Clinical and Immunological Evaluation of T cell- and Antibody-Inducing Viral Vector Vaccines against Blood-Stage Malar
Lead Research Organisation:
University of Oxford
Department Name: Medical Sciences Divisional Office
Abstract
Malaria remains a huge public health problem in the developing world. The development of an effective vaccine remains an important but elusive goal. Malaria is caused by a parasite that first infects the liver before moving into the blood where it causes disease. A few vaccines have been developed recently that can kill some parasites in the liver, however, there is still no vaccine that can kill parasites in the blood.
This research will test a new vaccine technology against the parasites in the blood. These vaccines, developed by scientists at the Jenner Institute, Oxford University, use viruses that are genetically engineered to look like malaria parasites. The work will test the safety and effectiveness of these vaccines in volunteers in clinical trials in Oxford, and importantly also study the immune responses produced by them. Scientists can then attempt to figure out which immune responses are killing the parasites. This research will also assess how malaria infection can interfere with immune responses in humans in both the UK and Africa. It is extremely important to understand these interactions between malaria parasites and the human immune system, because we can use this information to help design better vaccines in the future.
This research will test a new vaccine technology against the parasites in the blood. These vaccines, developed by scientists at the Jenner Institute, Oxford University, use viruses that are genetically engineered to look like malaria parasites. The work will test the safety and effectiveness of these vaccines in volunteers in clinical trials in Oxford, and importantly also study the immune responses produced by them. Scientists can then attempt to figure out which immune responses are killing the parasites. This research will also assess how malaria infection can interfere with immune responses in humans in both the UK and Africa. It is extremely important to understand these interactions between malaria parasites and the human immune system, because we can use this information to help design better vaccines in the future.
Technical Summary
The development of a highly effective malaria vaccine remains an important but elusive goal. To date, blood-stage malaria candidate vaccines, based primarily on protein-in-adjuvant formulations, have almost all been selected for clinical trials based on their ability to induce growth inhibitory antibodies - assessed using an in vitro assay that lacks T cells or monocytes. Despite these extensive efforts, these technologies have sadly shown limited or no success in clinical settings. A key contributing factor to these difficulties is our limited understanding of protective immune responses in vivo in humans against blood-stage parasites. However, there is growing evidence for the role of T cells and antibody Fc-mediated effector functions in immunity to blood-stage malaria and yet, to date, no vaccine has sought to induce such responses. This research seeks to address the merits of using viral vectored vaccines encoding blood-stage malaria antigens in humans in Phase I/IIa clinical trials. These vaccines induce strong and protective T cell and Th1-type antibody responses against encoded antigens in animal models, and now provide the first opportunity to address fundamental questions in humans regarding the contribution of cellular and antibody Fc-mediated immune responses to protective efficacy against blood-stage malaria.
This research will aim to assess the safety, immunogenicity and efficacy of viral vector blood-stage malaria vaccines; develop a new in vivo assay of antibody Fc effector function; and address fundamental questions about the immuno-modulatory effects of blood-stage parasite exposure on cellular immune responses in both malaria-na?ve and naturally-exposed individuals.
Summary of key goals:
1. Characterise the immunogenicity of viral vector blood-stage malaria vaccines in human volunteers using multi-functional flow cytometry and ELIspot assays for T cell responses as well as ELISAs, GIA assays and memory B cell ELIspot assays for humoral responses.
2. Assess IgG Fc effector functions in vivo by adoptive transfer of IgG from immunised volunteers into mice transgenic for different human Fc?Rs infected with a mouse malaria parasite chimeric for P. falciparum MSP119.
3. Attempt to correlate immunological readouts with efficacy in Phase IIa challenge studies.
4. Assess second generation vaccine strategies in humans using combinations of viral vector and protein-in-adjuvant vaccines.
5. Assess the effects of blood-stage malaria parasite exposure in UK volunteers on cellular and humoral immune responses.
6. Undertake baseline studies in African adults and children to measure i) cellular immune responses to blood-stage antigens, and ii) assess antibody Fc effector functions against MSP119 using the transgenic mouse model.
This research will aim to assess the safety, immunogenicity and efficacy of viral vector blood-stage malaria vaccines; develop a new in vivo assay of antibody Fc effector function; and address fundamental questions about the immuno-modulatory effects of blood-stage parasite exposure on cellular immune responses in both malaria-na?ve and naturally-exposed individuals.
Summary of key goals:
1. Characterise the immunogenicity of viral vector blood-stage malaria vaccines in human volunteers using multi-functional flow cytometry and ELIspot assays for T cell responses as well as ELISAs, GIA assays and memory B cell ELIspot assays for humoral responses.
2. Assess IgG Fc effector functions in vivo by adoptive transfer of IgG from immunised volunteers into mice transgenic for different human Fc?Rs infected with a mouse malaria parasite chimeric for P. falciparum MSP119.
3. Attempt to correlate immunological readouts with efficacy in Phase IIa challenge studies.
4. Assess second generation vaccine strategies in humans using combinations of viral vector and protein-in-adjuvant vaccines.
5. Assess the effects of blood-stage malaria parasite exposure in UK volunteers on cellular and humoral immune responses.
6. Undertake baseline studies in African adults and children to measure i) cellular immune responses to blood-stage antigens, and ii) assess antibody Fc effector functions against MSP119 using the transgenic mouse model.
