Bacterial ADP-ribosylating toxins: form, function, and recombinant vaccine development.

Abstract

No products of the biotechnology revolution will likely have a greater legacy than recombinant vaccines. Clinical efficacy trials of new acellular pertussis vaccines have recently been completed; among them, a vaccine containing a genetically modified pertussis toxin showed superior effectiveness in protection against disease caused by Bordetella pertussis. The foundations for this vaccine derive from the work of many investigators, but most notably: Japanese researchers who demonstrated the potential for subcomponents of B. pertussis, and particularly pertussis toxin, to confer protective immunity; research teams in Italy and the United States who cloned and sequenced the pertussis toxin operon; and our own group who molecularly dissected the toxin molecule to produce recombinant analogs of this heterohexameric protein that retained protective immunogenicity yet lacked the intrinsic enzyme activity that results in the adverse reactogenic effects of immunization. Another result of the research leading to this new pertussis vaccine is an intimate understanding of the relationship between form and function in the ADP-ribosylating toxins with AB5 architecture, including the structure of their catalytic domains their immunologic and adjuvant properties, characteristics and possible pathologic consequences of host cell receptor recognition, and the assembly and subunit interactions of these complex multimeric proteins.