基于B群脑膜炎奈瑟球菌候选抗原进行疫苗开发的研究进展

流行性脑脊髓膜炎（流脑）是一种由脑膜炎奈瑟球菌引发的严重呼吸道传染病。随着脑膜炎球菌多糖疫苗和多糖-蛋白质结合疫苗的应用,大部分于人群中广泛流行的致病性脑膜炎奈瑟球菌（血清A、C、W135、Y群）已得到了有效控制。然而,这也导致B群脑膜炎奈瑟球菌引发的流脑的占比增多。此文综述了目前已发现的B群脑膜炎球菌疫苗候选抗原,以及基于这些抗原已经获批和正在研发的B群脑膜炎球菌疫苗,以期帮助研究人员进行新型B群脑膜炎球菌疫苗的研发。     

脑膜炎球菌病的流行病学及疫苗(待续)

脑膜炎球菌是唯一能导致全球流行性脑脊髓膜炎(流脑)流行的病因.全球范围内90％的病例是由A、B、C、Y和W135群所致.欧美国家主要流行菌群为B、C和Y群;亚洲和非洲主要是A、C和W135群.A、C、Y和W135群多糖疫苗能有效控制流脑暴发,但由于在婴儿中免疫原性差,应用并不广泛.发达国家在引进C群结合疫苗后,C群流脑发病数迅速下降.A、C、Y和W135群结合疫苗的研制成功有望控制这些群导致的流脑流行.以外膜囊、外膜蛋白和基因组来源的表面蛋白为目标的B群疫苗研究取得不同程度的进展.     

脑膜炎球菌新疫苗：Menveo

脑膜炎是指覆盖脑部和脊髓的薄膜发生的严重炎症，可导致脑和神经系统的永久性损害。流行性脑膜炎（简称流脑）是由脑膜炎奈瑟菌（又称脑膜炎球菌）引起的一种化脓性脑膜炎。本病菌除引起流脑和败血症外，还可以引起肺炎、心包炎和关节炎等，统称脑膜炎球菌病。部分患者爆发起病，若治疗不及时，可在数小时内迅速致死，即使幸存，也可能留下耳聋、失明等严重后遗症。因此脑膜炎球菌疫苗一直是疫苗开发的焦点所在。     

脑膜炎球菌病的流行病学及疫苗(续)

脑膜炎球菌是唯一能导致全球流行性脑脊髓膜炎(流脑)流行的病因.全球范围内90％的病例是由A、B、C、Y和W135群所致.欧美国家主要流行菌群为B、C和Y群;亚洲和非洲主要是A、C和W135群.A、C、Y和W135群多糖疫苗能有效控制流脑暴发,但由于在婴儿中免疫原性差,应用并不广泛.发达国家在引进C群结合疫苗后,C群流脑发病数迅速下降.A、C、Y和W135群结合疫苗的研制成功有望控制这些群导致的流脑流行.以外膜囊、外膜蛋白和基因组来源的表面蛋白为目标的B群疫苗研究取得不同程度的进展.     

脑膜炎球菌疫苗研究与疾病防控策略初探

此文介绍了脑膜炎球菌的特点、传播途径、流行趋势及危害性,讨论了防控流行性脑脊髓膜炎暴发的相关策略,并对目前国内外脑膜炎球菌疫苗的研究现状进行了阐述和评价.     

不同稀释液配制的结合疫苗免疫持久性研究

目的 了解分别用Al(OH)3佐剂、生理盐水配制Hib结合疫苗和A、C群脑膜炎球菌结合疫苗的免疫持久性.方法 分别用两种稀释液配制Hib结合疫苗和A、C群脑膜炎球菌结合疫苗,各自免疫小鼠,采集分离血清用ELISA测定血清IgG抗体滴度,计算血清抗体GMT和阳转率及不同免疫针次的免疫持久性.结果 两种稀释液配制的Hib结合疫苗和A、C群脑膜炎球菌结合疫苗均可产生明显的抗体应答和免疫记忆反应,但在刺激机体快速产生免疫应答,加强免疫后的回忆反应,抗体滴度及免疫持久性方面有明显差异.生理盐水配制的结合疫苗较Al(OH)3盐水配制的结合疫苗可刺激机体快速产生抗体应答,但Al(OH)3盐水配制的结合疫苗具有更好的抗体GMT和免疫持久性.结论 Al(OH)3盐水配制的结合疫苗具有较好的免疫原性.     

ACYW135群脑膜炎球菌多糖疫苗的研制

目的 通过研究冷酚与粗糖的混合比例、粗糖提纯时的质量浓度和乳糖保护剂的用量来制备符合规定的ACYW135群脑膜炎球菌多糖疫苗.方法 发酵细菌,提取A、C、W135、Y群脑膜炎球菌多糖粗制品,以不同的纯化工艺纯化A、C、W135、Y群脑膜炎球菌多糖.将4种纯化的多糖原液按一定比例混合,加入乳糖作为保护剂,冷冻干燥制成ACYW135群脑膜炎球菌多糖疫苗.结果 通过比较不同纯化工艺制备的多糖,确定最佳提纯条件为多糖与冷酚的体积比为1∶1,粗糖提纯时的质量浓度为6 g/L.检测按此纯化条件制备的ACYW135群脑膜炎球菌多糖疫苗显示,3批疫苗的水分含量分别为1.7％、2.0％和2.1％,疫苗的A、C、W135、Y群脑膜炎球菌多糖含量和回收率分别都≥50 μg/剂和80％,符合相关规定的要求.结论 按确定的工艺成功制备ACYW135群脑膜炎球菌多糖疫苗.     

B群脑膜炎球菌的分子流行病学与疫苗设计

脑膜炎球菌是一种严格的人类病原菌,主要引起发病率和病死率均较高的流行性脑脊髓膜炎和败血症.过去对脑膜炎球菌的研究主要以血清学实验为基础.随着分子生物学技术的发展,B群脑膜炎球菌的分子流行病学研究取得了极大的进展,获得的研究成果为疫苗开发与评价提供了重要的依据.此文对B群脑膜炎球菌的分子流行病学及其疫苗设计进行简要论述.     

疫苗研究与开发:脑膜炎球菌病

本文对抗脑膜炎球菌病疫苗的研究开发现状进行综述.该病由脑膜炎球菌引起,它是导致严重脑膜炎和败血症的主要病因,具有流行性.大部分疾病由五个血清群(A、B、C、Y和W135)引起,而A群仍是唯一导致大规模流行的血清群,主要发生在非洲,在亚洲也有流行.欧洲和美洲大部分病例由B群和C群引起.b型流感嗜血杆菌(Hib)和肺炎链球菌结合疫苗的成功经验为开发预防脑膜炎球菌病的多糖结合疫苗铺平了道路.欧洲几个国家C群结合疫苗的广泛接种证明这种疫苗具有免疫原性,可以诱导免疫记忆,降低带菌率,为普通人群带来群体免疫.开发中的一种价廉的单价A群结合疫苗为消灭非洲国家大规模流行带来了希望.多价(A、C、Y、W135)结合疫苗也在开发中,一种已被批准.B群外膜蛋白疫苗正在开发.没有B群疫苗将难以在全球有效预防脑膜炎球菌病.     

脑膜炎球菌疫苗

本文讨论了脑膜炎球菌疫苗的研制现状和效力.重点讨论了采用传统和逆向疫苗学方法研制的B群脑膜炎球菌疫苗的效力.     

Meningococcal glycoconjugate vaccines

Neisseria meningitidis is a major cause of invasive bacterial infections worldwide. For this reason, efforts to control the disease have been directed at optimizing meningococcal vaccines and implementing appropriate vaccination policies. In the past, plain polysaccharide vaccines containing purified capsular polysaccharides A, C, Y and W135 were developed, but failed to protect infants, who are at greatest risk. Experience with the conjugate Haemophilus vaccine suggested that this approach might well empower meningococcal vaccines. Thus, a very efficacious vaccine against serogroup C Neisseria meningitis was optimized and has been widely used in developed nations since 1999. On the basis of epidemiological changes in the circulation of pathogenic serogroups in the United States, a quadrivalent conjugate vaccine against A, C, Y and W135 serogroups (Menactra?) has been developed and was approved by the U.S. FDA (Food and Drug Administration) in 2005. Recently, another tetravalent conjugate meningococcal vaccine (Menveo?) has been licensed and made available in the United States of America and in the European Union. Finally, in response to large epidemics caused by serogroup A meningococcus in Africa, a new, safe, immunogenic and affordable vaccine has been developed. This review highlights the evolution of conjugate meningococcal vaccines in general and discusses how this kind of vaccine can contribute to preventing meningococcal disease.     

History of Meningococcal Outbreaks in the United States: Implications for Vaccination and Disease Prevention

Invasive meningococcal disease caused by Neisseria meningitidis presents a significant public health concern. Meningococcal disease is rare but potentially fatal within 24 hours of onset of illness, and survivors may experience permanent sequelae. This review presents the epidemiology, incidence, and outbreak data for invasive meningococcal disease in the United States since 1970, and it highlights recent changes in vaccine recommendations to prevent meningococcal disease. Relevant publications were obtained by database searches for articles published between January 1970 and July 2015. The incidence of meningococcal disease has decreased in the United States since 1970, but serogroup B meningococcal disease is responsible for an increasing proportion of disease burden in young adults. Recent serogroup B outbreaks on college campuses warrant broader age‐based recommendations for meningococcal group B vaccines, similar to the currently recommended quadrivalent vaccine that protects against serogroups A, C, W, and Y. After the recent approval of two serogroup B vaccines, the Advisory Committee on Immunization Practices first updated its recommendations for routine meningococcal vaccination to cover at‐risk populations, including those at risk during serogroup B outbreaks, and later it issued a recommendation for those aged 16–23 years. Meningococcal disease outbreaks remain challenging to predict, making the optimal disease management strategy one of prevention through vaccination rather than containment. How the epidemiology of serogroup B disease and prevention of outbreaks will be affected by the new category B recommendation for serogroup B vaccines remains to be seen.     

Meningococcal vaccines

Neisseria meningitidis is a major world-wide cause of meningitis. N. meningitidis related diseases have become more pronounced in the last decade and changes in meningococcal-associated disease have opened new opportunities for prevention and vaccine development. Although multivalent vaccines have been developed against the N. meningitidis serogroups A, C, W-135, and Y, four of the most common serogroups, the diversity of N. meningitidis has increased the number of challenges for the development of an effective vaccine against all currently identified strains. Without the development of a vaccine against serogroup B, it will be difficult to effectively prevent global meningococcal disease. This review provides a background on N. meningitidis biology and focuses on the current status of meningococcal research and vaccine development. In addition, the efficacy of the currently marketed N. meningitidis vaccines will be discussed.     

Serogroup B meningococcal vaccines

Neisseria meningitidis causes severe, often fatal septicemia and meningitis. Polysaccharide vaccines that offer protection against infection with meningococcal serogroups A, C, Y and W-135 are effective in older children and adults, and have been widely used. New polysaccharide-conjugate vaccines against one or more of these serogroups are now in use or under accelerated development; however, a broadly protective vaccine against infection by serogroup B N meningitidis is not yet available. Serogroup B contributes significantly to the burden of meningococcal disease in many industrialized countries where both epidemic and endemic serogroup B infections occur. Vaccines effective against specific strains responsible for serogroup B epidemic disease have been developed, but the development of a safe serogroup B vaccine that is cross protective against multiple strains and is effective in infants and young children is a challenge. In spite of these difficulties, promising approaches stemming from a better understanding of meningococcal pathogenesis and of the genetics of serogroup B N meningitidis continue to evolve. Progress toward an effective serogroup B vaccine, an important addition for meningococcal disease prevention, is the focus of this review. The epidemiology and pathogenesis of meningococcal disease are detailed, along with discussion of the challenges faced in the development of efficacious serogroup B vaccines.     

Meningococcal disease: the advances and challenges of meningococcal disease prevention

Vaccination as a means to prevent meningococcal disease caused by Neisseria meningitidis is critical given the abrupt onset and rapid progression of this disease. Five serogroups--A, B, C, W-135, and Y--are responsible for the majority of cases. In developed countries, infants have the greatest risk of disease, with a smaller secondary peak observed in late adolescence. Vaccines utilizing the polysaccharide capsule are poorly immunogenic in young children but can reduce the incidence of meningococcal carriage in high risk groups. In contrast, protein conjugate vaccines to polysaccharide capsules A, C, W-135, and Y have broadened the population protection from disease but their effect on meningococcal carriage and transmission is yet unknown except for monovalent meningococcal C conjugate that has been shown to reduce carriage. Challenges remain in providing direct protection to infants and protection against meningococcal B disease. To date, outer membrane vesicle vaccines have been used to control meningococcal B disease in epidemic settings and vaccine candidates against subcapsular antigens are in development, but a vaccine that confers long-lasting protection is unavailable.     

B群脑膜炎球菌疫苗的研究现状及挑战

疫苗的免疫接种是预防传染病的最有效方法之一。近年以来随着生物技术迅猛发展,B群脑膜炎球菌疫苗的研究也取得了突破性发展,应用反向疫苗学技术开发的新型B群脑膜炎球菌疫苗已陆续被欧洲医药管理局和美国食品和药品管理局批准上市。尽管目前国内尚未批准相关产品上市,但一些企业和研究院所已在加紧研发。为了进一步了解B群脑膜炎球菌疫苗,推动国内B群脑膜炎球菌疫苗的研发,综述不同类型B群脑膜炎球菌疫苗的研究现状及其面临的挑战。     

Meningococcal disease in international travel: vaccine strategies

International travel and migration facilitate the rapid intercontinental spread of meningococcal disease. Serogroup A, and to a lesser extent serogroup C, have been responsible for pandemics in the past (mainly in Africa), but in recent years there was an international outbreak due to W135 related to the Hajj pilgrimage. The high carriage rates, persistence and transmissibility, in combination with the high case fatality rate of the Hajj-associated W135 outbreak clone, certainly raise considerable concern about the public health consequences of widespread dissemination of this organism and the potential for future epidemics. Indeed, the now evolving W135 epidemic in Africa mandates that the bivalent meningococcal vaccine should be replaced by the tetravalent meningococcal vaccine, covering A, C, Y and W135 serogroups. The currently available polysaccharide tetravalent meningococcal vaccine, albeit associated with high seroconversion and efficacy rates, has several shortcomings: it is not immunogenic in young children, duration of protective immunity is short, and it has minimal or no effect on nasopharyngeal carriage and therefore transmission of the organism. Immunogenicity of polysaccharide vaccines can be improved by chemical conjugation to a protein carrier, thereby eliciting a T-cell-dependent antibody response. In contrast to polysaccharide vaccines, conjugate vaccines are immunogenic in young infants, induce long-term protection, and reduce nasopharyngeal carriage. The tetravalent conjugate vaccine will be a leap forward in the control of meningococcal epidemics in affected countries. It will also boost the uptake of meningococcal vaccines in travelers, because the duration of protection is longer and it eliminates the problem of immune hyporesponsiveness of serogroup C with repeated dosing. The small risk of travel-associated disease for the general traveler and the unpredictable nature of epidemics make it difficult to provide evidence-based vaccine recommendations. The current recommendation is to vaccinate all Hajj pilgrims, travelers to areas with current outbreaks, travelers to the sub-Saharan meningitis belt, and high-risk individuals (i.e., those with immunodeficiencies).     

基于中英两国药典对比分析我国儿童免疫规划疫苗质量标准综述

通过对比中英两国药典关于儿童免疫规划疫苗质量标准的规定,可看出国内当下儿童免疫规划疫苗质量标准有领先之处亦有不足,中国在重组乙肝和甲肝灭活疫苗游离的甲醛标准、A群流脑多糖与A群C群流脑多糖疫苗抗原、蛋白质及核酸的含量标准、百白破疫苗中的破伤风原液的抗原纯度标准、重组乙肝和吸附百白破联合疫苗的铝含量标准规定上要严于英国。而英国在A群流脑多糖以及A群C群流脑多糖疫苗的热原规定、脊髓灰质炎减毒活疫苗的病毒滴度标准规定上严于中国。我们应当取长补短,参考英国药典提升我国儿童免疫规划疫苗质量标准,以促进我国疫苗质量和国际接轨。