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。     

SanofiPasteur用于儿童的脑膜炎疫苗获得FDA批准

赛诺菲-安万特（Sanofi-Aventis）公司的疫苗部SanofiPasteur于10月19日宣布，其脑膜炎共轭疫苗（meningococcalconjugatevaccine，Menactra）获得FDA批准，扩大适应证至包括2—10岁的儿童。该疫苗为A，C，Y和W．135群脑膜炎球菌多糖白喉类毒素结合物疫苗，是第一个也是惟一获得美国FDA许可用于预防脑膜炎球菌疾病的四价共轭疫苗，首次于2005年获得FDA批准用于11—55岁的青少年和成年人的免疫接种。本疫苗可针对引起脑膜炎球菌感染的5种（A，C，Y和W-135群脑膜炎双球菌）最常见的细菌血清群提供预防。在美国尚无预防B群脑膜炎球菌感染的疫苗。     

短讯

辉瑞研发的脑膜炎球菌B群疫苗获得FDA的快速批准本刊讯前不久,辉瑞公司宣布,美国食品和药品管理局(FDA)已经快速批准了TRUMENBA?(B群脑膜炎球菌疫苗)用于10~25岁人群主动免疫预防B群脑膜炎奈瑟菌导致的侵袭性疾病。这一疫苗获批的依据是,疫苗对美国流行的4个B群的代表性菌株诱导的血清杀菌活性免疫反应结果,其预防不同亚型的B群菌株的效果尚未确定。作为快速审批过程的一部分,辉瑞将继续完成其正在进行的     

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.     

脑膜炎球菌疫苗研究进展

1969年,美国Gotschlish等采用十六烷基三甲基溴化铵提取脑膜炎球菌的大分子多糖抗原,成功制备荚膜多糖疫苗,证明免疫效果良好.然而,多糖疫苗对婴幼儿的免疫原性较弱,因而人们研制了单价和多价多糖一蛋白结合疫苗,目前部分结合疫苗已进入临床或上市.鉴于B群脑膜炎球菌多糖的免疫原性极弱,人们开发了外膜蛋白疫苗.研究表明,部分外膜蛋白疫苗对婴儿及儿童有较好的免疫原性及安全性.此外,通过基因工程技术研制DNA疫苗也不失为预防脑膜炎球菌感染的一种免疫策略.     

EMA建议批准葛兰素史克脑膜炎球菌疫苗

欧洲药品管理局(EMA)已建议批准葛兰素史克公司脑膜炎球菌结合疫苗,用于治疗成人及1岁以上儿童的脑膜炎球菌病。该疫苗针对的是脑膜炎奈瑟菌A、C、W-135及Y群。人用医药产品委员会(CHMP)表示:"考虑到对奈瑟菌有一个良好的利益—     

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.     

B群脑膜炎球菌疫苗研究进展

 脑膜炎球菌是引起流行性脑脊髓膜炎的主要病原菌,是全球重要的公共卫生问题。目前仍缺少安全有效的疫苗用于控制和预防B群脑膜炎球菌引起的感染。此文对B群脑膜炎球菌疫苗研究进展及存在问题进行综述。     

C群脑膜炎球菌荚膜多糖结合疫苗的研制

目的对C群脑膜炎球菌多糖-破伤风类毒素结合疫苗进行研制。方法将C群脑膜炎球菌多糖在溴化氰(CNBr)的活化下,以1,6己二酰肼(ADH)作为连接子与精制破伤风类毒素(TT)在碳二亚胺(EDAC)作用下结合,制成C群脑膜炎球菌多糖结合疫苗原液,加保护剂冻干后制成C群脑膜炎球菌多糖结合疫苗。结果制备的冻干C群脑膜炎球菌多糖结合疫苗各项指标均达到了质控标准。该疫苗安全性及免疫原性良好。结论已成功研制出冻干C群脑膜炎球菌多糖结合疫苗,该制备工艺是可行的。     

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.     

Safety and efficacy of meningococcal group C conjugate vaccines

The UK was the first country to implement a universal vaccination programme with conjugate polysaccharide vaccines against Neisseria meningitidis group C. This article reviews the pre- and postlicensure data on their efficacy and safety 3 years after the introduction of the programme. Local reactogenicity data compare favourably with other routine vaccinations and no specific increase in adverse reactions has been associated with their use in infant vaccination programmes. Self-limiting systemic reactions such as fever, myalgia, headaches and irritability have commonly been observed in prelicensure studies. Passive postlicensure safety monitoring of suspected adverse reactions has identified a large number of reports, generally of reactions deemed non-serious and reversible. An Expert Working Group has concluded the balance of benefits and risks to be overwhelmingly favourable. Further safety data are expected from large data-linkage studies. Present efficacy estimates, based on active surveillance of case numbers, vaccine failures and coverage rates, are approximately 90% for all age groups. A significant fall in the number of cases attributable to meningococcal group C infection has been observed in the age group of < 20 years. The annual number of fatalities from confirmed meningococcal C disease in the same population has fallen from 67 to 5 cases within a 2-year period.     

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.     

脑膜炎球菌疫苗的研究和开发现状

流行性脑脊髓膜炎(流脑)是一个世界性公共卫生问题,发病率和死亡率都较高.此文从细菌遗传学特征、流脑的流行趋势、疫苗供应现状、可供选择的候选疫苗及其筛选方法等方面讨论了脑膜炎球菌疫苗(特别是B群脑膜炎球菌疫苗)的研究和开发现状.     

Strategies for development of universal vaccines against meningococcal serogroup B disease: the most promising options and the challenges evaluating them

A vaccine inducing protection against most of the circulating variants of serogroup B meningococcal strains is not yet available. A number of plausible options are currently under investigation. A conjugate vaccine based on a modified capsular polysaccharide might well work, but has safety concerns from molecular mimicry between group B sialic acid and human tissue. Recently, however, the group B capsule has been shown to contain de-N-acetyl sialic acid residues that do not cross react with normal host tissues and can then be the target of bactericidal antibodies. Potentially, this polysaccharide structure could form the basis of a safe and protective group B vaccine. Outer membrane vesicles (OMVs) from Neisseria lactamica avoid the immunodominant and highly strain specific immune response against the PorA protein, and are reported to elicit cross reactive protection in mice against lethality from challenge with meningococcal group B bacteria. However, the serum antibody responses lack bactericidal activity, and the mechanisms of protection are unknown. A number of universal, cross-reactive antigens have been identified through "reverse vaccinology" and successfully tested as recombinant protein vaccines. Promising results have also been demonstrated using OMV vaccines prepared from strains engineered for upregulation of conserved, cross-reactive antigens. This approach takes advantage of experience gained with conventional wild-type OMV vaccines and the large number of new antigens identified through sequencing the genome of N. meningitidis. Initial studies show that the traditional use of detergents to decrease toxicity by extraction of lipopolysaccharides (LPS) should, if possible, be omitted in order to avoid extraction of important lipoproteins. In the absence of detergent extraction, clinical OMV formulations with acceptable toxicity may still be achieved by constructing vaccine production strains with genetically detoxified LPS. Thus, a MenB vaccine might be designed based on non-cross-reactive capsular antigens, OMV vaccines from genetically modified strains, recombinant proteins or a combination of these approaches. Given all of the recent data available and experience gained, the possibility for development of a universal vaccine for prevention of group B meningococcal disease looks promising. For evaluation of vaccine formulations relying on cross-reactive proteins, selection of strains for representation of the global epidemiological situation will be of outmost importance. Defining criteria for establishing and revising such strain collections is currently ongoing and will be a key element in developing and evaluating new protein based vaccines in the time to come.     

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.     

Development of new vaccines against meningococcal disease

Meningococcal diseases continue to have a major public health impact in many countries. Five major groups of Neisseria meningitidis (A, B, C, Y and W135) are responsible for most meningoccocal diseases. Plain polysaccharides vaccines for Nelsseria meningitidis groups A, C, Y and W-135 have been in use for approximately 20 years, both to prevent invasive disease in high-risk population and to control disease outbreaks. However, these conventional meningococcal vaccines induce a relatively short-lasting T-cell independent immune response, are not effective in children under two years of age and can induce hyporesponsiveness. New meningococcal group C conjugate vaccines have since been developed, which offer solid advantages over the currently licensed plain polysaccharide vaccines. There is still no vaccine available against the serogroup B, which is a major cause of invasive disease. This report summarises the different approaches to the development of vaccines against the pathogenic meningococci.     

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.