Clinical and immunological evaluation of new malaria vaccines encoding the Thrombospondin Related Adhesion Protein

Bejon, Philip (2007). Clinical and immunological evaluation of new malaria vaccines encoding the Thrombospondin Related Adhesion Protein. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000ea1f

Abstract

Malaria causes around 2 million deaths per year, and the mortality appears to be rising. A prophylactic vaccination is urgently needed. A viral vectored vaccination regimen has been developed in Oxford to induce T cell responses reactive to pre-erythrocytic antigens of Plasmodium falciparum malaria. I conducted a series of studies to evaluate the clinical outcome and immunological response to the vaccine. I analysed PCR data from experimental sporozoite challenge studies in the UK, and showed that vaccination reduced the numbers of parasites completing their pre-erythrocytic development. I conducted preliminary studies to explore the safety and immunogenicity of vaccination in adults and then children in Kilifi, Kenya.

Antigen insert, multiple versus single priming, different batches of vaccine (in one instance) and pre-vaccination immunity influenced the reactogenicity and immunogenicity of vaccination. Enhanced memory responses were seen with novel alternating vector regimens.

Having established immunogenicity, safety, and preliminary evidence of efficacy, I then conducted a large efficacy trial in the field, randomizing 406 children to either active vaccination or control. The primary outcome was time to first episode of febrile malaria. Although the regimen was immunogenic, the magnitude of T cell responses was lower than in previous studies. 346 children were vaccinated according to protocol. Episodes of febrile malaria were more frequent in the FFM ME-TRAP group (52/171 vs 401175 among controls), but this was not statistically significant (95% confidence interval 0.83 to 2.08, P=0.55 by logrank). Among children vaccinated with FFM ME-TRAP, there was no correlation between immunogenicity and malaria incidence.

I examined factors in the cohort of children that may have influenced immunogenicity. Malaria was more immunosuppressive than other parasitic infections, and is therefore the factor most likely to impact the development of investigational T cell inducing vaccines in malaria endemic areas.