Coincorporation of LpxL1 and PagL Mutant Lipopolysaccharides into Liposomes withNeisseria meningitidis Opacity Protein: Influence on Endotoxic and Adjuvant Activity

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Abstract
Wild-type lipopolysaccharide (LPS) ofNeisseria meningitidisnormally contains six acyl chains. Penta-acylated LPS forms were generated through inactivation of thelpxL1gene or through the expression of theBordetella bronchiseptica pagLgene inN. meningitidis. The resulting LPS species, designated LpxL1 LPS and PagL LPS, respectively, display reduced endotoxic activity compared to wild-type LPS. Here, we determined the adjuvant potential of PagL LPS by comparison with the broadly used LpxL1 LPS. We also investigated the potential benefit for adjuvanticity of coincorporating these LPS species, together with the meningococcal opacity-associated protein OpaJ as a model antigen, in a liposomal delivery system. PagL LPS showed a higher endotoxic activity than LpxL1 LPS, and their incorporation into liposomes significantly reduced their endotoxic activity as determined by measuring the induction of interleukin-6 (IL-6) production in a murine macrophage cell line. To determine the adjuvant effect, BALB/c mice were immunized with OpaJ-containing liposomes and either free LPS or LPS coincorporated into the proteoliposomes. OpaJ-containing liposomes adjuvanted with AlPO4or not adjuvanted at all were included as control groups. In the appropriate dose, PagL LPS showed a superior adjuvant effect compared with LpxL1 LPS, and for both LPS types, free LPS showed a higher adjuvant effect than when coincorporated into the liposomes, as evidenced by higher titers of IgG2a and IgG2b antibodies against OpaJ+meningococci and higher bactericidal titers. In conclusion, PagL LPS is a better adjuvant than LpxL1 LPS, but coincorporation of either LPS into proteoliposomes did not improve their adjuvant activity.

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