Development of a novel adjuvant platform for neonatal vaccines against pertussis
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Whooping cough is a common childhood disease caused by infection with the bacteria Bordetella pertussis or Bordetella parapertussis. Although previously considered under control within developed countries due to widespread vaccination, whooping cough has undergone a resurgence in many developed countries, with recent outbreaks underscoring the need for new and more effective vaccines. Most crucially, there is a need for vaccines that can be administered during the neonatal period, to protect infants at their most susceptible, and vaccines that will provide long-lasting protection. Due to the functional differences of the neonatal immune system as compared to the adult, there are specific difficulties that must be overcome when attempting to create a vaccine that will be effective in the neonate. The objective of the current research was to examine the immunogenicity of several adjuvants, including CpG ODN, IDRP, and PP, in order to design a combined novel adjuvant platform that could be used with our pertussis vaccine antigen, PTd. After selection of each adjuvant component, we tested the ability of various adjuvant formulations to induce Th1 and Th2 humoral responses in both adult and neonatal mice. We found that a 1:2:1 ratio of CpG ODN: IDRP: PP was most effective, and that pre-complexation of the IDRP and CpG ODN components induced significantly higher Th1 (IgG2a) antibody titres than non-complexed vaccines. Our vaccine platform induced strong Th1 and Th2 antibody titres in both adult and neonatal BALB/c mice, with the immune response being of a mixed Th1/Th2 type. The Th1 type humoral response to our vaccine platform was significantly higher than that seen using current commercial vaccines such as Quadracel®, or when using the standard vaccine adjuvant alum. This Th1 antibody response was extremely long-lasting, with strong IgG2a titres being found up to 2 years post-vaccination. When examining the cell-mediated immune response in adult and neonatal BALB/c mice, a strong secretory IFN-g (Th1) response was present post-vaccination in the splenocytes of platform-vaccinated mice, with a large number of IFN-g secreting cells present. The IL-5 (Th2) response was found to be decreased in mice that received our novel vaccine as compared to mice vaccinated with Quadracel®, with no detectable cytokine secreted by stimulated splenocytes in vitro, and few to no IL-5 secreting cells visible through ELISPOT. To further improve our vaccine, a second antigen, pertactin (PRN), was added to the formulation. Upon live bacterial challenge, mice that received the two-antigen vaccine were completely protected against infection, and showed strong humoral response. This full protection and clearance was superior to the results seen using Quadracel®. Finally, the variability and cell-recruitment functions of the adjuvant platform were examined. The adjuvant platform successfully induced a strong mixed Th1 and Th2 humoral response when combined with the vaccine antigen HBsAg, with a significant increase in the Th1 (IgG2a) antibody response. Replacing the CpG ODN component of the adjuvant platform with Poly I:C through and using various immunization routes also resulted in an induction of IgG2a titres. Thus we have developed a novel vaccine formulation against B.pertussis that induces strong humoral and cell-mediated immune responses in both adult and neonatal mice, with these responses being both long-lasting and protective against infection. Our novel adjuvant platform itself has been shown to be adaptable for use with other vaccine antigens and through several routes of administration, and there is the possibility of adjusting the components while maintaining efficacy.
DegreeDoctor of Philosophy (Ph.D.)
DepartmentSchool of Public Health
ProgramVaccinology and Immunotherapeutics
SupervisorGerdts, Volker; Babiuk, Lorne A.
CommitteeMutwiri, George; Gordon, John R.; Townsend, Hugh
Copyright DateOctober 2012