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The Development of a New Pertussis Booster Formulation via the Implementation of New Adjuvants and Utilization of Alternate Routes of Administration

DeJong, M;

Pertussis (whooping cough) is a respiratory disease caused by airborne transmission of the Gram-negative bacterium, Bordetella pertussis. Prior to the development of the first pertussis vaccines (whole cell (wP) vaccines), the incidence of pertussis was in the hundreds of thousands of cases per year, which led to the death of many children, as the infection is most severe in younger populations. Thankfully, the wP formulation resulted in a dramatic decrease in the number of annual pertussis cases, nearly eradicating the disease. However, as wP contained the whole B. pertussis bacterium (and its lipooligosaccharide (LOS)), reactogenicity issues became apparent, leading to vaccine hesitancy amongst the public. Researchers in Japan had been testing the efficacy of an acellular pertussis (aP, DTaP, Tdap) vaccine, which contained select antigens rather than the whole bacterium, and found that it was capable of inducing high levels of antibodies against B. pertussis virulence factors. Further, the vaccine was much safer and elicited very minor side effects when compared to its wP counterpart. As a result, the wP vaccines were soon phased out in the United States and replaced with DTaP, the primary vaccine formulation. Yet, it soon became apparent that the duration of protection elicited by DTaP was short-lived, which prompted the implementation of an aP booster formulation, known as Tdap. The switch from wP to aP formulations coincides with a resurgence of pertussis cases in the United States, as well as in other countries that utilized aP vaccines. Research into the immune responses induced by both vaccine formulations has concluded that wPs induce a Th1 polarized immune response, which results in the activation of the cell-mediated immunity that is needed to clear B. pertussis from the respiratory tract and recover from infection. The aP vaccines, on the other hand, induce Th2 polarized immunity, which has been shown to provider neither long-lived immunity nor complete clearance of the pathogen from the respiratory tract, which allows for its transmission to another host. Because of this, there has been an ongoing effort to improve the immune responses induced by aP vaccines such that a more efficacious and durable immune response is elicited. In this dissertation, we aimed to evaluate the inclusion of new adjuvants into aP vaccine formulations as well as the utilization of intranasal vaccination. First, we determined the ability of the CpG 1018 adjuvant to improve the immunity afforded by the current booster, Tdap. In this study, mice were immunized with either Tdap or Tdap + CpG 1018 and then challenged with B. pertussis. We observed an increased clearance of B. pertussis from the respiratory tract, as well as an increase in serological responses to pertussis vaccine antigens. Further, in an effort to evaluate this formulation’s ability to protect against strains that have mutated, mice were challenged with either a strain of B. pertussis that expressed the virulence factor pertactin (PRN) or did not express PRN. Overall, the use of this adjuvant was able to protect against both strains, suggesting that the immunity provided could withstand the variability seen with the evolution of B. pertussis. We then aimed to evaluate a lipid A mimetic created via Bacterial Enzymatic Combinatorial Chemistry (BECC438b) as an adjuvant to include in DTaP. We determined the protection afforded by administering the DTaP + BECC438b formulation either intramuscularly or intranasally. The combination of the DTaP + BECC438b formulation and intranasal vaccination resulted in the most profound changes in the resulting immune response, as there was a decrease in bacterial burden within the respiratory tract as well as a robust induction of mucosal immune responses when compared to mock-vaccinated, challenged (MVC) mice. Further, the intranasally vaccinated mice had an increase in the expression of genes involved in both the activation and regulation of immune system processes. As a result of seeing such profound differences in the protective immune responses as a result of intranasal vaccination, we aimed to determine the effect of including an intranasally administered pertussis vaccine into the current vaccine schedule. All pertussis vaccines are administered intramuscularly; therefore, we felt it was essential to understand how these two routes and their respective immune responses would interact. We theorized that intramuscular priming would “push” immune responses out into the systemic circulation and establish robust adaptive immunity, while the intranasal booster would “pull” these responses to the site of vaccination or infection (in this case, the nasal cavity). The results of this study demonstrated the benefit of utilizing just one intranasal booster vaccine, as there was increase bacterial clearance throughout the respiratory tract as well as the induction of mucosal immune responses. The loss of an intramuscular booster had no effect on the induction of systemic immune responses. Further, when either a lipid A mimetic (BECC438b) or β-glucan (IRI-1501) was added to the formulation, the effects of the intranasal booster were more pronounced. Taken together, the data in this dissertation build upon the established knowledge regarding the next generation of pertussis vaccines. Not only did we demonstrate efficacy as a result of implementing new adjuvants, but we also highlighted the importance of intranasal vaccination. The vaccines tested in this thesis serve as a stepping stone toward future studies that will help combat the resurgence of pertussis.