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Next generation vaccines against respiratory pathogens: lessons from SARS CoV2 and Bordetella pertussis

Shamseldin, Mohamed Medhat Samir Ibrahim Ahmed
http://orcid.org/0000-0002-5324-1145
http://rave.ohiolink.edu/etdc/view?acc_num=osu1718984789903027

Abstract Details

2024, Doctor of Philosophy, Ohio State University, Microbiology.
Respiratory pathogens entail many bacteria and viruses that cause upper or lower respiratory tract diseases. The severity and transmissibility of respiratory pathogens vary widely, with some agents able to cause large outbreaks of severe diseases and even pandemics. Two examples of such pathogens that have recently gained global attention are SARS-CoV2, a newly emerging zoonotic coronavirus that caused the COVID-19 pandemic, and Bordetella pertussis, the causative agent of whooping cough, recently designated as an emerging pathogen by the National Institute of Allergy and Infectious Diseases (NIAID). Vaccines have been one of the most important measures to counteract respiratory pathogens. Multiple elements are involved in vaccine design to maximize the benefits and minimize the potential side effects. That includes the use of adjuvants that induce a strong favorable immune response, selecting the right antigens that are likely to be protective and also selecting the route of immunization that would induce immune response at the mucosal entry sites. I addressed all this strategies in my thesis. The adjuvant Bordetella colonization factor A (BcfA) is an outer membrane protein derived from Bordetella bronchiseptica. Previously, in our lab, we combined BcfA and Alum in a subunit vaccine formula against B. pertussis, and the vaccine led to better protection and a TH1/TH17 polarized immune profile. However, the molecular mechanisms underlying this phenotype still need to be elucidated. In the first part, I investigated the mechanism of action of BcfA. Initial pattern recognition receptors (PRR) screening identified TLR2 and TLR4 as potential BcfA receptors. Ex vivo analysis using murine bone marrow-derived dendritic cells (BMDCs) further confirmed that finding as it showed the ability of BcfA to induce the expression of costimulatory molecules and the secretion of innate cytokines, it also indicated a greater dependence of BcfA on TLR4. Finally, IV we proved that BcfA could maintain its adjuvant activity in vivo, as evidenced by its ability to stimulate lung DCs when administered intranasally and to induce antigen-specific T-cell response upon systemic administration. Next, I developed a subunit vaccine against SARS-CoV2. The vaccine formula contains a stabilized spike antigen modified with six proline substitutions, along with BcfA and Alum as adjuvants. The vaccine was administered via the prime pull regimen, where the mice were primed via the intramuscular route and boosted intranasally to draw the immune response toward the respiratory tract. The vaccine formula successfully induced antigen-specific immune response both systemically and mucosally in the form of IgAs, IgGs, and TH1/TH17 polarized CD4+ T cells. Adding BcfA has attenuated Alum-induced TH2 response, which has been linked to various vaccine-associated side effects. The immune response was maintained up to three months post-immunization and was associated with reduced viral titer in the lung and nose of infected mice and improved pathology. Finally, I used immunopeptidomics to identify putative vaccine candidates to incorporate into the currently used acellular pertussis vaccine (aPV), the main vaccine utilized in most developed countries since the 1990s. The recent resurgence of pertussis cases in the US and worldwide cast doubts about the vaccine efficacy and the duration of protection it confers. A potential strategy to improve the aPV efficacy is to use bacterial antigens that could efficiently stimulate a robust CD4+ T-cell response. In our quest for such antigens, we treated BMDCs with heat-killed B. pertussis bacteria and purified the MHC class II-presented bacterial epitopes. Those epitopes were interrogated for their binding affinity to murine and human MHC class II using the IEDB platform, and top candidates were selected for further pursuit. The top candidates were screened for their in vivo immunogenicity by evaluating their ability to stimulate CD4+ T cells isolated from mice or humans exposed to B pertussis before, either through vaccination or infection. We ended with a shortlist of peptides with predicted high MHC class II binding affinity and in vivo immunogenicity that could be tested as subunit vaccines against B. pertussis.
Purnima Dubey (Advisor)
225 p.
Biomedical Research; Immunology; Microbiology; Virology
Vaccines, SARS-CoV2, Pertussis, T cells, respiratory pathogens.

Recommended Citations

Citations

  • Shamseldin, M. M. S. I. A. (2024). Next generation vaccines against respiratory pathogens: lessons from SARS CoV2 and Bordetella pertussis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1718984789903027

    APA Style (7th edition)

  • Shamseldin, Mohamed. Next generation vaccines against respiratory pathogens: lessons from SARS CoV2 and Bordetella pertussis. 2024. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1718984789903027.

    MLA Style (8th edition)

  • Shamseldin, Mohamed. "Next generation vaccines against respiratory pathogens: lessons from SARS CoV2 and Bordetella pertussis." Doctoral dissertation, Ohio State University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=osu1718984789903027

    Chicago Manual of Style (17th edition)

osu1718984789903027
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This open access ETD is published by The Ohio State University and OhioLINK.