ZnuD, a Potential Candidate for a Simple and Universal Neisseria meningitidis Vaccine

Abstract

c Neisseria meningitidis serogroup B (MenB) is a major cause of bacterial sepsis and meningitis, with the highest disease burden in young children. Available vaccines are based on outer membrane vesicles (OMVs) obtained from wild-type strains. However, particularly in toddlers and infants, they confer protection mostly against strains expressing the homologous protein PorA, a major and variable outer membrane protein. In the quest for alternative vaccine antigens able to provide broad MenB strain coverage in younger populations, but potentially also across all age groups, ZnuD, a protein expressed under zinc-limiting conditions, may be considered a promising candidate. Here, we have investigated the potential value of ZnuD and show that it is a conserved antigen expressed by all MenB strains tested except for some strains of clonal complex ST-8. In mice and guinea pigs immunized with ZnuD-expressing OMVs, antibodies were elicited that were able to trigger complement-mediated killing of all the MenB strains and serogroup A, C, and Y strains tested when grown under conditions of zinc limitation. ZnuD is also expressed during infection, since anti-ZnuD antibodies were detected in sera from patients. In conclusion, we confirm the potential of ZnuD-bearing OMVs as a component of an effective MenB vaccine.

Zinc Piracy as a Mechanism of Neisseria meningitidis for Evasion of Nutritional Immunity

“…In addition, these studies might reveal new strategies to combat these pathogens. We have recently demonstrated that ZnuD is an excellent candidate for the development of a broadly cross-protective vaccine against N. meningitidis [10], [40]. Here, we demonstrated that the CbpA protein was produced in all meningococcal strains examined indicating that its expression, unlike that of many other surface-exposed proteins of N. meningitidis , is not prone to phase variation.…”

Metal homeostasis and resistance in bacteria

“…These recent insights have suggested new vaccine strategies that target metal transport systems. For example, the outer membrane Zn(II) uptake transporter ZnuD in Neisseria meningitidis 144 and the Mn(II) uptake systems MntC in S. aureus 145 and PsaA in S. pneumoniae 146 were both identified as potential vaccine targets. To develop new and effective antimicrobial therapies, it will be crucial to better understand how bacteria manage metal homeostasis and to identify the mechanisms and timing of metal sequestration and intoxication by the host.…”

Antigenic Potential of a Highly Conserved Neisseria meningitidis Lipopolysaccharide Inner Core Structure Defined by Chemical Synthesis

“…Naturally occurring immunoglobulin (Ig)G and IgM antibodies specific for DgalE LPS core glycolipid were earlier detected in healthy and infected persons via ELISA, demonstrating the immunogenicity of the DgalE LPS core (Plested et al, 2000). To examine whether antibodies specific for synthetic LPS core structures are present in humans who have been exposed to N. meningitidis, we performed glycan array screenings of sera from convalescent patients who recovered from N. meningitidis infection (n = 11), asymptomatic N. meningitidis carriers (n = 11), and healthy individuals (n = 15) (Hubert et al, 2013; Figure 3). Glycan array analysis revealed that IgG antibodies in human sera showed exclusive binding to meningococcal tetrasaccharide 1 and trisaccharide 5, while there was only weak binding to trisaccharide 2.…”

“…Human Sera Convalescent sera used have been published recently (Hubert et al, 2013). Sera from healthy individuals carrying or not carrying N. meningitidis were obtained from human volunteers, with permission of the Ethics Committee of the Medical Faculty of the Julius-Maximilians-University.…”