Modified pathogens for use as vaccines

摘要

Described herein are microorganisms that are modified so that they have an increased ability to be recognized by the innate immune system of a eukaryote, relative to an unmodified microorganism. A microorganism may be a gram-negative bacterium that has been modified to produce high potency lipopolysaccharide, e.g., Yersinia pestis expressing LpxL. Such modified microorganisms may be used as vaccines for protection against an infection by the unmodified microorganism. They may also be used as delivery vehicles of one or more heterologous antigens, e.g., antigens from pathogens or those associated with a hyperproliferative eukaryotic cell.

主权项

1. A method for protecting a mammal from infection by a gram-negative pathogen, comprising administering to a mammal an effective amount of a vaccine comprising at least about 100 colony forming units (c.f.u.) of a transgenic gram-negative bacterium that is derived from a wild-type bacterium that does not comprise high potency lipopolysaccharide (LPS), wherein said transgenic bacterium comprises said high potency lipopolysaccharide (LPS) and comprises a heterologous nucleic acid sequence encoding an acyltransferase that permits the transgenic bacterium to produce high potency LPS,
a) wherein the heterologous nucleic acid sequence is at least about 80% identical to a nucleic acid sequence comprising SEQ ID NO: 1, b) wherein said nucleic acid sequence encodes a LPS biosynthetic enzyme LpxL, c) wherein said LpxL comprises an amino acid sequence which is at least about 90% identical to SEQ ID NO: 4, and d) wherein said transgenic bacterium has reduced virulence relative to a control bacterium that contains a mutation in said heterologous nucleic acid sequence.