Neisseria meningitidis is a major cause of bacterial meningitis in sub-Saharan Africa. Generating new vaccines is challenging because they must be affordable yet protect against a range of serogroups, mainly A, W, X, predominant in this region. One strategy to achieve this is to use OMVs, outer membrane blebs naturally shed by Gram negative bacteria. These lend themselves to clean, low cost production at an industrial scale. Previous studies have shown that meningococcal non-detergent extracted OMVs (nOMVs) that over-express factor H binding protein (fHbp) variant1, a major N. meningitidis protective antigen can induce in mice antibodies with broader bactericidal activity against African isolates, then recombinant fHbp. So nOMVs are an encouraging avenue for generating cross-protective vaccines. Despite this potential and the multiple reports on their viability as vaccine platforms, remarkably little is understood about the nature of the immune response against OMVs. In this study we describe the immune response to nOMVs generated from an African serogroup W isolate, genetically modified to inhibit the pro-inflammatory activities of lipidA. Further genetic modifications have resulted in the nOMVs being devoid of capsule antigen and overexpression of the predominant fHbp variant among A and X African isolates. Mutation of lipidA results in an approximate 100-fold reduction in IL-6 production in vitro and 1000-fold reduction in TLR4 stimulation. To investigate how such a potential reduction in reactogenicity influenced antibody responses in vivo, mice were immunized with 1μg of chimeric nOMVs for 7days. Despite the dramatic difference in cytokine production in vitro, only small differences were observed in antibody titers and numbers of antibody secreting cells between wt and nOMVs with modified lipidA. Amongst specific antigens within the nOMVs, the anti-fHbp response was similar. These and other data show the power of this platform for driving robust antibody responses that recognize multiple serotypes of meningococcus.