Research Project
3141063
Laboratory studies have shown that pertussis toxin (PT) is an important antigen for immunity to pertussis, and clinical data indicate that chemically inactivated PT is 78% efficacious in protecting children from severe disease. A problem of chemical inactivation is retention of immunogenic properties of PT, while inactivating its toxic activities in a manner that prevents reversion of toxic activity. Toxic activities of PT require an ADP-ribosyltransferase active S1 subunit associated with a B- oligomer which is required for binding PT to cells. It has been found that oligonucleotide site-directed mutagenesis of the S1 gene can significantly inactivate S1 to allow Bordetella pertussis to secrete immunogenic holotoxin analogs with toxic activity equal to the level of residual enzyme activity. One such antigenic cross-reactive material (CRM), CRM 3201, has been identified at Praxis. Phase II studies will (a) continue site-directed mutagenesis of the S1 gene to eliminate enzyme activity, (b) transfer these mutant S1 genes into B. pertussis and (c) identify and evaluate holotoxin CRMs which are enzymatically inactive, nontoxic, immunogenic, stable and protective antigens for animals. Such a CRM would be a candidate to replace chemical toxoids of PT in acellular pertussis vaccines. These phase II studies will support and lead to studies of the safety and immunogenicity of a PT CRM vaccine in adults, toddlers and infants.
