Evaluating new malaria vaccine candidates
A highly effective malaria vaccine remains gravely needed. Vaccine-induced protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill <em>Plasmodium</em>-infected liver cells. A new strategy, prime-target vaccination, involves sequential viral-vectored vac...
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| Format: | Thesis |
| Language: | English |
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2021
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| _version_ | 1824459203294527488 |
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| author | Noé, A |
| author2 | Spencer, A |
| author_facet | Spencer, A Noé, A |
| author_sort | Noé, A |
| collection | OXFORD |
| description | A highly effective malaria vaccine remains gravely needed. Vaccine-induced protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill <em>Plasmodium</em>-infected liver cells. A new strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver-resident memory CD8+ T cells (TRM) are necessary for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunological responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary. This, however, is not feasible at scale in human trials. This thesis explores the early response, kinetics and transcriptomics of CD8+ T cells in mice vaccinated with prime-target. Adoptively transferred liver TRM preferentially homed to the liver and <em>Plasmodium</em>-specific CD8+ T cells peaked shortly after intravenous boost. These T cells were present in the liver and blood, and expressed several molecules suggestive of tissue residency and liver-homing. In a human efficacy study of prime-target vaccination, multi-omic analyses were performed on hepatic fine needle aspirates and peripheral blood samples to study liver TRM and their circulating counterparts. While these peripheral 'TRM-like cells' differed to bona fide TRM in certain features, such as leucocyte adhesion and T cell differentiation, they were phenotypically similar and indistinguishable in terms of T cell residency transcriptional signatures. Single cell analyses identified several subpopulations, mutual clonality, and indicated a potential developmental trajectory shared between TRM and TRM-like cells. This thesis demonstrates the potential for using TRM-like cells as a correlate of prime-target induced protection against liver-stage malaria. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. This work provides a blueprint for understanding and monitoring liver TRM induced by a new liver-stage malaria vaccine approach. |
| first_indexed | 2025-02-19T04:38:03Z |
| format | Thesis |
| id | oxford-uuid:8395d343-f5d7-498d-afc9-64066d5dcd23 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:38:03Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:8395d343-f5d7-498d-afc9-64066d5dcd232025-02-11T15:55:37ZEvaluating new malaria vaccine candidatesThesishttp://purl.org/coar/resource_type/c_db06uuid:8395d343-f5d7-498d-afc9-64066d5dcd23EnglishHyrax Deposit2021Noé, ASpencer, AHill, ABiswas, SA highly effective malaria vaccine remains gravely needed. Vaccine-induced protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill <em>Plasmodium</em>-infected liver cells. A new strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver-resident memory CD8+ T cells (TRM) are necessary for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunological responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary. This, however, is not feasible at scale in human trials. This thesis explores the early response, kinetics and transcriptomics of CD8+ T cells in mice vaccinated with prime-target. Adoptively transferred liver TRM preferentially homed to the liver and <em>Plasmodium</em>-specific CD8+ T cells peaked shortly after intravenous boost. These T cells were present in the liver and blood, and expressed several molecules suggestive of tissue residency and liver-homing. In a human efficacy study of prime-target vaccination, multi-omic analyses were performed on hepatic fine needle aspirates and peripheral blood samples to study liver TRM and their circulating counterparts. While these peripheral 'TRM-like cells' differed to bona fide TRM in certain features, such as leucocyte adhesion and T cell differentiation, they were phenotypically similar and indistinguishable in terms of T cell residency transcriptional signatures. Single cell analyses identified several subpopulations, mutual clonality, and indicated a potential developmental trajectory shared between TRM and TRM-like cells. This thesis demonstrates the potential for using TRM-like cells as a correlate of prime-target induced protection against liver-stage malaria. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. This work provides a blueprint for understanding and monitoring liver TRM induced by a new liver-stage malaria vaccine approach. |
| spellingShingle | Noé, A Evaluating new malaria vaccine candidates |
| title | Evaluating new malaria vaccine candidates |
| title_full | Evaluating new malaria vaccine candidates |
| title_fullStr | Evaluating new malaria vaccine candidates |
| title_full_unstemmed | Evaluating new malaria vaccine candidates |
| title_short | Evaluating new malaria vaccine candidates |
| title_sort | evaluating new malaria vaccine candidates |
| work_keys_str_mv | AT noea evaluatingnewmalariavaccinecandidates |