New Generation Of Vaccines Research Articles

Extracellular Vesicles in Viral Pathogenesis: A Case of Dr. Jekyll and Mr. Hyde.

Secretion of extracellular vesicles (EVs) is a fundamental property of living cells. EVs are known to transfer biological signals between cells and thus regulate the functional state of recipient cells. Such vesicles mediate the intercellular transport of many biologically active molecules (proteins, nucleic acids, specific lipids) and participate in regulation of key physiological processes. In addition, EVs are involved in the pathogenesis of multiple diseases: infectious, neurodegenerative, and oncological. The current EV classification into microvesicles, apoptotic bodies, and exosomes is based on their size, pathways of cellular biogenesis, and molecular composition. This review is focused on analysis of the role of EVs (mainly exosomes) in the pathogenesis of viral infection. We briefly characterize the biogenesis and molecular composition of various EV types. Then, we consider EV-mediated pro- and anti-viral mechanisms. EV secretion by infected cells can be an important factor of virus spread in target cell populations, or a protective factor limiting viral invasion. The data discussed in this review, on the effect of EV secretion by infected cells on processes in neighboring cells and on immune cells, are of high significance in the search for new therapeutic approaches and for design of new generations of vaccines.

WITHDRAWN: New Generation of vaccines and convalescent plasma therapy for management of CoV-2: Perspectives from the UK and potential deployment in the current global pandemic

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.transci.2021.103051. The duplicate article has therefore been withdrawn.The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Review on Novel Bacterial Antigen Identification Methods for the Development of Candidate Vaccine

This review mainly focused on methods that are used for identifying novel bacterial antigens that can use in recombinant subunit vaccine development. Particularly, it describes the processes involved in reverse vaccinology, genomic function, bioinformatics and immunological approaches and some associated complementary technologies such as proteomics that can be used in identification of new and potentially useful vaccine antigens. Results obtained from the application of these methods are forming basis for a new generation of vaccine for use in the control of bacterial infections of humans and animals.

Porcine Reproductive and Respiratory Syndrome Virus Reverse Genetics and the Major Applications.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a positive sense, single-stranded RNA virus that is known to infect only pigs. The virus emerged in the late 1980s and became endemic in most swine producing countries, causing substantial economic losses to the swine industry. The first reverse genetics system for PRRSV was reported in 1998. Since then, several infectious cDNA clones for PRRSV have been constructed. The availability of these infectious cDNA clones has facilitated the genetic modifications of the viral genome at precise locations. Common approaches to manipulate the viral genome include site-directed mutagenesis, deletion of viral genes or gene fragments, insertion of foreign genes, and swapping genes between PRRSV strains or between PRRSV and other members of the Arteriviridae family. In this review, we describe the approaches to construct an infectious cDNA for PRRSV and the ten major applications of these infectious clones to study virus biology and virus–host interaction, and to design a new generation of vaccines with improved levels of safety and efficacy.

New horizons in adjuvants for vaccine development.

Adjuvant molecules, particularly toll like receptor (TLR) agonists have been in development for decades, though until now only a natural TLR 4 ligand (mono-phosphoryl lipid A, MPL) has been incorporated into licensed vaccine products, in formulations than enhance and complement the MPL activity. The inclusion of MPL-based formulations into vaccines has been based on enhancing antibody responses to subunit antigens, and has provided important proof-of-concept for enhancing desired immune responses to defined molecular targets. Challenges remain in adjuvant development, particularly for those that stimulated effective T cell responses for both preventative and therapeutic vaccines. The discovery of molecules, many based on RNA, that stimulate innate and adaptive immune responses and have the ability to stimulate potent CD8 T cell responses, has opened the door for development of a new generation of vaccines.

Application of Outer Membrane Protein-Based Vaccines Against Major Bacterial Fish Pathogens in India.

Aquaculture is one of the fastest-growing food-producing sectors in the world. However, its growth is hampered by various disease problems due to infectious microorganisms, including Gram-negative bacteria in finfish aquaculture. Disease control in aquaculture by use of antibiotics is not recommended as it leads to antibiotic residues in the final product, selection, and spread of antibiotic resistance in the environment. Therefore, focus is on disease prevention by vaccination. All Gram-negative bacteria possess surface-associated outer membrane proteins (OMPs), some of which have long been recognized as potential vaccine candidates. OMPs are essential for maintaining the integrity and selective permeability of the bacterial membrane and play a key role in adaptive responses of bacteria such as solute and ion uptake, iron acquisition, antimicrobial resistance, serum resistance, and bile salt resistance and some adhesins have virulence attributes. Antigenic diversity among bacterial strains even within the same bacterial species has constrained vaccine developments, but OMPs that are conserved across serotypes could be used as potential candidates in vaccine development, and several studies have demonstrated their efficacy and potential as vaccine candidates. In this review, we will look into the application of OMPs for the design of vaccines based on recombinant proteins, subunit vaccines, chimeric proteins, and DNA vaccines as new-generation vaccine candidates for major bacterial pathogens of fish for sustainable aquaculture.

Antibodies and Protection in Systemic Salmonella Infections: Do We Still Have More Questions than Answers?

Salmonella causes grave systemic infections in humans and other animals and provides a paradigm for other diseases in which the bacteria have both intracellular and extracellular lifestyles. New generations of vaccines rely on the essential contribution of the antibody responses for their protection. The quality, antigen specificity, and functions associated with antibody responses to this pathogen have been elusive for a long time. Recent approaches that combine studies in humans and genetically manipulated experimental models and that exploit awareness of the location and within-host life cycle of the pathogen are shedding light on how humoral immunity to Salmonella operates. However, this area of research remains full of controversy and discrepancies. The overall scenario indicates that antibodies are essential for resistance against systemic Salmonella infections and can express the highest protective function when operating in conjunction with cell-mediated immunity. Antigen specificity, isotype profile, Fc-gamma receptor usage, and complement activation are all intertwined factors that still arcanely influence antibody-mediated protection to Salmonella.

Outer Membrane Vesicles of Helicobacter pylori 7.13 as Adjuvants Promote Protective Efficacy Against Helicobacter pylori Infection.

Helicobacter pylori(H. pylori), a gram-negative bacterium in the human stomach with global prevalence, is relevant to chronic gastrointestinal diseases. Due to its increasing drug resistance and the low protective efficacy of some anti-H. pylori vaccines, it is necessary to find a suitable adjuvant to improve antigen efficiency. In our previous study, we determined that outer membrane vesicles (OMVs), a multicomponent secretion generated by gram-negative bacteria, of H. pylori were safe and could induce long-term and robust immune responses against H. pylori in mice. In this study, we employed two common vaccines, outer membrane proteins (OMPs) and whole cell vaccine (WCV) to assess the adjuvanticity of OMVs in mice. A standard adjuvant, cholera toxin (CT), was used as a control. Purified H. pylori OMVs used as adjuvants generated lasting anti-H. pylori resistance for 12 weeks. Additionally, both systematic and gastric mucosal immunity, as well as humoral immunity, of mice immunized with vaccine and OMVs combinations were significantly enhanced. Moreover, OMVs efficiently promoted Th1 immune response, but the response was skewed toward Th2 and Th17 immunity when compared with that induced by the CT adjuvant. Most importantly, OMVs as adjuvants enhanced the eradication of H. pylori. Thus, OMVs have potential applications as adjuvants in the development of a new generation of vaccines to treat H. pylori infection.

In Silico Design of Multi-Epitope ESAT-6:Ag85b:Fcγ2a Fusion Protein as a Novel Candidate for Tuberculosis Vaccine

: Mycobacterium tuberculosis (MTB), which is the causative agent of tuberculosis (TB), is among the most important infectious bacteria with high morbidity and mortality rates worldwide. Bacilli Calmette-Guerin (BCG) vaccine has been discovered for about a century, and it is considered as a major vaccine for humans. However, some factors, such as its attenuated nature and its inefficacy against the latent form of the disease, have led to the use of alternative vaccines. Multi-epitope subunit vaccines are new-generation vaccines that are being developed in clinical trial phases. For the production of a subunit vaccine, the selection of immunodominant antigens and targeted delivery systems to antigen presenting cells (APCs) are considered as basic parameters. In the present study, we designed the novel multi-epitope ESAT-6:Ag85B:Fcγ2a, which was evaluated completely by various online tools as an optimum vaccine against TB. The early secreted antigenic target of 6 kDa (ESAT-6) and antigen 85B (Ag85B) are two immunodominant antigens, and Fcγ2a is a targeted delivery system. This vaccine candidate can be used for future preclinical studies.

Structure of P46, an immunodominant surface protein from Mycoplasma hyopneumoniae: interaction with a monoclonal antibody.

Mycoplasma hyopneumoniae is a prokaryotic pathogen that colonizes the respiratory ciliated epithelial cells in swine. Infected animals suffer respiratory lesions, causing major economic losses in the porcine industry. Characterization of the immunodominant membrane-associated proteins from M. hyopneumoniae may be instrumental in the development of new therapeutic approaches. Here, the crystal structure of P46, one of the main surface-antigen proteins, from M. hyopneumoniae is presented and shows N- and C-terminal α/β domains connected by a hinge. The structures solved in this work include a ligand-free open form of P46 (3.1 Å resolution) and two ligand-bound structures of P46 with maltose (2.5 Å resolution) and xylose (3.5 Å resolution) in open and closed conformations, respectively. The ligand-binding site is buried in the cleft between the domains at the hinge region. The two domains of P46 can rotate with respect to each other, giving open or closed alternative conformations. In agreement with this structural information, sequence analyses show similarities to substrate-binding members of the ABC transporter superfamily, with P46 facing the extracellular side as a functional subunit. In the structure with xylose, P46 was also bound to a high-affinity (Kd = 29 nM) Fab fragment from a monoclonal antibody, allowing the characterization of a structural epitope in P46 that exclusively involves residues from the C-terminal domain. The Fab structure in the complex with P46 shows only small conformational rearrangements in the six complementarity-determining regions (CDRs) with respect to the unbound Fab (the structure of which is also determined in this work at 1.95 Å resolution). The structural information that is now available should contribute to a better understanding of sugar nutrient intake by M. hyopneumoniae. This information will also allow the design of protocols and strategies for the generation of new vaccines against this important swine pathogen.

Overview of multistage subunit tuberculosis vaccines: advantages and challenges

To date, tuberculosis (TB) infection, is the most threatening infectious disease in all humans around the world. Mycobacterium tuberculosis is a facultative intracellular bacterium, possesses an exclusive life-cycle inside the macrophages, as one of the most important cells in the innate immune system. As soon as entrance in the lungs, bacteria actively replicate, but intracellular conditions such as hypoxia and nutrient starvation, lead to low replication of bacteria, or nonreplicating state. While Bacillus Calmette-Guerin vaccine is the most usable vaccine, especially in children and against active form, but this vaccine has no more protection in infected adults to latent forms of disease. Among the new generation of vaccines, fusion multistage subunit vaccines have prodigious effect on immune responses. By virtue of simultaneous presence of both expressed antigens from active and latent forms of TB in the structure of these recombinant subunit vaccines, they can strongly induce immune responses against all stages of the disease. The findings suggest subunit vaccines are the best candidates for immunization against TB, by virtue of their high safety, ease of production, specificity, and utilization of mycobacterial immunodominant antigens. Fusion multistage subunit vaccines, as novel subunit vaccines are the most ideal target for proper prevention against TB infection. Due to simultaneous use of both expressed antigens in active and latent forms of TB, these vaccines are able to induce strong immune responses versus all of TB stages.

Nanoparticles as Adjuvants in Vaccine Delivery.

Nanotechnology provides an excellent platform for the development of a new generation of vaccines. These are based on purified subunit proteins or polysaccharides, recombinant proteins, synthetic peptides, or nucleic acids. These types of vaccines may be insufficiently immunogenic, thus requiring adjuvants that augment their immunogenicity. Nanoparticles (NPs) can act as adjuvants for vaccines, hence they are referred to as a nano-adjuvant (NA). NPs can either encapsulate or adsorb the vaccine antigen or DNA in an appropriate formulation, thus increasing stability, cellular uptake, and immunogenicity. In addition, the biodistribution and systemic release of a vaccine can also be controlled by different NA formulations. This review provides an overview of the classification of NAs and also addresses factors influencing the stability, release, and immunogenicity of the formulated vaccine. A basic understanding of these factors enables a more rational design of NA formulations. Applications of NAs and key challenges in their formulation development are also discussed.

Potential Vaccines for Treating Crohn's Disease

CD is an inflammatory disease of the GIT and can affect several parts of the digestive system. There is a relationship between impaired mucosal barrier in the GIT of IBD patients and the role of bacteria such as MAP in CD. Apart from different therapeutic approaches for treating CD, development of a vaccine is a novel modality. In the present article, most available therapeutic opportunities in the last decade, especially the possibility of vaccines against CD, are reviewed. According to the search, availability of a new generation of vaccines against CD is expected specially tolerogenic ex vivo-derived DC-based vaccines. Regarding different locations of the challenge and the variety of clinical manifests of CD and also the type of resident antigen-presenting cells and their traffic in different parts of GIT, the results of immunotherapy with DC-based vaccines may vary case by case.

Eradication of peste des petits ruminants: Application of new research to guide and facilitate the global elimination of the disease

Peste des petits ruminants (PPR) is a highly contagious viral disease of domestic and wild small ruminants caused by the peste des petits ruminants virus (PPRV), which belongs to the genus Morbilivirus in the family Paramyxoviridae. The PPRV causes disease in goats and sheep, as well as in wild ruminants, such as gazelle, deer, antelope, Nubian ibex, gemsbok and others. PPR was first recorded in early 1942 in Ivory Coast, West Africa, and spread to around 70 countries in Africa, the Middle East and Asia – regions that are home to over 80% of the world’s sheep and goats. Until 2018, PPR had never been detected in Europe. On 24th June 2018, however, the Bulgarian authorities reported cases of PPR in sheep in the village of Voden, Bolyarovo municipality of Yambol region, on the border with the Thrace region of Turkey. It was the first occurrence of PPR in Bulgaria and in the European Union (EU). The control and eventual eradication of PPR is now one of the top priorities for the Food and Agriculture Organization (FAO) and the World Organization for Animal Health (OIE). In 2015, the international community agreed on a global strategy for PPR eradication, setting 2030 as a target date for elimination of the disease. The aim of this paper was to highlight future research that could be performed to guide and facilitate the PPR eradication programme. Such research includes studies on PPR transmission and epidemiology, as well as the development and application of new-generation PPR vaccines capable of differentiating infected from vaccinated animals (DIVA). Moreover, there is a need for research to improve and adapt existing diagnostic techniques as well as to develop novel PPRV recognition methods, such as a lateral flow device for in-field use, that accelerate decisions about the implementation of control measures.

The need & the issues related to new-generation typhoid conjugate vaccines in India

The low- and middle-income countries bear the highest burden of typhoid fever in the world. India, along with other South Asian countries, has a significant incidence of typhoid fever among young children though there is a paucity of published data on community burden. In spite of the availability of Vi-polysaccharide (Vi-PS) and conjugated Vi-PS vaccines, these are not adequately utilized in India and in the neighbouring countries. To address many shortcomings of the unconjugated Vi-PS vaccines, typhoid conjugate vaccines (TCVs) are developed by conjugating Vi-PS with different carrier proteins. Three such vaccines using tetanus toxoid as a carrier protein are already licensed in India. Several other Vi-PS conjugates are currently in various stages of development. The current review provides an update on the existing and upcoming new TCVs along with a detailed discussion on the various issues involved with their clinical use and limitations.

Vaccinal Preventon of Anthrax in the Russian Federation and Its Immediate Prospects

Th e purpose of the work is to show the possibilities of vaccine prophylaxis of anthrax in the Russian Federation and its immediate prospects. Th e article is dedicated to the vaccine preparations, available in Russia and abroad in the arsenal of medical remedies at present, to the history of their creation, to the eff ectiveness of their use and to the main directions of the improving of the vaccine prevention. Th e eff orts to develop a new generation of vaccines are aimed mainly at the increasing of the safety of vaccines, reducing the frequency of their administration and improving their production technologies. Th e combined anthrax vaccine developed in the USSR can be used in the emergency prophylaxis of anthrax along with antibiotics. The development of vaccines based on immunogenic antigens synthesized by recombinant producers solves the problem of residual virulence and reactogenicity, as well as the problem of increasing stability and reduction of doses of modern anthrax vaccines. In the nearest future it is necessary: to develop an industrial technology of the production of anthrax vaccines based on recombinant strains – hyperproducers of protective antigen and include them in the prophylaxis and treatment regimens of anthrax infection; to develop scientifi c and methodological approaches and vaccines for mass immunization against anthrax; to evaluate the possibility of using new adjuvants for the construction of anthrax vaccines, more eff ective and safer than the existing ones

Foot-and-Mouth Disease Virus: Immunobiology, Advances in Vaccines and Vaccination Strategies Addressing Vaccine Failures-An Indian Perspective.

A mass vaccination campaign in India seeks to control and eventually eradicate foot-and-mouth disease (FMD). Biosanitary measures along with FMD monitoring are being conducted along with vaccination. The implementation of the FMD control program has drastically reduced the incidence of FMD. However, cases are still reported, even in regions where vaccination is carried out regularly. Control of FMD outbreaks is difficult when the virus remains in circulation in the vaccinated population. Various FMD risk factors have been identified that are responsible for FMD in vaccinated areas. The factors are discussed along with strategies to address these challenges. The current chemically inactivated trivalent vaccine formulation containing strains of serotype O, A, and Asia 1 has limitations including thermolability and induction of only short-term immunity. Advantages and disadvantages of several new-generation alternate vaccine formulations are discussed. It is unfeasible to study every incidence of FMD in vaccinated animals/areas in such a big country as India with its huge livestock population. However, at the same time, it is absolutely necessary to identify the precise reason for vaccination failure. Failure to vaccinate is one reason for the occurrence of FMD in vaccinated areas. FMD epidemiology, emerging and re-emerging virus strains, and serological status over the past 10 years are discussed to understand the impact of vaccination and incidences of vaccination failure in India. Other factors that are important in vaccination failure that we discuss include disrupted herd immunity, health status of animals, FMD carrier status, and FMD prevalence in other species. Recommendations to boost the search of alternate vaccine formulation, strengthen the veterinary infrastructure, bolster the real-time monitoring of FMD, as well as a detailed investigation and documentation of every case of vaccination failure are provided with the goal of refining the control program.

Effect of the Hydrophilic-Hydrophobic Balance of Antigen-Loaded Peptide Nanofibers on Their Cellular Uptake, Cellular Toxicity, and Immune Stimulatory Properties.

Recently, nanofibers (NFs) formed from antigenic peptides conjugated to β-sheet-forming peptides have attracted much attention as a new generation of vaccines. However, studies describing how the hydrophilic-hydrophobic balance of NF components affects cellular interactions of NFs are limited. In this report, three different NFs were prepared by self-assembly of β-sheet-forming peptides conjugated with model antigenic peptides (SIINFEKL) from ovalbumin and hydrophilic oligo-ethylene glycol (EG) of differing chain lengths (6-, 12- and 24-mer) to investigate the effect of EG length of antigen-loaded NFs on their cellular uptake, cytotoxicity, and dendritic cell (DC)-stimulation ability. We used an immortal DC line, termed JAWS II, derived from bone marrow-derived DCs of a C57BL/6 p53-knockout mouse. The uptake of NFs, consisting of the EG 12-mer by DCs, was the most effective and activated DC without exhibiting significant cytotoxicity. Increasing the EG chain length significantly reduced cellular entry and DC activation by NFs. Conversely, shortening the EG chain enhanced DC activation but increased toxicity and impaired water-dispersibility, resulting in low cellular uptake. These results show that the interaction of antigen-loaded NFs with cells can be tuned by the EG length, which provides useful design guidelines for the development of effective NF-based vaccines.

Evidence for the Cytoplasmic Localization of the L-α-Glycerophosphate Oxidase in Members of the "Mycoplasma mycoides Cluster".

Members of the “Mycoplasma mycoides cluster” are important animal pathogens causing diseases including contagious bovine pleuropneumonia and contagious caprine pleuropneumonia, which are of utmost importance in Africa or Asia. Even if all existing vaccines have shortcomings, vaccination of herds is still considered the best way to fight mycoplasma diseases, especially with the recent and dramatic increase of antimicrobial resistance observed in many mycoplasma species. A new generation of vaccines will benefit from a better understanding of the pathogenesis of mycoplasmas, which is very patchy up to now. In particular, surface-exposed virulence traits are likely to induce a protective immune response when formulated in a vaccine. The candidate virulence factor L-α-glycerophosphate oxidase (GlpO), shared by many mycoplasmas including Mycoplasma pneumoniae, was suggested to be a surface-exposed enzyme in Mycoplasma mycoides subsp. mycoides responsible for the production of hydrogen peroxide directly into the host cells. We produced a glpO isogenic mutant GM12::YCpMmyc1.1-ΔglpO using in-yeast synthetic genomics tools including the tandem-repeat endonuclease cleavage (TREC) technique followed by the back-transplantation of the engineered genome into a mycoplasma recipient cell. GlpO localization in the mutant and its parental strain was assessed using scanning electron microscopy (SEM). We obtained conflicting results and this led us to re-evaluate the localization of GlpO using a combination of in silico and in vitro techniques, such as Triton X-114 fractionation or tryptic shaving followed by immunoblotting. Our in vitro results unambiguously support the finding that GlpO is a cytoplasmic protein throughout the “Mycoplasma mycoides cluster.” Thus, the use of GlpO as a candidate vaccine antigen is unlikely to induce a protective immune response.

Universal Influenza Virus Vaccines That Target the Conserved Hemagglutinin Stalk and Conserved Sites in the Head Domain.

Due to limitations of current influenza virus vaccines, new vaccines that mediate broad protection and show high efficacy against seasonal and pandemic viruses are urgently needed. The conserved stalk of the viral hemagglutinin has been identified as potential target antigen for this new generation of vaccines. A vaccination strategy based on chimeric hemagglutinin (cHA), which refocuses the immune response toward the stalk domain and the conserved neuraminidase, is currently being tested in clinical trials. Here we discuss how to improve the cHA antigens to generate vaccine candidates that both induce a broad antistalk response and target conserved immunosubdominant epitopes in the head domain of the hemagglutinin. These novel constructs, termed mosaic hemagglutinins, should provide enhanced protection and should be tested in clinical trials to assess their improved potential as universal influenza virus vaccine candidates.