Author ORCID Identifier
Semester
Spring
Date of Graduation
2026
Document Type
Dissertation
Degree Type
PhD
College
School of Medicine
Department
Microbiology, Immunology, and Cell Biology
Committee Chair
Heath Damron
Committee Member
Brian Peppers
Committee Member
Jonathan Busada
Committee Member
Ivan Martinez
Committee Member
Tracy Liu
Abstract
Highly infectious respiratory pathogens are a significant threat to public health due to their ability to spread in unprotected populations rapidly. Vaccination is highly efficacious in protecting the population from both newly emerging pathogens, such as the SARS-CoV-2 virus, and familiar endemic pathogens like the B. pertussis bacterium. However, problems such as mutations in protective antigens and waning vaccine-induced immune responses over time threaten to leave the population susceptible to disease outbreaks. In this work, we evaluate novel vaccine technology and vaccination strategies to improve the vaccine-induced immunity produced by SARS-CoV-2 or B. pertussis vaccines within preclinical mouse models. We found that a genetically modified attenuated influenza virus that expressed the RBD region of the SARS-CoV-2 spike protein ΔNA(RBD) served as an effective intranasal vaccine for protecting against COVID-19 in K18hACE2 mice. ΔNA(RBD) vaccination afforded increased protection from challenge with lethal delta or non-lethal omicron strains of the virus. During the COVID-19 pandemic, mRNA vaccinations were administered alongside traditional protein vaccines within the human population for the first time. We investigated whether the presence of mRNA vaccine alongside the DTaP vaccine would alter DTaP-induced immunity and increase protection granted towards B. pertussis. Mice that received both DTaP and COVID-19 mRNA vaccine had a greater reduction in B. pertussis bacterial burden within the lower respiratory tract following aerosol challenge than mice vaccinated with DTaP alone. We also found that administration of both DTaP and COVID-19 mRNA vaccine altered the antibody repertoire, cytokine profile, and cell populations within the lymph node following vaccination. Our next studies further investigated the use of the mRNA platform in the context of B. pertussis. We employed mRNA genetic adjuvants encoding for the cytokine IL-6 or the chemokine CXCL13 alongside a low 1/160th human dose of a 10-antigen B. pertussis mRNA vaccine, DTP-10. Both genetic adjuvants increased IgG antibody responses to whole-B. pertussis compared to DTP-10 alone. Both DTP-10 and DTP-10 plus IL-6 or CXCL13 provided similar significant reductions in B. pertussis bacterial burden within the upper and lower respiratory tracts when challenged four weeks after the booster dose of vaccine. Another cohort of mice that received the same vaccine had their serum antibody responses monitored for over 300 days before being rechallenged. We found that the inclusion of IL-6 or CXCL13 genetic adjuvants to DTP-10 increased the longevity of anti-B. pertussis IgG responses. This work showed that genetic adjuvants are capable of improving vaccine-induced immune responses, but further developments are still needed to maximize their efficacy. The next studies switched gears from adjuvants to investigating additional B. pertussis proteins for use as protective vaccine antigens. The Sphb1, RTX, and BrkA TcfA and FIM3 proteins proved to be immunogenic in C57BL/6 mice when adjuvanted with aluminum hydroxide and when included on the Spontaneous Nanoliposome Antigen Particles (SNAP) vaccine platform. They also afforded mice a reduced bacterial burden following aerosol challenge with B. pertussis. Additionally, a SNAP vaccine that utilized the PTxA antigen could induce IgG specific to PT and grant reduced white blood cell levels in mice following PT challenge. This work shows the potential benefit of additional B. pertussis protective antigens in current or next-generation B. pertussis vaccines. We believe these findings demonstrate that novel vaccine strategies and technologies can be employed to combat the threat posed by upper respiratory pathogens.
Recommended Citation
Rader, Nathaniel Aaron, "Evaluation of novel vaccination methods towards respiratory pathogens" (2026). Graduate Theses, Dissertations, and Problem Reports. 13294.
https://researchrepository.wvu.edu/etd/13294