Developing whole cell vaccines with tailored immunogenicity through combinatorial engineering of lipid A


Bordetella pertussis, causes whooping cough, or pertussis, a serious disease of infants. Infants are vaccinated against pertussis worldwide. Whole cell pertussis vaccines are used in most of the developing world. They give good protection against disease but cause adverse reactions in many infants, attributed to the endotoxin activity of the lipid A region of B. pertussis LPS. This led to the development of acellular pertussis vaccines that protect infants from serious disease but induce a sub-optimal immunity. This is associated with a resurgence of pertussis in a number of the developed world countries using these vaccines. Thus, there is a need to develop improved pertussis vaccines that can be used worldwide. 

In this project we will demonstrate the approach of genetically modifying B. pertussis lipid A to not only reduce its toxicity, but to engineer novel, beneficial immunogenicity (adjuvant activity). This will produce a novel pertussis WCV that is safer, and that induces superior immunity, to current ones.

This project addresses an unmet need to develop novel pertussis vaccines to combat pertussis resurgence and that are affordable worldwide. It will demonstrate proof-of-principle for the approach of engineering whole cell vaccines for specified immune responses that will be widely applicable to a wide range of bacteria. This includes some for which whole cell vaccines are already in use, others for which vaccines are being sought and in the future, novel pathogens for which vaccines might be needed.

Project outcomes

Combinatorial genetic engineering of the lipid A of Bordetella pertussis was performed, resulting in a panel of 50 B. pertussis lipid A variant strains. The immunogenicity of these strains was measured using in vitro assays and those strains inducing responses different from those to WT were identified. Interestingly, strains with both increased and decreased responses were generated by this approach. 

Four strains with specific immunogenicity profiles are being tested for toxicity using assays validated for toxicity testing of pertussis vaccines. This project has identified strains that are candidates for further development for novel whole cell pertussis vaccines that have improved safety and efficacy profiles compared to current pertussis vaccines.

Andrew PrestonDr Andrew Preston
Reader in Microbial Pathogenesis
University of Bath (UK)

Antonio Sanchez, Laboratory of Biologicals and Reagents of Mexico, S.A. of C.V. (Birmex), National Institutes of Health (Mexico)