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Abstract: We addressed the hypothesis that meningococcal secreted proteins (MSPs) can elicit protective immunity against meningococcal disease. Endotoxin-depleted MSP preparations were used to immunise a group of 15 six-week-old BALB/c mice (25μg MSPs/dose mixed with Freund''s complete adjuvant) on days 0, 14 and 21. Mice were challenged 2 weeks later with 107 colony forming units of live Neisseria meningitidis strain MC58 (serogroup B, ET-5). Negative and positive control groups of 15 mice each were injected with adjuvant only, or a live attenuated strain of MC58, respectively. Seven out of 15 mice (47%) from the negative control group died after 72h of challenge, whereas none of test or positive control group died. Protection afforded by the anti-MSP immune response can be at least partly attributed to complement-mediated bacterial lysis, detectable in vitro using the serum of immunised mice. Murine anti-MC58 MSP sera were bactericidal against homologous and five unrelated ET-5 serogroup B strains. However, failed to kill strains from other hypervirulent clonal lineages belonging to the same or different serogroups, despite the presence of cross-reactive antibodies detectable by immunoblotting. Similar sera raised against MSPs from an isolate belonging to the ET-37 electropherotype lineage were bactericidal against all tested isolates of this lineage and, in addition, against some but not all isolates belonging to the ET-5 lineage. FACS analysis of intact bacteria treated with anti-MSPs confirmed surface-binding of antibodies. [Copyright &y& Elsevier]