HIV-1 polymorphism: a challenge for vaccine development - a review

The perspective for the development of anti-HIV/AIDS vaccines became a target sought by several research groups and pharmaceutical companies. However, the complex virus biology in addition to a striking genetic variability and the limited understanding of the immunological correlates of protection have made this an enormous scientific challenge not overcome so far. In this review we presented an updating of HIV-1 subtypes and recombinant viruses circulating in South American countries, focusing mainly on Brazil, as one of the challenges for HIV vaccine development. Moreover, we discussed the importance of stimulating developing countries to participate in the process of vaccine evaluation, not only testing vaccines according to already defined protocols, but also working together with them, in order to take into consideration their local information on virus diversity and host genetic background relevant for the vaccine development and testing, as well as including local virus based reagents to evaluate the immunogenicity of the candidate vaccines.     

Development of recombinant antigen vaccines for the control of theileriosis

Immunization against Theileria parva involves infection with sporozoites and simultaneous treatment with a long-acting tetracycline. For T. annulata, immunization is achieved by inoculation of attenuated schizont-infected lymphocytes. The two methods are inadequate because of the use of live organisms and the methods are also bedevilled by the multiplicity of strains, particularly of T. parva. For these reasons, alternative methods of control are being sought. In this review an attempt is made to highlight advances towards subunit vaccines against T. parva and T. annulata. Several candidate antigens which are thought to induce protective responses have been identified and recombinant DNA technology is being employed to produce these antigens in bulk. Relevant antigens may be delivered as subunit vaccines by using recombinant vaccinia virus or attenuated Salmonella spp. as carriers of the genes expressing these antigens. It is likely that effective vaccines against T. parva and T. annulata will have to elaborate immune responses against both the sporozoite and schizont stages of the parasite.     

In Silico Design of a New Multi-Epitope Peptide-Based Vaccine Candidate Against Q Fever

Molecular Biology - Novel types of the vaccines with high immunogenicity and low risks, including epitope-based vaccines, are sought. Among zoonotic disease, Q fever caused by Coxiella burnetii is...     

Development of mRNA Vaccines/Therapeutics and Their Delivery System

The rapid development of mRNA vaccines has contributed to the management of the current coronavirus disease 2019 (COVID-19) pandemic, suggesting that this technology may be used to manage future outbreaks of infectious diseases. Because the antigens targeted by mRNA vaccines can be easily altered by simply changing the sequence present in the coding region of mRNA structures, it is more appropriate to develop vaccines, especially during rapidly developing outbreaks of infectious diseases. In addition to allowing rapid development, mRNA vaccines have great potential in inducing successful antigen-specific immunity by expressing target antigens in cells and simultaneously triggering immune responses. Indeed, the two COVID-19 mRNA vaccines approved by the U.S. Food and Drug Administration have shown significant efficacy in preventing infections. The ability of mRNAs to produce target proteins that are defective in specific diseases has enabled the development of options to treat intractable diseases. Clinical applications of mRNA vaccines/therapeutics require strategies to safely deliver the RNA molecules into targeted cells. The present review summarizes current knowledge about mRNA vaccines/therapeutics, their clinical applications, and their delivery strategies.     

Rabies Virus Glycoprotein with a Consensus Amino Acid Sequence and a Lysosome Targeting Signal Causes Effective Production of Antibodies in DNA-Immunized Mice

Safe and effective anti-rabies vaccines are intensely sought worldwide. DNA vaccines have already shown their efficacy and safety and have occupied a special place in the field. Two prototype anti-rabies DNA vaccines were compared for the potential to induce virus-specific antibody production. One vector contained a codon-optimized gene with a territory-adapted consensus sequence of the rabies virus glycoprotein. The other one expressed the same glycoprotein in fusion with a c-CD63 lysosome targeting motif at the C terminus. ELISA of serum samples from immunized mice showed that the c-CD63 variant induced more efficient antibody production and shifted the IgG2a/IgG1 ratio towards the Th2-type immune response. The results gave grounds to believe that the approach successfully applied to the rabies glycoprotein may help to develop new-generation anti-rabies vaccines.     

疫苗诱导机体免疫应答机制研究

人类接种疫苗已有200多年的历史,疫苗的应用使得历史上流行的多种传染病得以消灭或控制,挽救了无数人的生命。疫苗免疫机制是全世界疫苗研究者亟待解决的问题。对疫苗免疫机制的一些新认识,极大地促进了疫苗研发。对疫苗天然免疫机制的揭示,在疫苗株的筛选、疫苗免疫效果预测等方面展现了巨大的应用价值。某些疫苗在接种后存在的低应答与无应答现象,在对其免疫机制的探索中得到了解释。此外,对疫苗佐剂免疫机制的揭示,加速了新型疫苗佐剂的研发与应用。对疫苗免疫机制研究中的一些新进展进行了综述。     

Antigen-displaying lipid-enveloped PLGA nanoparticles as delivery agents for a Plasmodium vivax malaria vaccine

The parasite Plasmodium vivax is the most frequent cause of malaria outside of sub-Saharan Africa, but efforts to develop viable vaccines against P. vivax so far have been inadequate. We recently developed pathogen-mimicking polymeric vaccine nanoparticles composed of the FDA-approved biodegradable polymer poly(lactide-co-glycolide) acid (PLGA) "enveloped" by a lipid membrane. In this study, we sought to determine whether this vaccine delivery platform could be applied to enhance the immune response against P. vivax sporozoites. A candidate malaria antigen, VMP001, was conjugated to the lipid membrane of the particles, and an immunostimulatory molecule, monophosphoryl lipid A (MPLA), was incorporated into the lipid membranes, creating pathogen-mimicking nanoparticle vaccines (VMP001-NPs). Vaccination with VMP001-NPs promoted germinal center formation and elicited durable antigen-specific antibodies with significantly higher titers and more balanced Th1/Th2 responses in vivo, compared with vaccines composed of soluble protein mixed with MPLA. Antibodies raised by NP vaccinations also exhibited enhanced avidity and affinity toward the domains within the circumsporozoite protein implicated in protection and were able to agglutinate live P. vivax sporozoites. These results demonstrate that these VMP001-NPs are promising vaccines candidates that may elicit protective immunity against P. vivax sporozoites.     

保护性病毒抗原的筛选策略及其在新型疫苗研发中的应用

随着疫苗研发技术的发展,新型疫苗在传染病的预防中得到了广泛应用。由于新型疫苗安全性良好,因此其在烈性病疫苗的应用中有着得天独厚的优势,然而研制新型疫苗的前提是筛选出保护性抗原。随着各种组学研究的发展,针对真核生物的多种生物信息学方法代表着最前沿的技术手段。相对于真核细胞,病毒具有更为简单的结构,对应着相对简单的研究方法,未来的保护性抗原筛选策略,需要结合生物信息学和传统分子生物学方法的优势。本文分别从宿主和病毒入手,论述了病毒保护性抗原的筛选策略,列举了一系列基于真核细胞开发的可能用于保护性抗原筛选的生物信息学方法,并总结了应用保护性抗原进行新型疫苗设计的案例,以便加深对病毒保护性抗原筛选策略的认知,为新型疫苗的研发提供借鉴。     

Cancer therapy using a self-replicating RNA vaccine.

'Naked' nucleic acid vaccines are potentially useful candidates for the treatment of patients with cancer, but their clinical efficacy has yet to be demonstrated. We sought to enhance the immunogenicity of a nucleic acid vaccine by making it 'self-replicating'. We accomplished this by using a gene encoding an RNA replicase polyprotein derived from the Semliki forest virus, in combination with a model antigen. A single intramuscular injection of a self-replicating RNA immunogen elicited antigen-specific antibody and CD8+ T-cell responses at doses as low as 0.1 microg. Pre-immunization with a self-replicating RNA vector protected mice from tumor challenge, and therapeutic immunization prolonged the survival of mice with established tumors. The self-replicating RNA vectors did not mediate the production of substantially more model antigen than a conventional DNA vaccine did in vitro. However, the enhanced efficacy in vivo correlated with a caspase-dependent apoptotic death in transfected cells. This death facilitated the uptake of apoptotic cells by dendritic cells, providing a potential mechanism for enhanced immunogenicity. Naked, non-infectious, self-replicating RNA may be an excellent candidate for the development of new cancer vaccines.     

Historical Advances in Structural and Molecular Biology and How They Impacted Vaccine Development

Vaccines are among the greatest tools for prevention and control of disease. They have eliminated smallpox from the planet, decreased morbidity and mortality for major infectious diseases like polio, measles, mumps, and rubella, significantly blunted the impact of the COVID-19 pandemic, and prevented viral induced cancers such as cervical cancer caused by human papillomavirus. Recent technological advances, in genomics, structural biology, and human immunology have transformed vaccine development, enabling new technologies such as mRNA vaccines to greatly accelerate development of new and improved vaccines. In this review, we briefly highlight the history of vaccine development, and provide examples of where advances in genomics and structural biology, paved the way for development of vaccines for bacterial and viral diseases.     

全球冠状病毒疫苗专利分析

冠状病毒是一类可感染人类和动物的RNA病毒,可引起严重急性呼吸综合征(SARS)和中东呼吸综合征(MERS)等严重疾病。新型冠状病毒是以前从未在人体中发现的冠状病毒新毒株,其人际传播迅速,引起了各国政府的高度重视并积极寻求疫苗防控对策。基于冠状病毒疫苗领域全景专利,在综合对比分析该领域的全部专利的发展趋势、主要国家和主要机构的专利产出的同时,重点揭示了其中的人用相关疫苗的发展与分布情况以及重点分析了人用疫苗产品的研发现状,以期为我国冠状病毒疫苗领域的科研工作者和管理决策者提供参考数据。     

Streptococcus pneumoniae proteomics: determinants of pathogenesis and vaccine development

Streptococcus pneumoniae is a major pathogen that is responsible for a variety of invasive diseases. The bacteria gain entry initially by establishing a carriage state in the nasopharynx from where they migrate to other sites in the body. The worldwide distribution of the bacteria and the severity of the diseases have led to a significant level of interest in the development of vaccines against the bacteria. Current vaccines, based on the bacterial polysaccharide, have a number of limitations including poor immunogenicity and limited effectiveness against all pneumococcal serotypes. There are many challenges in developing vaccines that will be effective against the diverse range of isolates and serotypes for this highly variable bacterial pathogen. This review considers how proteomic technologies have extended our understanding of the pathogenic mechanisms of nasopharyngeal colonization and disease development as well as the critical areas in developing protein-based vaccines.     

The development of subunit and synthetic vaccines using recombinant DNA technology

Vaccination of humans and animals against invasion by pathogenic organisms is an effective and integral component of preventive medicine. Traditionally, vaccines have been prepared from various forms of killed or attenuated whole organisms. Such killed or attenuated vaccines presumably retain some of the important antigenic determinants of the organism which can elicite an effective immune response in the vaccinated host. Major drawbacks encountered with these types of vaccines include the introduction of undesirable side-effects after vaccination, as well as induction of only partial protection in some cases. In addition to killed or attenuated vaccines, partially purified antigenic determinants from the whole organism have been used as vaccines. However, the cost and difficulties involved in preparation of the purified antigen often make this an uneconomical approach. Within the last decade, the advent of recombinant DNA technology has brought about a new approach in the preparation of vaccines. In this review, some of the recent developments in several research areas leading to the production of effective vaccines will be presented to demonstrate the promising future of this new approach to vaccine development.     

Traditional and novel approaches to flavivirus vaccines

Yellow fever, dengue, Japanese encephalitis and tick-borne encephalitis viruses are the medically most important members of the Flavivirus genus composed primarily of arboviruses. In this paper, we review the commercially available traditional flavivirus vaccines against yellow fever, Japanese encephalitis, and tick-borne encephalitis, as well as modern approaches to flavivirus vaccines. Formalin inactivation technology has been employed to produce killed vaccines. Flaviviruses have been attenuated by multiple passages in animal tissues and cell cultures to produce empirical live attenuated vaccines. The use of traditional methods is being pursued to develop vaccines against other flavivirus diseases, such as dengue, and to improve existing vaccines, such as for Japanese encephalitis. With the recent development of infectious clones, rational approaches to attenuated flavivirus vaccines have employed the introduction of specific mutations into wild type viruses and chimerisation between different viruses. Novel methods for delivery of live vaccines, such as inoculation of infectious DNA or RNA, have been described. Other approaches, such as the construction of protein subunit, expression vector-based and naked DNA vaccines, have been proposed to create alternate vaccine candidates.     

植物口服疫苗的研究进展

植物口服疫苗是通过转基因植物生产,通过口服的方式预防疾病的生物制品.作为一种新型疫苗,其研究开始于三十几年前.由于植物口服疫苗可以最大程度地降低传统疫苗的潜在风险,在疫苗生产中具有优势,因此拥有良好的商业生产前景.植物疫苗价格低廉,生产过程安全,可产生与注射疫苗相似效价效果,无论是在控制养殖业抗生素滥用的情况下作为替代...     

口蹄疫新型疫苗及其免疫特性研究进展

口蹄疫是世界性重大动物疫病,接种疫苗是预防该病的重要策略之一。随着现代分子生物学技术的发展,对一些新型口蹄疫疫苗如亚单位疫苗、活载体疫苗、核酸疫苗、可饲疫苗、多表位疫苗等的研究和探索已全面展开。我们简要介绍了近年涌现的口蹄疫新型疫苗,以为口蹄疫分子疫苗的设计提供参考。     

Production in Saccharomycescerevisiae of MS2 virus-like particles packaging functional heterologous mRNAs

Recently, DNA bacteriophages (M13, lambda) have been genetically engineered to transfer genes into mammalian cells. Although efficiencies observed are still relatively low, this opens the possibility of using these viruses as a new class of transfection agents not only for fundamental research purposes but also in gene therapy protocols or in other applications like vaccination. In this respect, it has been shown that a lambda bacteriophage engineered to express the hepatitis B surface antigen in mammalian cells could elicit an immune response against this antigen in mice and rabbits without any specific targeting of the bacteriophage. These impressive results would be even more encouraging if they could be obtained with an RNA bacteriophage, as RNA vaccines are preferred over DNA vaccines for safety reasons. Up to now, RNA bacteriophages have never been engineered for gene delivery. In this paper, we have sought to determine whether such a vector could be obtained by engineering the RNA bacteriophage MS2. We show that MS2 can be produced as virus-like particles (VLPs) in Saccharomyces cerevisiae and is able to package functional heterologous mRNAs, provided that these mRNAs contain the MS2 packaging sequence. For instance, linking the MS2 packaging sequence to the human growth hormone (hGH) mRNA enabled the packaging of this particular mRNA in MS2 VLPs. Functionality in eukaryotic systems of packaged mRNAs was confirmed by showing that mRNAs purified from VLPs can be efficiently translated in vitro and in cell cultures. The high stability of MS2 could, therefore, make MS2 VLPs a very powerful carrier for RNA vaccines.     

Composition of acellular pertussis and combination vaccines: a general review.

Since the development and introduction of the acellular pertussis vaccine in Japan in the early eighties, we have come a long way in using this component in combination with other vaccines. However, the basic problem in development of an effective and safe pertussis vaccine is that the antigens to induce complete protection against clinical pertussis and the precise mechanism by which pertussis vaccine confers immunity is yet unknown. Hence, the composition of future acellular pertussis vaccine remains an open issue. Recently, acellular pertussis vaccine has been licensed for the booster doses in the U.S.A. and for primary immunization of infants in Italy and Germany. A multicentric trial has been carried out to compare the serological response and adverse reactions of 13 acellular pertussis vaccines. These vaccines contained one or more of the four components, i.e. FHA, PT, 69 kDa OMP and fimbriae. All vaccines were associated with substantially fewer and less adverse reactions and were more immunogenic with respect to antibodies against the added antigens. DTP vaccines in the near future will have combinations of other components and the key antigen for combination will be acellular pertussis component which is going to replace whole cell pertussis component in DTP vaccines. In view of this, manufacturers like ourselves from the developing countries are still groping in the dark, uncertain whether we should have a single component acellular pertussis vaccine or multicomponent one. This will have a major impact on the cost of production, the final cost of the combination vaccines and the regulatory issues that we will have to tackle in view of the recent thinking on harmonization in the pharmaceutical industry.     

From SARS-CoV to SARS-CoV-2: safety and broad-spectrum are important for coronavirus vaccine development

The global pandemic of COVID-19 caused by SARS-CoV-2 (also known as 2019-nCoV and HCoV-19) has posed serious threats to public health and economic stability worldwide, thus calling for development of vaccines against SARS-CoV-2 and other emerging and reemerging coronaviruses. Since SARS-CoV-2 and SARS-CoV have high similarity of their genomic sequences and share the same cellular receptor (ACE2), it is essential to learn the lessons and experiences from the development of SARS-CoV vaccines for the development of SARS-CoV-2 vaccines. In this review, we summarized the current knowledge on the advantages and disadvantages of the SARS-CoV vaccine candidates and prospected the strategies for the development of safe, effective and broad-spectrum coronavirus vaccines for prevention of infection by currently circulating SARS-CoV-2 and other emerging and reemerging coronaviruses that may cause future epidemics or pandemics.     

Development of mRNA vaccines against respiratory syncytial virus (RSV)

Respiratory syncytial virus (RSV) is a single-stranded negative-sense RNA virus that is the primary etiologic pathogen of bronchitis and pneumonia in infants and the elderly. Currently, no preventative vaccine has been approved for RSV infection. However, advances in the characterization, and structural resolution, of the RSV surface fusion glycoprotein have revolutionized RSV vaccine development by providing a new target for preventive interventions. In general, six different approaches have been adopted in the development of preventative RSV therapeutics, namely, particle-based vaccines, vector-based vaccines, live-attenuated or chimeric vaccines, subunit vaccines, mRNA vaccines, and monoclonal antibodies. Among these preventive interventions, MVA-BN-RSV, RSVpreF3, RSVpreF, Ad26. RSV.preF, nirsevimab, clesrovimab and mRNA-1345 is being tested in phase 3 clinical trials, and displays the most promising in infant or elderly populations. Accompanied by the huge success of mRNA vaccines in COVID-19, mRNA vaccines have been rapidly developed, with many having entered clinical studies, in which they have demonstrated encouraging results and acceptable safety profiles. In fact, Moderna has received FDA approval, granting fast-track designation for an investigational single-dose mRNA-1345 vaccine against RSV in adults over 60 years of age. Hence, mRNA vaccines may represent a new, more successful, chapter in the continued battle to develop effective preventative measures against RSV. This review discusses the structure, life cycle, and brief history of RSV, while also presenting the current advancements in RSV preventatives, with a focus on the latest progress in RSV mRNA vaccine development. Finally, future prospects for this field are presented.