Murine mAbs that were produced by immunization with a vaccine containing the N-propionyl derivative of Neisseria meningitidis group B (MenB) capsular polysaccharide (NPr MBPS) mediate protective responses against MenB but were not reactive with unmodified MBPS or chemically identical human polysialic acid (PSA). Recently, we showed that some of the mAbs were reactive with MBPS derivatives that contain de-N-acetyl sialic acid residues. In this study we evaluated the immunogenicity of de-N-acetyl sialic acid-containing derivatives of PSA (de-N-acetyl PSA) in mice. Four de-N-acetyl PSA Ags were prepared and conjugated to tetanus toxoid, including completely de-N-acetylated PSA. All of the vaccines elicited anti-de-N-acetyl PSA responses (titers >/=1/10,000), but only vaccines enriched for nonreducing end de-N-acetyl residues by treatment with exoneuraminidase or complete de-N-acetylation elicited high titers against the homologous Ag. Also, nonreducing end de-N-acetyl residue-enriched vaccines elicited IgM and IgG Abs of all subclasses that could bind to MenB. The results suggest that the zwitterionic characteristic of neuraminic acid, particularly at the nonreducing end, may be important for processing and presentation mechanisms that stimulate T cells. Abs elicited by all four vaccines were able to activate deposition of human complement proteins and passively protect against challenge by MenB in the infant rat model of meningococcal bacteremia. Some vaccine antisera mediated bactericidal activity against a N. meningitidis group C strain with human complement. Thus, de-N-acetyl PSA Ags are immunogenic and elicit Abs that can be protective against MenB and N. meningitidis group C strains.