关键词： CNS cancer   Immunotherapy   Tumour vaccines   Tumour virus infections   Virology  

摘要： Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity;elicit Th1-promoting inflammation;and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. Here we devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro;they recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in murine tumor models.

关键词： Computational biology and bioinformatics   Immunology   Viral evolution  

摘要： Vaccination has essentially eradicated poliovirus. Yet, its mutation rate is higher than that of viruses like HIV, for which no effective vaccine exists. To investigate this, we infer a fitness model for the poliovirus viral protein 1 (vp1), which successfully predicts in vitro fitness measurements. This is achieved by first developing a probabilistic model for the prevalence of vp1 sequences that enables us to isolate and remove data that are subject to strong vaccine-derived biases. The intrinsic fitness constraints derived for vp1, a capsid protein subject to antibody responses, are compared with those of analogous HIV proteins. We find that vp1 evolution is subject to tighter constraints, limiting its ability to evade vaccine-induced immune responses. Our analysis also indicates that circulating poliovirus strains in unimmunized populations serve as a reservoir that can seed outbreaks in spatio-temporally localized sub-optimally immunized populations.

关键词： Affordable IPV   Aluminium hydroxide adjuvant   Booster vaccination   Immunogenicity   Polio   Primary vaccination  

摘要： Background: A dose-sparing inactivated polio vaccine (IPV-Al), obtained by adsorption of inactivated virus to an aluminium hydroxide adjuvant, can help mitigate global supply and the cost constraints of IPV. The objective of this trial was to demonstrate the non-inferiority of IPV-Al to standard IPV. Methods: This phase 3, observer-blinded, randomised, controlled trial was conducted at 5 investigational sites in the Philippines. Infants not previously vaccinated with any polio vaccines were randomised to receive three IPV-AI (n = 502) or IPV vaccinations (n = 500) at 6, 10 and 14 weeks of age plus a booster vaccination at 9 months. The primary endpoint was type-specific seroconversion, defined as an antibody titre >= 4-fold higher than the estimated maternal antibody titre and a titre >= 8, one month after the primary vaccination series. Results: Seroconversion rates following primary vaccination with IPV-Al (483 infants in the per-protocol analysis set) or IPV (478 infants) were: polio type 1, 97.1% versus 99.0%;type 2, 94.2% versus 99.0%;and type 3, 98.3% versus 99.6%. IPV-Al was non-inferior to IPV, as the lower 95% confidence limits of the treatment differences were above the predefined 10%-point limit: type 1, -1.85% (-3.85;-0.05);type 2, -4.75% (-7.28;-2.52);type 3, -1.24 (-2.84;0.13). The booster effect (geometric mean titre (GMT) post-booster / GMT pre-booster) was: type 1, 63 versus 43;type 2, 54 versus 47;type 3, 112 versus 80. IPV-Al was well tolerated with a safety profile comparable to that of IPV. Serious adverse events were recorded for 29 infants (5.8%, 37 events) in the IPV-Al group compared to 28 (5.6%, 48 events) in the IPV group. Conclusion: Non-inferiority of IPV-Al to IPV with respect to seroconversion was confirmed and a robust booster response was demonstrated. Both vaccines had a similar safety profile. (C) 2019 The Author(s). Published by Elsevier Ltd.

关键词： oral poliovirus vaccine   acute flaccid paralysis   X-linked agammaglobulinemia   Bruton tyrosine kinase   HIV-exposed but uninfected  

摘要： Primary B-cell immunodeficiencies are risk factors for the generation of vaccine-derived polioviruses. We report immunodeficiency-associated vaccine-derived poliovirus serotype 3 in an 11-week-old boy with X-linked agammaglobulinemia. Unique characteristics of this case include early age of presentation, high viral evolutionary rate, and the child's perinatal exposure to human immunodeficiency virus.

关键词： 脊髓灰质炎疫苗   脊灰疫苗   脊髓灰质炎减毒活疫苗   脊髓灰质炎灭活疫苗   含麻疹成分疫苗   免疫规划   常规免疫   适龄儿童  

摘要： 1月7日,国家卫健委发布《我国调整免疫规划脊髓灰质炎疫苗和含麻疹成分疫苗免疫程序》,这意味着我国将改变2016年以来实施的适龄儿童常规免疫第1剂次接种脊灰灭活疫苗,第2、3、4剂次接种脊灰减毒活疫苗程序。具体来说,调整后适龄儿童将在2月龄和3月龄各接种1剂次脊髓灰质炎灭活疫苗,4月龄和4周岁各接种1剂次2价脊髓灰质炎减毒活疫苗。

关键词： 全球   脊髓灰质炎病毒   疫苗供应   封存与认证   第十八次会议  

摘要： 2019年10月15日,WHO-UNICEF与IPV/OPV生产商、国家封存监管机构(National Authority for Containment,NAC)关于脊髓灰质炎(脊灰)病毒封存与疫苗采购的第十八次磋商会议在瑞士日内瓦召开。世界卫生组织(WHO)、联合国儿童基金会(United Nations International Children′s Emergency Fund,UNICEF)、全球消灭脊灰行动(Global Polio Eradication Initiative,GPEI)策略委员会、相关国家封存监管机构、IPV/OPV生产厂家的相关代表出席了会议。会议围绕阻断脊灰病毒的传播、扩大脊灰疫苗生产的监管审批途径、新产品的创新与研发及其对供应可能产生的影响、脊灰病毒的封存与认证、Sabin IPV研发最新进展等内容进行了主题报告;对《2019~2023年脊灰尾声战略》进行了全面的介绍和分享,脊灰疫苗生产商与WHO、UNICEF有了充分的交流,进一步加强了参与全球消灭脊灰行动的各个组织、协会、生产商与国家监管机构之间的合作,推进了全球消灭脊灰行动策略的部署。

关键词： 吸附无细胞百日咳   白喉   破伤风   乙型肝炎   Sabin株灭活脊髓灰质炎   加强免疫   安全性  

摘要： 目的评价不同剂量配比及制备工艺的吸附无细胞百日咳-白喉-破伤风-乙型肝炎-Sabin株灭活脊髓灰质炎联合疫苗(DTaP-HepB-sIPV)免疫大鼠后加强免疫效果及安全性。方法以中、低剂量与铝佐剂相互配伍的不同sIPV配方设计4个DTaP-HepB-sIPV联合疫苗实验组,即中剂量含铝佐剂sIPV组(A组)、中剂量不含铝佐剂sIPV组(B组)、低剂量含铝佐剂sIPV组(C组)、低剂量不含铝佐剂sIPV组(D组),并设相应各组分的对照组和Infanrix hexaTM疫苗参考组。以已完成3剂基础免疫的Wistar大鼠为实验动物,在全程免疫第16个月接种1剂次加强免疫,进行安全性评价,并比较加强免疫前后各组大鼠血清中各组分抗体水平、中和抗体几何平均滴度(GMT)及阳转率,同时观察加强免疫对大鼠外周血中淋巴细胞的影响。结果加强免疫后未观察到不良反应,大鼠接种部位未见红肿、硬结、溃烂等现象,且各组大鼠体重维持稳定。加强免疫后30 d,各组大鼠各型别脊灰病毒中和抗体均为阳性,Ⅰ、Ⅱ、Ⅲ型抗体阳转率A组分别为100%、71.4%、85.7%,B组分别为71.4%、85.7%、100%,C组分别为80%、80%、100%,D组分别为71.4%、100%、85.7%;A组诱导的各型别脊灰病毒中和抗体GMT均高于B组,且可达到或超过参考组;B、D组诱导产生的各型脊灰病毒中和抗体GMT均能达到同等剂量相应对照组水平。加强免疫后,各组百白破各组分抗体GMT有5~106倍增长,联合疫苗实验组GMT与对照组相比,总体上差异无统计学意义(P>0.05)。加强免疫后,乙肝抗体阳转率乙肝对照组为66.7%,B组为55.6%,C组为50%,A组为16.7%,D组为14.3%,参考组为0%;各组Anti-HBsAg水平有不同程度的升高,但两两相比,各组差异均无统计学意义(P>0.05)。结论DTaPHepB-sIPV具有良好的安全性,sIPV中剂量含铝佐剂的DTaP-HepB-sIPV联合疫苗所诱导的各抗体水平更加稳定持久,可作为未来疫苗最佳配比的参考。

摘要： 近日,世卫组织宣布非洲地区已根除野生脊髓灰质炎病毒。这标志着自1980年根除天花,第2种在非洲广泛传播的病毒得到根除。脊髓灰质炎俗称小儿麻痹症,是婴幼儿易感的急性传染病,可通过接种疫苗预防。世卫组织说,非洲最近一例脊灰病例于2016年8月份出现在尼日利亚,经世卫组织有关认证部门多年考察,非洲现已符合"无脊灰"标准。

关键词： 脊髓灰质炎病毒Ⅲ型Sabin株   假病毒   ELISA抗体检测法   中和试验   D抗原  

摘要： 脊髓灰质炎病毒(poliovirus,PV)是造成五岁以下儿童麻痹瘫痪的主要病原微生物,有Ⅰ、Ⅱ、Ⅲ三个血清型。1955年灭活脊髓灰质炎疫苗(Inactivated poliovirus vaccine,IPV)和 1963 年口服脊髓灰质炎减毒活疫苗(Oral poliovirus vaccine,OPV)的相继应用以及全球对该病毒的管理与监控,脊灰发病率逐年下降。世界卫生组织(WHO)于1988年发起全球根除脊髓灰质炎行动(GPEI),继2015年9月宣布消灭了脊灰Ⅱ型野生病毒后,于2019年10月24日宣布全球又消灭了脊灰病毒Ⅲ型野生病毒,当前全球仅有Ⅰ型野生毒株在阿富汗和巴基斯坦两个国家流行。此外,由于OPV的使用,疫苗相关麻痹性脊髓灰质炎病例(vaccine-associated paralytic poliomyelitis,VAPP)和疫苗衍生病毒(vaccine-derived poliovirus,VDPV)备受关注。目前全球针对脊髓灰质炎病毒的任务是完全根除,针对这一目的,我们不仅要消除现在流行的Ⅰ型野生毒株,还必须消除VAPP、VDPV以及由感染患者排入环境中的长期存活的脊髓灰质炎病毒,VDPV主要是OPV免疫人体后由于机体免疫缺陷或者其他原因减毒株在体内恢复其毒力与传播性变为有致病能力的一种病毒,包括循环型疫苗衍生病毒(circulating vaccine-derived poliovirus,cVDPVs)和免疫缺陷型疫苗衍生病毒(immunodeficiency-associated vaccine-derived poliovirus,iVDPVs)在全球根除脊髓灰质炎病毒这一背景下,灭活的脊髓灰质炎病毒疫苗终将替代减毒活疫苗。与此同时,脊髓灰质炎病毒根除最后阶段,WHO第三版《世界卫生组织全球行动计划》(GAPⅢ)中指出脊髓灰质炎病毒需在BSL-3实验室进行操作且全球只有少数实验室可以保存脊髓灰质炎病毒减毒株。为满足一般实验室的工作需求,急需可替代真病毒的中和抗体检测新方法。本研究就构建脊髓灰质炎病毒Ⅲ型Sabin株假病毒以检测人群中脊髓灰质炎病毒抗体水平展开。首先以脊髓灰质炎病毒Ⅲ型Sabin株为参考,通过构建表达SabinⅢ型衣壳蛋白P1质粒(pcDNA3.1-P1),将其与含T7RNA聚合酶、P1段被Iuciferase所替代的脊髓灰质炎病毒骨架质粒(酶切体外转录为RNA)共转染293T细胞,包装出只具备一次性感染细胞能力的脊髓灰质炎Ⅲ型Sabin株假病毒代替真病毒作为检测工具。经测定,假病毒颗粒的直径约为30 nm且形态与相应的真病毒相似,可用于评价血清中和抗体效价。同时,本研究对检测脊髓灰质炎病毒Ⅲ型Sabin株D抗原ELISA方法进行了改造,将其改良成检测抗脊灰抗体。首先,包被牛抗脊髓灰质炎病毒Ⅲ型Sabin株D抗原IgG,BSA封闭后添加D抗原,然后同时加入兔抗脊髓灰质炎病毒Ⅲ型Sabin株D抗原IgG和人血清进行竞争性结合,最后加入羊抗兔酶标抗体,改造后的方法可作为以检测血清中和抗体效价的替代方法。该实验确定酶标抗体不与血清发生反应,同时也确定了 ELISA板上所包抗原的最适浓度,酶标抗体稀释度1:1000。通过参考临床血清脊髓灰质炎病毒Ⅲ型Sabin株微量中和试验的结果,找到血清中和效价较高的血清作为该研究的样品,得出R2=0.972的OD值标准曲线。用该方法对来自昆明地区8份血清的中和抗体滴度进行检测,得到血清抗体阳性率与传统微量中和试验法中和抗体阳性率均为75%,两种方法无显著性差异。综上,本实验通过脊髓灰质炎病毒Ⅲ型Sabin株假病毒的构建以及ELISA方法的改进,建立了安全可靠的替代活病毒测定血清中和抗体的新方法。在脊髓灰质炎消灭的最后阶段,对人群中血清抗体的检测和监控人群中抗脊髓灰质炎病毒Ⅲ型Sabin株保护率,防止该型病毒再次爆发。