Carbohydrate based multi-component vaccine against Bordetella pertussis

Project summary Whooping cough, also known as pertussis, is one of the leading causes of mortality and morbidity of children caused by the Gram-negative bacterium Bordetella pertussis (Bp). Pertussis is a vaccine preventable disease. However, despite the high vaccination coverage in the world, the incidence rate of pertussis has resurged during the past decade, which is correlated with limitations of the current acellular pertussis vaccines (aPV). Thus, there is an urgent need for new and more effective anti-pertussis vaccines. In this project, an interdisciplinary team has been assembled integrating state-of-the-art synthetic chemistry, microbiology, and vaccinology to develop next generation of anti-pertussis vaccines. There are three aims in this project. In aim 1, the pertussis associated glycan antigens will be synthesized for the first time. New synthetic strategies will be developed to overcome the synthetic challenges associated with the assembly of the complex carbohydrate structures. In aim 2, the synthetic glycans will be conjugated with a powerful carrier, the bacteriophage Qβ. The availability of diverse structurally well-defined synthetic antigens will enable the deciphering of the protective epitope structure. The lead Qβ-glycan conjugates eliciting antibodies with high bactericidal activities will be established and immune mechanisms will be studied to gain a deeper understanding of immune activation. In aim 3, Qβ-glycan conjugate will be integrated with pertussis toxin. This multi-component construct can potentially provide a potent one-two punch against Bp by not only neutralizing the exotoxins, but also killing the bacteria. The efficacy of the construct in preventing pertussis infections will be established in clinically relevant murine models. This work will set the groundwork to understand the factors influencing anti-pertussis glycan immune responses and provide an exciting new approach to combat pertussis.