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Development of immunogenic, distributable, and equitable SARS-CoV-2 vaccines

Khan, Muhammad Sohaib (2023) Development of immunogenic, distributable, and equitable SARS-CoV-2 vaccines. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The COVID-19 pandemic underscores the critical need for effective vaccines against SARS-CoV-2. This thesis investigates diverse aspects of SARS-CoV-2 vaccine development, emphasizing immunogenicity and innovative strategies. The study comprises multiple chapters, each providing valuable insights into vaccine design and optimization. We initially demonstrated that a single subcutaneous or intranasal immunization with an adenovirus-based SARS-CoV-2 vaccine induces robust humoral and cellular immune responses in mice. This research validates the efficacy of adenovirus-based vaccines for SARS-CoV-2. Next, we investigated next-generation SARS-CoV-2 vaccine approaches incorporating proteins outside of spike using an adenovirus-vectored vaccine expressing the S1-N fusion protein. By incorporating multiple antigenic targets, this research aims to broaden the immune response, exploring its propensity for increasing cellular immunity, the potential for eliciting protective immune responses, and compatibility with protein subunit boosters. After outlining the immunogenic approach of SARS-CoV-2 S1 subunit protein vaccines, I next worked to evaluate a trivalent variant-specific SARS-CoV-2 S1 subunit protein vaccine in BALB/c mice in Chapter 4. This research demonstrates that the trivalent vaccine induces broad humoral immune responses, enhancing the potential for comprehensive protection against SARS-CoV-2 variants. Furthermore, we worked to evaluate the S1 protein subunit vaccine approaches as a booster in aged mice in Chapter 5. The study reveals that the booster vaccination elicits robust humoral immune responses, offering insights into enhancing immune responses in older populations. Chapter 6 investigates the immunogenicity of a tetravalent SARS-CoV-2 S1 subunit protein vaccine in SIV-infected rhesus macaque controllers. The research demonstrates the vaccine's ability to elicit robust humoral and cellular immune responses in a more advanced animal model and in animals with preexisting viral infection. Finally, I explored the development of chimeric spike protein vaccines for both SARS-CoV-2 and MERS. This research contributes to the expansion of vaccine strategies against related coronaviruses.
Overall, this thesis provides important insights into SARS-CoV-2 vaccine development, and innovative strategies. The findings advance our understanding of vaccine immunogenicity, broaden the scope of protection, and address the unique challenges posed by aging and immunocompromised populations. This research contributes to global efforts in combating the COVID-19 pandemic, informing strategies to prevent future outbreaks of emerging pathogens.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Khan, Muhammad Sohaibmuk18@pitt.edumuk18
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorGambotto,
Committee ChairBarratt-Boyes, Simonsmbb@pitt.edusmbb
Committee MemberHartman, Amyhartman2@pitt.eduhartman2
Bruno, Tulliatbruno@pitt.edutbruno
Date: 24 August 2023
Date Type: Publication
Defense Date: 6 July 2023
Approval Date: 24 August 2023
Submission Date: 25 July 2023
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 283
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: SARS-CoV-2, Vaccines, Immunology, Next-Generation Vaccine, Betacoronavirus
Date Deposited: 24 Aug 2023 13:34
Last Modified: 24 Aug 2023 13:34

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