Vectored Blood Stage Malaria Vaccine
Lead Research Organisation:
University of Oxford
Department Name: Wellcome Trust Centre for Human Genetics
Abstract
Malaria is one of the greatest causes of infectious mortality globally but no vaccine is available. The blood-stage of the parasite?s life-cycle is the one that causes all the symptoms of disease and very often death. Many vaccines against this stage have been tested in clinical trials but always with disappointing results. However, all these vaccine comprised protein components of the parasite mixed with a chemical adjuvant designed to try and increase the immune response to the vaccine. Quite different types of vaccine are now showing promise in other diseases such as HIV/AIDS, tuberculosis and even the liver-stage of malaria. These vectored vaccines use a crippled safe virus to produce the malaria antigen inside the injection site of the vaccinee. This generates qualitatively and quantitatively different immune responses to protein/adjuvant vaccines.
Using a rodent malaria model we have found excellent protection using such vectored vaccines against blood-stage malaria and have gone on to make the corresponding vectors that target the major human parasite Plasmodium falciparum. In this application we propose to test a pair of vectored vaccines against the blood-stage of malaria for the first time in humans. We will use a well developed and safe infectious mosquito biting procedure to test whether the vaccine is effective in volunteers. This study should provide a critical test of the possibility that such vectored vaccines could be useful in protecting people against the important blood-stage of malaria.
Using a rodent malaria model we have found excellent protection using such vectored vaccines against blood-stage malaria and have gone on to make the corresponding vectors that target the major human parasite Plasmodium falciparum. In this application we propose to test a pair of vectored vaccines against the blood-stage of malaria for the first time in humans. We will use a well developed and safe infectious mosquito biting procedure to test whether the vaccine is effective in volunteers. This study should provide a critical test of the possibility that such vectored vaccines could be useful in protecting people against the important blood-stage of malaria.
Technical Summary
A highly effective vaccine against malaria should have a major impact on the global disease burden. Blood stage vaccines offer the prospect of substantially reducing rates of severe disease while allowing some natural immunity to develop. However, the development of protein/adjuvant vaccines against blood-stage malaria has proved very difficult. Following up evidence that cellular immunity against blood-stage parasites may contribute to protection, we have made the surprising observation that high level protection against rodent blood-stage malaria can be induced by vectored vaccines. In particular priming with an adenoviral vector and boosting with MVA, each encoding the P. yoelii MSP-1(42) antigen, induced high level protection with just two immunisations. This protection was largely antibody mediated but, additionally, vaccine-induced CD8 T cells reduced liver-stage parasite numbers.
We have used the same vectors with a P. falciparum insert to generate antibody responses which have strong growth inhibitory activity against different strains of this parasite in in vitro assays.
We propose to undertake the first clinical trial of a vectored blood-stage vaccine against malaria. The insert encodes both of the dimorphic variants of PfMSP1(42) and four more N-terminal conserved regions. A potent simian adenoviral vector, that avoids anti-vector immunity problems associated with human adenoviral vectors, will be used as a priming agent and MVA will be used to boost further both antibody and T cell responses. After dose optimisation in a phase I trial, efficacy will be assessed by sporozoite challenge and quantitation of parasite growth rates in vivo.
This proof-of-concept trial will assess the potential utility of leading vectored vaccines against blood-stage malaria, should allow evaluation of several assays as correlates of blood-stage protective immunity, and may point the way towards defining a highly effective multi-stage vectored malaria vaccine.
We have used the same vectors with a P. falciparum insert to generate antibody responses which have strong growth inhibitory activity against different strains of this parasite in in vitro assays.
We propose to undertake the first clinical trial of a vectored blood-stage vaccine against malaria. The insert encodes both of the dimorphic variants of PfMSP1(42) and four more N-terminal conserved regions. A potent simian adenoviral vector, that avoids anti-vector immunity problems associated with human adenoviral vectors, will be used as a priming agent and MVA will be used to boost further both antibody and T cell responses. After dose optimisation in a phase I trial, efficacy will be assessed by sporozoite challenge and quantitation of parasite growth rates in vivo.
This proof-of-concept trial will assess the potential utility of leading vectored vaccines against blood-stage malaria, should allow evaluation of several assays as correlates of blood-stage protective immunity, and may point the way towards defining a highly effective multi-stage vectored malaria vaccine.
