RESUMO
Antimicrobial resistance (AMR) is one of the most critical threats to global public health in the 21st century, causing a large number of deaths every year in both high-income and low- and middle-income countries. Vaccines and monoclonal antibodies can be exploited to prevent and treat diseases caused by AMR pathogens, thereby reducing antibiotic use and decreasing selective pressure that favors the emergence of resistant strains. Here, differences in the mechanism of action and resistance of vaccines and monoclonal antibodies compared to antibiotics are discussed. The state of the art for vaccine technologies and monoclonal antibodies are reviewed, with a particular focus on approaches validated in clinical studies. By underscoring the scope and limitations of the different emerging technologies, this review points out the complementary of vaccines and monoclonal antibodies in fighting AMR. Gaps in antigen discovery for some pathogens, as well as challenges associated with the clinical development of these therapies against AMR pathogens, are highlighted.
Assuntos
Antibacterianos , Anticorpos Monoclonais , Humanos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Animais , Farmacorresistência Bacteriana/imunologia , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/uso terapêutico , Infecções Bacterianas/imunologia , Infecções Bacterianas/tratamento farmacológicoRESUMO
Tularemia is caused by subspecies of Francisella tularensis and can manifest in a variety of disease states, with the pneumonic presentation resulting in the greatest mortality. Despite decades of research, there are no approved vaccines against F. tularensis in the United States. Traditional vaccination strategies, such as live-attenuated or subunit vaccines, are not favorable due to inadequate protection or safety concerns. Because of this, novel vaccination strategies are needed to combat tularemia. Here we discuss the current state of and challenges to the tularemia vaccine field and suggest novel vaccine approaches going forward that might be better suited for protecting against F. tularensis infection.
Assuntos
Francisella tularensis , Tularemia , Humanos , Tularemia/prevenção & controle , Vacinas Bacterianas/uso terapêutico , Vacinas Atenuadas , VacinaçãoRESUMO
Syphilis is a sexually or vertically (mother to fetus) transmitted disease caused by the infection of Treponema pallidum subspecie pallidum (TPA). The incidence of syphilis has increased over the past years despite the fact that this bacterium is an obligate human pathogen, the infection route is well known, and the disease can be successfully treated with penicillin. As complementary measures to preventive campaigns and early treatment of infected individuals, development of a syphilis vaccine may be crucial for controlling disease spread and/or severity, particularly in countries where the effectiveness of the aforementioned measures is limited. In the last century, several vaccine prototypes have been tested in preclinical studies, mainly in rabbits. While none of them provided protection against infection, some prototypes prevented bacteria from disseminating to distal organs, attenuated lesion development, and accelerated their healing. In spite of these promising results, there is still some controversy regarding the identification of vaccine candidates and the characteristics of a syphilis-protective immune response. In this review, we describe what is known about TPA immune response, and the main mechanisms used by this pathogen to evade it. Moreover, we emphasize the importance of integrating this knowledge, in conjunction with the characterization of outer membrane proteins (OMPs), to expedite the development of a syphilis vaccine that can protect against TPA infection.
Assuntos
Sífilis , Animais , Humanos , Coelhos , Sífilis/epidemiologia , Sífilis/prevenção & controle , Treponema pallidum , Imunidade , Vacinas Bacterianas/uso terapêuticoRESUMO
The gram-negative bacterium Helicobacter pylori is the most common chronic bacterial infection and the main cause of gastric cancer. Due to the increasing antimicrobial resistance of H. pylori, the development of an efficacious vaccine is a valid option to protect from disease or infection and ultimately prevent gastric cancer. However, despite more than 30 years of research, no vaccine has entered the market yet. This review highlights the most relevant previous preclinical and clinical studies to allow conclusions to be drawn on which parameters need special attention in the future to develop an efficacious vaccine against H. pylori and thus prevent gastric cancer.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/prevenção & controle , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/microbiologia , Vacinas Bacterianas/uso terapêutico , Infecções por Helicobacter/complicações , Infecções por Helicobacter/prevenção & controle , VacinaçãoRESUMO
Vaccines can be highly effective tools in combating antimicrobial resistance as they reduce infections caused by antibiotic-resistant bacteria and antibiotic consumption associated with disease. This Review looks at vaccine candidates that are in development against pathogens on the 2017 WHO bacterial priority pathogen list, in addition to Clostridioides difficile and Mycobacterium tuberculosis. There were 94 active preclinical vaccine candidates and 61 active development vaccine candidates. We classified the included pathogens into the following four groups: Group A consists of pathogens for which vaccines already exist-ie, Salmonella enterica serotype Typhi, Streptococcus pneumoniae, Haemophilus influenzae type b, and M tuberculosis. Group B consists of pathogens with vaccines in advanced clinical development-ie, extra-intestinal pathogenic Escherichia coli, Salmonella enterica serotype Paratyphi A, Neisseria gonorrhoeae, and C difficile. Group C consists of pathogens with vaccines in early phases of clinical development-ie, enterotoxigenic E coli, Klebsiella pneumoniae, non-typhoidal Salmonella, Shigella spp, and Campylobacter spp. Finally, group D includes pathogens with either no candidates in clinical development or low development feasibility-ie, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Helicobacter pylori, Enterococcus faecium, and Enterobacter spp. Vaccines are already important tools in reducing antimicrobial resistance and future development will provide further opportunities to optimise the use of vaccines against resistance.
Assuntos
Antibacterianos , Enterococcus faecium , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Vacinas Bacterianas/uso terapêutico , Escherichia coli , Farmacorresistência BacterianaRESUMO
Background: Orally or sublingually administered lysates of mixed respiratory pathogenic bacteria have been used in Europe, Asia, and other parts of the world, but not the United States, since the mid 1950s, first to prevent recurrent respiratory tract infections, later to prevent wheezing and asthma exacerbations associated with respiratory infections, and, more recently, for the treatment of allergic rhinitis. The apparent success of this treatment contrasts with the negative experience of treating with injections of similar mixed respiratory bacterial vaccines (MRBV or BV) to prevent asthma exacerbations associated with respiratory infections that was once common practice but abandoned â¼50 years ago. Methods: Textbooks and articles on the use of injected BVs to prevent asthma exacerbations associated with respiratory infections were reviewed, including a number of, randomized, double-blind, placebo controlled (RDBPC) studies the results of which were predominantly negative that contributed to the abandonment of this treatment. Also reviewed were more recent articles from Europe and China, which report both clinical and immunologic support for the use of the orally and sublingually administered mixed respiratory bacterial lysates (MRBL or BL). Results: A review of five RDBPC studies of the parenteral use of BVs for prevention of asthma exacerbations conducted by leading international allergists in the 1950s and 1960s showed, in a combined 532 patients, an overall reduction of asthma attacks by 4.9% over placebo. However, in five studies in 1126 patients of oral or sublingual treatment with BLs, the reduction in respiratory infections, wheezing episodes, and asthma exacerbations was 42.6% over placebo. Conclusion: Reported results with oral and sublingual BLs are far superior to the historical performance of injected BVs. Possible reasons for this difference are discussed, but none is clearly responsible for the difference in clinical results.
Assuntos
Asma , Infecções Respiratórias , Rinite Alérgica , Humanos , Sons Respiratórios , Asma/tratamento farmacológico , Infecções Respiratórias/prevenção & controle , Vacinas Bacterianas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
PURPOSE OF REVIEW: To discuss recently discovered mechanisms of action of some bacterial vaccines that may account for their clinical benefit in the prevention of recurrent wheezing and asthma exacerbations in infants and early childhood. RECENT FINDINGS: Trained immunity has been shown to confer innate immune cells with a quite long-term nonspecific protection against a broad spectrum of pathogens. Inducers of trained immunity include some bacterial vaccines. Trained immunity-based vaccines (TIbV) of bacterial origin have the capability to induce nonspecific responses to a variety of pathogens, including respiratory viruses, in addition to their nominal bacterial antigens. Clinical data, from epidemiological surveys to well designed randomized clinical trials, indicate that TIbV formulated with bacteria prevent respiratory tract infections of viral cause, such as those associated with recurrent wheezing or asthma exacerbation, in children. Administration of these vaccines by the mucosal route may be important for their outcome in respiratory infections. SUMMARY: Mucosal bacterial immunotherapy, including certain TIbV, confer protection against a broad spectrum of pathogens, such as viruses, through a mechanism mediated by trained immunity. Clinical studies on the use of these preparations against recurrent wheezing reflect these mechanistic effects. These findings open a new avenue for the development of new strategies for this condition.
Assuntos
Asma , Infecções Respiratórias , Criança , Lactente , Pré-Escolar , Humanos , Sons Respiratórios , Adjuvantes de Vacinas , Infecções Respiratórias/prevenção & controle , Infecções Respiratórias/tratamento farmacológico , Bactérias , Vacinas Bacterianas/uso terapêuticoRESUMO
The bacterial genus Bartonella comprises numerous emerging pathogens that cause a broad spectrum of disease manifestations in humans. The targets and mechanisms of the anti-Bartonella immune defense are ill-defined and bacterial immune evasion strategies remain elusive. We found that experimentally infected mice resolved Bartonella infection by mounting antibody responses that neutralized the bacteria, preventing their attachment to erythrocytes and suppressing bacteremia independent of complement or Fc receptors. Bartonella-neutralizing antibody responses were rapidly induced and depended on CD40 signaling but not on affinity maturation. We cloned neutralizing monoclonal antibodies (mAbs) and by mass spectrometry identified the bacterial autotransporter CFA (CAMP-like factor autotransporter) as a neutralizing antibody target. Vaccination against CFA suppressed Bartonella bacteremia, validating CFA as a protective antigen. We mapped Bartonella-neutralizing mAb binding to a domain in CFA that we found is hypervariable in both human and mouse pathogenic strains, indicating mutational antibody evasion at the Bartonella subspecies level. These insights into Bartonella immunity and immune evasion provide a conceptual framework for vaccine development, identifying important challenges in this endeavor.
Assuntos
Anticorpos Neutralizantes , Antígenos de Bactérias , Bacteriemia , Infecções por Bartonella , Bartonella , Sistemas de Secreção Tipo V , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Bacteriemia/imunologia , Bacteriemia/microbiologia , Bacteriemia/prevenção & controle , Vacinas Bacterianas/genética , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/uso terapêutico , Bartonella/genética , Bartonella/imunologia , Infecções por Bartonella/imunologia , Infecções por Bartonella/microbiologia , Infecções por Bartonella/prevenção & controle , Clonagem Molecular , Evasão da Resposta Imune , Camundongos , Sistemas de Secreção Tipo V/imunologia , VacinaçãoRESUMO
INTRODUCTION: Recurrent urinary tract infections (rUTIs) affect 5-10% of women, resulting in an enormous healthcare and society burden. Uromune® is a polybacterial sublingual vaccine with an excellent clinical benefit in rUTI prophylaxis. This study assesses the impact of sublingual vaccination on healthcare resource use and expenditures associated with this pathology. METHODS: A quasi-experimental, pretest-posttest, single center study including women with rUTI and vaccinated with Uromune® in real-life clinical practice was performed. Variables were the need of healthcare resources, collected prospectively during two follow-up years, and the rUTI-associated expenditure, calculated using the micro-costing methodology; these were compared before and after vaccination. RESULTS: A total of 166 women {mean (standard deviation [SD]) urinary tract infection episodes/year 6.19 (2.15)} were included. After vaccination, annual consultations with a primary care physician (PCP) (43.9%), emergency room visits (71.8%), urinary analysis (90.0%), and ultrasound exams (35.6%) decreased compared to pre-vaccination (all p < 0.001). Per patient consumption in antibiotics, PCP consultations, emergency room visits, and complementary exams significantly decreased (all p < 0.02), resulting in a reduction in healthcare expenditure per patient/year from mean (SD) 1,001.1 (655.0) to 497.1 (444.4) EUR. CONCLUSION: Sublingual bacterial vaccination with Uromune® decreased healthcare resource use and associated expenditure in women with rUTI, representing an optimal strategy to reduce rUTI-associated healthcare and economic burden.
Assuntos
Infecções Urinárias , Antibacterianos/uso terapêutico , Vacinas Bacterianas/uso terapêutico , Análise Custo-Benefício , Feminino , Humanos , Recidiva , Infecções Urinárias/tratamento farmacológicoRESUMO
The clinical symptoms of shigellosis, a gastrointestinal infection caused by Shigella spp. range from watery diarrhea to fulminant dysentery. Endemic infections, particularly among children in developing countries, represent the majority of clinical cases. The situation is aggravated due to the high mortality rate of shigellosis, the rapid dissemination of multi-resistant Shigella strains and the induction of only serotype-specific immunity. Thus, infection prevention due to vaccination, encompassing as many of the circulating serotypes as possible, has become a topic of interest. However, vaccines have turned out to be ineffective so far. Outer membrane vesicles (OMVs) are promising novel targets for vaccination. OMVs are constitutively secreted by Gram-negative bacteria including Shigella during growth. They are composed of soluble luminal portions and an insoluble membrane and can contain toxins, bioactive periplasmic and cytoplasmic (lipo-) proteins, (phospho-) lipids, nucleic acids and/or lipopolysaccharides. Thus, OMVs play an important role in bacterial cell-cell communication, growth, survival and pathogenesis. Furthermore, they modulate the secretion and transport of biomolecules, the stress response, antibiotic resistance and immune responses of the host. Thus, OMVs serve as novel secretion machinery. Here, we discuss the current literature and highlight the properties of OMVs as potent vaccine candidates because of their immunomodulatory, antigenic and adjuvant properties.
Assuntos
Proteínas da Membrana Bacteriana Externa/imunologia , Vacinas Bacterianas/uso terapêutico , Disenteria Bacilar/prevenção & controle , Shigella/crescimento & desenvolvimento , Animais , Vacinas Bacterianas/farmacologia , Modelos Animais de Doenças , Desenvolvimento de Medicamentos , Disenteria Bacilar/imunologia , Humanos , Viabilidade Microbiana/efeitos dos fármacos , Shigella/efeitos dos fármacos , Shigella/metabolismo , VacinaçãoRESUMO
BACKGROUND: This field trial was designed to evaluate the efficacy of a new trivalent vaccine containing porcine circovirus type 2a and 2b (PCV2a/b), and Mycoplasma hyopneumoniae at three independent locations. METHODS: Three farms were selected based on their history of PCV2 and M. hyopneumoniae co-infection. Each farm housed a total of 60, 3-day-old pigs that were randomly allocated to one of three treatment groups. Pigs were administered the trivalent vaccine intramuscularly with either a 1.0 ml dose at 3 and 24 days of age or a 2.0 ml dose at 21 days of age in accordance with the manufacturer's recommendations. RESULTS: Clinically, the average daily weight gain of the one-dose and two-dose vaccinated groups within all three farms was significantly higher (p < 0.05) than those of unvaccinated animals during the growing (70-112 days of age), finishing (112-175 days of age) and overall (3-175 days of age) stages of production. One-dose and two-dose vaccinated animals elicited neutralizing antibodies and interferon-γ-secreting cells (IFN-γ-SC), which reduced the amount of PCV2 in terms of blood load and reduced the severity of lymphoid lesions when compared with unvaccinated animals. Similarly, one-dose and two-dose vaccinated animals elicited IFN-γ-SC, which reduced the amount of M. hyopneumoniae in terms of laryngeal load and reduced the severity of lung lesions. CONCLUSIONS: The intramuscular administration of either one or two doses of trivalent vaccine was not significantly different in any of the evaluated parameters. The results of field trial demonstrated that the trivalent vaccine was efficacious in the protection of swine herds where PCV2d and M. hyopneumoniae were in active circulation.
Assuntos
Infecções por Circoviridae , Circovirus , Mycoplasma hyopneumoniae , Doenças dos Suínos , Vacinas Virais , Animais , Vacinas Bacterianas/uso terapêutico , Infecções por Circoviridae/prevenção & controle , Infecções por Circoviridae/veterinária , Interferon gama , Suínos , Doenças dos Suínos/prevenção & controleRESUMO
Trichinellosis is a foodborne zoonosis caused by Trichinella spiralis (T. spiralis) that not only causes considerable economic losses for the global pig breeding and food industries, but also seriously threats the health of human. Therefore, it is very necessary to develop an effective vaccine to prevent trichinellosis. In this study, the invasive Lactobacillus plantarum (L. plantarum) expressing fibronectin-binding protein A (FnBPA) was served as a live bacterial vector to deliver DNA to the host to produce a novel oral DNA vaccine. Co-expressing T. spiralis SS1 and murine interleukin-4 (mIL-4) of DNA vaccine were constructed and subsequently delivered to intestinal epithelial cells via invasive L. plantarum. At 10 days after the third immunization, the experimental mice were challenged with 350 T. spiralis infective larvae. The results found that the mice orally vaccinated with invasive L. plantarum harboring pValac-SS1/pSIP409-FnBPA not only stimulated the production of anti-SS1-specific IgG, Th1/Th2 cell cytokines, and secreted(s) IgA but also decreased worm burden and intestinal damage. However, the mice inoculated with invasive L. plantarum co-expressing SS1 and mIL-4 (pValac-SS1-IL-4/pSIP409-FnBPA) induced the highest protective immune response against T. spiralis infection. The DNA vaccine delivered by invasive L. plantarum provides a novel idea for the prevention of T. spiralis infection.
Assuntos
Vacinas Bacterianas/uso terapêutico , Endodesoxirribonucleases/genética , Proteínas de Helminto/genética , Interleucina-4/genética , Lactobacillus plantarum/imunologia , Vacinas Baseadas em Ácido Nucleico/uso terapêutico , Trichinella spiralis/imunologia , Triquinelose/prevenção & controle , Administração Oral , Animais , Western Blotting , Endodesoxirribonucleases/imunologia , Imunofluorescência , Proteínas de Helminto/imunologia , Interleucina-4/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Triquinelose/imunologia , Vacinas Sintéticas/uso terapêuticoRESUMO
PURPOSE: To assess the efficacy of prophylaxis for urinary tract infections (UTI) in a two-year follow-up in women with StroVac compared to a therapy with Nitrofurantoin over three months. MATERIALS AND METHODS: All patients with documented recurrent urinary tract infections (rUTI) were offered vaccination with StroVac or therapy with three months Nitrofurantoin 100 mg once daily for three months at patient's choice. Only patients with a follow-up of at least 24 months were included. All episodes with signs of UTI were documented and urine culture was performed. Success was defined as one or none UTI per 12 months, documented by urine culture. StroVac booster injection was offered 12 months after primary vaccination at patient's choice. RESULTS: 173 patients were included in this study, 124 in the StroVac group, 49 chose Nitrofuratoin. In the first 12 months, 86.8% of patients in the StroVac group and 91.8% in Nitrofurantoin group were successful (p = 0.22). Side effects were noted in 2.3% in the StroVac group causing discontinuation of therapy, whereas in the Nitrofurantoin group 18.4% stopped medication premature, mostly due to mild diarrhoea. In the second year 79.3% of patients in the StroVac group were still successful, most of them had undergone booster injection. In contrast, in the Nitrofurantoin group only 59.2% of patients were still successful (p = 0.03). CONCLUSION: StroVac is an effective and lasting non-antibiotic prophylaxis for rUTI, easy to administer with low rates of adverse events and should be offered to patients with rUTI.
Assuntos
Anti-Infecciosos Urinários/uso terapêutico , Vacinas Bacterianas/uso terapêutico , Nitrofurantoína/uso terapêutico , Infecções Urinárias/prevenção & controle , Adulto , Idoso , Vacinas Bacterianas/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , RecidivaRESUMO
BACKGROUND: As part of the global Invasive Bacterial Vaccine-Preventable Diseases Surveillance Network, 12 African countries referred cerebrospinal fluid (CSF) samples to South Africa's regional reference laboratory. We evaluated the utility of real-time polymerase chain reaction (PCR) in detecting and serotyping/grouping Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae (HNS). METHODS: From 2008 to 2017, CSF samples collected from children <5 years old with suspected meningitis underwent routine microbiology testing in-country, and 11 680 samples were submitted for HNS PCR at the regional reference laboratory. Unconditional logistic regression, with adjustment for geographic location, was performed to identify factors associated with PCR positivity. RESULTS: The overall HNS PCR positivity rate for all countries was 10% (1195 of 11 626 samples). In samples with both PCR and culture results, HNS PCR positivity was 11% (744 of 6747 samples), and HNS culture positivity was 3% (207 of 6747). Molecular serotype/serogroup was assigned in 75% of PCR-positive specimens (762 of 1016). Compared with PCR-negative CSF samples, PCR-positive samples were more often turbid (adjusted odds ratio, 6.80; 95% confidence interval, 5.67-8.17) and xanthochromic (1.72; 1.29-2.28), had elevated white blood cell counts (6.13; 4.71-7.99) and high protein concentrations (5.80; 4.34-7.75), and were more often HNS culture positive (32.70; 23.18-46.12). CONCLUSION: PCR increased detection of vaccine-preventable bacterial meningitis in countries where confirmation of suspected meningitis cases is impeded by limited culture capacity.
Assuntos
Haemophilus influenzae/genética , Meningites Bacterianas/diagnóstico , Neisseria meningitidis/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Streptococcus pneumoniae/genética , África Oriental/epidemiologia , África Austral/epidemiologia , Vacinas Bacterianas/uso terapêutico , Pré-Escolar , Feminino , Haemophilus influenzae/isolamento & purificação , Humanos , Lactente , Recém-Nascido , Masculino , Meningites Bacterianas/epidemiologia , Meningites Bacterianas/genética , Técnicas de Diagnóstico Molecular , Neisseria meningitidis/isolamento & purificação , Vigilância em Saúde Pública , Streptococcus pneumoniae/isolamento & purificaçãoRESUMO
Background: Vaccination is one of the most effective public health interventions. We investigate the impact of vaccination activities for Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae, and yellow fever over the years 2000-2030 across 112 countries. Methods: Twenty-one mathematical models estimated disease burden using standardised demographic and immunisation data. Impact was attributed to the year of vaccination through vaccine-activity-stratified impact ratios. Results: We estimate 97 (95%CrI[80, 120]) million deaths would be averted due to vaccination activities over 2000-2030, with 50 (95%CrI[41, 62]) million deaths averted by activities between 2000 and 2019. For children under-5 born between 2000 and 2030, we estimate 52 (95%CrI[41, 69]) million more deaths would occur over their lifetimes without vaccination against these diseases. Conclusions: This study represents the largest assessment of vaccine impact before COVID-19-related disruptions and provides motivation for sustaining and improving global vaccination coverage in the future. Funding: VIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill and Melinda Gates Foundation (BMGF) (BMGF grant number: OPP1157270 / INV-009125). Funding from Gavi is channelled via VIMC to the Consortium's modelling groups (VIMC-funded institutions represented in this paper: Imperial College London, London School of Hygiene and Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Métiers, Emory University, National University of Singapore). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: TBH, MJ, XL, SE-L, JT, KW, NMF, KAMG); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). We also acknowledge funding from the UK Medical Research Council and Department for International Development, which supported aspects of VIMC's work (MRC grant number: MR/R015600/1).JHH acknowledges funding from National Science Foundation Graduate Research Fellowship; Richard and Peggy Notebaert Premier Fellowship from the University of Notre Dame. BAL acknowledges funding from NIH/NIGMS (grant number R01 GM124280) and NIH/NIAID (grant number R01 AI112970). The Lives Saved Tool (LiST) receives funding support from the Bill and Melinda Gates Foundation.This paper was compiled by all coauthors, including two coauthors from Gavi. Other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Assuntos
Infecções Bacterianas/prevenção & controle , Vacinas Bacterianas/uso terapêutico , COVID-19 , Saúde Global , Modelos Biológicos , SARS-CoV-2 , Infecções Bacterianas/epidemiologia , HumanosRESUMO
Clostridium difficile is a spore-forming gram-positive bacterium, recognized as the primary cause of antibiotic-associated nosocomial diarrhoea. Clostridium difficile infection (CDI) has emerged as a major health-associated infection with increased incidence and hospitalization over the years with high mortality rates. Contamination and infection occur after ingestion of vegetative spores, which germinate in the gastro-intestinal tract. The surface layer protein and flagellar proteins are responsible for the bacterial colonization while the spore coat protein, is associated with spore colonization. Both these factors are the main concern of the recurrence of CDI in hospitalized patients. In this study, the CotE, SlpA and FliC proteins are chosen to form a multivalent, multi-epitopic, chimeric vaccine candidate using the immunoinformatics approach. The overall reliability of the candidate vaccine was validated in silico and the molecular dynamics simulation verified the stability of the vaccine designed. Docking studies showed stable vaccine interactions with Toll-Like Receptors of innate immune cells and MHC receptors. In silico codon optimization of the vaccine and its insertion in the cloning vector indicates a competent expression of the modelled vaccine in E. coli expression system. An in silico immune simulation system evaluated the effectiveness of the candidate vaccine to trigger a protective immune response.
Assuntos
Vacinas Bacterianas/imunologia , Vacinas Bacterianas/uso terapêutico , Clostridioides difficile/imunologia , Clostridioides difficile/patogenicidade , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/imunologia , Biologia Computacional/métodos , Escherichia coli/metabolismo , HumanosRESUMO
Drug resistance of Klebsiella pneumoniae severely threatens human health. Overcoming the mechanisms of K. pneumoniae resistance to develop novel vaccines against drug-resistant K. pneumoniae is highly desired. Here, we report a technology platform that uses high pressure to drive drug-resistant K. pneumoniae to pass through a gap, inducing the formation of stable artificial bacterial biomimetic vesicles (BBVs). These BBVs had little to no bacterial intracellular protein or nucleic acid and had high yields. BBVs were efficiently taken up by dendritic cells to stimulate their maturation. BBVs as K. pneumoniae vaccines had the dual functions of inducing bacteria-specific humoral and cellular immune responses to increase animals' survival rate and reduce pulmonary inflammation and bacterial loads. We believe that BBVs are new-generation technology for bacterial vesicle preparation. Establishment of this BBV vaccine platform can maximally expand preparation technology for vaccines against drug-resistant K. pneumoniae.
Assuntos
Vacinas Bacterianas/uso terapêutico , Materiais Biomiméticos/uso terapêutico , Vesículas Extracelulares/imunologia , Infecções por Klebsiella/terapia , Klebsiella pneumoniae/imunologia , Animais , Vacinas Bacterianas/síntese química , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/toxicidade , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/toxicidade , Fracionamento Celular/métodos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Feminino , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Klebsiella pneumoniae/química , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , PressãoRESUMO
Bacterial secretory systems are essential for virulence in human pathogens. The systems have become a target of alternative antibacterial strategies based on small molecules and antibodies. Strategies to use components of the systems to design prophylactics have been less publicized despite vaccines being the preferred solution to dealing with bacterial infections. In the current review, strategies to design vaccines against selected pathogens are presented and connected to the biology of the system. The examples are given for Y. pestis, S. enterica, B. anthracis, S. flexneri, and other human pathogens, and discussed in terms of effectiveness and long-term protection.