We describe a model of vaccine based on detoxified endotoxin (LPS) conserving the supramolecular structure of micelles. Detoxification of LPS from Neisseria meningitidis group A, strain A1 (LPS A1), has been achieved by complex formation with a synthetic anti-endotoxin peptide (SAEP 2) binding to the lipid A moiety of LPS A1 with high affinity. Following subcutaneous injection in SW mice, LPS A1/SAEP 2 complex induced high titers of boostable IgG antibodies against the immunotype determinants of LPS A1, cross-reactive with group B LPS in either purified or cell-associated form. These antibodies were able to functionally fix and activate homologous and heterologous species of complement after binding to LPS A1-coated sheep erythrocytes. None of the IgG antibodies induced were specific for lipid A or SAEP 2 and none of the IgG antibodies cross-reacted with heterologous LPS. The purified IgG polyclonal antibodies significantly inhibited serum TNF production in CD1 mice intravenously challenged by homologous but not heterologous LPS. The immunogenic properties of LPS A1/SAEP 2 complex, investigated by the kinetic, magnitude and sub-isotype composition of the polyclonal antibodies induced, were comparable to those of a glycoconjugate obtained by covalent binding of LPS A1, detoxified by SAEP 2, to BSA working as a T-cell dependent carrier protein. The results obtained suggest that LPS behaves in vivo as a T-cell dependent antigen. The strategy of properly delivering to the immune system of mammalians, non-toxic LPS fully expressing its supramolecular antigenic structure, represents a novel approach for development of a new generation of R- and S-LPS/SAEP complex-based vaccines for prophylaxis of specific Gram-negative infections leading to sepsis and endotoxemia.
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