The 4CMenB (Bexsero
R
) vaccine contains detergent-extracted outer membrane vesicles (OMVs) from a
Neisseria meningitidis
(
Nm
) group B strain NZ98/254 and three recombinant
Nm
protein antigens: Neisseria adhesin A (NadA), Factor H binding protein (FHbp, as the C-terminal protein in the GNA2091-FHbp fusion), and Neisserial Heparin Binding Antigen (NHBA, as the N-terminal protein in the NHBA-GNA1030 fusion). Previous work has shown that 4CMenB generates serum antibodies to
Nm
and
Neisseria gonorrhoeae
(
Ng)
OMV proteins and lipooligosaccharide (LOS). Mounting evidence indicates 4CMenB can partially protect against mucosal infections with
Ng
. The immunologic basis for
Ng
cross protection remains to be fully elucidated. Ten paired human sera obtained pre- and post-immunization with 4CMenB (1 month after a third vaccine dose) were used in ELISAs and in Western blots to determine IgG and IgA serum responses to OMVs from
Nm
strain NZ98/254 (OMV
Nm
) and two
Ng
strains, 1291 and CNG20 (OMV
Ng
), and gonococcal recombinant NHBA (rNHBA
Ng
) proteins. Post 4CMenB sera, but not pre-sera, showed strong IgG and variable IgA responses to the OMV
Nm
but lower (2–11-fold difference in signal intensity) recognition of OMV
Ng
. All post (not pre) 4CMenB sera showed strong IgG, but variable IgA, recognition of rNHBA
Ng
by ELISAs and Western blots. Three post 4CMenB sera at 10% (v/v) concentration had serum bactericidal activity (SBA) against
Ng
strains 1291 and CNG20 (~30–40% killing), not seen in paired pre-sera. These data confirmed 4CMenB-induced cross-reactive functional antibody responses to
Ng
. In competitive SBA assays, in which sera were pre-incubated with rNHBA, minimal SBA against
Nm
strain NZ98/254 was titrated away. However, most of the SBA against
Ng
strains 1291 and CNG20 required NHBA-specific antibodies, and the Δ
nhba
mutants were resistant to killing by post 4CMenB sera. Removing NHBA-specific and LOS-specific OMV antibodies simultaneously decreased SBA significantly more than the sum of removing individual antibodies alone, suggesting synergy between anti-NHBA and anti-OMV antibodies. Anti- NHBA
Nm
antibodies induced by 4CMenB vaccination cross react with NHBA
Ng
and substantially contribute to the bactericidal response toward
Ng
induced by the vaccine.
