Date of Award

Spring 2018

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Professor Samuel McConkey

Funder/Sponsor

European Vaccine Initiative

Keywords

Malaria, Vaccine, Clinical Trial, Ireland

Abstract

Plasmodium falciparum (P. falciparum) malaria remains a significant cause of mortality and morbidity throughout the world. Development of an effective vaccine would be key intervention to reduce the considerable social and economic impact of malaria. Following review of previous work on malaria vaccines, we conducted a Phase Ia, non-randomized clinical trial in 24 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding the circumsporozoite protein (CS) of P. falciparum. ChAd63-MVA CS administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to CS. With a priming ChAd63 CS dose of 5x109 vp responses peaked at a mean of 1947 SFC/million Peripheral Blood Mononuclear Cells (PBMC) (median 1524) measured by ELISpot 7 days after the MVA boost and showed a mixed CD4+ / CD8+ phenotype. With a higher priming dose of ChAd63 CS dose 5x1010 vp T cell responses did not increase (mean 1659 SFC/million PBMC, median 1049). Serum IgG responses to CS were modest and peaked at day 14 post ChAd63 CS (median antibody concentration for all groups at day 14 of 1.3µg/ml (range 0 – 11.9), but persisted throughout late follow up (day 140 median antibody concentration groups 1B & 2B 0.9µg/ml (range 0 – 4.7). ChAd63-MVA is a safe and immunogenic delivery platform for the CS antigen in humans which warrants efficacy testing. Use of ChAd63-MVA viral vector, expressing various antigens, is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where both cellular and humoral immune responses are required for protection. Both vaccines proceeded on to phase IIa controlled human malaria infection challenge and showed some protection. The overall project to produce an effective malaria vaccine continues. This work was a step along the path to that goal.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

7.87 MB

Comments

A thesis submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2018.

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