Preparatory phase II for the malaria vaccine candidate NPC-SE36/CpG
Project Completed
Please click to see the final report.

Introduction and Background of the Project


SE36 is a blood stage malaria vaccine candidate that primarily targets young children in endemic areas to reduce morbidity and mortality due to malaria. Though in principle all stages of parasite development are potential vaccine targets, the blood stage is the one that causes the symptoms of malaria and its complications, and thus has a public health impact. A blood-stage vaccine, either alone or as a component of a multi-stage vaccine, is needed to protect against clinical or epidemic malaria.

Early stage clinical trials have demonstrated that the BK-SE36 vaccine, SE36 recombinant protein and aluminium hydroxide gel, has acceptable reactogenicity, has no unexpected safety signals and was immunogenic. Vaccine responders experienced less malaria infection and have lower risk of developing clinical symptoms.  Moreover, a better immune response was achieved in Japanese adults when CpG-ODN (K3) adjuvant was added to the formulation. A safety and immunogenicity phase Ib trial is currently underway in adults to 1-year old children in Burkina Faso with this new formulation. Preliminary results do not indicate unexpected safety concerns. This project builds on these initial trials and allows the next step in further clinical development, before initiation of phase II proof-of-concept clinical trial.


Project objectives

Test the quality of a new and larger batch of SE36 vaccine adsorbed on aluminium hydroxide  (NPC-SE36 vaccine), manufacture new CpG-ODN (K3) adjuvant GMP lot; and select sites and prepare protocol for phase IIb clinical trial. Successful development of a large-scale formulation will enable us to have full evaluation of GMP produced vaccine that can be used for multi-site trials. Moreover, a well-designed phase IIb protocol with selected clinical sites ready to implement the phase IIb clinical trial would address the safety and efficacy of NPC-SE36 in a malaria endemic area. 


Project design

The project aims to: 1) Conduct pre-clinical studies on the new GMP lot of NPC-SE36 to show suitable formulation for clinical trial testing and importation. 2) Deliver a new GMP lot of CpG-ODN (K3) as adjuvant for clinical trials. 3) Select phase IIb clinical trial sites and prepare clinical trial documentation.

How can your partnership (project) address global health challenges?

Despite significant improvement in malaria control over the last two decades, malaria remains a deadly disease, causing an estimated 228 million cases and 405,000 deaths in 2018 according to the World Health Organisation (WHO).

As a preventive tool, malaria vaccines are ideally suited to tackle the major challenge of malaria control: the growing resistance of the parasite to both insecticides and drug 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. With modest protection, the development of RTS,S has been an important proof-of-concept that vaccine development in malaria is indeed possible. However, a vaccine that aims to reduce morbidity of malaria is important for public health. There is broad consensus within the global health community that more efficacious, second-generation vaccine(s) is(are) urgently needed, one with high overall efficacy and less number of vaccinations for implementation.

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 target the life cycle stage when the malaria parasite is circulating in the human blood, causing symptoms and clinical signs that can lead to severe morbidity and even death. SE36 has an acceptable safety profile, was immunogenic, overcame most of the challenges of blood-stage malaria vaccine candidates and showed favourable results in a follow-up study in Uganda. The current project forms an integral part of our plans to deliver an appropriate large-scale formulation of SE36, develop a clinical trial protocol and identify trial sites before initiation of phase IIb proof-of-concept trials.

Role and Responsibility of Each Partner

The partnership brings together leading institutions from Germany,  Japan  and  Burkina Faso with long-standing experience and interest in the development of malaria vaccines. The partnership is led by the European Vaccine Initiative, Germany  (EVI) which will be responsible for the overall coordination and management of the programme activities and will lead the protocol development and dossier preparation. The Research Institute for Microbial Diseases (RIMD), Osaka University, as scientific developer of the vaccine, will lead in quality control tests for the new vaccine lot, coordinate the toxicological safety study and will also coordinate for the GMP manufacture of the new CpG-ODN (K3) lot.  As development partner and clinical sponsor, Nobelpharma, Japan will lead and provide the new GMP grade NPC-SE36 batch from the new GMP manufacturer for the planned pre-clinical studies; as well as coordinate, with RIMD, the GMP manufacture of the new CpG-ODN (K3) lot.  NPC will also lead for regulatory consultations and site selection visits.  As partner in Burkina Faso, Groupe de Recherche Action en Santé  (GRAS) will be involved in the phase II protocol and study dossier preparation. Having worked for more than a decade in clinical trials and involved in networking with various accomplished African medical research centers/organizations, GRAS will help in trial site selection and evaluation process in Africa.

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.

Final Report

1. Project objective

Early-stage clinical trials with BK-SE36 or BK-SE36/CpG show the potential of SE36 as a blood-stage malaria vaccine. A suitable formulation and larger manufacturing scale are needed for further clinical development. The project sought to undertake the technology transfer to a new GMP manufacturer. Additionally, studies are ongoing to search alternative methods to gel filtration chromatography to streamline the purification process of SE36. The capsid Virus-Like Particle (cVLP) platform technology is also explored for higher, longer-lasting antibody responses to overcome immune tolerance. Lastly, the project aimed at evaluating the persistence/longevity of the immune responses elicited by BK-SE36/CpG.


2. Project design

Manufacturing activities included (1) preparation of new formulation of SE36 with aluminium, (2) GMP production of CpG(K3) adjuvant and (3) improvement of large-scale manufacture of SE36. Parallel activities included (4) combination of SE36 with cVLP, Clinical activities focused on (5) the preparation of a phase 2 clinical trial protocol synopsis and (6) identification of a clinical CRO. Additionally, (7) a follow-up study was carried on children aged 5-10 years vaccinated with BK-SE36/CpG that showed lower risk of malaria infection compared to the control arm. Vaccinees sera were collected 32 months after last dose for specific SE36 antibody titre measurement.


3. Results, lessons learned

New GMP CpG(K3) adjuvant batch was manufactured with a shelf life of 3 years. Tests are ongoing to extend the stability up to 5 years. A new GMP (NPC-SE36) vaccine batch was manufactured using a plasmid carrying kanamycin resistance gene and new source of aluminium hydroxide gel. Small scale batch analysis indicated that product physicochemical properties are similar to those of the previous BK-SE36 vaccine product. Immunogenicity studies confirmed similarity of the potency of both vaccines. Three GMP production runs (30L) were successfully completed, and manufacturing reproducibility was confirmed. However, the release of clinical trial batches for regulatory (PMDA) inspection and shipping purposes are facing delay, with timeline and supply of raw materials and availability of equipments affected by the COVID-19 pandemic and geopolitical situation in Europe.

In parallel, optimization of the culture conditions and modification in the purification process of inclusion bodies resulted in higher yield (1g/5g cell paste) and higher purity (>90% purity) of SE36 protein. Additionally, several tag-versions of recombinant SE36 protein were constructed, purified and, together with University of Copenhagen, coupled with various cVLP for immunogenicity testing in mice.

After intensive discussion with the projects collaborators, agreement was reached on the phase 2 field trial design, objectives and sample size resulting in a finalised protocol synopsis. The sponsor also identified and selected a CRO to conduct the phase 2 clinical trial.

A follow-up study of BK-SE36/CpG phase Ib trial participants from the cohort of children aged 5-10 years evaluated the long-term persistence/longevity of the immune response. At year 3 (32 months after the booster dose, 2 years after the end of the primary trial), 83% of children had detectable anti-SE36 total IgG antibody vs. 27% in the control group (possibly due to natural infection). The difference was statistically significant between groups (p = 0.039). The highest antibody titres were in the BK-SE36/CpG group and the lowest in the control group (p = 0.003).  A natural boosting phenomenon could explain the sustained level of immune responses long time after the last vaccination.