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Awarded Amount$2,781,588DiseaseMalariaInterventionVaccineDevelopment StagePhase1 Clinical DevelopmentCollaboration PartnersResearch Institute for Microbial Diseases (RIMD), Osaka University , Medical Center for Translational Research (MTR), Osaka University Hospital , Nobelpharma Co., Ltd. , Institut de Recherche en Sciences de la Santé (IRSS) , European Vaccine Initiative (EVI)Past Project
Introduction and Background of the Project
BK-SE36 is a blood stage malaria vaccine candidate that primarily targets young children in endemic areas to control parasitemia, resulting in reduction of morbidity and mortality. A blood-stage antigen as a malaria vaccine is also desirable to deal with epidemic transmission patterns, as it is uncertain how changing transmission patterns may impact malaria severity. Though in principle all stages of parasite development are potential vaccine targets, the blood stage is the one that causes disease symptoms and complications, and thus would have a public health role. Previous phase Ib clinical trials in Africa have demonstrated that (i) BK-SE36 -SE36 antigen adjuvanted with aluminium hydroxide gel (AHG)- is safe, with lower risk of acquiring clinical malaria as well as against malaria infection in vaccine responders, and (ii) that an even better immune response against BK-SE36 can be achieved in adults when using a different formulation of the antigen with K3 CpG adjuvant (BK-SE36/CpG).
With the aim to further evaluate the use of the K3 CpG adjuvant in the formulation of this particular malaria vaccine candidate, in this project a clinical trial will be conducted using BK-SE36/CpG to address potential safety issues and further assess the functionality of the induced antibodies, with the ultimate goal to assess which formulation of the BK-SE36 vaccine should be used in populations exposed to malaria in Africa. In terms of combination vaccines, the trial will also provide important safety data for the utility of BK-SE36 and the usefulness K3 CpG as an immune-enhancing adjuvant.
The project will assess the safety and reactogenicity of 3 doses of the malaria vaccine candidate BK-SE36, formulated with the TLR9 ligand K3 CpG-ODN, via intramuscular route in healthy African adults and children exposed to the parasite Plasmodium falciparum.
Moreover, the humoral immune response to the vaccine antigen administered intramuscularly will be assessed by measuring the level of IgG in all subjects participating in the clinical trial.
The trial will be a double blind, single-dosage, randomized, controlled, age de-escalating phase Ib clinical trial. The site will be in Burkina Faso, a West African country that, to date, shows no evidence of decline in malaria incidence and with children under five years of age as the population at highest risk. One hundred thirty five healthy subjects in 3 age cohorts (adults > 21-years-old; 5-10 years-old, and 12-24 month-old) will be participating in the trial to received either BK-SE36 or a control vaccine. Although the first-in-man clinical trials with Japanese malaria naïve volunteers showed that the vaccine was well tolerated, the cautious staggered design will ensure safety of the volunteers in the malaria exposed population, as this is the first time the vaccine formulation will be evaluated in malaria endemic areas. The current trial of BK-SE36 in Burkina Faso is proceeding as scheduled. Based on the recently completed trial in Japan, it is expected that BK-SE36/CpG is a better formulation than BK-SE36. Administration will be done twice at 28 day interval with a booster dose four months after. The age limit was set to 12 months, excluding those receiving EPI (Expanded Progam on Immunization) vaccines to avoid any vaccine interference and provide straightforward assessment of BK-SE36/CpG. There will be 11 visits on the trial site and volunteers can visit anytime. Institutional ethical committees, a Scientific Advisory Committee, an independent Local Safety Monitor, and regulatory authorities will provide approvals and oversight for the conduct of the trial. Follow-up of all vaccinees will be done at least until one year after first vaccination.
How can your partnership (project) address global health challenges?
Despite significant improvement over the last two decades or so, malaria remains a deadly disease, causing an estimated 214 million cases of malaria and 438.000 deaths in 2015 according to the World Health Organisation (WHO).
As a prevention tool, malaria vaccines are ideally suited to tackle the major challenge of malaria control: the growing resistance of the parasite to both insecticides and treatment. Long-term support for research and development into effective malaria vaccines, including support for the further clinical development of promising vaccine candidates, is therefore vital and of the highest global disease priority. Consequently, malaria vaccine development is one of the explicit priority research needs identified by WHO and by the Malaria Vaccine Funders Group which asks for the development of second generation vaccines with protective efficacy of at least 75% against clinical malaria, to be licensed by 2030.
What sort of innovation are you bringing in your project?
So far no vaccine has been licensed against malaria. The currently most advanced malaria vaccine is RTS,S. However, although the development of RTS,S has been an important proof of concept that demonstrated that the development of vaccines against malaria is indeed possible, RTS,S is unlikely to be the tool ultimately to be used in the final push for global malaria eradication due to its a rather modest overall efficacy and the need for a series of several vaccinations. There is broad consensus within the global health community that more efficacious, second-generation vaccines are urgently needed.
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. Blood stage antigens such as SE36 (the antigen included in BK-SE36) come from the life cycle stage where the malaria parasite is in the human blood and which is responsible for the symptoms which we know as malaria. It is widely agreed that blood stage antigen will be one of the components that will be included in future second generation malaria vaccines. BK-SE36 previously demonstrated to be a promising malaria blood stage vaccine candidate, and the further characterization of this vaccine candidate using an improved formulation that aims to further increase the immunogenicity of the antigen is the particular innovation of the current project.
Role and Responsibility of Each Partner
The partnership brings together leading institutions from Burkina Faso, Germany and Japan with long-standing experience and interest in the development of malaria vaccines. The partnership is led by the European Vaccine Initiative which will be responsible for the overall coordination and management of the programme activities. The Research Institute for Microbial Diseases, Osaka University, will be responsible for coordination in Japan, logistics support and provision of the GMP-grade investigational product BK-SE36/CpG, whereas the Institut de Recherche en Sciences de la Santé, Burkina Faso, will be responsible for the conduct of the Phase Ib clinical trial in Africa. The Medical Center for Translational Research, Osaka University Hospital, will serve as medical adviser, and Nobelpharma, Japan, will be responsible for the oversight of the study. The partnership supports the sponsor in ensuring the conduct of the clinical trial in accordance with ICH-GCP and local regulations.
Others (including references if necessary)
Horii T, et al. Evidences of protection against blood-stage infection of Plasmodium falciparum by the novel protein vaccine SE36. Parasitol Int. 2010: 59(3):380-386. doi: 10.1016/j.parint.2010.05.002.
Palacpac NM, et al. Phase 1b randomized trial and follow-up study in Uganda of the blood-stage malaria vaccine candidate BK-SE36. PLoS One. 2013:8(5):e64073. doi: 10.1371/journal.pone.0064073
Tougan T, et al. TLR9 adjuvants enhance immunogenicity and protective efficacy of the SE36/AHG malaria vaccine in nonhuman primate models. Hum Vaccin Immunother. 2013:9: 283-90. doi: 10.4161/hv.22950
Yagi M, et al. Antibody titres and boosting after natural malaria infection in BK-SE36 vaccine responders during a follow-up study in Uganda. Sci Rep. 2016: 6:34363. doi: 10.1038/srep34363.
Tougan T, et al. Molecular camouflage of Plasmodium falciparum merozoites by binding of host vitronectin to P47 fragment of SERA5.Sci Rep.2018:8:5052. doi:10.1038/s41598-018-23194-9.
This project was built on the success of previous GHIT supported studies (RFP-2013-001 and G2014-109) to advance the clinical development of the blood-stage malaria vaccine SE36 formulated with K3 CpG adjuvant (BK-SE36/CpG). The G2016-106 project sought to demonstrate the safety and immunogenicity of three full doses of BK-SE36/CpG administered intramuscularly over a period of 12 months in a Burkinabe population exposed to malaria. For the first time, the utility of a third booster dose in a malaria endemic setting and the use of K3 CpG-ODN were tested on 1-2-year-old children.
The trial was designed as a double blind, single-dosage, randomised, controlled, age de-escalating, phase Ib clinical trial in Burkina Faso. One hundred thirty-five (135) healthy adults and children were included in three age cohorts: 21–45-year-old (Cohort 1, n=45), 5–10-year-old (Cohort 2, n=45) and 12–24 months (Cohort 3, n=45). Participants in each cohort were randomised into BK-SE36/CpG and control arms in a 2:1 ratio with each subject receiving 3 doses of the study vaccine. The start of each cohort was staggered and based on safety data of previous cohort(s). All participants were followed for a year.
3.Results, lessons learned
In the phase Ib clinical trial conducted in Burkina Faso, the BK-SE36/CpG malaria vaccine administered at full dose and with a three-dose regimen, showed an acceptable safety profile with mild to moderate local and systemic solicited adverse events. No safety concerns were raised in any age cohort and the safety profile was comparable to the control rabies vaccine. BK-SE36/CpG was immunogenic. A third dose resulted in high anti-SE36 IgG antibody titers in all cohorts. As expected, the youngest cohort showed a more robust response with higher anti-SE36 IgG antibody titres at any timepoint after vaccination.
In all cohorts, epitope mapping of sera from BK-SE36/CpG vaccinees showed predominant reactivity to synthetic peptides 7-9 spanning the SE36 protein. Sera from younger cohorts showed broader reactivity. Highest reactivity was observed to SE36 intrinsically unstructured regions.
Trends towards reduced risk for malaria incidences (first or only episode and multiple episodes) were seen only in Cohort 2 subjects receiving the BK-SE36/CpG vaccine, while Cohort 1 and 3 had less reported malaria cases during the study. Although interpreted with caution, due to small study sample size, clinical malaria incidences in BK-SE36/CpG and control arm based on measured fever (≥ 38°C) and presence of P. falciparum ≥5000/µL in 5–10-year-old, showed statistically lower rate ratio for first (or only) clinical malaria incidences in BK-SE36/CpG vaccinees compared to the control (0.26, p=0.024 for first (or only) and 0.31, p=0.055 for all episodes). These results strongly support the conduct of proof-of-concept studies for BK-SE36/CpG.