Introduction and Background of the Project

Introduction

Malaria prevention currently relies on two WHO-recommended strategies: drug-based chemoprevention and vaccination. While both approaches have substantially reduced malaria morbidity and mortality, they face important limitations. Chemoprevention requires frequent dosing, leading to adherence challenges and increasing vulnerability to drug resistance. Vaccines such as RTS,S and R21 provide meaningful protection but require multiple doses and booster schedules to maintain efficacy during seasonal transmission.1

Monoclonal antibodies (mAbs) offer a compelling complementary approach to malaria prophylaxis. A single subcutaneous or intramuscular administration can provide immediate, high-level protection against all Plasmodium falciparum strains, overcoming adherence barriers and reducing resistance risk. Passive immunization is particularly well suited for seasonal malaria prevention, where short periods of high-risk demand rapid and durable protection. This strategy aligns directly with GHIT’s RFP priorities for low-cost, single-injection mAbs capable of providing 4–6 months of seasonal coverage.

Our development approach builds on decades of scientific and clinical insights generated through malaria vaccine development, particularly RTS,S, the first WHO-recommended malaria vaccine. Extensive clinical data demonstrates a strong association between antibodies targeting the circumsporozoite (CS) protein and protection against malaria. Seasonal vaccination studies further validate the CS protein as a highly effective target, achieving protection levels comparable to or exceeding those of chemoprevention when immunity is appropriately timed.

Recent clinical success of CS-targeting monoclonal antibodies has further de-risked this strategy, providing strong evidence for feasibility. By leveraging advances in antibody engineering to enhance potency, extend half-life, and ensure broad strain coverage, our program aims to deliver a scalable, single-dose prophylactic intervention for young African children and other vulnerable populations, addressing a critical unmet need in global malaria control.

Project Objective

The goal of this project is to secure a WHO policy recommendation and financing for a mAb that prevents P. falciparum malaria in children younger than 3 years of age living in sub-Saharan Africa. The use of this intervention could be expanded to 6–10-year-old children and pregnant women, the other two target populations with the greatest morbidity and mortality from malaria. Our initial use-case is induction of high-level protection with a single SC dose prior to the rainy season in regions with seasonal malaria transmission.  Following completion of G2021-111 and G2023-219 grants, the Partners are now progressing to perform a first-in-human (FIH) Phase 1 clinical study to evaluate the safety and pharmacokinetics (PK) profile of the mAb in healthy adults. 

The GSK-TC-001 mAb, the precursor of which was isolated from an RTS,S/AS01 vaccinated and protected clinical study volunteer, has been engineered to confer half-life extension and enhanced Fragment crystallizable (Fc) receptor function, and has undergone a selection process for safety and biological activity. With GHIT support (G2021-111 and G2023-219), we have manufactured a pre-master cell bank, developed upstream and downstream processes, manufactured a lot suitable for toxicological evaluations, and successfully conducted a good laboratory practice toxicology study. With the subsequent funding (G2023-219), we manufactured drug substance and drug product lots, prepared reagents for human PK and anti-drug antibody (ADA) assays needed in clinical studies and are currently preparing the application to seek competent regulatory authorities’ approval for the FIH study.

Project Design

This project will advance the clinical development of the monoclonal antibody GSK-TC-001 through completion of a first-in-human (FIH) Phase 1 study, development of exploratory functional assays, and preparation for subsequent Phase 2 clinical evaluation.

Objective 1: Complete a Phase 1 safety, tolerability, and PK study.

A FIH Phase 1a clinical trial will evaluate the safety, tolerability, PK, and immunogenicity of GSK-TC-001 in healthy, malaria-naïve adults. Regulatory, ethics, and site preparation activities will be completed in advance to minimize delays. Participants will be enrolled into sequential dose-escalation cohorts receiving single SC or IV doses, with placebo controls.  Participants will be followed for up to 52 weeks following dosing. PK and ADA analyses will inform dose selection and feasibility of a subsequent Phase 2) study. Successful completion will support a Phase 1 go/no-go decision.

Objective 2: Develop exploratory functional assays to support the clinical program.

Feasibility of functional assays aligned with the mechanism of action of GSK-TC-001 will be assessed, including reagent sourcing and pilot testing. Selected assays will undergo development and qualification to support future clinical sample testing, with the goal of identifying at least one assay fit for purpose.

Objective 3: Prepare for subsequent Phase 2 clinical development.

Preparatory activities will assess Phase 2 development pathways, including the potential role of CHMI studies, selection of study populations, availability of reagents, and alignment with the evolving malaria intervention landscape. This work will culminate in a draft protocol synopsis, partner shortlist, and updated integrated Product Development Plan (iPDP) to enable rapid progression to the next clinical stage.

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

In 2024, there were 282 million clinical cases and 610.000 deaths from malaria. Case incidence rose in the period 2015–2024 from 58 to 64 cases per 1,000 population at risk, highlighting the lack of recent progress in improving malaria control and thereby the urgent need for new interventions to benefit those at greatest risk.2

SMC in children living in the Sahel region of Africa is associated with high efficacy (~80%); however, implementation challenges associated with monthly dosing and drug resistance in eastern and southern Africa have limited its impact. Newly introduced malaria vaccines are modestly efficacious when delivered via EPI in the first 2 years of life (4 doses) but offer similar levels of efficacy to SMC (~75%) when delivered using a hybrid approach (i.e., EPI + seasonal boosting) in highly seasonal settings. However, this approach will likely require a hybrid approach (EPI + mass campaign) to deliver the necessary 5 doses over the first 3 years of life when children are most vulnerable.

mAbs offer the potential to overcome many of the limitations of prophylactic drugs and vaccines by providing high-level protection against all P. falciparum strains following a single administration in areas of high seasonal transmission. Importantly, mAbs offer the potential to reduce the implementation burden on already challenged health systems. Our primary focus will be on the prevention of disease and death in young African children, accelerating elimination and suppressing outbreaks among at-risk populations.

What sort of innovation are you bringing in your project?

GSK-TC-001 represents a novel approach to malaria prevention, engineered specifically to address the operational and biological limitations of existing interventions. Unlike current antibody or vaccine strategies that require repeated dosing or complex delivery, GSK-TC-001 is designed for single-dose subcutaneous administration, combining enhanced Fc effector functions with an extended half-life to provide durable protection suitable for seasonal malaria prevention in high-burden, low-resource settings.

The antibody was derived from an individual protected by RTS,S/AS01 vaccination, capturing naturally protective immune features and translating them into a scalable biologic. Preclinical studies demonstrate a favorable safety profile and robust biological activity, supporting its potential to deliver sustained protection with minimal healthcare system burden.

This program is distinguished by its advanced state of readiness. With support from GHIT (G2021-111 and G2023-219), GSK-TC-001 has progressed through GMP manufacturing and completion of required non-clinical studies, positioning the program for near-term regulatory submission and first-in-human evaluation. Together, these attributes establish GSK-TC-001 as a differentiated, deployment-focused innovation with the potential to transform malaria prevention strategies in vulnerable populations.

Role and Responsibility of Each Partner

PATH will manage the project and ensure the milestones are met and the project is delivered on time and budget. PATH will serve as GSK’s technical partner for trial implementation and will assess and plan post-Phase 1 clinical studies, including gathering the necessary information to enable decisions to be made on future clinical studies, including whether to pursue a controlled human malaria infection (CHMI) study, and ensure maintenance of the iPDP. 

GSK will be the regulatory sponsor responsible for conduct and oversight of the Phase 1 safety and pharmacokinetic (PK) study, and all trial-related activities.  They will also be responsible for all aspects related to the clinical trial material, including the implementation of the stability study. They will also ensure the development of PK and ADA clinical assays before the start of the project, to enable the testing of human samples from the study.

Ehime will be responsible for developing and ensuring appropriate qualifications of exploratory and functional clinical assays to support and inform the ongoing clinical development program.

Others (including references if necessary)

1. World Health Organization website. Publications page. Seasonal malaria chemoprevention with sulfadoxine–pyrimethamine plus amodiaquine in children: a field guide. Accessed July 25, 2025. https://www.who.int/publications/i/item/9789240073692

2. World Health Organization. World Malaria Report 2025. Accessed February 10, 2026. https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-20245