轮状病毒减毒活疫苗(Rotarix~(TM))作为攻毒模型的初步研究

正轮状病毒仍是引起脱水腹泻的最常见病因,在发展中国家尤为典型。这些国家的儿童为免疫攻毒试验研究提供了一个契机,可以迅速评估可能提高保护力的新型候选疫苗。本文作者评估了轮状病毒减毒活疫苗(RotarixTM)作为减毒活病毒攻毒试剂的效果。作者共纳入22名在6周龄和10周龄时接受两剂标准剂量的RotarixTM的赞比亚婴儿,进行了一项开放标签的探索性研究。第一剂疫苗为初免剂,第28天的第二剂疫苗为减毒活病毒攻毒剂。     

轮状病毒灭活疫苗和减毒活疫苗序贯免疫的体液免疫应答效果

目的:评价采用轮状病毒灭活疫苗进行初始免疫,减毒活疫苗进行加强免疫的序贯免疫方案的体液免疫应答效果。方法:将实验小鼠随机分为4组(口服疫苗组、序贯疫苗组、口服对照组及序贯对照组),按相应方案免疫后,ELISA检测血清轮状病毒特异性IgG和IgA、肠道轮状病毒特异性IgA;微量中和实验检测血清病毒特异性中和抗体;同时采用ELISA分析口服活疫苗后病毒排出情况。结果:与对照组相比,序贯疫苗组小鼠产生的轮状病毒特异性血清IgG、IgA、中和抗体及肠道IgA水平显著升高。与口服疫苗组相比,序贯疫苗组的免疫方案诱发的轮状病毒特异性血清IgG、IgA、中和抗体水平显著升高,肠道IgA水平两组间没有显著差异。同时,与口服疫苗组相比,序贯疫苗组中轮状病毒灭活疫苗进行的初始免疫未影响第一次口服活疫苗后病毒的排出量和排出时间,但序贯疫苗组第二次口服活疫苗后病毒的排出量迅速减少,排毒时间快速缩短,与口服疫苗组第三次服苗后病毒的排出量和排出时间相似。结论: 轮状病毒灭活疫苗和减毒活疫苗序贯免疫可有效诱发小鼠全身和黏膜局部的体液免疫应答,该方案将有可能成为轮状病毒疫苗临床应用的候选方案。     

人3型副流感病毒及其疫苗的研究进展

人3型副流感病毒(Human Parainfluenza Virus type 3,HPIV-3)是引起婴幼儿严重细支气管炎及肺炎等下呼吸道疾病的主要病原体,其在发达国家和发展中国家都造成了沉重的疾病负担。迄今,对HPIV-3感染的预防和治疗都还没有有效的疫苗和药物,因此WHO将HPIV-3疫苗列为未来重点研发的疫苗。近年来,随着重组技术和反向遗传学的发展,HPIV-3疫苗的研制取得了重要进展,部分疫苗已进入临床评价阶段。就HPIV-3的生物学特性如病毒结构特征、复制过程、流行病学特征,以及近年来传统冷适应减毒活疫苗、亚单位疫苗、以反向遗传学为基础的新型减毒活疫苗的研制成果及临床试验进展作简要综述。     

呼吸道合胞病毒疫苗研究进展

呼吸道合胞病毒(RSV)是引起婴幼儿支气管炎和肺炎的主要原因,并可致免疫缺陷病人显著发病和死亡,RSV疫苗已被WHO列为全球最优先发展的疫苗之一。经过几十年的研究,虽然取得了显著进展,但尚未有RSV疫苗上市。目前RSV疫苗的研究主要集中于亚单位疫苗、减毒活疫苗和DNA疫苗等,其中亚单位疫苗和减毒活疫苗被认为最有前途,已分别进行了的临床试验。     

HIV/艾滋病疫苗:策略及展望

全球范围内艾滋病的流行使发展安全有效的疫苗势在必行。本文讨论了各种不同类型的艾滋病疫苗的优点和缺点,包括传统疫苗(灭活疫苗、减毒活疫苗)和新型疫苗(病毒颗粒样疫苗、重组亚单位疫苗、重组活载体病毒疫苗),同时也指出了发展艾滋病疫苗所面临的挑战,如病毒的变异、没有充足的动物模型和HIV感染免疫系统本身。概述了正在进行的艾滋病疫苗的临床试验,并对下一步研究进行了展望。     

人呼吸道合胞病毒减毒活疫苗的研究进展

人呼吸道合胞病毒(Respiratory syncytial virus,RSV)是一种可引起严重下呼吸道疾病的病原体,易感人群为婴幼儿、老年人及免疫力低下者。目前尚无针对RSV的疫苗和特异而有效的抗病毒药物。研究发现,减毒活疫苗不产生疾病增强效应,在母传抗体的存在下仍可复制,且有较强的免疫原性,被认为是最有希望的RSV疫苗。就RSV减毒活疫苗的研究进展作一综述。     

轮状病毒母体抗体会干扰轮状病毒活疫苗吗?

<正>引言:对包括已注册的轮状病毒疫苗在内的口服活疫苗的以往经验表明,与发达国家相比,在发展中国家中的疫苗效力有降低的趋势。这一差异背后原因尚未十分明确。在发展中国家,轮状病毒感染是地方性的,并且母体抗体水平很高,经胎盘传递母体抗体和母乳摄取可能会减弱婴幼儿对疫苗的反应。本实验检测了发展中国家背景下轮状病毒流行及母源血、脐带血、初乳和母乳中轮状病毒抗体水平。     

轮状病毒致腹泻机制的研究进展

轮状病毒(Rotavirus,RV)是发展中国家致5岁内婴幼儿胃肠道感染,引起感染性腹泻的重要原因,每年因此而死亡的病例高达600,000多人.[1]近年来对此的研究也越来越多,但是其引起腹泻的具体病理生理机制始终未达成统一的说法.目前主要是有两种假说,即轮状病毒非结构蛋白4 (NSP4)假说和肠道神经系统(ENS)假说.对于轮状病毒腹泻的预防及治疗,现阶段主要是进行减毒活疫苗预防,但其疗效不甚令人满意,并且有可能导致肠梗阻.[2-3]本文将对轮状病毒致婴幼儿腹泻的可能机制及其研究进展进行综述,此外,针对其独特的致病机制将讨论轮状病毒感染可能的预防策略.     

呼吸道合胞病毒mRNA疫苗的研究进展

呼吸道合胞病毒(respiratory syncytial virus, RSV)是引起急性呼吸道感染的主要病原体之一,给婴幼儿和老年人带来了沉重的疾病负担。自福尔马林灭活呼吸道合胞病毒疫苗(FI-RSV)失败以来,RSV疫苗研究进展缓慢。但近年随着对RSV F蛋白(fusion protein, F)结构研究的不断深入,RSV的候选疫苗取得了快速进展,RSV的候选疫苗种类也逐渐增多,包括RSV mRNA疫苗、重组载体疫苗、亚单位疫苗、病毒样颗粒疫苗、减毒活疫苗和嵌合疫苗等。其中,RSV mRNA疫苗具有成本低、免疫原性强、生产工艺简单、研发周期短、安全性高和易于标准化生产等特点,适合应对新发传染性疾病的防控。现就RSV疫苗的研究现状、RSV mRNA疫苗发展历程及临床研究进展作一概述。     

反向遗传学技术在流感病毒减毒活疫苗研究中的应用进展

流感病毒是一种威胁人类健康的重要病原体,具有季节流行性,可以引起暴发性感染,对公共卫生及经济带来打击。接种疫苗是目前保护人类免受流感病毒感染的最佳医疗干预措施。安全性与有效性的平衡是疫苗研发追求的目标,减毒活疫苗则能够实现两者平衡,有望在预防免疫中发挥巨大作用。随着反向遗传学技术的成熟,其在流感病毒减毒活疫苗的研发中也发挥着越来越大的作用,使减毒病毒株的构建更加简便,减毒方法更加多元。本文主要就反向遗传学技术在流感病毒减毒活疫苗研发中的应用进行简要综述。     

Understanding reduced rotavirus vaccine efficacy in low socio-economic settings

Introduction

Rotavirus vaccine efficacy ranges from >90% in high socio-economic settings (SES) to 50% in low SES. With the imminent introduction of rotavirus vaccine in low SES countries, understanding reasons for reduced efficacy in these settings could identify strategies to improve vaccine performance.

Methods

We developed a mathematical model to predict rotavirus vaccine efficacy in high, middle and low SES based on data specific for each setting on incidence, protection conferred by natural infection and immune response to vaccination. We then examined factors affecting efficacy.

Results

Vaccination was predicted to prevent 93%, 86% and 51% of severe rotavirus gastroenteritis in high, middle and low SES, respectively. Also predicted was that vaccines are most effective against severe disease and efficacy declines with age in low but not high SES. Reduced immunogenicity of vaccination and reduced protection conferred by natural infection are the main factors that compromise efficacy in low SES.

Discussion

The continued risk of severe disease in non-primary natural infections in low SES is a key factor underpinning reduced efficacy of rotavirus vaccines. Predicted efficacy was remarkably consistent with observed clinical trial results from different SES, validating the model. The phenomenon of reduced vaccine efficacy can be predicted by intrinsic immunological and epidemiological factors of low SES populations. Modifying aspects of the vaccine (e.g. improving immunogenicity in low SES) and vaccination program (e.g. additional doses) may bring improvements.     

Rotavirus Vaccines: New Strategies and Approaches

Rotaviruses cause an infectious disease that is the main cause of severe diarrhea in children all over the world and one of the factors that determine the level of child mortality. Only live attenuated vaccines are currently used against rotavirus infection. These vaccines are efficient, but a range of side effects, including intussusception risk, is characteristic of them. Complications associated with the use of existing vaccines usually occur in the case of oral administration and develop as the attenuated live vaccines start to replicate in the human intestine. Thus, there is a need for development of modern, efficient, and safe preparations for the prevention of rotavirus infection. These preparations should be incapable of reproduction (replication) in the organism after vaccination. Recombinant vaccines represent a new generation of vaccines against rotavirus infection, and the development and testing of such vaccines, including those intended for parenteral administration, has progressed considerably during recent years. The complex antigenic structure of the rotavirus is one of the problems associated with the production of these vaccines. The present review summarizes published data on genetic and antigenic diversity of rotavirus strains and geographic localization of epidemiologically significant virus variants. The role of capsid proteins in the emergence of immune response against the virus and the current state of research on new candidate recombinant vaccines against rotavirus infection are discussed.     

Immunoreactivity of chimeric proteins carrying poliovirus epitopes on the VP6 of rotavirus as a vector

Rotavirus and poliovirus continue to present significant risks and burden of disease to children in developing countries. Developing a combined vaccine may effectively prevent both illnesses and may be advantageous in terms of maximizing compliance and vaccine coverage at the same visit. Recently, we sought to generate a vaccine vector by incorporating multiple epitopes into the rotavirus group antigenic protein, VP6. In the present study, a foreign epitope presenting a system using VP6 as a vector was created with six sites on the outer surface of the vector that could be used for insertion of foreign epitopes, and three VP6-based PV1 epitope chimeric proteins were constructed. The chimeric proteins were confirmed by immunoblot, immunofluorescence assay, and injected into guinea pigs to analyze the epitope-specific humoral response. Results showed that these chimeric proteins reacted with anti-VP6F and -PV1 antibodies, and elicited antibodies against both proteins in guinea pigs. Antibodies against the chimeric proteins carrying PV1 epitopes neutralized rotavirus Wa and PV1 infection in vitro. Our study contributes to a better understanding of the use of VP6-based vectors as multiple-epitope delivery vehicles and the epitopes displayed in this form could be considered for development of epitope-based vaccines against rotavirus and poliovirus.     

Modern features of the epidemiology and prophylaxis of influenza

Modern concepts concerning influenza pandemics and epidemics in different countries of the world are presented. The influenza epidemics of the last decade in different countries of the world and their specific features linked with the "drifting" variability of influenza virus have been analyzed. Information on influenza morbidity during the last 30 years is given; on the basis of this information the role of vaccinal prophylaxis and mainly the mass vaccination of school children and students, is shown. The results of the efficacy of such vaccines as live influenza vaccine, American split vaccine, Russian live recombinant vaccine and Grippovac (1995-1996), as well as new-generation vaccine Grippol (1998), are presented. The prospects of the combined use of specific and unspecific prophylaxis have been determined.     

轮状病毒VP4亚单位疫苗研究进展

轮状病毒是全球范围内导致5岁以下婴幼儿严重腹泻的主要病原体,造成了巨大的经济负担和社会负担。疫苗预防接种是控制轮状病毒感染最为有效的手段,但在轮状病毒导致的死亡率较高的非洲和亚洲部分低收入国家,目前已经上市的轮状病毒疫苗的有效性较低,且会增加肠套叠的风险。更加安全、有效的轮状病毒疫苗对于降低轮状病毒感染导致的发病率和死亡率具有重要意义。目前,各国科研人员试图从多个方面提高轮状病毒疫苗的有效性,非复制型基因工程亚单位疫苗是目前轮状病毒疫苗研究的主要方向。文中就目前轮状病毒亚单位疫苗,特别是基于VP4蛋白的亚单位疫苗的研究进展进行了综述,以期对轮状病毒疫苗的发展提供借鉴意义。     

The Coronavirus pandemic – 2022: Viruses,variants & vaccines

Since the beginning of the COVID-19 pandemic in 2019–2020, Cytokine & Growth Factor Reviews has published several Special Issues focused on the biology, pathogenesis and therapeutic options in the treatment of COVID-19 infection, including articles on the involvement of the chemokine system in the cytokine storm in COVID-19, intervention in the early stages of COVID-19 pneumonia, the therapeutic value of corticosteroid treatment, early clinical intervention with type 1 interferons, progress in vaccine development, and organ specific complications of COVID-19. By 2022, multiple highly efficacious vaccines are available and are being administered in countries around the world, therapeutic options have been clinically evaluated and approved, and SARS-CoV-2 has arguably become the most thoroughly studied virus in history. But, with progress has also come unanticipated problems – misinformation, anti-vaxxers, opposition to protective masks, and politically motivated interference disguised as knowledge. With this issue of CGFR, we continue to document the global coronavirus pandemic and provide an update on the emergence of viral variants, the global effort to administer vaccines and the impediments to progress posed by misinformation and anti-vaccine sentiment.     

Evaluation of vaccines against enteric infections: a clinical and public health research agenda for developing countries

Enteric infections are a major cause of morbidity and mortality in developing countries. To date, vaccines have played a limited role in public health efforts to control enteric infections. Licensed vaccines exist for cholera and typhoid, but these vaccines are used primarily for travellers; and there are two internationally licensed vaccines for rotavirus, but they are mainly used in affluent countries. The reasons that enteric vaccines are little used in developing countries are multiple, and certainly include financial and political constraints. Also important is the need for more cogent evidence on the performance of enteric vaccines in developing country populations. A partial inventory of research questions would include: (i) does the vaccine perform well in the most relevant settings? (ii) does the vaccine perform well in all epidemiologically relevant age groups? (iii) is there adequate evidence of vaccine safety once the vaccines have been deployed in developing countries? (iv) how effective is the vaccine when given in conjunction with non-vaccine cointerventions? (v) what is the level of vaccine protection against all relevant outcomes? and (vi) what is the expected population level of vaccine protection, including both direct and herd vaccine protective effects? Provision of evidence addressing these questions will help expand the use of enteric vaccines in developing countries.     

Co-Expression of Anti-Rotavirus Proteins (Llama VHH Antibody Fragments) in Lactobacillus: Development and Functionality of Vectors Containing Two Expression Cassettes in Tandem

Rotavirus is an important pediatric pathogen, causing severe diarrhea and being associated with a high mortality rate causing approximately 500 000 deaths annually worldwide. Even though some vaccines are currently available, their efficacy is lower in the developing world, as compared to developed countries. Therefore, alternative or complementary treatment options are needed in the developing countries where the disease burden is the largest. The effect of Lactobacillus in promoting health and its use as a vehicle for delivery of protein and antibody fragments was previously shown. In this study, we have developed co-expression vectors enabling Lactobacillus paracasei BL23 to produce two VHH fragments against rotavirus (referred to as anti-rotavirus proteins 1 and 3, ARP1 and ARP3) as secreted and/or surface displayed products. ARP1 and ARP3 fragments were successfully co-expressed as shown by Western blot and flow cytometry. In addition, engineered Lactobacillus produced VHH antibody fragments were shown to bind to a broad range of rotavirus serotypes (including the human rotavirus strains 69M, Va70, F45, DS1, Wa and ST3 and simian rotavirus strains including RRV and SA11), by flow cytometry and ELISA. Hereby, we have demonstrated for the first time that when RRV was captured by one VHH displayed on the surface of co-expressor Lactobacillus, targeting other epitope was possible with another VHH secreted from the same bacterium. Therefore, Lactobacillus producing two VHH antibody fragments may potentially serve as treatment against rotavirus with a reduced risk of development of escape mutants. This co-expression and delivery platform can also be used for delivery of VHH fragments against a variety of mucosal pathogens or production of other therapeutic molecules.     

Hepatitis vaccines: recent advances

Despite the availability of hepatitis A vaccines that might provide protection for decades, hepatitis B vaccines that provides protection for at least 15 years and the recent introduction of a combined hepatitis A and B vaccine, these infections continue to spread in both the developed and developing world. Hepatitis A vaccine coverage has been limited to high-risk groups: such a selective immunisation policy is unlikely to have a major impact. If adequate immunogenicity in infants is confirmed, dosing schedules can be improved and the costs of vaccination reduced, universal paediatric immunisation with combined hepatitis A and B products is likely to result in the eventual eradication of these infections. In the interim, novel hepatitis A vaccines are being investigated and additional studies on hepatitis A vaccine immunogenicity in infants are in progress. Worldwide use of hepatitis B vaccines for the newborn, young children and high-risk groups should control this infection and obviate the need for a vaccine against hepatitis D. Newer hepatitis B vaccines that may reduce the likelihood of non-responsiveness and have immunotherapeutic value are under study. A recombinant hepatitis E vaccine for use in endemic regions is currently in clinical trials. The development of an effective hepatitis C vaccine has been agonisingly slow and many impediments have been recognised. These include the lack of a susceptible small animal, a high degree of hepatitis C virus (HCV) genomic diversity and failure to produce high quantities of HCV in tissue culture. The development of a novel HCV replicon system may be a major breakthrough. Nonetheless, it may still be exceedingly difficult to produce a vaccine that uniformly provides sterilising immunity; the possibility of developing a hepatitis C vaccine that can prevent chronic infection is an exciting concept that requires further investigation. Advances in recombinant technology, the use of novel genetic (DNA-based) vaccines, expression of hepatitis antigens in plants and improved adjuvants also hold considerable promise.