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Gram-negative Outer Membrane Vesicles in Vaccine Development

Vaccine Adjuvant Properties of Probiotic Bacteria

Abstract: Vaccine-preventable diseases are still responsible for the deaths of more than 1 million children under the age of 5 years annually, mostly in developing countries. A substantial number of these deaths are due to pneumococcal bacteria and infections with rotavirus. Important issues faced by the WHO, governments, vaccine manufacturers, and international organizations such as UNICEF and the Global Alliance for Vaccines and Immunization (GAVI) are the cost-effective introduction of these life-saving vaccines in resource-poor countries where there is a considerable disease burden, and achieving high rates of completion of vaccination schedules remains elusive. Problems with vaccine coverage and vaccine delivery in these regions are significant, as in some cases large proportions of the target population do not receive adequate vaccination. Consequently, there is a need to develop more effective vaccination strategies that can provide adequate protection with reduced schedules. To date, emphasis has been placed on identifying novel vaccine antigens and adjuvants that induce stronger protective immune responses, as well as developing mucosally-administered vaccines. These approaches would have enormous benefits in allowing safe administration of vaccines in remote areas and may overcome the necessity for multiple doses. In this regard, the use of probiotic bacteria as novel mucosal adjuvants to enhance existing vaccine specific-immune responses offers an exciting new approach. In this review, we discuss the evidence for the role of probiotics in enhancing vaccine responses and provide justification for further investigation into their clinical effects and mechanisms of action. ... Read more

Why Is Coinfection with Influenza Virus and Bacteria So Difficult to Control?

Abstract: Influenza viruses are genetically labile pathogens which avoid immune detection by constantly changing their coat proteins. Most human infections are caused by mildly pathogenic viruses which rarely cause life-threatening disease in healthy people, but some individuals with a weakened immune system can experience severe complications. Widespread infections with highly pathogenic strains of influenza virus are less common, but have the potential to cause enormous death tolls among healthy adults if infection rates reach pandemic proportions. Increased virulence has been attributed to a variety of factors, including enhanced susceptibility to coinfection with common strains of bacteria. The mechanisms that facilitate dual infection are a major focus of current research, as preventative measures are needed to avert future pandemics. ... Read more

The Contribution of Non-human Primate Models to the Development of Human Vaccines

Abstract: The non-human primates (NHPs) model in biomedical research has contributed to the study of human infectious, autoimmune, oncogenic, and neurological diseases. This review focuses on the importance of NHP models in vaccine development for tuberculosis, pertussis, Dengue, group A streptococcus (Streptococcus pyogenes) infection, HIV infection, and certain diseases in the elderly (influenza, for example). From understanding disease pathogenesis and mechanisms of protection, to assessing vaccine safety and efficacy, we discuss selected cases where the importance of the use of NHP models is highlighted. ... Read more

Small Protein-mediated Quorum Sensing in a Gram-negative Bacterium: Novel Targets for Control of Infectious Disease

Abstract: Control of Gram-negative bacterial infections of plants and animals remains a major challenge because conventional approaches are often not sufficient to eradicate these infections. One major reason for their persistence seems to be the capability of the bacteria to grow within biofilms that protect them from adverse environmental factors. Quorum sensing (QS) plays an important role in the formation of biofilms. In QS, small molecules serve as signals to recognize bacterial cell population size, leading to changes in expression of specific genes when a signal has accumulated to some threshold concentration. The small protein Ax21 (Activator of XA21-mediated immunity), serves as a QS factor that regulates biofilm formation and virulence in the Gram-negative bacterium, Xanthomonas oryzae pv. oryzae. Knowledge of small protein-mediated QS in Gram-negative bacteria can be used to develop new methods to control persistent Gram-negative infections. ... Read more

Rotavirus Diversity and Evolution in the Post-Vaccine World

Abstract: Rotaviruses (RVs) are a large genetically diverse population of segmented double-stranded (ds) RNA viruses that are important causes of gastroenteritis in many animal species. The human RVs are responsible for the deaths of nearly 450,000 infants and young children each year, most occurring in developing countries. Recent large-scale sequencing efforts have revealed that the genomes of human RVs typically consist of phylogenetically linked constellations of eleven dsRNA segments. The presence of such preferred constellations indicate that the human RV genes have co-evolved to produce protein sets that work optimally together to support virus replication. Two of the viral genes encode virion outer capsid proteins (VP7 and VP4) whose antigenic properties define the G/P type of the virus. From year-to-year and place-to-place, the G/P type of human RVs associated with disease can fluctuate dramatically, phenomena that can be associated with the presence and behavior of genetically distinct RV clades. The recent introduction of two live attenuated RV vaccines (RotaTeqTM and RotarixTM) into the childhood vaccination programs of various countries has been highly effective in reducing the incidence of RV diarrheal disease. Whether the widespread use of these vaccines will introduce selective pressures on human RVs, triggering genetic and antigenic changes that undermine the effectiveness of vaccinations programs, is uncertain and will require continued surveillance of human RVs. ... Read more

New Developments in Vaccine Research -- Unveiling the Secret of Vaccine Adjuvants

Abstract: Since the first mass vaccination against smallpox and its eventual eradication, many more vaccines have been developed based on advances in bacteriology and virology and the use of attenuated live or killed whole pathogens. Immunological discoveries have allowed the development of more refined anti-toxin and conjugate vaccines, while biotechnology provided the tools for rationally designed, genetically engineered vaccines. Many challenges remain in developing safer and more effective vaccines against the more complex diseases such as tuberculosis and HIV-AIDS, and for the rapid protection against newly emerging pathogens or pathogen strains. These vaccines are likely to require the isolation of the "protective" antigenic molecules from the whole pathogen, as well as ways to deliver these to induce effective immune responses with minimal side effects. It has long been recognized that most antigens require the addition of an "adjuvant," an ill-defined substance that non-specifically triggers the innate immune system and boosts an immune response, with aluminum-based adjuvants the most commonly used in most present vaccines. Recent immunological breakthroughs have uncovered that the innate immune system has a much higher degree of complexity than previously thought and can be activated along a wide range of different pathways, depending on the engagement of different innate immune receptors. This in turn determines the type of immune response that will be generated against the vaccine antigens or pathogens. Harvesting the complexity and exquisite specificity of this innate immune system has inspired a new direction in vaccine research, towards the generation of novel adjuvant formulations, tailored to induce defined immune responses effective against specific pathogens. This review gives a brief overview of vaccine development and summarizes different aspects of adjuvant formulation that may influence their activity and specificity. ... Read more

Probiotics -- A Viable Therapeutic Alternative for Enteric Infections Especially in the Developing World

Abstract: This review focuses on the most recent advances in the application of probiotics as potential therapeutics for the developing world, from the treatment of chronic and acute enteric infections and their associated diarrheal complexes to the development of designer probiotics for controlling HIV and as novel mucosal vaccine delivery vehicles. ... Read more

Clostridium difficile Infection Prevention: Biotherapeutics, Immunologics, and Vaccines

Abstract: We are in the midst of a resurgence of Clostridium difficile infection (CDI) in North America and Europe for which morbidity and mortality are higher than ever seen. C. difficile has risen in frequency to become the most common healthcare-associated infection pathogen, exceeding methicillin-resistant Staphylococcus aureus in many hospitals. Protection against CDI is thought to be mediated first by the normal bacterial microbiota, supplemented by an adaptive immune antibody response directed primarily at C. difficile toxins. Treatment of CDI is with antimicrobials that also further disrupt the protective bacterial microbiota leaving the patient susceptible to recurrent CDI. In addition, patients most susceptible to CDI, the advanced elderly, may already have a limited immune response and fail to increase their adaptive immune response with infection. The importance of both of these protective modalities has been demonstrated by 1) the success of fecal microbiota to restore "colonization resistance" for patients with multiple recurrences of CDI, and 2) the marked reduction in CDI recurrences with the use of intravenous monoclonal antibodies directed against toxin A and toxin B as an adjunct to antimicrobial treatment. Anti-toxin vaccines, passive monoclonal anti-toxin antibodies, and non-toxigenic C. difficile (to restore colonization resistance) are already undergoing patient clinical trials. The opportunity to prevent CDI is compelling and future research should focus on understanding the critical elements of the microbiota needed to restore colonization resistance and on development of novel immunologic strategies that include systemic and mucosal vaccines and passive immune modulators. ... Read more

Vaccines and Autoimmune Diseases of the Adult

Abstract: Infectious agents contribute to the environmental factors involved in the development of autoimmune diseases possibly through molecular mimicry mechanisms. Hence, it is feasible that vaccinations may also contribute to the mosaic of autoimmunity. Evidence for the association of vaccinations and the development of these diseases is presented in this review. Infrequently reported post-vaccination autoimmune diseases include systemic lupus erythematosus, rheumatoid arthritis, inflammatory myopathies, multiple sclerosis, Guillain-Barré syndrome, and vasculitis. In addition, we will discuss macrophagic myofasciitis, aluminum containing vaccines, and the recent evidence for autoimmunity following human papilloma virus vaccine. ... Read more

All Eyes on the Next Generation of HIV Vaccines: Strategies for Inducing a Broadly Neutralizing Antibody Response

Abstract: HIV-1 broadly neutralizing antibodies (BNAbs) develop after several years of infection through a recursive process of memory B cell adaptation and maturation against co-evolving virus quasispecies. Advances in single-cell sorting and memory B cell antibody cloning methods have identified many new HIV BNAbs targeting conserved epitopes on the HIV envelope (env) protein. 3D crystal structures and biophysical analyses of BNAbs bound to invariant virus structures expressed on monomeric gp120, epitope scaffolds, core structures, and native trimers have helped us to visualize unique binding interactions and paratope orientations that have been instrumental in guiding vaccine design. A paradigm shift in the approach to structure-based design of HIV-1 envelope immunogens came recently after several laboratories discovered that native viral envelopes or "env-structures" reverse-engineered to bind with high affinity to a handful of broadly neutralizing antibodies did not in fact bind the predicted germline precursors of these broadly neutralizing antibodies. A major challenge for HIV-1 B cell vaccine development moving forward is the design of new envelope immunogens that can trigger the selection and expansion of germline precursor and intermediate memory B cells to recapitulate B cell ontogenies associated with the maturation of a broadly neutralizing antibody response. Equally important for vaccine development is the identification of delivery systems, prime-boost strategies, and synergistic adjuvant combinations that can induce the magnitude and quality of antigen-specific T follicular helper (TFH) cell responses needed to drive somatic hypermutation (SHM) and B cell maturation against heterologous primary virus envelopes. Finding the combination of multi-protein envelope immunogens and immunization strategies that can evolve a potent broadly neutralizing antibody response portends to require a complex vaccine regimen that might be difficult to implement on any scale. This perspective strives to integrate recent insights into mechanisms associated with the evolution of an HIV-1 broadly neutralizing antibody response with current immunogen design and proffers a novel immunization strategy for skewing TH17/TFH cell responses that can drive B cell adaptation and affinity maturation associated with a broadly neutralizing antibody response. ... Read more

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