The discovery and development of a novel vaccine to protect against Neisseria meningitidis Serogroup B Disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Zlotnick GW
PROVIDER: S-EPMC4514153 | biostudies-other | 2015
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Neisseria meningitidis serogroup A capsular polysaccharide (MenA CPS) consists of (1 → 6)-2-acetamido-2-deoxy-α-D-mannopyranosyl phosphate repeating units, O-acetylated at position C3 or C4. Glycomimetics appear attractive to overcome the CPS intrinsic lability in physiological media, due to cleavage of the phosphodiester bridge, and to develop a stable vaccine with longer shelf life in liquid formulation. Here, we generate a series of non-acetylated carbaMenA oligomers which are proven more stable than the CPS. An octamer (DP8) inhibits the binding of a MenA specific bactericidal mAb and polyclonal serum to the CPS, and is selected for further in vivo testing. However, its CRM197 conjugate raises murine antibodies towards the non-acetylated CPS backbone, but not the natural acetylated form. Accordingly, random O-acetylation of the DP8 is performed, resulting in a structure (Ac-carbaMenA) showing improved inhibition of anti-MenA CPS antibody binding and, after conjugation to CRM197, eliciting anti-MenA protective murine antibodies, comparably to the vaccine benchmark.
| S-EPMC7477203 | biostudies-literature
Project description: Not available
| S-EPMC2958009 | biostudies-literature
Project description:Neisseria meningitidis is a nasopharyngeal commensal of humans which occasionally invades the blood to cause septicaemia. The transcriptome of N. meningitidis strain MC58 grown in human blood for up to 4 hours was determined and around 10% of the genome was found to be differentially regulated. The nuo, pet and atp operons, involved in energy metabolism, were up-regulated, while many house-keeping genes were down-regulated. Genes encoding protein chaperones and proteases, involved in the stress response; complement resistant genes encoding enzymes for LOS sialylation and biosynthesis; and fHbp (NMB1870) and nspA (NMB0663), encoding vaccine candidates, were all up-regulated. Genes for glutamate uptake and metabolism, and biosynthesis of purine and pyrimidine were also up-regulated. Blood grown meningococci are under stress and undergo a metabolic adaptation and energy conservation strategy. The localisation of four putative outer membrane proteins encoded by genes found to be up-regulated in blood was assessed by FACS using polyclonal mouse antisera, and one (NMB0390) showed evidence of surface expression, supporting its vaccine candidacy.
| S-EPMC3382141 | biostudies-literature
Project description:Serogroup A Neisseria meningitidis has repeatedly caused widespread epidemics of meningitis and septicemia throughout the 20th century. Recently, in a limited collection of strains, epidemic serogroup A isolates were found to have elevated mutation rates that was caused by defects in mismatch repair pathways. To ascertain the role of these mutators in the epidemic spread of this serogroup, the prevalence of hypermutability in a collection of 95 serogroup A N. meningitidis invasive isolates was determined. Overall mutability in Neisseriae can be described by measuring both missense mutation rates as well as phase variation frequencies of "contingency loci." Fifty-seven percent of serogroup A isolates possessed elevated mutability, which could be divided into two classes: intermediate and high level. Eleven of 20 high-level mutators, with phase variation rates >100-fold higher than wild-type isolates, were defective in mismatch repair. Ten of the 34 intermediate mutators possessing >10-fold increases in phase variation rates could be partially complemented by a wild-type mutL allele. A high prevalence of mutators in epidemic isolates indicates that hypermutability may play a major role in the transmission of this pathogen. The added diversity derived from increased phase variation rates may allow fixation of mutator alleles more frequently during epidemic spread.
| S-EPMC122909 | biostudies-literature
Project description:Sepsis and meningitis caused by Neisseria meningitidis serogroup B (NMGB) are serious diseases in infants and young adults, but no effective vaccine is available. The capsular polysaccharide (PS) of NMGB has poor immunogenicity and a structural similarity to polysialic acid (PSA) on neuronal tissue that may elicit autoantibodies. Using HmenB3, a protective and nonautoreactive monoclonal antibody (MAb) to NMGB capsular PS, we produced an anti-idiotypic MAb, Naid60, which mimics the capsular PS of NMGB. We produced an anti-anti-idiotypic MAb, MoB34, by using the immunogenic site on Naid60 responsible for inducing the anti-NMGB PS antibody response. MoB34 elicited the complement-mediated killing of representative strains of serogroup B meningococci. MoB34 did not bind to CHP-134, a neuroblastoma cell line expressing alpha(2-8) PSA, or to mouse brain cryosections at a high concentration. Naid60-keyhole limpet hemocyanin immunization inhibited the growth of live NMGB in intraperitoneally challenged mice; in contrast, three of five control mice developed bacteremia. Thus, Naid60 has an immunogenic site that elicits antibodies with bactericidal activity against NMGB and no autoimmunity to PSA. We suggest that the immunogenic region of Naid60 is a candidate for the development of a new vaccine against NMGB.
| S-EPMC1230893 | biostudies-literature
Project description:Invasive meningococcal disease (IMD) is a major public health concern because of its high case fatality, long-term morbidity, and potential to course with outbreaks. IMD caused by Nesseira meningitidis serogroup B has been predominant in different regions of the world like Europe and only recently broadly protective vaccines against B serogroup have become available. Two protein-based vaccines, namely 4CMenB (Bexsero®) and rLP2086 (Trumenba®) are currently licensed for use in different countries against MenB disease. These vaccines came from a novel technology on vaccine design (or antigen selection) using highly specific antigen targets identified through whole-genome sequence analysis. Moreover, it has the potential to confer protection against non-B meningococcus and against other Neisserial species such as gonococcus. Real-world data on the vaccine-use are rapidly accumulating from the UK and other countries which used the vaccine for control of outbreak or as part of routine immunization program, reiterating its safety and efficacy. Additional data on real-life effectiveness, long-term immunity, and eventual herd effects, including estimates on vaccine impact for cost-effectiveness assessment are further needed. Given the predominance of MenB in Europe and other parts of the world, these new vaccines are crucial for the prevention and public health control of the disease, and should be considered.
| S-EPMC6793463 | biostudies-literature
Project description:A bivalent factor H binding protein (fHBP) vaccine for the prevention of disease caused by Neisseria meningitidis serogroup B is currently in clinical development. Since fHBP is also expressed by other meningococcal serogroups, anti-fHBP antibodies may have bactericidal activity against meningococci independent of serogroup. To begin examining the susceptibility of other meningococcal serogroups to anti-fHBP antibodies, meningococcal serogroup C invasive isolates (n = 116) were collected from the Centers for Disease Control and Prevention's Active Bacterial Core surveillance (ABCs) sites during 2000-2001. These isolates were analyzed for the presence of the fhbp gene. All serogroup C isolates contained the gene, and sequence analysis grouped the proteins into two subfamilies, A and B. Flow cytometry analysis demonstrated that fHBP was expressed on the surface of ~70% of isolates in vitro with varying levels of expression. fHBP was accessible to antibodies on the cell surface even in the presence of the polysaccharide capsule. Nine isolates from different geographic regions were identified which harboured an identical single nucleotide deletion that could result in a truncated subfamily B fHBP. Analysis by flow cytometry using a polyclonal fHBP antibody preparation revealed that a subpopulation of each of these isolates expressed fHBP. Rabbit and non-human primate immune sera generated with bivalent fHBP vaccine were tested for bactericidal activity against a panel of diverse serogroup C clinical isolates using human complement. Sera from both species demonstrated serum bactericidal antibody activity against the serogroup C isolates tested. These promising findings suggest that a bivalent fHBP vaccine may be capable of providing protection against meningococcal disease caused by both serogroup C and B.
| S-EPMC3367671 | biostudies-literature
Project description:During February 2011-June 2012, invasive infection with Neisseria meningitidis serogroup W was identified in 11 persons in southeastern China. All isolates tested had matching or near-matching pulsed-field gel electrophoresis patterns and belonged to multilocus sequence type 11. The epidemiologic investigation suggested recent transmission of this clonal complex in southeastern China.
| S-EPMC3810921 | biostudies-literature
Project description:We evaluated two formulations of a new combined Haemophilus influenzae type b (Hib)-meningococcal serogroup C (MenC)-tetanus toxoid (TT) conjugated vaccine and two formulations of a new MenC-TT vaccine (trials 711202/001 and 711202/008; clinical trial register numbers NCT00135486 and NCT00135564 [www.ClinicalTrials.gov]). A total of 520 healthy infants were randomized to receive primary vaccination (at 2, 3, and 4 months) with either MenC-TT plus diphtheria-tetanus-acellular pertussis (DTPa)-hepatitis B virus (HBV)-inactivated poliovirus (IPV)/Hib, Hib-MenC-TT plus DTPa-HBV-IPV, or MenC-CRM(197) plus DTPa-HBV-IPV/Hib (control). At 12 to 15 months, subjects received a polysaccharide challenge with meningococcal polysaccharide C plus a DTPa-HBV-IPV/Hib booster. Immune responses were assessed 1 month after dose 2, 1 month after dose 3, and prior to and 1 month after the booster. After primary vaccination, there was no difference between groups in seroprotection rates as measured by titers of serum bactericidal antibody (SBA) to MenC (> or = 1:8) or concentrations of anti-polyribosyl ribitol phosphate (PRP) antibody (> or = 0.15 microg/ml). Prior to the booster, there was no difference between groups in SBA seroprotection rates, whereas anti-PRP seroprotection rates were significantly higher after priming with Hib-MenC-TT. Booster doses induced large increases in SBA and anti-PRP antibodies in primed groups, indicating successful priming with induction of immune memory. Reactogenicity and safety were similar in all groups during the primary and booster phases. A novel combined Hib-MenC-TT conjugate vaccine induced MenC and Hib responses comparable to those induced by licensed monovalent vaccines. A Hib-MenC-TT conjugate vaccine provides vaccination against two major pathogens in a single injection and is a suitable candidate for use in primary or booster vaccination schedules.
| S-EPMC1865605 | biostudies-literature
Project description:Neisseria meningitidis is a human pathogen, which, in spite of antibiotic therapy, is still a major cause of mortality due to sepsis and meningitis. Here we describe NadA, a novel surface antigen of N. meningitidis that is present in 52 out of 53 strains of hypervirulent lineages electrophoretic types (ET) ET37, ET5, and cluster A4. The gene is absent in the hypervirulent lineage III, in N. gonorrhoeae and in the commensal species N. lactamica and N. cinerea. The guanine/cytosine content, lower than the chromosome, suggests acquisition by horizontal gene transfer and subsequent limited evolution to generate three well-conserved alleles. NadA has a predicted molecular structure strikingly similar to a novel class of adhesins (YadA and UspA2), forms high molecular weight oligomers, and binds to epithelial cells in vitro supporting the hypothesis that NadA is important for host cell interaction. NadA induces strong bactericidal antibodies and is protective in the infant rat model suggesting that this protein may represent a novel antigen for a vaccine able to control meningococcal disease caused by three hypervirulent lineages.
| S-EPMC2193550 | biostudies-literature