- RFP Year2014
- Awarded Amount$999,999
- Development StagePhase1 Clinical Development
- Collaboration PartnersResearch Institute for Microbial Diseases (RIMD), Osaka University, Centre National de Recherche et de Formation sur le Paludisme (CNRFP), European Vaccine Initiative (EVI)
Introduction and Background of the Project
The principal objective of this project is to advance the clinical development of the BK-SE36 vaccine candidate with the ultimate long-term goal to develop an effective prevention tool for clinical malaria. Malaria is caused by the Plasmodium parasite, the most deadly species being caused by Plasmodium falciparum. Despite a reduction in the overall malaria mortality over the last decade or so, on global level malaria remains the most important parasitic disease with substantial morbidity and mortality.
The Plasmodium parasite has a complex life cycle, different stages of the parasite can be found in different hosts (mosquitoes and man) and in different organs of the human body during infection. BK-SE36 is a so-called blood stage malaria vaccine candidate that is primarily intended for young children in endemic areas to control levels of the malaria parasite, resulting in reduction of morbidity and mortality caused by the disease. In this project, a phase Ib clinical trial with the BK-SE36 vaccine candidate will be conducted in Burkina Faso with the aim to (i) compare the clinical trial results from Burkina Faso with those from a previous clinical trial conducted in Uganda which has slightly different malaria disease characteristics, (ii) test the vaccine candidate in a younger age group (0-5 years old) that has not been included so far in any of the other clinical trial testing of BK-SE36, and (iii) generate additional information on safety, immunogenicity and possible efficacy. In addition, the project aims to conduct a follow-up study of Japanese volunteers that participated in a first-in-man trial of BK-SE36 with a different adjuvant, a substance that enhances a persons’ response to the vaccine. The follow-up study would allow long term evaluation of the safety and immunogenicity of BK-SE36/CpG.
How can your partnership (project) address global health challenges?
The partnership brings together leading institutions from Japan, Burkina Faso and Germany -RIMD, CNRFP and EVI, respectively. All have long-standing experience in the development of malaria vaccines and which have joined their complementary expertise with the objective to accelerate the development of the BK-SE36 vaccine candidate.
All three partners -two public research organisations and one Product Development Partnership (PDP)- are non-profit organisations which have come together in this proposal thanks to their shared interest and their strong commitment to develop technologies for the control and eradication of malaria, the parasitic disease with the highest disease burden on a global level.
What sort of innovation are you bringing in your project?
So far no vaccine has been licensed against malaria. It is expected that in the future a highly effective malaria vaccine will need to combine several antigens from different stages of the malaria parasite´s life cycle. So-called blood stage antigens, coming from the stage where the malaria parasite is in the human blood and the stage responsible for the symptoms which we know as malaria, will be one of the components that will be included in such multi-stage malaria vaccines. BK-SE36 in particular was demonstrated by RIMD in previous clinical trials to be a promising malaria blood stage vaccine candidate and the further characterization of this vaccine candidate in this project will be the next step in the potential incorporation of BK-SE36 in a combination malaria vaccine.
With the use of the novel adjuvant K3 CpG, BK-SE36/CpG is envisioned to target groups with reduced immune function (adults in malaria endemic areas, immunosuppressed individuals or travelers from non-endemic areas). The long term safety and immunogenicity evaluation in humans of BK-SE36/CpG is necessary for further clinical development.
Role and Responsibility of Each Partner
Professor Toshihiro Horii is the Principal Scientist/Collaborator for RIMD and the inventor of the BK-SE36 malaria vaccine. He is responsible for the oversight of the cGMP production of the vaccine and the GLP tests for new adjuvants for BK-SE36, providing with his team support and advice for BK-SE36 clinical trial as well as acting as sponsor representative. In addition, the team will perform ELISA on the BK-SE36 phase Ib trial subject samples to determine the humoral immune response and protective epitopes in individuals who were not infected with P. falciparum. SERA5 polymorphism studies will also be done for the parasites obtained from infected individuals. RIMD team is in charge of the follow-up study of the BK-SE36/CpG phase Ia clinical trial.
EVI executive director Dr Odile Leroy is the coordinator of the project. EVI is responsible for the overall coordination and management of the work program objectives, the BK-SE36 phase Ib clinical trial in Burkina Faso and the follow-up trial of the BK-SE36 CpG phase Ia clinical trial in Japan. EVI´s key role includes oversight of the phase Ib clinical trial, ad-hoc technical support and overview of process development, adjuvant selection and testing. The BK-SE36 phase Ib clinical trial sponsor has delegated to EVI the monitoring activities, investigational site visits and audits. EVI support to sponsor also includes the development and review of all aspects of the clinical BK-SE36 development plan.
CNRFP plays a major role in the conduct of pivotal phase I clinical trials. Dr Sodiomon Sirima is the Principal Investigator of the BK-SE36 phase Ib clinical trial with the overall responsibility and coordination of conduct of clinical trial. The CNRFP is also in charge of the T cell cytokines determination, the malaria diagnosis and gametocytes detection in clinical trial phase Ib subject samples. The sponsor has delegated to CNRFP its responsibility toward the Burkina Faso regulatory authorities and the clinical trial and data management as well as the statistical analyses.
Others (including references if necessary)
Research Institute for Microbial Diseases (RIMD), Osaka University
RIMD was established 1934 and is composed of three research divisions for comprehensive studies on microbial diseases and three attached centers for specialised research on infectious disease and genome information. Besides basic studies on identification of pathogens and determination of pathogenic mechanisms, RIMD has developed vaccines and diagnostics. To translate RIMD research findings into practical applications such as vaccine production, RIMD has long worked in partnership with a public-service corporation, the Research Foundation for Microbial Diseases of Osaka University (BIKEN, established 1934). Together, both institutes continue to serve the public interest and contribute to promotion of global health.
European Vaccine Initiative (EVI)
EVI -initially established in 1998 as European Malaria Vaccine Initiative (EMVI)- is a leading European PDP supporting the development of effective, accessible, and affordable vaccines against malaria and other diseases of poverty in low income populations. To date, EVI has achieved to support the development of 32 different vaccine preparations of which 16 malaria vaccine candidates were progressed into early clinical development (phase I). Three malaria vaccine candidates were transitioned to phase II clinical development to partner organisations established in sub-Saharan Africa.
Centre National de Recherche et de Formation sur le Paludisme (CNRFP)
CNRFP is a research institution funded by the Ministry of Health of Burkina Faso in 1983 as a need to foster quality research that will contribute to evidence-based decision making for the policymakers in Burkina Faso. The institution has its main offices in Ouagadougou and has a well-developed network of satellite field sites throughout the country. Among these satellites sites two are well set up with clinical research facilities and are permanently maintained. CNRFP has played a major role in the conduct of pivotal studies that contributed to major policy changes in the malaria field and has been involved in a large number of malaria vaccine development projects.
1. Project objective
The objective is to advance the clinical development of BK-SE36, a blood-stage malaria vaccine that has previously shown encouraging immunogenicity results in Japanese adults and Ugandan subjects aged 6-32 years. A phase Ib trial was planned to test the BK-SE36 vaccine in younger groups of children aged 1-5 years in Burkina Faso where malaria is rampant.
Additionally, a follow-up study of Japanese volunteers that participated in the first-in-man trial of BK-SE36 with a new adjuvant that is expected to enhance immune response, CpG-ODN (K3), was carried out to assess the vaccines’ (designated as BK-SE36/CpG) long term safety and immunogenicity.
2. Project design
The trial was designed as a double blinded, randomized, controlled, age deescalating, phase Ib clinical trial in Burkina Faso using either intramuscular or subcutaneous vaccination of full dose BK-SE36 vaccine. The participants aged 12-24 months or 25-60 months were to receive the vaccine on three occasions and followed for one year.
In the BK-SE36/CpG one year follow up study, consent was obtained from the Japanese volunteers to visit the clinic every three months and the safety and persistence of the immune response to vaccination was evaluated.
3. Results, lessons learned
In the phase Ib clinical trial conducted in Burkinabe children, BK-SE36 vaccine was deemed safe and well tolerated. The vaccine induced an immune response with IgG titers that increased following the second immunisation and after the booster dose. A booster dose maybe necessary in malaria endemic areas. Furthermore as anticipated, the increase in IgG titers after the vaccinations was more pronounced in the younger cohort (12-24 months) than in older children (25-60 months) and this was observed for both intramuscular and subcutaneous route of vaccination.
After one year follow-up of malaria naïve Japanese adults vaccinated with the BK-SE36/CpG vaccine, no change was observed in the laboratory indicators/markers for autoimmune disease confirming the safety of the vaccine. Moreover, the immune response (IgG) elicited by the vaccine remained high even after one year, the response was directed toward a conserved region of SE36 protein, suggesting that the vaccine is also promising against different parasite strains. In addition, this conserved region has no strict structural requirement in order to elicit protective antibodies.
Safety and immunogenicity results support the continuation of the clinical development of the BK-SE36/CpG in children living in malaria endemic regions, the target population of the vaccine.