Author ORCID Identifier

https://orcid.org/0000-0002-5782-5658

Semester

Summer

Date of Graduation

2024

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Mariette Barbier

Committee Co-Chair

Fredrick Damron

Committee Member

Fredrick Damron

Committee Member

Slawomir Lukomski

Committee Member

Jennifer Franko

Committee Member

Stanley Hileman

Abstract

Whooping cough, or pertussis, is a highly infectious respiratory disease caused by infection with the Gram-negative bacterial pathogen Bordetella pertussis. Pertussis affects all age groups and populations; however, it is most severe in infants who are too young to receive vaccinations and remains a global health concern with more than­­­­ 200,000 cases reported globally in 2023. Vaccines against pertussis have been available in the United States since the 1940’s with the development and widespread use of whole cell pertussis vaccines. Following their introduction, the incidence of pertussis was controlled and limited to fewer than 5,000 cases per year. Despite their demonstrated efficacy, whole cell pertussis vaccines were highly immunogenic and variable in nature and often led to worrisome, severe side effects. Due to this, whole cell vaccines were replaced with lesser reactogenic acellular pertussis vaccines in the 1990’s, which are still in use to this day in most industrialized countries. After the introduction of acellular pertussis vaccines, there has been an increase in reported pertussis cases and several noteworthy pertussis outbreaks, such as the U.S. outbreak in 2012 which resulted in over 50,000 reported cases and 20 deaths, and the 2024 outbreak in the Czech Republic which experienced its highest pertussis incidence since the 1960s. This reemergence of pertussis calls for the development of next-generation pertussis vaccines which address and overcome the pitfalls of current acellular vaccines. There are many hypotheses for why acellular pertussis vaccines have triggered this resurgence, including bacterial evolution in response to selective pressure on acellular vaccine antigens, increased rates of reporting, as well as the short-lived duration of immunity that follows acellular vaccination. The overall objective of the worked covered in this thesis is to address an additional pitfall of acellular pertussis vaccines, that being their limited breadth of antigen coverage and lack thereof of functional immune responses that can promote bacterial clearance. In these studies, we employed a murine model of vaccination and B. pertussis challenge in which novel and redesigned pertussis antigens were assessed for their capability to invoke robust humoral immune responses and subsequently protect against respiratory infection of B. pertussis. At the onset of this work, we identified several immunogenic proteins contained in whole cell vaccines that were immunogenic in mice when formulated as peptide-based conjugate vaccines. Although immunogenic, these peptides were insufficient to elicit protection against B. pertussis in mice. Next, we characterized the immunogenicity and protective efficacy of several peptide-based vaccines derived from iron acquisition surface receptors expressed by B. pertussis that were previously found to be upregulated upon infection. Similarly, these vaccines were immunogenic, however they failed to confer protection against B. pertussis in mice either alone or in combination with a subprotective dose of DTaP. Finally, instead of characterizing novel antigens, we sought to redesign an antigen in acellular vaccines known as filamentous hemagglutinin. Toward this goal, we designed a truncated antigen based on the mature C-terminal domain of filamentous hemagglutinin that was fused to virus-like particles. This vaccine was demonstrated to be highly immunogenic and conferred significant protection against B. pertussis when evaluated against a B. pertussis strain lacking pertussis toxin. Overall, this work identified several immunogenic antigens, either novel or redesigned, that have promise as protective antigens against B. pertussis that could be included in the next generation of pertussis vaccines. Additionally, this work sheds light on the complexity of characterizing vaccine antigens against B. pertussis in preclinical model and lays the groundwork for future exploration of other antigens and vaccine platforms.

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