Vaccine-induced reprogramming of innate immunity to stimulate broad protection against diverse pathogens
Abstract/Contents
- Abstract
- Immunological memory is a fundamental property of the adaptive immune system. Vaccination stimulates the generation of antigen-specific memory B and T cells which can last a lifetime and respond in a heightened manner to a subsequent encounter with the specific pathogen. Emerging evidence suggests that the innate immune response, which has long been thought to be short-lived, can also display a memory-like behavior by remembering an encounter with a microbe and responding more vigorously upon a secondary encounter with a diverse array of microbes. Unlike memory in the adaptive immune system, which is highly antigen-specific, "innate memory" appears to be antigen agnostic. However, the immunological basis of such "innate memory" is poorly defined, and is the subject of this thesis. Here, we used a systems biological approach to analyze the immune responses to adjuvanted and live attenuated vaccines. We mapped out the single cell transcriptomic and epigenomic landscape of lymph nodes following vaccination of mice with an adjuvant that targets TLRs (3M-052, a TLR7/8 agonist emulsified in alum [3M-052/alum]), and the live attenuated yellow fever vaccine (YF-17D). We found 3M-052/alum was capable of inducing a persistent innate antiviral signature in myeloid cells, suggesting the promising use of this adjuvant in enhancing long-lasting innate immunity. In addition, we profiled the immune mechanisms to BCG vaccination, a live attenuated vaccine that has been regarded to have broadly protective effects against diverse pathogens. Our findings revealed the feedback of the BCG-specific CD4 T cells in imprinting an antiviral state in myeloid, and epithelial cells in the lung through IFN-g signaling, leading to protection against SARS-CoV-2 and influenza. These findings provide a framework for the immunological parameters in the design of a broadly protective vaccine against diverse pathogens. We then applied this knowledge to design an adjuvanted vaccine strategy for achieving broad protection. We found repeated intranasal immunization with liposomes containing the TLR ligands GLA/3M-052 and ovalbumin to be potentially effective in antiviral activity against SARS-CoV-2 and influenza. These results pave the way for harnessing the innate immune system in developing a universal vaccine that protects against multiple pathogens.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Lee, Wei Qi Audrey |
|---|---|
| Degree supervisor | Pulendran, Bali |
| Thesis advisor | Pulendran, Bali |
| Thesis advisor | Davis, Mark |
| Thesis advisor | Engleman, Edgar |
| Thesis advisor | Khatri, Purvesh |
| Degree committee member | Davis, Mark |
| Degree committee member | Engleman, Edgar |
| Degree committee member | Khatri, Purvesh |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Department of Microbiology and Immunology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Wei Qi Audrey Lee. |
|---|---|
| Note | Submitted to the Department of Microbiology and Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/qj358xk3945 |
Access conditions
- Copyright
- © 2023 by Wei Qi Audrey Lee
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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