- Awarded Year2016
- Awarded Amount$595,650
- Development StageAntigen Identification
- Collaboration PartnersEhime University, PATH Malaria Vaccine Initiative
Introduction and Background of the Project
There is an unprecedented opportunity to eliminate malaria from the developing world through the discovery and development of new tools designed to interrupt multiple stages of the parasite life cycle. Such efforts include the development of new curative drugs, vector control methods, and vaccines that prevent the spread of disease. This project seeks to complement these efforts through the discovery of novel vaccines that block parasite transmission from human to mosquito, thereby reducing spread of infection and contributing to elimination within a population. While such “transmission-blocking” vaccines (TBVs) have been an objective of malaria vaccine researchers for many years, new approaches to the discovery and optimization of antigen targets, as well as novel ways to focus the immune system, are now applicable to vaccine design. Our project is based on a solid foundation of existing information, leverages new technology, and will be implemented by a proven collaboration of scientists. We will dissect a protein found on the sexual-stage parasite, Pfs230, to identify antigenic regions that elicit the most potent vaccine responses, generate these using scalable systems suitable for their production, and present these antigens using the latest technology to augment immune responses using nanoparticle delivery.
Objective 1: Generate fragments of Pfs230 that mimic the intact native protein and identify those that, as antigens, elicit the most potent transmission-blocking antibodies.
The Pfs230 protein is a well established transmission-blocking target antigen; however, its utility has been limited by the inability to produce the protein due to its large size and complex structure. This project will dissect the Pfs230 protein and employ Ehime University's cell-free technology that adapts well to complex malaria proteins.
Objective 2: Efficiently produce Pfs230 antigens retaining potent immunogenicity.
We will build on recent published results (including from the applicant) that have identified systems suitable for both early vaccine discovery and product development to produce novel potent Pfs230 antigens using scalable expression systems.
Objective 3: Generate vaccine candidates suitable for advancement to testing in humans.
We will build on recent discoveries (including by the applicant and its partners) and leverage novel nanoparticle delivery platforms for the presentation of native configuration Pfs230 on particles which lead to augmented immunogenicity.
This proposal will employ cutting-edge technology to achieve its goals and objectives and deploy successful partnerships, including with the world-renowned malaria vaccine discovery investigator, Dr. Takafui Tsuboi, of Ehime University.
Objective 1: The production of Pfs230 protein as a vaccine antigen has proved challenging, due to its complex structure that includes more than 60 cysteines. Our strategy is to divide the Pfs230 protein into folding regions for expression in the wheat germ cell-free system (WGCFS).
Objective 2: While the WGCFS is preferred for the initial characterization of vaccine antigens, it is not applicable to the production of vaccines for clinical testing and development. In keeping with MVI’s goal of rapid translation of innovative vaccines to the clinic, we will employ production of the most active Pfs230 antigens in insect cell scalable production, which has major advantages for malaria antigens. MVI has also focused on identification of analytical testing protocols to assure native configuration of antigens.
Objective 3: Recent results indicate that display of antigens on a virus-like nanoparticle augments immunogenicity. We will employ two recently discovered nanoparticle platforms for display of the selected Pfs230 antigens. These platforms are designed to maintain the native configuration of the antigens consistent with our overall design objectives. The nanoparticles will be used for the presentation of the most potent Pfs230 antigens.
How can your partnership (project) address global health challenges?
Despite the successful scale-up of multiple interventions, there were an estimated 212 million cases of malaria and an estimated 429,000 malaria deaths worldwide in 2015, according to the most recent WHO World Malaria Report. Vaccines are urgently needed to help control malaria and to support future elimination and eventual eradication efforts.
While drugs and insecticides have had a significant impact on the burden of disease, resistance poses an ongoing challenge. A TBV that prevents human-to-mosquito transmission could break the cycle of parasite transmission, and thus play an important role in malaria elimination and eradication. The availability of a TBV vaccine would represent a critical additional tool for the fight against malaria that would work in synergy with other interventions, since blocking transmission of the parasite would reduce the pressure on other measures, by slowing the development of resistance and thus extending their effectiveness.
This proposal aims at fast-tracking the discovery and validation of the most potent target Pfs230 domain for full vaccine development.
What sort of innovation are you bringing in your project?
This project will employ Ehime University's cutting-edge WGCFS technology to tackle the challenges of producing a complex and large protein like Pfs230. We will employ state-of-the-art nanoparticle platforms that are designed to maintain the native configuration of the antigens and enable the formulation of vaccine nanoparticles more efficientlt than is possible using traditional conjugation. The nanoparticle platform has the advantage of effectively augmenting immune responses and thus can help us accelerate the development of a Pfs230 nanoparticle vaccine candidate for human testing.
Role and Responsibility of Each Partner
MVI is the coordinating institution and driving force for this proposed project. MVI has a long track record in malaria vaccine development and will ensure the fast-tracking of the identification and testing of the most potent Pfs230 candidate.
The Ehime University team will focus on the production of domains covering the entire Pf230 antigen in the WGCFS, which will then be used (1) to raise polyclonal antibodies and (2) as reference materials to benchmark testing of the scalable expression system. MVI's Reference Laboratory at the US National Institutes of Health will make available of its qualified standard membrane feeding assay (SMFA) to assess vaccine function. The SMFA is an ex vivo assay used to measure the transmission-blocking potential of antibodies elicited in response to vaccination with a TBV.
Others (including references if necessary)
1. World Health Organization (WHO). World Malaria Report 2016. Geneva: WHO; 2016.