Whooping cough is caused by an infection of the upper respiratory tract with Bordetella pertussis. This disease is effectively controlled by the current vaccine which consists of killed whole B. pertussis cells. Although efficacious, the present vaccine produces unacceptable side effects. The major protective antigen in whooping cough vaccines is pertussis toxin. Chemically inactivated pertussis toxin vaccines have been produced with reduced side effects and reasonable efficacy, however, these products suffer from reduced antigenicity and difficulties in vaccine manufacture processing. In addition, residual activity may exist from reversion or incomplete chemical inactivation. Using site-specific DNA mutagenesis, we modified E. coli subclones of pertussis toxin and used these constructs to replace the chromosomal copy of the toxin gene in B. pertussis vaccine strain 3779. The resulting new strain produces a fully genetically detoxified form of pertussis toxin which is strongly immunoprotective and can be used as a vaccine antigen without chemical inactivation. In a recently competed NIAID-supported clinical trial in Sweden and Italy, pertussis toxin emerged as an essential component of any new whooping cough vaccine. One of the most successful acellular pertussis vaccines used in this clinical trial contained a genetically altered version of pertussis toxin that was developed from basic research generated through this intramural research project. Molecular studies are currently underway in our laboratory to develop higher yield Bordetella strains to enhance expression of pertussis toxin for use in acellular and conjugate vaccine manufacture. In addition, an avirulent, live attenuated B. pertussis vaccine is being developed which is capable of delivering other immunoprotective antigens such as proteins from HIV and Hepatitis C Virus and well as the protective pertussis antigens.
