These investigations examine possible enhancement of resistance to Gram-negative bacillary infections by immunization with antigens shared by most Enterobacteriaceae and Pseudomonadaceae. Active and passive immunization with an antigen present in the basal, core portion of lipopolysaccharide (LPS) (Re mutant of S. minnesota) have been shown to induce significant protection against lethal challenge with heterologous bacilli and LPS. Similarly, patients with high titers of antibody to the Re mutant at the onset of bacteremia experienced shock and a fatal outcome only 1/3 as often as those with low titers. Field trials by others have demonstrated that administration of human antisera against the J5 mutant (Rc chemotype) of E. coli was associated with a 2-fold reduction in fatality in Gram-negative bacteremia. Immunization of volunteers with preparations derived from Re and J5 mutants to develop vaccines for field trials of the relative efficacy of antiserum to each mutant in the treatment of bacteremia will be continued. In addition, """"""""modified glycolipids"""""""", alone, and conjugated with polypeptides and proteins have been prepared to develop component vaccines for induction of active rather than passive protection. """"""""Modified glycolipids"""""""" have been shown to induce earlier antibody titers and serum protective activity than whole cell vaccines. These have also been coupled with protein carriers and shown to produce a """"""""booster"""""""" or anamnestic response of antibody and protective levels with substantial increase in IgG. Previous studies have demonstrated that protective activity after primary immunization, resides chiefly with IgM antibody but recent studies have suggested that """"""""booster"""""""" doses of """"""""modified glycolipid"""""""" and conjugated vaccines induce an anamnestic response with IgG exerting the greatest protective activity. Protective IgG antibody would have considerable clinical and commercial utility (easier, standardized methods of preparation and repeated courses of volunteer immunization). Studies with component vaccines are being extended to evaluate their feasibility and safety. Immunologic cross-reactivity, already demonstrated between LPS and glycolipids of the Re and J5 mutants, will be further evaluated to characterize the immunodeterminant responsible for induction of protective antibody. Mouse monoclonal antibodies to both the Re and J5 mutants are being characterized and several have been shown to protect against challenge with K. pneumoniae and E. coli. Similarly, human monoclonal antibodies have been prepared and are being characterized.
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| McCabe, W R; DeMaria Jr, A; Berberich, H et al. (1988) Immunization with rough mutants of Salmonella minnesota: protective activity of IgM and IgG antibody to the R595 (Re chemotype) mutant. J Infect Dis 158:291-300 |
| Bjornson, B H; Agura, E; Harvey, J M et al. (1988) Endotoxin-associated protein: a potent stimulus for human granulocytopoietic activity which may be accessory cell independent. Infect Immun 56:1602-7 |
| Johns, M A; Sipe, J D; Melton, L B et al. (1988) Endotoxin-associated protein: interleukin-1-like activity on serum amyloid A synthesis and T-lymphocyte activation. Infect Immun 56:1593-601 |
| DeMaria Jr, A; Johns, M A; Berberich, H et al. (1988) Immunization with rough mutants of Salmonella minnesota: initial studies in human subjects. J Infect Dis 158:301-11 |
