Susceptibility of Meningococcal Strains Responsible for Two Serogroup B Outbreaks on U.S. University Campuses to Serum Bactericidal Activity Elicited by the MenB-4C Vaccine

Abstract

M eningococcal serogroup B outbreaks involving a total of 14 cases occurred on two university campuses in the United States in 2013 and 2014 (1). The outbreak at university A, which is located in New Jersey, started in March 2013 with a total of 9 cases documented in the campus population or in close contacts of the students (2). The outbreak at university B, which is located in California, started in November 2013 with a cluster of four cases (1). These cases were later connected to a fifth case in a student enrolled at university B, which had occurred 7 months earlier. The strains from the two outbreaks were from different clonal complexes and therefore were not epidemiologically related.In response to these campus outbreaks, the U.S. Food and Drug Administration approved the immunization of the students with a serogroup B meningococcal vaccine (Bexsero; Novartis Vaccines and Diagnostics) (2), which at the time was licensed in Europe, Canada, and Australia. The vaccine contains four primary components, each capable of eliciting complement-mediated serum bactericidal activity (3, 4), and is referred to here as MenB-4C. The four antigens are factor H binding protein (FHbp), neisserial heparin binding antigen (NHba), neisserial adhesin A (NadA), and a porin protein (PorA) with variable region (VR) sequence type P1.7-2,4 contained in outer membrane vesicles (OMV) (3, 4). Since most of the anti-PorA bactericidal activity is directed to VR2, a match between the vaccine PorA and strain PorA is usually described as sharing the P1.4 VR2 antigen (5).The purpose of the present study was to investigate the expression of MenB-4C vaccine antigens in representative isolates from each of the outbreaks and the susceptibility of the isolates to serum bactericidal activity induced by MenB-4C vaccination. We also assessed the contribution of anti-FHbp antibodies in eliciting serum bactericidal activity. MATERIALS AND METHODSMeningococcal outbreak strains. We received 15 case isolates from the Meningitis Laboratory, Meningitis and Vaccine Preventable Diseases Branch, Centers for Disease Control and Prevention (CDC), Atlanta, GA. Of these, 10 isolates were from the university A outbreak, and 5 were from the university B outbreak. The CDC provided data on the date of isolation, source (blood or cerebrospinal fluid [CSF] sample), multilocus sequence type (MLST), PorB amino acid sequence type, and amino acid sequence variants of the FHbp, NadA, NHba, and PorA vaccine antigens. The isolates from university A were from sequence type 409 (ST-409), which is uncommon in the United States but part of the more common ST-41/44 clonal complex. The isolates from university B were all from ST-32, which is a common ST/clonal complex among invasive serogroup B case isolates from the west coast of the United States (6).Control strains. The strains used as controls are summarized in Table 1 and were previously described. Neisseria meningitidis strain NZ98/254 is a relatively low expresser of FHbp identification (ID) 14 (subfamily B) (7) and was use...

A meningococcal NOMV-FHbp vaccine for Africa elicits broader serum bactericidal antibody responses against serogroup B and non-B strains than a licensed serogroup B vaccine

“…Resistance to anti-FHbp bactericidal antibody is likely explained by binding of human FH to the MenB-4C vaccine antigen, which in a previous study in human FH TG mice greatly impaired anti-FHbp bactericidal responses [31]. The low anti-NHba bactericidal activity also was not entirely unexpected, having been reported with hyperimmune mouse anti-NHba antiserum and human complement in 2003 against serogroup B strains [39] and, more recently, in sera from immunized humans or rhesus macaques [40, 41]. Whether the lack anti-NHba bactericidal activity elicited by MenB-4C against the African strains in the present study represented intrinsic resistance to anti-NHba antibody and/or low serum anti-NHba titers (Supplemental Figure S3), will require further study.…”

Breadth and Duration of Meningococcal Serum Bactericidal Activity in Health Care Workers and Microbiologists Immunized with the MenB-FHbp Vaccine

“…Six of the case isolates had FHbp subfamily A, and eight had FHbp subfamily B. Six case isolates were from recent outbreaks on U.S. college campuses (Princeton University [15,19], University of California, Santa Barbara [15], Ohio University [18], Santa Clara University [20,43], a college in Rhode Island [16,34], and Rutgers University [13]). Two additional case isolates were from patients hospitalized between 2009 and 2013 in Quebec, Canada, during a period of hyperendemic serogroup B disease (17).…”

Impaired Immunogenicity of Meningococcal Neisserial Surface Protein A in Human Complement Factor H Transgenic Mice

“…To determine the role of anti-FHbp antibodies in the serum bactericidal activity elicited by the control meningococcal NOMV vaccine, we depleted anti-FHbp antibodies from the postimmunization serum as previously described (24). In brief, we utilized cyanogen bromide-activated Sepharose coupled with recombinant FHbp ID 1, which contained a single amino acid substitution, R41S, that abrogated the binding of human serum FH without affecting the ability of the mutant antigen to deplete the anti-FHbp antibodies from the serum (25). In the present study, we created serum pools from each vaccine group by combining equal volumes of serum from each mouse.…”

“…In the present study, we created serum pools from each vaccine group by combining equal volumes of serum from each mouse. The adequacy of depletion of serum anti-FHbp antibody was quantified by an ELISA, which was performed as previously described (24,25).…”