Antibacterial Vaccines Research Articles

Pharmacological effects of ginseng on infectious diseases.

Ginseng has been traditionally used as an herbal nutritional supplement in Asian countries, including Korea, China, Japan, and Vietnam for several millennia. Most studies have focused on the role of ginseng on anti-oxidative stress, anti-inflammatory, and anti-cancer activities. Recently, modulator activities of ginseng on the immune responses during pathogenic bacterial and viral infections and beneficial effects of ginseng in infectious diseases have been elucidated. In vivo and in vitro studies revealed the potential of ginseng extracts and ginsenosides Rg1, Rg3, Rb1, Rb2, Rb3, compound K, Re, Rd, Rh2 for treatment of several infectious diseases. The molecular mechanisms of these effects mainly involve inflammatory cytokines (TNF-α, IL-6, IL-1β, IFN-γ, IL-10), apoptotic pathway (bcl-2, bcl-xL), PI3K/Akt pathway, MAPKs pathway, JAK2/STAT5, NF-κB pathway, and the inflammasome. In this review, we will summarize the current knowledge on the effects of ginseng in the immune responses during the infections and its bioactivities on the prevention of infectious diseases as well as its underlying mechanisms. Moreover, the therapeutic potential of ginseng as an anti-bacterial and anti-viral medication and vaccine adjuvant will be discussed as well.

Immune mechanisms of community-acquired pneumonia and copd due to infectious etiology and methods of immunotherapy

Novadays a growing number of immunodependent diseases observed. There are 3 main groups of diseases of the immune system: immunodeficiency, allergic and autoimmune diseases. Also at the foundation of the brocken functions of the immune system could be the age of the patients, the chronic diseases, the localization of the inflammatory process, etiological characterization of the pathogen and various disorders of the immune system, especially in the case of existing genetic defects. In recent years, the increasing significance of conditionally pathogenic microflora in the development of pathology associated with the infection. Community-acquired pneumonia and chronic obstructive pulmonary disease (COPD) are characterized by high morbidity and mortality. The inclusion in the traditional therapy drugs with immunomodulatory effects helps enhance the action the treatment. Azoximer bromide could helps to reduce the duration and severity of the disease and reduce the incidence of severe forms of the disease. Also in recent years, the immunomodulatory drugs are of special interest immunomodulators of bacterial origin on the basis of which are constructed of antibacterial therapeutic vaccine. All of the above indicates the need to further develop pathogenetic, including immunocorrecting therapy, especially in severe disease.

Zinc Immunology and Zn2+ Ions Binding Anti-Bacterial Vaccine Activity for Bacterial Cell Walls against Gram-Positive and Gram-Negative Bacteria

Zinc Immunology and Zn2+ Ions Binding Anti-Bacterial Vaccine Activity for Bacterial Cell Walls against Gram-Positive and Gram-Negative Bacteria

Chemical synthesis of glycans and applications in carbohydrate-based vaccines

Carbohydrates play important roles in many biological processes. However, the lack of resources of structurally-defined carbohydrates and their weak immunogenicity have always restricted the development of chemical glycobiology especially carbohydrate-based vaccines. The progress in chemical synthesis of carbohydrates and glycoconjugates has greatly promoted the development of carbohydrate-based vaccines including antibacterial vaccines, anti-tumor vaccines and anti-HIV vaccines. The use of one-pot glycosylation strategy and solid-phase glycosylation strategy is able to synthesize oligosaccharides and even polysaccharides more effectively than before. Glycoconjugates produced by combining the carbohydrate antigens and proper protein carriers improve the immunogenicity of carbohydrates. This review covers the general methods and strategies of carbohydrate chemical synthesis, and the recent development of carbohydrate-based vaccines, and also summarizes related work of our group, hoping to offer readers better understanding of chemical glycobiology especially carbohydrate-based vaccines.

The growth of Scottish salmon (Salmo salar) aquaculture 1979–2016 fits a simple two-phase logistic population model

Annual Scottish salmon production rose from 520 to 162,817 t over the years 1979–2016. This production growth is modelled using a logistic population model. Factors limiting production capacity include social, economic, regulatory and environmental factors (which change with time), while the growth in production is the product of changes in number of farms and productivity per farm. The model identifies fundamental differences occurring relatively abruptly around 1992. Pre 1992 the growth was extensive in nature with the number of farms increased exponentially (35% per year, 1979–1989) but productivity per farm increased relatively slowly (11% per farm per year) giving overall growth rate and with a relatively high 31.2% loss of fish. Since 1992 growth has been through intensification as the number of farms has fallen but productivity per farm increased rapidly in association with lower 20.3% loss of fish, which is in turn associated with a rapid uptake of antibacterial vaccine use. This simple model fails to predict a drop in production during 2004–2008 associated with a period of high exchange rate (£/$) and intense competition from Chile and Norway. After 2008, production resumes the pattern of increase predicted by the model as fitted from 1992 to 2003. Production is now approaching the historically fitted capacity, so further increase requires changes within the aquaculture industry that will increase carrying capacity such as increased productivity per unit biomass (better health, faster growth). For major increases in salmon production more substantial changes will be required, potentially offshore production will allow for more farms farm with larger biomasses, but this requires technical advances.

The Escherichia coli Type III Secretion System 2 Has a Global Effect on Cell Surface.

ABSTRACTMany strains of Escherichia coli carry a 29,250-bp ETT2 pathogenicity island (PAI), which includes genes predicted to encode type III secretion system (T3SS) components. Because it is similar to the Salmonella pathogenicity island 1 (SPI-1) system, encoding a T3SS in Salmonella enterica, it was assumed that ETT2 also encodes a secretion system injecting effectors into host cells. This assumption was checked in E. coli serotype O2—associated with urinary tract infections and septicemia—which has an intact ETT2 gene cluster, in contrast to most strains in which this cluster carries deletions and mutations. A proteomic search did not reveal any putative secreted effector. Instead, the majority of the secreted proteins were identified as flagellar proteins. A deletion of the ETT2 gene cluster significantly reduced the secretion of flagellar proteins, resulting in reduced motility. There was also a significant reduction in the transcriptional level of flagellar genes, indicating that ETT2 affects the synthesis, rather than secretion, of flagellar proteins. The ETT2 deletion also resulted in additional major changes in secretion of fimbrial proteins and cell surface proteins, resulting in relative resistance to detergents and hydrophobic antibiotics (novobiocin), secretion of large amounts of outer membrane vesicles (OMVs), and altered multicellular behavior. Most important, the ETT2 deletion mutants were sensitive to serum. These major changes indicate that the ETT2 gene cluster has a global effect on cell surface and physiology, which is especially important for pathogenicity, as it contributes to the ability of the bacteria to survive serum and cause sepsis.

Abstract LB-304: Customizable, in vitro protein glycosylation for antibacterial and anti-cancer vaccines

Abstract Changes in protein glycosylation are important hallmarks of cancer biology, serving as biomarkers for cancer progression and predictors of cancer prognosis. Moreover, tumor-associated carbohydrate antigens (TACAs) provide potential targets for therapeutic and prophylactic interventions. However, development of anti-cancer immunotherapies and vaccines directed against TACAs has been limited due to the significant challenges associated with synthesizing proteins bearing defined glycan structures in vivo. These challenges arise due to the complex, non-templated nature of the glycosylation process and the inability to control glycosylation components at precise ratios in living cells. To address these challenges, we describe a novel cell-free glycoprotein synthesis (CFGpS) technology that seamlessly integrates protein biosynthesis with asparagine-linked (N-linked) protein glycosylation. The platform is flexible and modular, allowing the decoration of proteins with structurally diverse, yet homogeneous glycans, including the eukaryotic trimannosyl N-glycan (mannose3-N-acetylglucosamine2, Man3GlcNAc2), which forms the core of all tumor-associated N-glycans. We demonstrate the utility of this platform through the production of antibacterial glycoconjugate vaccines directed against the highly infectious pathogenic bacterium Franciscella tularensis. Importantly, we are able to synthesize and glycosylate a variant of E. coli maltose binding protein (MBP) that has been shown to elicit humoral and cell-based immunity to polysaccharide antigens in mice. Our work demonstrates a novel approach for the customizable glycosylation of immunogenic proteins with TACAs in a cell-free system. The ability of the CFGpS platform to synthesize defined glycan structures uniquely enables the production of novel antibacterial and anti-cancer vaccines. Citation Format: Jessica C. Stark, Thapakorn Jaroentomeechai, Rachel S. Dubner, Karen J. Hsu, Cameron Glasscock, Matthew P. DeLisa, Michael C. Jewett. Customizable, in vitro protein glycosylation for antibacterial and anti-cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-304.

The Elusive Anti-Candida Vaccine: Lessons From the Past and Opportunities for the Future.

Candidemia is a bloodstream fungal infection caused by Candida species and is most commonly observed in hospitalized patients. Even with proper antifungal drug treatment, mortality rates remain high at 40–50%. Therefore, prophylactic or preemptive antifungal medications are currently recommended in order to prevent infections in high-risk patients. Moreover, the majority of women experience at least one episode of vulvovaginal candidiasis (VVC) throughout their lifetime and many of them suffer from recurrent VVC (RVVC) with frequent relapses for the rest of their lives. While there currently exists no definitive cure, the only available treatment for RVVC is again represented by antifungal drug therapy. However, due to the limited number of existing antifungal drugs, their associated side effects and the increasing occurrence of drug resistance, other approaches are greatly needed. An obvious prevention measure for candidemia or RVVC relapse would be to immunize at-risk patients with a vaccine effective against Candida infections. In spite of the advanced and proven techniques successfully applied to the development of antibacterial or antiviral vaccines, however, no antifungal vaccine is still available on the market. In this review, we first summarize various efforts to date in the development of anti-Candida vaccines, highlighting advantages and disadvantages of each strategy. We next unfold and discuss general hurdles encountered along these efforts, such as the existence of large genomic variation and phenotypic plasticity across Candida strains and species, and the difficulty in mounting protective immune responses in immunocompromised or immunosuppressed patients. Lastly, we review the concept of “trained immunity” and discuss how induction of this rapid and nonspecific immune response may potentially open new and alternative preventive strategies against opportunistic infections by Candida species and potentially other pathogens.

Advances and Opportunities in Nanoparticle- and Nanomaterial-Based Vaccines against Bacterial Infections.

As the dawn of the postantibiotic era we approach, antibacterial vaccines are becoming increasingly important for managing bacterial infection and reducing the need for antibiotics. Despite the success of vaccination, vaccines remain unavailable for many pressing microbial diseases, including tuberculosis, chlamydia, and staphylococcus infections. Amid continuing research efforts in antibacterial vaccine development, the advancement of nanomaterial engineering has brought forth new opportunities in vaccine designs. With increasing knowledge in antibacterial immunity and immunologic adjuvants, innovative nanoparticles are designed to elicit the appropriate immune responses for effective antimicrobial defense. Rationally designed nanoparticles are demonstrated to overcome delivery barriers to shape the adaptive immunity. This article reviews the advances in nanoparticle- and nanomaterial-based antibacterial vaccines and summarizes the development of nanoparticulate adjuvants for immune potentiation against microbial pathogens. In addition, challenges and progress in ongoing antibacterial vaccine development are discussed to highlight the opportunities for future vaccine designs.

Interplay of Carbohydrate and Carrier in Antibacterial Glycoconjugate Vaccines.

Bacterial infections are a serious health concern and are responsible for millions of illnesses and deaths each year in communities around the world. Vaccination is an important public health measure for reducing and eliminating this burden, and regions with comprehensive vaccination programs have achieved significant reductions in infection and mortality. This is often accomplished by immunization with bacteria-derived carbohydrates, typically in conjunction with other biomolecules, which induce immunological memory and durable protection against bacterial human pathogens. For many species, however, vaccines are currently unavailable or have suboptimal efficacy characterized by short-lived memory and incomplete protection, especially among at-risk populations. To address this challenge, new tools and techniques have emerged for engineering carbohydrates and conjugating them to carrier molecules in a tractable and scalable manner. Collectively, these approaches are yielding carbohydrate-based vaccine designs with increased immunogenicity and protective efficacy, thereby opening up new opportunities for this important class of antigens. In this chapter we detail the current understanding of how carbohydrates interact with the immune system to provide immunity; how glycoengineering, especially in the context of glycoconjugate vaccines, can be used to modify and enhance immune responses; and current trends and strategies being pursued for the rational design of next-generation glycosylated antibacterial vaccines. Graphical Abstract.

Multicomponent polysaccharide-protein bioconjugation in the development of antibacterial glycoconjugate vaccine candidates.

A new synthetic strategy for the development of multivalent antibacterial glycoconjugate vaccines is described. The approach comprises the utilization of an isocyanide-based multicomponent process for the conjugation of functionalized capsular polysaccharides of S. pneumoniae and S. Typhi to carrier proteins such as diphtheria and tetanus toxoids. For the first time, oxo- and carboxylic acid-functionalized polysaccharides could be either independently or simultaneously conjugated to immunogenic proteins by means of the Ugi-multicomponent reaction, thus leading to mono- or multivalent unimolecular glycoconjugates as vaccine candidates. Despite the high molecular weight of the two or three reacting biomolecules, the multicomponent bioconjugation proved highly efficient and reproducible. The Ugi-derived glycoconjugates showed notable antigenicity and elicited good titers of functional specific antibodies. To our knowledge, this is the only bioconjugation method that enables the incorporation of two different polysaccharidic antigens to a carrier protein in a single step. Applications in the field of self-adjuvanting, eventually anticancer, multicomponent vaccines are foreseeable.

Toxoid Vaccination against Bacterial Infection Using Cell Membrane-Coated Nanoparticles.

As nanoparticles exhibit unique properties attractive for vaccine development, they have been progressively implemented as antigen delivery platforms and immune potentiators. Recently, cell membrane-coated nanoparticles have provided a novel approach for intercepting and neutralizing bacterial toxins by leveraging their natural affinity to cellular membranes. Such toxin-nanoparticle assemblies, termed nanotoxoids, allow rapid loading of different types of toxins and have been investigated for their ability to effectively confer protection against bacterial infection. This topical review will cover the current progress in antibacterial vaccine nanoformulations and highlight the nanotoxoid platform as a novel class of nanoparticulate vaccine. We aim to provide insights into the potential of nanotoxoids as a platform that is facile to implement and can be broadly applied to help address the rising threat of super pathogens.

Immune stealth-driven O2 serotype prevalence and potential for therapeutic antibodies against multidrug resistant Klebsiella pneumoniae

Emerging multidrug-resistant bacteria are a challenge for modern medicine, but how these pathogens are so successful is not fully understood. Robust antibacterial vaccines have prevented and reduced resistance suggesting a pivotal role for immunity in deterring antibiotic resistance. Here, we show the increased prevalence of Klebsiella pneumoniae lipopolysaccharide O2 serotype strains in all major drug resistance groups correlating with a paucity of anti-O2 antibodies in human B cell repertoires. We identify human monoclonal antibodies to O-antigens that are highly protective in mouse models of infection, even against heavily encapsulated strains. These antibodies, including a rare anti-O2 specific antibody, synergistically protect against drug-resistant strains in adjunctive therapy with meropenem, a standard-of-care antibiotic, confirming the importance of immune assistance in antibiotic therapy. These findings support an antibody-based immunotherapeutic strategy even for highly resistant K. pneumoniae infections, and underscore the effect humoral immunity has on evolving drug resistance.

POSSIBILITIES OF USE OF IMMUNE MODULATORS IN COMPLEX THERAPY OF COMMUNITY-ACQUIRED PNEUMONIAS

Community-acquired pneumonia (CAP) has been one the most pressing issues of healthcare due to high morbidity and mortality that are stable. Analysis of literature shows similar trends in the character of immune response of patients with CAP, precisely - formation of immune response via humoral route (Th2) with suppression of cell immune response (Thl), whereas lack of cellular and humoral mechanisms of immunity and dysbalanced cytokine portion determine severity of the infection course. Inclusion of immune modulators into traditional therapy allows to enhance the response to the therapy already being administered. One of the national immune modulators is azoximer bromide (polyoxidonium), its administration allows to reduce the length and severity of the disease, as well as reduce the frequency of development of prolonged forms. Also, immune modulators of bacterial origin have received special interest as of late, and antibacterial therapeutic vaccines are being constructed based on them. Immunovac VP-4 polycomponent vaccine is distinguishable among the national preparations. Clinical-immunological effect of the vaccine has been studied in recent years on different pathologies and methods of administration in adults and children. Features of Immunovac VP-4 effect confirm the primary character of alterations in the immune system, that is the background of a certain pathology and is the reason for inclusion of immune modulating preparations into basic therapy of the diseases.

Study of Antigenic Activity of Experimental Samples of the Conjugated Vaccines Based on Synthetic Oligosaccharide Ligands and CRM197 Carrier Protein against <i>Candida albicans, Aspergillus fumigatus</i> and <i>Pseudomonas aeruginosa</i>

By now there is no effective treatment for a number of socially significant bacterial and fungal diseases. β-(1→3)-glucans are the principal components of the cell wall of fungi, including Candida albicans, Aspergillusfumigatus and other. At the same time, β-(1→3)-glucans are absent in mammals and man, that makes them promising components of carbohydrate-protein conjugated vaccines for the prevention and treatment of fungal infections. Alginic acid, constructed of β-(1→ 4)-linked mannuronic acid are extracellular polysaccharides produced by Pseudomonas aeruginosa. The protein CRM197 is a non toxic derivative of diphtheria toxin, which is widely used as a safe carrier in conjugated vaccines. The purpose of this study was to investigate the antigenic activity of experimental samples of the conjugated vaccines based on synthetic oligosaccharide ligands and CRM197 carrier protein in the competitive enzyme-linked immunosorbent assay. Two-time immunization Balb/c mice with experimental samples of the conjugated vaccines induced the formation of high titers of specific antibodies. High antibody’s avidity to their oligosaccharide ligands was shown in competitive ELISA. These data suggest the relevance of further preclinical trials of the conjugated antifungal vaccine against Candida and Aspergillus and antibacterial vaccine against Pseudomonas.

The antimicrobial activity of nanoparticles: present situation and prospects for the future.

Nanoparticles (NPs) are increasingly used to target bacteria as an alternative to antibiotics. Nanotechnology may be particularly advantageous in treating bacterial infections. Examples include the utilization of NPs in antibacterial coatings for implantable devices and medicinal materials to prevent infection and promote wound healing, in antibiotic delivery systems to treat disease, in bacterial detection systems to generate microbial diagnostics, and in antibacterial vaccines to control bacterial infections. The antibacterial mechanisms of NPs are poorly understood, but the currently accepted mechanisms include oxidative stress induction, metal ion release, and non-oxidative mechanisms. The multiple simultaneous mechanisms of action against microbes would require multiple simultaneous gene mutations in the same bacterial cell for antibacterial resistance to develop; therefore, it is difficult for bacterial cells to become resistant to NPs. In this review, we discuss the antibacterial mechanisms of NPs against bacteria and the factors that are involved. The limitations of current research are also discussed.

An Overview of Structural Features of Antibacterial Glycoconjugate Vaccines That Influence Their Immunogenicity.

Bacterial cell-surface-derived or mimicked carbohydrate moieties that act as protective antigens are used in the development of antibacterial glycoconjugate vaccines. The carbohydrate antigen must have a minimum length or size to maintain the conformational structure of the antigenic epitope(s). The presence or absence of O-acetate, phosphate, glycerol phosphate and pyruvate ketal plays a vital role in defining the immunogenicity of the carbohydrate antigen. The nature of the carrier protein, spacer and conjugation pattern used to develop the glycoconjugate vaccine also defines its overall spatial orientation which in turn affects its avidity and selectivity of interaction with the desired target(s). In addition, the ratio of carbohydrate to protein in glycoconjugate vaccines also makes an important contribution in determining the optimum immunological response. This Review article presents the importance of these variables in the development of antibacterial glycoconjugate vaccines and their effects on immune efficacy.

Glycoengineered Outer Membrane Vesicles as a Platform for Vaccine Development.

As we enter into the postantibiotic era, vaccines to prevent bacterial infections previously treatable with antibiotics are urgently needed. Most successful antibacterial vaccines are glycoconjugates, composed of cell surface carbohydrates chemically attached to a carrier protein. Glycoconjugate vaccines provide a safe and consistent strategy against polysaccharide-encapsulated pathogens. The best examples are the conjugate vaccines against Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis, all based on capsular polysaccharides. Although these types of vaccines are effective, their current manufacturing process presents multiple drawbacks, such as biosafety risks and batch-to-batch variability. Furthermore, inclusion of additional serotypes is extremely slow, mainly due to the intricate chemical methods of conjugation. Thus, novel platforms for antibacterial vaccines are required. Gram-negative bacteria are able to produce outer membrane vesicles (OMVs). OMVs are mainly composed of lipopolysaccharide (LPS), outer membrane and periplasmic proteins, and phospholipids. Although their biogenesis is poorly understood, it is known that OMVs are formed by blebbing of the outer membrane. OMVs are attractive candidates for novel vaccine delivery platforms due to their immunogenic properties, self-adjuvanticity, and capacity for enhancement by recombinant engineering. We have shown that OMVs can be engineered to display surface glycans from different bacteria and that these glycoengineered OMVs (geOMVs) are effective in diverse animal models of infection. Here we provide a detailed method for the design and preparation of geOMV displaying the O-antigen from a prominent uropathogenic Escherichia coli (UPEC) serotype, O25b, as a proof of concept for the use of geOMVs as vaccine candidates.

Identification and Design of Synthetic B Cell Epitopes for Carbohydrate-Based Vaccines.

Synthetic oligosaccharide-based vaccines are promising alternatives to conventional antibacterial carbohydrate vaccines prepared with isolated polysaccharides. Unlike polysaccharides, synthetic glycans are well defined, contaminant-free, and accessible even for pathogens that cannot be fermented or show limited carbohydrate biosynthesis in vitro. However, identifying synthetic glycan B cell epitopes that induce protective immunity has traditionally been a time-consuming trial-and-error process, as predicting the immunogenicity of an oligosaccharide by means of structure alone is not straightforward. We here describe how synthetic oligosaccharide epitopes for candidate vaccines can be rationally identified prior to preclinical immunogenicity studies. Epitopes are selected on the basis of their recognition by antibodies associated with protection from disease in humans or small animals. In addition, we show how murine antibody responses to a large oligosaccharide can inform the identification of a minimal B cell epitope that may help designing easy to synthesize vaccine candidates. The procedures, exemplified with a surface carbohydrate of Clostridium difficile, may serve as a guideline for selecting protective oligosaccharide epitopes for vaccines against infectious and malignant diseases.

Pathogen-induced secretory diarrhea and its prevention.

Secretory diarrhea is a historically known serious health implication around the world which primarily originates through pathogenic microorganisms rather than immunological or genetical disorders. This review highlights infective mechanisms of non-inflammatory secretory diarrhea causing pathogens, known therapeutics and their efficacy against them. These non-inflammatory diarrheal pathogens breach cell barriers, induce inflammation, disrupt fluid secretion across the epithelium by alteration in ion transport by faulting cystic fibrosis transmembrane conductance regulator (CFTR), calcium activated chloride channels and ion exchanger functions. Currently, a variety of prevention strategies have been used to treat these symptoms like use of antibacterial drugs, vaccines, fluid and nutritional therapy, probiotics and prebiotics as adjuncts. In progression of the need for a therapy having quick physiological effects, withdrawing the symptoms with a wide and safe therapeutic index, newer antisecretory agents like potent inhibitors, agonists and herbal remedies are some of the interventions which have come into light through greater understanding of the mechanisms and molecular targets involved in intestinal fluid secretion. Although these therapies have their own pros and cons inside the host, the quest for new antisecretory agents has been a successful elucidation to reduce burden of diarrheal disease.