Development and Immunogenicity of a Prototype Multivalent Group B Streptococcus Bioconjugate Vaccine.
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ABSTRACT:
SUBMITTER: Duke JA
PROVIDER: S-EPMC8793035 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pili of Group A Streptococcus (GAS) are surface-exposed structures involved in adhesion and colonisation of the host during infection. The major protein component of the GAS pilus is the T-antigen, which multimerises to form the pilus shaft. There are currently no licenced vaccines against GAS infections and the T-antigen represents an attractive target for vaccination. We have generated a multivalent vaccine called TeeVax1, a recombinant protein that consists of a fusion of six T-antigen domains. Vaccination with TeeVax1 produces opsonophagocytic antibodies in rabbits and confers protective efficacy in mice against invasive disease. Two further recombinant proteins, TeeVax2 and TeeVax3 were constructed to cover 12 additional T-antigens. Combining TeeVax1-3 produced a robust antibody response in rabbits that was cross-reactive to a full panel of 21 T-antigens, expected to provide over 95% vaccine coverage. These results demonstrate the potential for a T-antigen-based vaccine to prevent GAS infections.
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Project description:Shigellosis remains a major cause of diarrheal disease in developing countries and causes substantial morbidity and mortality in children. Vaccination represents a promising preventive measure to fight the burden of the disease, but despite enormous efforts, an efficacious vaccine is not available to date. The use of an innovative biosynthetic Escherichia coli glycosylation system substantially simplifies the production of a multivalent conjugate vaccine to prevent shigellosis. This bioconjugation approach has been used to produce the Shigella dysenteriae type O1 conjugate that has been successfully tested in a phase I clinical study in humans. In this report, we describe a similar approach for the production of an additional serotype required for a broadly protective shigellosis vaccine candidate. The Shigella flexneri 2a O-polysaccharide is conjugated to introduced asparagine residues of the carrier protein exotoxin A (EPA) from Pseudomonas aeruginosa by co-expression with the PglB oligosaccharyltransferase. The bioconjugate was purified, characterized using physicochemical methods and subjected to preclinical evaluation in rats. The bioconjugate elicited functional antibodies as shown by a bactericidal assay for S. flexneri 2a. This study confirms the applicability of bioconjugation for the S. flexneri 2a O-antigen, which provides an intrinsic advantage over chemical conjugates due to the simplicity of a single production step and ease of characterization of the homogenous monomeric conjugate formed. In addition, it shows that bioconjugates are able to raise functional antibodies against the polysaccharide antigen.
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Project description:Streptococcus pyogenes, also known as Group A Streptococcus (GAS), is a Gram-positive human-exclusive pathogen, responsible for more than 500 000 deaths annually worldwide. Upon infection, GAS commonly triggers mild symptoms such as pharyngitis, pyoderma and fever. However, recurrent infections or prolonged exposure to GAS might lead to life-threatening conditions. Necrotizing fasciitis, streptococcal toxic shock syndrome and post-immune mediated diseases, such as poststreptococcal glomerulonephritis, acute rheumatic fever and rheumatic heart disease, contribute to very high mortality rates in non-industrialized countries. Though an initial reduction in GAS infections was observed in high-income countries, global outbreaks of GAS, causing rheumatic fever and acute poststreptococcal glomerulonephritis, have been reported over the last decade. At the same time, our understanding of GAS pathogenesis and transmission has vastly increased, with detailed insight into the various stages of infection, beginning with adhesion, colonization and evasion of the host immune system. Despite deeper knowledge of the impact of GAS on the human body, the development of a successful vaccine for prophylaxis of GAS remains outstanding. In this review, we discuss the challenges involved in identifying a universal GAS vaccine and describe several potential vaccine candidates that we believe warrant pursuit.
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Project description:Group A Streptococcus (Strep A) leads to 600,000 deaths and 600 million cases of pharyngitis annually. Although long a promising target for vaccine development, how much funding should be allocated to develop a Strep A vaccine is unclear. We aim to calculate the optimal amount of global spending for Strep A vaccine development, the resulting benefits, and the social rate of return on this spending. We develop a model of optimal spending, from a global societal perspective, on research and development (R&D) for vaccines and treatments. The model takes as inputs total harm from the disease, the probability an R&D project succeeds, the cost of a project, and the fraction of total harm a success alleviates. Based on these inputs the model outputs an optimal amount of spending and a rate of return. We calibrate the model for Strep A. Optimal spending is estimated to be 2020 USD33 billion. This spending leads to 2020 USD1.63 trillion in benefits and a real return of 22.3% per year for thirty years. Sensitivity shows an optimal spending range of 15.9 billion to 58.5 billion, a benefits range of 1.6 trillion to 37.9 trillion, and a return range of 18.0–48.2%. Investment in a Strep A vaccine could create enormous benefits for comparatively little cost. It represents one of the highest return uses of public spending. Policy can promote Strep A vaccine development through direct funding of projects and by promoting financial mechanisms that allow the private sector to diversify its R&D investment.
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Project description:Extraintestinal pathogenic Escherichia coli (ExPEC) cause a wide range of clinical diseases such as bacteremia and urinary tract infections. The increase of multidrug resistant ExPEC strains is becoming a major concern for the treatment of these infections and E. coli has been identified as a critical priority pathogen by the WHO. Therefore, the development of vaccines has become increasingly important, with the surface lipopolysaccharide constituting a promising vaccine target. This study presents genetic and structural analysis of clinical urine isolates from Switzerland belonging to the serotype O25. Approximately 75% of these isolates were shown to correspond to the substructure O25B only recently described in an emerging clone of E. coli sequence type 131. To address the high occurrence of O25B in clinical isolates, an O25B glycoconjugate vaccine was prepared using an E. coli glycosylation system. The O antigen cluster was integrated into the genome of E. coli W3110, thereby generating an E. coli strain able to synthesize the O25B polysaccharide on a carrier lipid. The polysaccharide was enzymatically conjugated to specific asparagine side chains of the carrier protein exotoxin A (EPA) of Pseudomonas aeruginosa by the PglB oligosaccharyltransferase from Campylobacter jejuni. Detailed characterization of the O25B-EPA conjugate by use of physicochemical methods including NMR and GC-MS confirmed the O25B polysaccharide structure in the conjugate, opening up the possibility to develop a multivalent E. coli conjugate vaccine containing O25B-EPA.
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Project description:Peptide-based vaccine development represents a highly promising strategy for preventing Group A Streptococcus (GAS) infection. However, these vaccines need to be administered with the help of a delivery system and/or immune adjuvant. Cell-penetrating peptides (CPPs) have been used as a powerful tool for delivering various therapeutic agents, including peptides, as they can overcome the permeability barrier of cell membranes. Here, we used CPPs to deliver our lead lipopeptide-based vaccine (LCP-1). CPPs were anchored through a spacer to LCP-1-bearing multilamellar and unilamellar liposomes and administered to Swiss outbred mice. Tat47-57 conjugated to two palmitic acids via a (Gly)6 spacer (to form a liposome-anchoring moiety) was the most efficient system for triggering immune responses when combined with multilamellar liposomes bearing LCP-1. The immunostimulatory potential of a variety of other CPPs was examined following intranasal administration in mice. Among them, LCP-1/liposomes/Tat47-57 and LCP-1/liposomes/KALA induced the highest antibody titers. The antibodies produced showed high opsonic activity against clinically isolated GAS strains D3840 and GC2 203. The use of the CPP-liposome delivery system is a promising strategy for liposome-based GAS vaccine development.
| S-EPMC8151947 | biostudies-literature
Project description:IntroductionThere is a paucity of longitudinal data on the serotype-specific burden of invasive group B Streptococcus (GBS) disease from low-middle income countries, which could inform selection of vaccine epitopes.MethodsFrom 2005 to 2014, infants less than 90 days of age with invasive GBS disease were identified through sentinel laboratory and hospital admission surveillance at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa.ResultsWe identified 820 cases of invasive GBS disease, including 55% among newborns <7 days age (i.e. early-onset disease; EOD). The overall incidence (per 1,000 live births) of invasive GBS disease was 2.59 (95% CI: 2.42-2.77), including 1.41 (95% CI: 1.28-1.55) for EOD and 1.18 (95% CI: 1.06-1.30) in infants 7-89 days age (late-onset disease). Year-on-year, from 2005 to 2014, we observed a 9.4% increase in incidence of serotype Ia invasive disease (RR: 1.09; 95% CI: 1.04-1.15; p<0.001), and a 7.4% decline in serotype III invasive disease (RR: 0.93; 95% CI: 0.90-0.96; p<0.001). Overall, serotypes Ia (28.2%), III (55.4%) and V (7.9%) were the commonest disease causing serotypes.ConclusionsThe incidence of invasive GBS disease has remained persistently high in our setting, with some changes in serotype distribution, albeit mainly involving the same group of dominant serotypes.
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Project description:BackgroundGroup A streptococcus (GAS) is a serious human pathogen that affects people of different ages and socio-economic levels. Although vaccination is potentially one of the most effective methods to control GAS infection and its sequelae, few prototype vaccines have been investigated in humans. In this study, we report the safety and immunogenicity of a novel acetylated peptide-protein conjugate vaccine candidate MJ8VAX (J8-DT), when delivered intramuscularly to healthy adults.MethodsA randomized, double-blinded, controlled Phase I clinical trial was conducted in 10 healthy adult participants. Participants were randomized 4:1 to receive the vaccine candidate (N = 8) or placebo (N = 2). A single dose of the vaccine candidate (MJ8VAX), contained 50 μg of peptide conjugate (J8-DT) adsorbed onto aluminium hydroxide and re-suspended in PBS in a total volume of 0.5 mL. Safety of the vaccine candidate was assessed by monitoring local and systemic adverse reactions following intramuscular administration. The immunogenicity of the vaccine was assessed by measuring the levels of peptide (anti-J8) and toxoid carrier (anti-DT)-specific antibodies in serum samples.ResultsNo serious adverse events were reported over 12 months of study. A total of 13 adverse events (AEs) were recorded, two of which were assessed to be associated with the vaccine. Both were mild in severity. No local reactogenicity was recorded in any of the participants. MJ8VAX was shown to be immunogenic, with increase in vaccine-specific antibodies in the participants who received the vaccine. The maximum level of vaccine-specific antibodies was detected at 28 days post immunization. The level of these antibodies decreased with time during follow-up. Participants who received the vaccine also had a corresponding increase in anti-DT serum antibodies.ConclusionsIntramuscular administration of MJ8VAX was demonstrated to be safe and immunogenic. The presence of DT in the vaccine formulation resulted in a boost in the level of anti-DT antibodies.Trial registrationACTRN12613000030774.
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Project description:Extracellular proteins made by group A Streptococcus (GAS) play critical roles in the pathogenesis of human infections caused by this bacterium. Although many extracellular GAS proteins have been identified and characterized, there has been no systematic analysis of culture supernatant proteins. Proteins present in the culture supernatant of strains of serotype M1 (MGAS 5005) and M3 (MGAS 315) mutants lacking production of the major extracellular cysteine protease were separated by two-dimensional gel electrophoresis and identified by amino-terminal amino acid sequencing and interrogation of available databases, including a serotype M1 genome sequence. In the aggregate, amino-terminal amino acid sequence data for 66 protein spots were generated, 53 unique sequences were obtained, and 44 distinct proteins were identified. Sixteen of the 44 proteins had apparent secretion signal sequences and 27 proteins did not. Eight of the 16 proteins with apparent secretion signal sequences have not been previously described for GAS. Antibodies against most of the apparently secreted proteins were present in sera from mice infected subcutaneously with MGAS 5005 or MGAS 315. Humans with documented GAS infections (pharyngitis, acute rheumatic fever, and severe invasive disease) also had serum antibodies reacting with many of the apparently secreted proteins, indicating that they were synthesized in the course of GAS-human interaction. The genes encoding four of the eight previously undescribed and apparently secreted culture supernatant proteins were cloned, and the proteins were overexpressed in Escherichia coli. Western blot analysis with these recombinant proteins and sera from GAS-infected mice and humans confirmed the immunogenicity of these proteins. Taken together, the data provide new information about the molecular aspects of GAS-host interactions.
| S-EPMC97784 | biostudies-literature
Project description:BackgroundPoultry is the world's most popular animal-based food and global production has tripled in the past 20 years alone. Low-cost vaccines that can be combined to protect poultry against multiple infections are a current global imperative. Glycoconjugate vaccines, which consist of an immunogenic protein covalently coupled to glycan antigens of the targeted pathogen, have a proven track record in human vaccinology, but have yet to be used for livestock due to prohibitively high manufacturing costs. To overcome this, we use Protein Glycan Coupling Technology (PGCT), which enables the production of glycoconjugates in bacterial cells at considerably reduced costs, to generate a candidate glycan-based live vaccine intended to simultaneously protect against Campylobacter jejuni, avian pathogenic Escherichia coli (APEC) and Clostridium perfringens. Campylobacter is the most common cause of food poisoning, whereas colibacillosis and necrotic enteritis are widespread and devastating infectious diseases in poultry.ResultsWe demonstrate the functional transfer of C. jejuni protein glycosylation (pgl) locus into the genome of APEC χ7122 serotype O78:H9. The integration caused mild attenuation of the χ7122 strain following oral inoculation of chickens without impairing its ability to colonise the respiratory tract. We exploit the χ7122 pgl integrant as bacterial vectors delivering a glycoprotein decorated with the C. jejuni heptasaccharide glycan antigen. To this end we engineered χ7122 pgl to express glycosylated NetB toxoid from C. perfringens and tested its ability to reduce caecal colonisation of chickens by C. jejuni and protect against intra-air sac challenge with the homologous APEC strain.ConclusionsWe generated a candidate glycan-based multivalent live vaccine with the potential to induce protection against key avian and zoonotic pathogens (C. jejuni, APEC, C. perfringens). The live vaccine failed to significantly reduce Campylobacter colonisation under the conditions tested but was protective against homologous APEC challenge. Nevertheless, we present a strategy towards the production of low-cost "live-attenuated multivalent vaccine factories" with the ability to express glycoconjugates in poultry.
| S-EPMC8487346 | biostudies-literature