Introduction and Background of the Project

Introduction

Despite intensive control efforts in place, malaria remains one of the leading causes of morbidity and mortality, particularly in children under the age of five in sub-Saharan Africa. According to WHO report 2024, there were 263 million malaria cases and 597 000 deaths globally (of which 246 million and 569 000, respectively occurred in the WHO African Regions). Since 2020, an increase of malaria incidence was estimated especially in WHO African Region and WHO Eastern Mediterranean Region. The fight against malaria is hindered by the Plasmodium parasite’s ability to develop resistance to insecticides and antimalarial drugs, genome’s mutations that impact diagnostic tests, the complex parasite life cycle and ability to evade the host immune system, and the emergence of new mosquito vectors. Great progress is anticipated with the licensure and programmatic deployment of two anti-sporozoite vaccines, RTS,S/AS01 and R21/Matrix-M for the prevention of malaria in children under five living in moderate-to-high transmission areas. However, it is also acknowledged that vaccines targeting only one stage of the parasite’s life cycle may not provide complete protection and additional, complementary strategies are needed to ensure higher and durable efficacy to control blood-stage parasitemia and prevent morbidity and mortality.

This project builds on the success of previous GHIT-funded projects (G2013-105, G2014-109, G2016-106, G2019-208) to further advance the development of the promising blood-stage malaria vaccine candidate based on the N-terminal domain of Plasmodium falciparum serine repeat antigen-5 (SE36). Previous phase I trials in Uganda and Burkina Faso have shown that SE36 (absorbed to aluminium hydroxide gel (BK/SE36) or further adjuvanted with CpG (BKSE36/CpG) is well tolerated, has an acceptable safety profile and is immunogenic. However, improved immunogenicity and reduced cost-of-goods/cGMP manufacture would further support and facilitate future implementation in the target populations.

Project objective

Our goal is to fast-track the clinical development of the SE36/cVLP vaccine candidate and obtain supporting evidence for a safe and efficacious blood-stage vaccine that could be deployed as a stand-alone or potentially combined in a second-generation multi-stage malaria vaccine. The main objectives are to:

1. Manufacture a large GMP batch of SE36

2. Produce a GMP batch of SE36/cVLP

3. Conduct a GLP-compliant nonclinical toxicology study for SE36/cVLP + Sepivac SWE adjuvant

4. Prepare clinical trial documentation for the conduct of a phase I/IIa (CHMI) trial for SE36/cVLP (+/- Sepivac SWE) to assess safety, immunogenicity, and time-to-first episode of clinical malaria in malaria-naïve vaccinated subjects

Project design

The previous GMP manufacturing process for SE36 was largely based on the E. coli expression system with modest yield after several chromatography steps. Benefiting from recent collaborations and new adaptive vaccine technologies, we now propose to manufacture a larger batch of SE36 using a simplified, high-yield process in the Corynex expression system. Moreover, to increase the vaccine immunogenicity, SE36 antigens will be displayed on capsid virus-like particles (cVLP) ensuring unidirectional and high-density display. A previously manufactured small lab-scale batch of SE36/cVLP showed that coupling was stable and that coupled SE36 was highly immunogenic in the mouse model. Armed with this success, we now expand our efforts to manufacture a larger GMP batch of SE36/cVLP, conduct a GLP-compliant nonclinical toxicology study and prepare trial documentation to conduct a phase I/IIa trial with this newly optimised formulation of the SE36 vaccine candidate. A successful completion of these activities will set the stage for a first-in-human safety, immunogenicity and efficacy trial.

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

With the potential to induce higher efficacy and longer durability with fewer doses required, SE36/cVLP offers the possibility of a cost-effective blood-stage vaccine that could be deployed as a stand-alone or potentially combined in a second-generation, multi-stage malaria vaccine. The main goal is to reduce morbidity and mortality in individuals at risk of malaria in endemic areas.

What sort of innovation are you bringing in your project?

In our project we aim to employ a novel expression system, and a more efficient antigen presentation platform based on cVLP to reduce the overall manufacturing costs and improve the magnitude and longevity of the vaccine-induced immune response, with the ultimate goal to develop a safe, affordable and efficacious blood-stage malaria vaccine. 

Role and Responsibility of Each Partner

Most of the project partners have long-standing partner histories, building on previous and ongoing collaborations. The European Vaccine Initiative (EVI) is the Designated Development Partner responsible for management, coordination and ad-hoc scientific/regulatory support. RIMD, Osaka University (OU) and University of Copenhagen (UCPH) will respectively be responsible for coordination and scientific advice for SE36 and SE36/cVLP. AdaptVac will serve as technical adviser for cVLP manufacture and coupling to SE36. Eberhard Karls Universität of Tübingen (EKUT) will coordinate the preparation of phase I/IIa (CHMI) trial. Ajinomoto Co., Inc. will be the CDMO with the Corynex® system for SE36, supporting process development and GMP manufacturing of SE36, while Nobelpharma Co., Ltd. (NPC) will contribute to consultation for the development strategy.

Others (including references if necessary)

1. Persistence of anti-SE36 antibodies induced by the malaria vaccine candidate BK-SE36/CpG in 5–10-Year-Old Burkinabe children naturally exposed to malaria. Vaccines. 2024; 12(2):166. https://doi.org/10.3390/vaccines12020166

2. Safety and immunogenicity of BK-SE36/CpG malaria vaccine in healthy Burkinabe adults and children: a phase 1b randomised, controlled, double-blinded, age de-escalation trial. Frontiers in Immunology, 14, 1267372. https://doi.org/10.3389/fimmu.2023.1267372

3. Safety and immunogenicity of BK-SE36 in a blinded, randomized, controlled, age de-escalating phase Ib clinical trial in Burkinabe children. Frontiers in Immunology, 13, 978591. https://doi.org/10.3389/fimmu.2022.978591

4. World malaria report 2024 by WHO https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2024