Introduction and Background of the Project

Malaria represents one of the world’s most pressing public health problems. The mosquito-borne parasitic disease is a leading cause of death and illness, hitting hardest in low-income settings. Every year, malaria sickens hundreds of millions and kills hundreds of thousands of people, with most of the deaths occurring in young African children. The parasite has a complex lifecycle, is highly adaptable, and has co-evolved in humans for millennia. An effective and safe vaccine against malaria would be a powerful tool to eliminate the disease and would complement the tools that save lives today—bed nets, sprays, and drugs.

Highly efficacious vaccines that interrupt malaria transmission (VIMT) are urgently needed to help control malaria and support future elimination and eventual eradication efforts. Pre-erythrocytic (PE) vaccines that prevent mosquito-to-human transmission are highly desirable; they can prevent disease and death, as well as support elimination efforts by preventing infection, thereby breaking the cycle of transmission. Controlled human malaria infection (CHMI) models enable the determination of VIMT-PE vaccine efficacy in small numbers of volunteers.

The PATH Malaria Vaccine Initiative, a program of the US-based global nonprofit organization PATH, initiated a tripartite collaboration with Ehime University and CellFree Sciences Co. Ltd. (both based in Japan) for the identification and initial validation of novel PE malaria vaccine candidates. The concept is to generate monoclonal antibodies (mAbs) directed against a panel of PE antigens that are candidate targets of humoral immunity. These mAbs will be evaluated, via passive transfer studies, for their capacity to protect against parasite infection using the well-established CHMI model.

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

Despite the successful scale-up of multiple interventions, malaria still claims in excess of 650,000 lives annually, according to the 2012 World Health Organization World Malaria Report (1). Highly efficacious vaccines are urgently needed to help control malaria and support future elimination and eventual eradication efforts.

One of the needs identified in malaria vaccine development is a more rapid and conclusive approach to accelerate antigen validation studies in humans. CHMI models enable the determination of PE vaccine efficacy in small numbers of volunteers. To date, only a small number of the potential PE vaccine target antigens have been evaluated due to the long timelines and high cost of developing vaccine candidates. The most effective, RTS,S/AS01 vaccine candidate afforded 50% protection in this model, which has translated favorably to a similar level of vaccine efficacy in a Phase 3 clinical trial carried out in seven African countries.

This new project aims at supporting the evaluation of novel PE vaccine antigens. Evaluation of these antigens using conventional vaccine development approach is not financially feasible and is unlikely to lead to conclusive outcomes regarding target validation due to the high number of variables (e.g., delivery platform selection, adjuvant selection, variable immune responses, etc.). We plan to accelerate target validation for malaria vaccine development by employing a novel, translational research approach that uses mAbs—with demonstrated preclinical functional activity—in CHMI studies. This would enable validation of target antigens, and provide a critical reagent (i.e., protective mAb), prior to engaging in vaccine development efforts. If successful, this project will result in the identification of novel vaccine targets in a timely and cost-effective manner that would not be achieved with other approaches, affording a unique global health impact not reachable otherwise.

What sort of innovation are you bringing in your project?

This project proposal describes a joint malaria vaccine preclinical development project with Ehime University and CellFree Sciences to express and produce PE target antigens in the proprietary wheat germ cell-free protein expression system (WGCFS) developed at Ehime University. This WGCFS allows the production of milligram quantities of soluble proteins within a very short time, with proper conformational folding similar to that of native Plasmodium proteins, and hence, formation and exposure of relevant antigenic epitopes of the target proteins. Therefore, WGCFS-expressed proteins are perfectly amenable to high-throughput screening of very large numbers of malaria vaccine candidate antigens. As a result, we can obtain high-quality antibodies that can detect many more therapeutically and diagnostically important conformational epitopes that may have been missed by using antibodies raised against proteins expressed in other expression systems. These proteins will facilitate the production of highly functional mAbs that can be down-selected using a series of high-throughput binding and lower-throughput functional assays toward the eventual goal of identifying leads for humanization and clinical evaluation.

Hence, we are looking forward to applying a novel application that uniquely combines the successful wheat germ-based protein production system to generate high-quality P. falciparum PE-stage antigens for induction of mAbs that effectively block hepatocyte invasion by sporozoites. These antibodies will be used to support an efficient target validation strategy, using an established CHMI model, to assess their capacity to protect against infection. Targets associated with high levels of protection will be advanced to vaccine development efforts, with the protective mAbs serving as a critical development reagent. This proposal will enable the identification and clinical validation of novel malaria vaccine targets.

Others (including references if necessary)

1.    World Health Organization (WHO). World Malaria Report 2012. Geneva: WHO; 2012. http://www.who.int/malaria/publications/world_malaria_report_2012/report/en/index.html.

Final Report

1. Project objective 

Malaria remains one of the most pressing public health problems and is a leading cause of death and illness, hitting hardest young children in low-income settings. Highly efficacious vaccines that interrupt malaria transmission (VIMT) are needed to help control malaria and accelerate elimination and eventual eradication efforts. Pre-erythrocytic (PE) vaccines that prevent mosquito-to-human transmission can prevent disease and death, and support elimination efforts by preventing infection, thereby breaking the cycle of transmission. Controlled human malaria infection (CHMI) models enable the initial determination of VIMT-PE vaccine efficacy in small numbers of volunteers, thereby reducing the risk of failure in costly and complex endemic field studies.

2. Project design

With the financial support from GHIT, MVI has collaborated with Ehime University and CellFree Sciences (both based in Japan) on the validation of novel PE vaccine candidates. Identification and validation of novel target antigens is recognized as a critical unmet need in the malaria vaccine development community (See Goal 3 of the Malaria Vaccine Technology Roadmap). The concept is to generate monoclonal antibodies (mAbs) targeting a panel of PE antigens that are candidate targets of humoral immunity. These mAbs will be evaluated, via passive transfer studies, for their capacity to protect against parasite infection in preclinical models, and offer the potential for future evaluation in CHMI studies.

3. Results, lessons learned

A panel of PE-stage antigens have been expressed using a wheat germ cell-free system (WGCFS) to generate functional mAbs. Twenty-three novel antigens were successfully produced in the WGCFS and used to immunize mice. Screening of the resulting polyclonal antibodies for binding to the native sporozoites and inhibition of key parasite functions in vitro led to selection of 13 targets to advance. The selected antigens are being used to generate humanized mAbs that will be screened for functional activity. We anticipate making a Go/No-Go decision for advancement of a mAb candidate to a CHMI study in Q1 2017.

This strategy has the potential to accelerate efforts to develop more highly efficacious PE malaria vaccines by providing clinical evidence for the capacity of antibodies targeting novel antigens to prevent infection following CHMI. Such information would be translated into focused vaccine development efforts by using the protective antibodies as critical tools in immunogen design, with the knowledge that antibodies to that given antigen(s) protect humans from malaria parasite infection.