Abstract
The threat from invasive meningococcal disease (IMD) remains a serious source of concern despite the licensure and availability of vaccines. A limitation of current serogroup B vaccines is the breadth of coverage afforded, resulting from the capacity for extensive variation of the meningococcus and its huge potential for the generation of further diversity. Thus, the continuous search for candidate antigens that will compose supplementary or replacement vaccines is mandated. Here, we describe successful efforts to utilize the reverse vaccinology 2.0 approach to identify novel functional meningococcal antigens. In this study, eight broadly cross-reactive sequence-specific antimeningococcal human monoclonal antibodies (hmAbs) were cloned from 4 ml of blood taken from a 7-month-old sufferer of IMD. Three of these hmAbs possessed human complement-dependent bactericidal activity against meningococcal serogroup B strains of disparate PorA and 4CMenB antigen sequence types, strongly suggesting that the target(s) of these bactericidal hmAbs are not PorA (the immunodominant meningococcal antigen), factor-H binding protein, or other components of current meningococcal vaccines. Reactivity of the bactericidal hmAbs was confirmed to a single ca. 35 kDa protein in western blots. Unequivocal identification of this antigen is currently ongoing. Collectively, our results provide proof-of-principle for the use of reverse vaccinology 2.0 as a powerful tool in the search for alternative meningococcal vaccine candidate antigens.
Highlights
Neisseria meningitidis is a major obligate human pathogen that frequently colonizes the nasopharynx asymptomatically, in a state known as carriage [1]
To assess whether these plasmablasts represented a functional response to the meningococcal infection, total IgG purified from patient plasma was assayed for bactericidal activity
The antimeningococcal immune response in patient SM-P02 was exclusive of the antigenic components of 4CMenB as no reactivity of SM-P02 plasma IgG to the vaccine antigens was discerned in ELISAs, under the experimental conditions employed in this study (Figure 2B)
Summary
Neisseria meningitidis is a major obligate human pathogen that frequently colonizes the nasopharynx asymptomatically, in a state known as carriage [1]. For serogroup B strains, which account for more than 60% of IMD in the UK and Europe [11, 12], vaccine development has focused heavily on sub-capsular vaccine components owing to the unsuitability of the serogroup B capsule [13]. One of these vaccines, 4CMenB (or Bexsero®), is a protein-based vaccine whose major components are the factor-H binding protein (fHbp) (variant 1.1), Neisserial heparin-binding antigen (NHBA variant 2), Neisserial adhesin A (NadA variant 3), and the detergent-extracted outer membrane vesicle component of the New Zealand epidemic strain (with PorA variant P1.4) [14]. These limitations, coupled with the huge potential of the meningococcus to generate extensive antigenic diversity (leading to vaccine/immune escape) [23] justify the search for novel vaccine candidate antigens
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