Introduction and Background of the Project

Introduction

Investment in next-generation Plasmodium falciparum malaria vaccines is urgently needed as the current vaccines (RTS,S/AS01 and R21/Matrix-M) have limited efficacy and durability. This proposal builds on recent advances in both anti-infection and blood-stage (BS) malaria vaccinology and will endeavor to bring the two into a single candidate. This approach is expected to improve efficacy and durability, lower cost of goods, and reduce cold chain requirements, thereby improving vaccine access and uptake.

The two currently approved malaria vaccines function by reducing the number of sporozoites reaching the liver, thereby also reducing the number of merozoites escaping the liver and causing clinical disease. Very high merozoite levels in the blood have made BS malaria vaccine development difficult. However, recent candidates focused on a trimeric P. falciparum protein complex formed—RH5–CyRPA–RIPR (RCR) erythrocyte invasion complex—have shown early clinical efficacy, including in young African children. A multistage vaccine combining circumsporozoite protein (CS or CSP) and BS antigens may act synergistically and greatly increase overall protection compared to a single stage vaccine alone. This approach could help achieve the World Health Organization (WHO) preferred product characteristics (PPC) requirements for an improved malaria vaccine that reduces morbidity and mortality in at-risk individuals living in endemic areas.¹

This project will develop a multistage vaccine candidate based on the proven anti-infection CSP target and the promising BS PfRipr5 antigen. These will be delivered together on a single nanoparticle, AP205—which has shown excellent clinical safety and potency in Phase 3 testing for SARS CoV2—in combination with a potent adjuvant, SA-1 or SA-2.

Project objective

The objective of this project is to generate robust preclinical data to support the advancement of a multistage (CS + BS) particle-based malaria vaccine candidate formulated with a potent adjuvant. Under our central hypothesis, a vaccine targeting both pre-erythrocytic (CS) and erythrocytic (BS) stages will provide additive and/or synergistic protection against P. falciparum by interrupting two sequential lifecycle stages. This dual-targeting strategy is designed to reduce progression to clinical disease in individuals not achieving full protection with current CS-based vaccines (RTS,S/AS01, R21/Matrix-M). Milestones for this project include:

  1. Generation and testing of potent CS and BS immunogens on a proven particle delivery platform in in vivo efficacy models.

  2. Testing admixed combinations of CS and BS particle-based immunogens in in vivo efficacy models.

  3. Generation of a single particle displaying both CS and BS immunogens.

Project design

This project is built on the successful completion of the following activities:

  1. A reliable system for preclinical efficacy testing of CS vaccine candidates;

  2. Evidence that particle delivery is preferred for efficacy of CS immunogens;

  3. Access to a robust, Phase 3 clinically validated particle delivery platform for preclinical and clinical testing;

  4. Identification of a potent BS immunogen;

  5. Down-selection of the most potent region of PfRipr; and

  6. Access to potent TLR-7 agonist adjuvants.

The project will be initiated by generating and evaluating potent CS and BS immunogens displayed on the clinically validated AP205 particle platform and assessing their functional efficacy in vivo. After completing the individual antigen testing, we will proceed to evaluate the admixed combination of CS and BS immunogens presented on AP205 particles in vivo. This phase will determine whether co-administration preserves—or even enhances—the immunogenicity of each antigen, will identify potential immune interference or synergistic effects, and will define the optimal CS to BS ratio to be administered.

Once the admixed administration has been evaluated and ratios of CS to BS have been defined, a single, co-displayed particle that presents both CS and BS antigens on the AP205 platform will be constructed and characterized. This co-display approach on a single, easy-to-manufacture nanoparticle aligns with the project goal of simplified, cost-effective, multistage vaccine delivery.

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

Malaria incidence and mortality has increased from prior years, leading to an estimated 263,000,000 cases and 597,000 deaths in 2023.² While two P. falciparum anti-infection vaccines are available—RTS,S/AS01 and R21/Matrix-M—both offer limited efficacy, short durability of protection, and are relatively expensive compared to other routine vaccinations. There is an urgent need for new malaria vaccines that offer greater efficacy and durability at a lower cost compared to the existing vaccines.

Multiantigen, multistage vaccine candidates have the potential to confer additive or synergistic efficacy by targeting two sequential parasite lifecycle stages, thereby reducing the potential for progression to clinical disease and immune evasion concerns. Individuals not protected by CSP-based vaccines following controlled human malaria infection (CHMI) frequently exhibit delays in patency that translate to greater than 90% reduction in the number of merozoites emerging from the liver, thereby lowering the force of infection of the first cycle of asexual BS growth. Moderately efficacious BS vaccines would benefit from this lower initial force of infection while improving on overall vaccine efficacy compared to the current anti-infection vaccines. We endeavor to construct one particle with both the CS and BS antigens to improve vaccine efficacy while also lowering manufacturing cost thus enabling broader access. 

What sort of innovation are you bringing in your project?

This project represents a significant innovation in malaria vaccine development by integrating a multiantigen, multistage approach into a single, modular nanoparticle platform. Utilizing the AP205 virus-like particle (VLP) system, we aim to co-display CS and BS antigens on a single particle, streamlining vaccine manufacturing and formulation processes. This strategy is expected to enhance efficacy and durability while reducing production costs and cold chain requirements, thereby improving vaccine access and uptake in malaria-endemic regions.

The project aligns with the Global Health Innovative Technology (GHIT) Translational Research Program's objectives to identify novel antigen concepts and leverage platform technologies. By advancing the development of CS and BS immunogens on the AP205 platform, we build upon previous GHIT-supported projects focused on malaria vaccine development and the application of existing adjuvants. This approach not only addresses the challenges of antigen polymorphism and immune evasion in malaria but also offers a unified solution for comprehensive protection against disease.

Role and Responsibility of Each Partner

PATH brings extensive experience in product development and project management to oversee the grant, including financial administration. In addition, PATH has an agreement with GSK to enable the use of RTS,S/AS01 as a comparator for novel circumsporozoite protein (CS or CSP) vaccine development.³ This extensive experience in malaria vaccine development and our active agreement with GSK are directly relevant to the experiments proposed in this application.

Ehime has broad and comprehensive knowledge concerning malaria vaccines and, specifically, significant expertise in the production of novel malaria BS vaccine candidates and the non-clinical immunological testing proposed in this project. Ehime will provide access to the PfRipr5 construct for use in this project.

Sumitomo Pharma brings decades of vaccine and adjuvant research and development experience with a robust drug pipeline to the project. Sumitomo Pharma has advanced several vaccine candidates to nonclinical and clinical testing using their SA-1 and SA-2 adjuvants. The company will provide the SA-1 and SA-2 adjuvants for the proposed research and be involved in the experimental planning and data review for this project.

Staten Serum Institute (SSI) brings decades of experiences in translating scientific discoveries into clinically tested agents, specifically expertise in lead optimization, and product development experience in malaria vaccine research and development. SSI will be responsible for the design and production of CS vaccine antigens.

University of Copenhagen (UCPH) owns the invention of the cVLP technology (now fully licensed to AdaptVac). The cVLP technology has been supported for further clinical development of placental malaria vaccine candidates by GHIT (G2020-214), the European Union for Nipah virus vaccine development, and CEPI for filovirus vaccine development. Horizon Europe and the Danish government supported Phase 1–3 development for COVID-19 vaccine development. The know-how remains within the group, thereby providing vast experience in early phase development, transfer, and support during cGMP production at CMOs which will significantly de-risk the current project.

Others (including references if necessary)

  1. World Health Organization. Malaria vaccines: preferred product characteristics and clinical development considerations. Accessed July 23, 2025.

https://www.who.int/publications/i/item/9789240057463

  2. World Health Organization. World Malaria Report 2024. Accessed December 23, 2024. https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2024

  3. Locke E, Flores-Garcia Y, Mayer BT, et al. Establishing RTS,S/AS01 as a benchmark for comparison to next-generation malaria vaccines in a mouse model. npj Vaccines. 2024;9(1):1-14. doi:10.1038/s41541-024-00819-x