Rabbit and nonhuman primate models of toxin-targeting human anthrax vaccines.

The intentional use of Bacillus anthracis, the etiological agent of anthrax, as a bioterrorist weapon in late 2001 made our society acutely aware of the importance of developing, testing, and stockpiling adequate countermeasures against biological attacks. Biodefense vaccines are an important component of our arsenal to be used during a biological attack. However, most of the agents considered significant threats either have been eradicated or rarely infect humans alive today. As such, vaccine efficacy cannot be determined in human clinical trials but must be extrapolated from experimental animal models. This article reviews the efficacy and immunogenicity of human anthrax vaccines in well-defined animal models and the progress toward developing a rugged immunologic correlate of protection. The ongoing evaluation of human anthrax vaccines will be dependent on animal efficacy data in the absence of human efficacy data for licensure by the U.S. Food and Drug Administration.     

Rabbit and Nonhuman Primate Models of Toxin-Targeting Human Anthrax Vaccines

The intentional use of Bacillus anthracis, the etiological agent of anthrax, as a bioterrorist weapon in late 2001 made our society acutely aware of the importance of developing, testing, and stockpiling adequate countermeasures against biological attacks. Biodefense vaccines are an important component of our arsenal to be used during a biological attack. However, most of the agents considered significant threats either have been eradicated or rarely infect humans alive today. As such, vaccine efficacy cannot be determined in human clinical trials but must be extrapolated from experimental animal models. This article reviews the efficacy and immunogenicity of human anthrax vaccines in well-defined animal models and the progress toward developing a rugged immunologic correlate of protection. The ongoing evaluation of human anthrax vaccines will be dependent on animal efficacy data in the absence of human efficacy data for licensure by the U.S. Food and Drug Administration.     

Challenges to licensure of enterovirus 71 vaccines

Human enteroviruses usually cause self-limited infections except polioviruses and enterovirus 71 (EV71), which frequently involve neurological complications. EV71 vaccines are being evaluated in humans. However, several challenges to licensure of EV71 vaccines need to be addressed. Firstly, EV71 and coxsackievirus A (CA) are frequently found to co-circulate and cause hand-foot-mouth disease (HFMD). A polyvalent vaccine that can provide protection against EV71 and prevalent CA are desirable. Secondly, infants are the target population of HFMD vaccines and it would need multi-national efficacy trials to prove clinical protection and speed up the licensure and usage of HFMD vaccines in children. An international network for enterovirus surveillance and clinical trials is urgently needed. Thirdly, EV71 is found to evolve quickly in the past 15 years. Prospective cohort studies are warranted to clarify clinical and epidemiological significances of the antigenic and genetic variations between different EV71 genogroups, which is critical for vaccine design.     

Strategies for developing vaccines against acquired immunodeficiency syndrome

There exists an abundance of literature on the prospects for developing vaccines against the etiologic viral agent of acquired immunodeficiency syndrome (AIDS). Excellent reviews from a variety of investigators are available on this subject. It is our intention to review the literature relative to potential strategies for developing a successful AIDS vaccine and to impart some of our concerns on the different types of vaccine that are being tested. We have also focused on some vaccine strategies that have not received much attention in previous review articles. Finally, the role of animal models in assessing vaccine safety and efficacy against AIDS has been briefly described.     

Ensuring safety of DNA vaccines

In 1990 a new approach for vaccination was invented involving injection of plasmid DNA in vivo, which elicits an immune response to the encoded protein. DNA vaccination can overcome most disadvantages of conventional vaccine strategies and has potential for vaccines of the future. However, today 15 years on, a commercial product still has not reached the market. One possible explanation could be the technique's failure to induce an efficient immune response in humans, but safety may also be a fundamental issue. This review focuses on the safety of the genetic elements of DNA vaccines and on the safety of the microbial host for the production of plasmid DNA. We also propose candidates for the vaccine's genetic elements and for its microbial production host that can heighten the vaccine's safety and facilitate its entry to the market.     

Clinical application of antifungal pharmacodynamics

Studies of pharmacodynamics are used to develop dosing regimens that maximize safety and efficacy in clinical practice. Antifungal pharmacodynamics is a growing field, and studies are increasingly moving from the in vitro phase to animal models to clinical evaluations. Preclinical studies that determine pharmacodynamic predictors of efficacy and safety provide valuable data in the determination of a dosage regimen, but evaluations of antifungal pharmacodynamic parameters in vivo are less common. This article reviews areas where antifungal pharmacodynamics has been evaluated in clinical trials to develop principles that may be used in the pharmacotherapy of invasive mycoses.     

Review of Covid-19 vaccine clinical trials - A puzzle with missing pieces

A year after the initial outbreak of Covid-19 pandemic, several Phase III clinical trials investigating vaccine safety and efficacy have been published. These vaccine candidates were developed by different research groups and pharmaceutical companies with various vaccine technologies including mRNA, recombinant protein, adenoviral vector and inactivated virus-based platforms. Despite numerous successful clinical trials, participants enrolled in these trials are limited by trial inclusion and exclusion criteria, geographic location and viral outbreak situation. Many questions still remain, especially for specific subgroups, including the elderly, females with pregnancy and breastfeeding status, and adolescents. At the same time, vaccine efficacy towards asymptomatic infection and specific viral variants are still largely unknown. This review will cover vaccine candidates with Phase III clinical trial data released and discuss the scientific data available so far for these vaccine candidates for different subgroups of people and different viral variants.     

Experimental human challenge infections can accelerate clinical malaria vaccine development

Malaria is one of the most frequently occurring infectious diseases worldwide, with almost 1 million deaths and an estimated 243 million clinical cases annually. Several candidate malaria vaccines have reached Phase IIb clinical trials, but results have often been disappointing. As an alternative to these Phase IIb field trials, the efficacy of candidate malaria vaccines can first be assessed through the deliberate exposure of participants to the bites of infectious mosquitoes (sporozoite challenge) or to an inoculum of blood-stage parasites (blood-stage challenge). With an increasing number of malaria vaccine candidates being developed, should human malaria challenge models be more widely used to reduce cost and time investments? This article reviews previous experience with both the sporozoite and blood-stage human malaria challenge models and provides future perspectives for these models in malaria vaccine development.     

CpG-enriched plasmid enhances the efficacy of the traditional foot-and-mouth disease killed vaccine

A CpG-enriched recombinant plasmid (pUC18-CpG) as an adjuvant of FMD killed vaccine was tested for immunization and vaccination challenge in a porcine model. Our preliminary results had indicated that the recombinant plasmid could enhance the humoral immune response triggered by the traditional oil-adjuvant vaccine after the initial inoculation. A subsequent vaccination-challenge test showed an increased PD(50) value. Thus, coadministration of the recombinant plasmid with the oil-adjuvant vaccine helped illicit an immune response earlier than that elicited by giving the vaccine alone. Our results showed that pUC18-CpG can be a potent immunoadjuvant for the traditional FMD killed vaccine and can greatly enhance the traditional vaccine's efficacy when given in combination with it.     

Epidemiological designs for vaccine safety assessment: methods and pitfalls

Three commonly used designs for vaccine safety assessment post licensure are cohort, case-control and self-controlled case series. These methods are often used with routine health databases and immunisation registries. This paper considers the issues that may arise when designing an epidemiological study, such as understanding the vaccine safety question, case definition and finding, limitations of data sources, uncontrolled confounding, and pitfalls that apply to the individual designs. The example of MMR and autism, where all three designs have been used, is presented to help consider these issues.     

The E75 HER2/<Emphasis Type="Italic">neu</Emphasis> peptide vaccine

E75 (HER2/neu 369-377) is an immunogenic peptide from the HER2/neu protein which is overexpressed in many breast cancer patients. A large amount of preclinical work and a small number of Phase I trials have been completed evaluating the vaccine potential of the E75 peptide mixed with an immunoadjuvant. Our group has performed two concurrent E75 + GM-CSF Phase II trials in node-positive and node-negative disease-free breast cancer patients. These trials, totaling 186 patients, were designed to assess the ability of the E75 vaccine to prevent disease recurrence in these high risk patients. In this review article, we discuss the safety of the vaccine, the immunologic response to the peptide, and most importantly, the potential clinical benefit of the vaccine. The recurrence rate, mortality associated with recurrence, and the distribution of recurrences are presented and discussed. Additionally, the lessons learned from these trials to include optimal dosing and the need for booster inoculations are addressed. We also present data exploring possible explanations and mechanisms behind the potential clinical utility of this simple single epitope vaccine. Finally, we present some of the future directions for our Cancer Vaccine Development Program assessing multi-epitope peptide vaccines and combination immunotherapies.     

HIV Vaccine-Challenges and Opportunities

The need for an efficacious HIV/AIDS vaccine remains the highest priority of the world HIV/AIDS agenda. The generation of an efficacious HIV/AIDS vaccine proves an enormous scientific challenge. This article reviews the neutralizing antibody problem,elusive immune protection,im-munogen design,pre-existing anti-vector immunity and design of phase 3 vaccine trials and the challenges and opportunities in development of HIV/AIDS vaccine are discussed.     

新城疫壳聚糖微球疫苗免疫效果的研究

鸡新城疫是由新城疫病毒引起的鸡的一种急性、烈性、高度接触性传染病,是危害养禽业的最严重疫病之一。控制新城疫最根本的措施是进行有效的疫苗接种,目前常用的疫苗是弱毒活疫苗和灭活疫苗,但二者在实际应用中均存在一定的局限性。口服微球疫苗可以诱导较强的粘膜免疫;同时还能够诱导产生系统的体液免疫和细胞免疫,已成为ND疫苗研究的热点。以壳聚糖为囊材,新城疫La Sota抗原液为芯材,戊二醛为交联剂,制备出新城疫壳聚糖微球疫苗,通过了实验室安全检验和效力检验。将新城疫壳聚糖微球疫苗与LaSota活疫苗和新城疫油乳剂灭活苗分别免疫SPF鸡,利用MTT、血凝抑制法(HI)和ELISA等分别检测不同疫苗免疫后的细胞免疫、体液免疫和粘膜免疫抗体IgA,并在当免疫鸡HI抗体降到23的情况下进行了攻毒试验。结果表明,新城疫壳聚糖微球疫苗安全性好,免疫后可刺激机体产生较强的细胞免疫、体液免疫和局粘膜免疫,具有较好的保护作用。     

Safety of the malaria vaccine candidate, RTS,S/AS01E in 5 to 17 month old Kenyan and Tanzanian Children

The malaria vaccine candidate, RTS,S/AS01(E), showed promising protective efficacy in a trial of Kenyan and Tanzanian children aged 5 to 17 months. Here we report on the vaccine's safety and tolerability. The experimental design was a Phase 2b, two-centre, double-blind (observer- and participant-blind), randomised (1∶1 ratio) controlled trial. Three doses of study or control (rabies) vaccines were administered intramuscularly at 1 month intervals. Solicited adverse events (AEs) were collected for 7 days after each vaccination. There was surveillance and reporting for unsolicited adverse events for 30 days after each vaccination. Serious adverse events (SAEs) were recorded throughout the study period which lasted for 14 months after dose 1 in Korogwe, Tanzania and an average of 18 months post-dose 1 in Kilifi, Kenya. Blood samples for safety monitoring of haematological, renal and hepatic functions were taken at baseline, 3, 10 and 14 months after dose 1. A total of 894 children received RTS,S/AS01(E) or rabies vaccine between March and August 2007. Overall, children vaccinated with RTS,S/AS01(E) had fewer SAEs (51/447) than children in the control group (88/447). One SAE episode in a RTS,S/AS01(E) recipient and nine episodes among eight rabies vaccine recipients met the criteria for severe malaria. Unsolicited AEs were reported in 78% of subjects in the RTS,S/AS01(E) group and 74% of subjects in the rabies vaccine group. In both vaccine groups, gastroenteritis and pneumonia were the most frequently reported unsolicited AE. Fever was the most frequently observed solicited AE and was recorded after 11% of RTS,S/AS01(E) doses compared to 31% of doses of rabies vaccine. The candidate vaccine RTS,S/AS01(E) showed an acceptable safety profile in children living in a malaria-endemic area in East Africa. More data on the safety of RTS,S/AS01(E) will become available from the Phase 3 programme.     

HIV vaccine-challenges and opportunities

The need for an efficacious HIV/AIDS vaccine remains the highest priority of the world HIV/AIDS agenda. The generation of an efficacious HIV/AIDS vaccine proves an enormous scientific challenge. This article reviews the neutralizing antibody problem, elusive immune protection, immunogen design, pre-existing anti-vector immunity and design of phase 3 vaccine trials and the challenges and opportunities in development of HIV/AIDS vaccine are discussed. Foundation item: National High Technology Research and Development Program of China (2005AAZ18040)     

非天然氨基酸正交翻译技术：一种新型基因工程活病毒疫苗研发技术

非天然氨基酸正交翻译技术利用外源的非天然氨基酸氨酰tRNA合成酶(aaRS)基因和对应的tRNA基因构建非天然氨基酸正交翻译系统(Orthogonal translation system)。该正交翻译系统能利用终止密码子在蛋白翻译过程中将非天然氨基酸定点插入目标多肽链中。该技术不但是一种新的蛋白质生化研究工具,在新型基因工程病毒疫苗研究中更具有划时代的意义。利用人为构建的具有非天然氨基酸正交翻译系统的转基因细胞,通过在病毒复制的关键基因中引入提前终止密码子构建的突变病毒,在添加非天然氨基酸的情况下该基因仍能完整表达从而完成病毒的复制和传代,但该突变病毒在正常细胞(无非天然氨基酸正交翻译系统的宿主细胞)中因复制关键基因不能完整表达而无法复制传代,因而是一种复制缺陷型病毒。这种复制缺陷型病毒用作疫苗时兼具了减毒活疫苗免疫效果良好与灭活疫苗安全性高的优点,是一种较为理想的活病毒疫苗。文中简要综述了非天然氨基酸正交翻译技术在新型复制缺陷活病毒疫苗研究中的应用及其前景。     

Licensed DNA Vaccines against Infectious Hematopoietic Necrosis Virus (IHNV)

This article reviews some of the recent patents on DNA vaccines against fish viruses, in particular against the novirhabdovirus infectious hematopoitic necrosis virus (IHNV). Although very effective in protecting fish against IHNV, only one DNA vaccine has been approved to date for use in Canada. In Europe and in US, its commercialization is restricted due to safety concerns.     

Development of antileprosy vaccines

The absence of an effective antileprosy vaccine, capable of preventing the spread of leprosy hinders its control in endemic countries. Developing such a vaccine is highly difficult due to the absence of reproducible methods for the in vitro cultivation of Mycobacterium leprae. The results of field trials of earlier proposed vaccines (BCG and BCG in combination with killed M. leprae) are indicative of their insufficient efficacy. The article presents a review of literature, including historical information, current problems and the main approaches to the development of vaccine against leprosy.     

候选结核疫苗的评价模型

卡介苗作为目前唯一批准使用的预防结核疫苗,由于无法提供充足的保护力,目前结核病依然是严重危害人类健康的传染病,因此筛选优质候选疫苗迫在眉睫。所有候选疫苗进入临床试验前必须评价其安全性、免疫原性以及有效性。评价结果在一定程度上也预示候选疫苗在人体的免疫作用,也是目前评价候选疫苗是否优于传统卡介苗的依据。论述候选结核疫苗临床试验前所使用的体内和体外评价模型。对评价模型的充分认识将提高候选疫苗评价数据对人体临床试验的预测意义,也可更具体地执行实验动物的替代、减少和优化原则。     

Liposome-based cationic adjuvant formulations (CAF): Past,present, and future

The use of liposomes as vaccine adjuvants has been investigated extensively over the last few decades. In particular, cationic liposomal adjuvants have drawn attention, with dimethyldioctadecylammonium (DDA) liposomes as a prominent candidate. However, cationic liposomes are, in general, not sufficiently immunostimulatory, which is why the combination of liposomes with immunostimulators has arisen as a strategy in the development of novel adjuvant systems in recent years. One such adjuvant system is CAF01. In this review, we summarize the immunological properties making CAF01 a promising versatile adjuvant system, which was developed to mediate protection against tuberculosis (TB) but, in addition, has shown promising protective efficacy against other infectious diseases requiring different immunological profiles. Further, we describe the stabilization properties that make CAF01 suitable in vaccine formulation for the developing world, which in addition to vaccine efficacy, are important prerequisites for any novel TB vaccine to reach global implementation. The encouraging nonclinical data led to a preclinical vaccine toxicology study of the TB model vaccine, Ag85B-ESAT-6/CAF01, that concluded that CAF01 has a satisfactory safety profile to advance the vaccine into phase I clinical trials, which are scheduled to start in 2009.