, 和假设好保护反对阴道HSV-2 挑战在女性试验品。疫苗被测试了在二大, 双盲, 受控阶段III 试验在志愿者与一个伙伴以生殖疱疹疾病。在第一研究中, 847 个主题象seronegative 被选择了为HSV-1 和HSV-2, 但是在第二项研究中2491 个选择的主题被选择了只根据HSV-2 seronegativity 。疫苗是73% 有效反对生殖疱疹疾病在加倍seronegative 妇女。趋向往保护反对传染并且被观察了, 但图统计地不是重大的(少于48% 效力) 。最意想不到地, 然而, 疫苗不是有效的在妇女早先seropositive 为HSV-1 和在人, 不管他们的HSV seropositivity 状态。这建议, HSV-1 免疫是防护的反对HSV-2, 但令人满意的解释不是可利用的为什么亚单位疫苗似乎提供唯一性别具体保护。gD2 疫苗(Herpevac 的) 更加进一步的阶段III 效力试验是进展中与NIH 合作, 涉及大约7500 个人从18 到30 年纪, 双重HSV-1/HSV-2 seronegative 妇女。保护妇女的疫苗能被期望减少出生HSV 传染的率和有对生殖疱疹流行性传播的冲击。缺乏疫苗效力在HSV-1 被传染的个体然而会回报一点用途疫苗在发展中国家, HSV-1 传染是普遍存在的。
小说, 活变稀的HSV-2 候选人疫苗由Xenova/GSK 开发了使用缺乏根本糖蛋白gH 的一个复制被削弱的病毒突变体(ICP8 基因变化的) 基因作为残疾感染唯一周期(圆盘) 病毒疫苗。疫苗被测试了在阶段II 试验在美国作为治疗疫苗在HSV-2 seropositive 根据症状的患者。它被容忍了和很好导致中立化的抗体和CTL 在83% vaccinees 中, 但时差对再现和在病毒流出上的区别未被观察与控制比较。圆盘疫苗的发展被重新聚焦往它的用途作为预防疾病的疫苗。
其它活, 复制被削弱的疫苗当前是在发展中由Avant Immunotherapeutics 。是瑕疵的为复制和被削弱为潜在因素的创立的其它病毒突变体, 譬如突变体dl5–29, 是在发展一个preclinical 阶段。
活变稀的疫苗根据HSV-2 一个复制能干ICP10 突变体显现了出由AuRix 是在阶段II 临床研究中。
DNA 疫苗公式化显示了残缺不全的效力在动物模型中。同样, 整体被撤消的病毒疫苗没有显示效力和他们的发展被停止了。
