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Understanding drivers of experimental malaria sub-unit vaccine induced immunity in Tanzania volunteers

Mkindi, Catherine Gerald. Understanding drivers of experimental malaria sub-unit vaccine induced immunity in Tanzania volunteers. 2019, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_13218

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Abstract

Despite being a preventable and treatable disease, Plasmodium falciparum malaria remains a major threat, especially in children and pregnant women in sub-Saharan Africa. Considerable progress has been achieved during the past decade, however, these positive trends have stalled in 2017. Efforts towards better disease control and focal elimination are hindered by development and spread of insecticide and drug resistance, leaving a malaria vaccine as a required tool to complement these approaches. RTS, S a subunit pre-erythrocyte stage vaccine is the only advanced malaria vaccine that has received approval for pilot administration in three countries in sub-Saharan Africa. This vaccine is however challenged by low efficacy and fast waning of protection. There is, therefore, an urgent need for the development of more potent malaria vaccines. WHO targets malaria elimination by 2030 and achieving this goal will depend on stopping malaria transmission. This goal will largely depend on reducing asexual blood stage Plasmodium parasites – which are not only the cause of morbidity and mortality -but also responsible for the development of gametocytes. Induction of parasite growth inhibitory antibodies has been shown to be key for protection following natural exposure and therefore, many vaccine development approaches try to follow this guidance from nature.
In order to reach this goal of a highly protective vaccine targeting asexual blood stages with acceptable longevity of duration, more research is needed understand mechanisms of optimal induction of long-lived antibody responses in a population that is also affected from other co-infections like helminths or HIV. Therefore, this thesis aimed to 1) investigate a novel blood stage sub-unit malaria vaccine candidate, P27A, for its potential to induce long-lasting antibody responses when formulated in the novel adjuvant GLA-SE in malaria pre-exposed populations, 2) understanding magnitude and cytokine production of the CD4 T cell responses induced by this novel vaccine formulation and the interaction with ongoing helminth co-infections, 3) shed more light on the mechanism of GLA-SE adjuvant being able to induce high and long-lasting antibody responses by studying follicular helper T cells in peripheral blood, 4) implement lymph node excision biopsy in rural Tanzania for detailed investigation of germinal centre responses which are crucial for production of potent antibody response.
The antigen P27A, when formulated with GLA-SE, induced a robust humoral immunity, with enhanced production of cytophilic antibodies, IgG1 and IgG3 and expansion of CD4 Th1 cells producing IL2, TNFa and IFNg, and subsequent memory development. In addition, the adjuvant GLA-SE promoted the expansion of peripheral follicular helper T cells and recruitment of T cells bearing common T cell receptors, which is essential for a vaccine intended for the general population.
Advisors:Daubenberger, Claudia A. and Perreau, Matthieu
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Clinical Immunology (Daubenberger)
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13218
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (ix, 103 Seiten)
Language:English
Identification Number:
Last Modified:02 Sep 2019 12:42
Deposited On:02 Sep 2019 12:42

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