Developmental Clinical Studies - Clinical evaluation of an AdCh63-MVA PvDBP_RII vaccine for blood-stage Plasmodium vivax
Lead Research Organisation:
University of Oxford
Department Name: Central Admin - Research Services
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. Five different types of parasite cause malaria disease in humans. Most research in the last few decades has focussed on one of these parasites ? called Plasmodium falciparum. This parasite is responsible for most of the deaths every year due to malaria infection.
Many vaccines against blood-stage infection with Plasmodium falciparum have been tested in clinical trials but always with disappointing results. This is most likely because this parasite has many different ways to infect red blood cells. Consequently if a vaccine stops one invasion pathway, the parasite will simply switch to a different one and continue with the infection process.
A second malaria parasite, called Plasmodium vivax, is far more widespread worldwide. Although it doesn?t kill infected individuals, infection with this parasite causes a debilitating and severe illness that often relapses months or years later. This parasite, like Plasmodium falciparum, exerts a huge and unacceptable health burden on the wider developing world. However, this parasite may be more amenable to the effects of a blood-stage vaccine. It can only use a single invasion pathway to infect red blood cells, and a vaccine targeting this one pathway may stand a much greater chance of success.
Here we propose to use a new vaccine delivery technology to target this invasion pathway of Plasmodium vivax. Vectored vaccines use a crippled but safe virus to produce the malaria protein inside the injection site of the vaccinee. This technology has recently been shown to be safe and capable of inducing strong immune responses in human clinical trials at Oxford University. In this application we therefore propose to test a new pair of vectored vaccines against the blood-stage of Plasmodium vivax malaria for the first time in humans. We will develop these new vaccines and test their safety and immune-stimulating capacity in a clinical trial in healthy adult volunteers. This study should provide a critical test of the possibility that such vectored vaccines could be useful in inducing immune responses that may protect people against infection with the Plasmodium vivax form of malaria.
Many vaccines against blood-stage infection with Plasmodium falciparum have been tested in clinical trials but always with disappointing results. This is most likely because this parasite has many different ways to infect red blood cells. Consequently if a vaccine stops one invasion pathway, the parasite will simply switch to a different one and continue with the infection process.
A second malaria parasite, called Plasmodium vivax, is far more widespread worldwide. Although it doesn?t kill infected individuals, infection with this parasite causes a debilitating and severe illness that often relapses months or years later. This parasite, like Plasmodium falciparum, exerts a huge and unacceptable health burden on the wider developing world. However, this parasite may be more amenable to the effects of a blood-stage vaccine. It can only use a single invasion pathway to infect red blood cells, and a vaccine targeting this one pathway may stand a much greater chance of success.
Here we propose to use a new vaccine delivery technology to target this invasion pathway of Plasmodium vivax. Vectored vaccines use a crippled but safe virus to produce the malaria protein inside the injection site of the vaccinee. This technology has recently been shown to be safe and capable of inducing strong immune responses in human clinical trials at Oxford University. In this application we therefore propose to test a new pair of vectored vaccines against the blood-stage of Plasmodium vivax malaria for the first time in humans. We will develop these new vaccines and test their safety and immune-stimulating capacity in a clinical trial in healthy adult volunteers. This study should provide a critical test of the possibility that such vectored vaccines could be useful in inducing immune responses that may protect people against infection with the Plasmodium vivax form of malaria.
Technical Summary
The Need: Plasmodium vivax, one of the five Plasmodium species to cause human malaria, is the most widespread geographically and has been viewed, most certainly incorrectly, as a ?benign? parasite. In fact over 80 million cases of P. vivax malaria are reported annually, leading to severe morbidity for inhabitants of endemic areas as well as some mortality.
Rationale: In recent years, viral vectored vaccines have been developed targeting the P. falciparum blood-stage malaria antigens MSP1 and AMA1. In Phase I/IIa clinical trials these vectors have induced strong serum antibody responses, unprecedented levels of cellular immunity and the first demonstration of efficacy with these antigens, albeit modest, in a human sporozoite challenge study. Unlike P. falciparum which utilises multiple redundant invasion pathways for human erythrocyte invasion, P. vivax requires an interaction with the Duffy blood group antigen, which is mediated by region II of the P. vivax Duffy-binding protein (PvDBP_RII). Given the essential nature of this invasion pathway, this candidate P. vivax antigen stands a far greater chance of success in comparison to the widely tested merozoite targets of P. falciparum.
Solution & Development Plan: We have recently developed AdCh63 and MVA vectors expressing PvDBP_RII, and have shown in pre-clinical animal studies that, like for PfMSP1 and PfAMA1, these vectors induce strong antibody and cellular immunogenicity. This proposal aims to manufacture these two vectors to GMP and undertake a Phase Ia clinical trial to assess the safety, immunogenicity and in vitro efficacy of these new candidate vaccines for blood-stage P. vivax. If successful, these vaccines would be lead candidates for future efficacy testing.
Rationale: In recent years, viral vectored vaccines have been developed targeting the P. falciparum blood-stage malaria antigens MSP1 and AMA1. In Phase I/IIa clinical trials these vectors have induced strong serum antibody responses, unprecedented levels of cellular immunity and the first demonstration of efficacy with these antigens, albeit modest, in a human sporozoite challenge study. Unlike P. falciparum which utilises multiple redundant invasion pathways for human erythrocyte invasion, P. vivax requires an interaction with the Duffy blood group antigen, which is mediated by region II of the P. vivax Duffy-binding protein (PvDBP_RII). Given the essential nature of this invasion pathway, this candidate P. vivax antigen stands a far greater chance of success in comparison to the widely tested merozoite targets of P. falciparum.
Solution & Development Plan: We have recently developed AdCh63 and MVA vectors expressing PvDBP_RII, and have shown in pre-clinical animal studies that, like for PfMSP1 and PfAMA1, these vectors induce strong antibody and cellular immunogenicity. This proposal aims to manufacture these two vectors to GMP and undertake a Phase Ia clinical trial to assess the safety, immunogenicity and in vitro efficacy of these new candidate vaccines for blood-stage P. vivax. If successful, these vaccines would be lead candidates for future efficacy testing.
