Engineering improved protein treatment and prevention strategies for Bordetella pertussis

In 2020, now more than ever, the toll that infectious diseases can take on our society is apparent. Therapeutics and vaccines offer promising solutions, but ineffective target selection and design can make these efforts futile. Bordetella pertussis, the causative agent of whooping cough, is the leading cause of vaccine preventable deaths worldwide. Despite high vaccination coverage, it accounts for ~1% of fatalities of children under the age of five annually. The current vaccine largely contributes to this statistic. Among the many vaccine inefficiencies, the protection it offers wanes over time, the vaccine prevents symptoms but not colonization or asymptomatic transmission, and bacterial strains have evolved their expression of several vaccine antigens rendering them ineffective targets. This lack of efficacy is especially dangerous to infants too young to receive the vaccine as they are at highest risk for serious and fatal outcomes. The work in this thesis establishes a multi-faceted approach to tackle this pertussis problem. We discover and engineer antibodies to two pertussis virulence factors, pertussis toxin and pertactin, and show their effectiveness in treating and reducing infection in B. pertussis mouse and baboon models. We also provide a solution to the problem by developing a novel antigen that can improve the acellular vaccine, a derivative of the adenylate cyclase toxin, RTX. We show that adenylate cyclase toxin is essential for bacterial virulence and that robust immunization elicited, anti-RTX responses can readily neutralize the toxin’s effects in vivo and significantly reduce lethality. Together these efforts, of treatments to prevent serious disease and an improved vaccine to prevent pertussis altogether, can save countless lives.