Title: Development of viral vector combination vaccine strategies targeting both pre-erythrocytic and blood-stage malaria

PhD Student: Simone Claudia de Cassan

Supervisors: Prof. Adrian Hill (Oxford University, United Kingdom) and Prof. Alan Thomas (BioMedical Primate Research Centre, the Netherlands)

Collaborators: Dr. Simon Draper (Oxford University, United Kingdom)

In recent years, recombinant viral vectors administered in heterologous prime-boost regimes have been developed as approaches to target both the liver- and blood-stages of malaria infection. This work employed various vectors but the most promising regimes involve priming with replication-defective adenoviruses (Ads) and boosting with the poxvirus vector modified virus Ankara (MVA). Priming with a recombinant adenovirus and boosting with recombinant MVA eight weeks later has now been shown to induce remarkably strong T cell and antibody responses in animal models, and a clinical trial of this approach using the TRAP pre-erythrocytic antigen is in progress.

Adenovirus prime-poxvirus boost regimes are the most effective pre-erythrocytic vaccine approach to inducing liver-stage protection with subunit vaccines in both P. berghei and P. yoelii. Recently an adenovirus-MVA prime-boost regime, using vectors expressing the P. yoelii MSP-142 blood-stage antigen, could induce potent antibody and T cell responses, capable of providing partial protection against the late liver-stage parasites and complete protection against blood-stage malaria infection (Draper et al. submitted). Adenovirus and MVA vectors encoding P. falciparum MSP-1 and AMA-1 antigens are also highly immunogenic in mice and strong growth inhibitory activity has been induced.

Extensive studies in the HIV field have shown that vectored vaccines can be used as mixtures and clinical trials of such mixtures are in progress as HIV vaccines. This suggests that evaluating vectored malaria vaccines as mixtures might be an effective approach to generating strong pre-erythrocytic and blood stage protection.

This EMVDA PhD programme would focus on the development of combination vaccine approaches targeting liver- and blood-stage malaria, aiming to maintain maximal immunogenicity and efficacy of each component viral vaccine. Immunological studies into antigenic competition would be required, as well as studies using vaccine mixtures versus bi-cistronic viral vectors, and same versus separate site administration. Our laboratory is well set up to study the immunogenicity of each component vaccine using state of the art assays such as multi-parameter flow cytrometry. Using established P. yoelii CSP and MSP-1 models, vaccine efficacy in mice against the sporozoite, liver-stage and blood-stage forms can be assayed in house. Results can be translated directly to P. falciparum vaccine candidates, using vectors expressing ME-TRAP and PfMSP-1 and/or AMA-1. As well as assessing immunogenicity, the efficacy of these P. falciparum combination vaccines will be studied using i) in vitro growth inhibition assays against blood-stage P. falciparum, and ii) P. berghei sporozoite challenges (due to the presence of the Pb9 CSP epitope in the ME-TRAP multi-epitope string). The findings from this PhD programme could be directly translated into phase I / II clinical trials using existing facilities.