- Awarded Year2014
- Awarded Amount$766,098
- Development StageTarget Identification
- Collaboration PartnersEhime University, PATH Malaria Vaccine Initiative
Introduction and Background of the Project
Despite the successful scale-up of multiple interventions, there were 207 million cases of malaria and an estimated 627,000 lives were claimed in 2013, according to WHO’s World Malaria Report. While drugs and insecticides have had a significant impact on the burden of disease, the development of resistance poses an ongoing challenge. New tools, including highly efficacious vaccines that interrupt malaria transmission, are urgently needed to help control malaria and support future elimination and eventual eradication efforts. An effective malaria transmission-blocking vaccine (TBV) would prevent human-to-mosquito transmission, breaking the cycle of transmission, and thereby accelerate malaria parasite elimination and eradication. The target of TBVs - sexual-stage parasites - represent a major bottleneck in the parasite lifecycle and blocking development of these very few sexual-stage parasites can have a major impact on reducing mosquito infectivity and transmission to susceptible humans.
The availability of a TBV would add a critical tool to the fight against malaria by working in synergy with current interventions, since blocking transmission of the parasite would reduce the pressure on other measures, thereby slowing the development of resistance and thus extending their effectiveness.
TBVs would enable “acceleration to zero”, and ensure that parasite reintroduction is prevented, by providing an ‘immunological bed net’ that prevents parasite transmission. By virtue of the inherent properties of vaccines, this impact would be achieved in a manner that is independent of user behavior and the temporal and spatial constraints associated with other interventions, ensuring maximal impact even in the most challenging environments.
Despite increased recent interest in the development of TBVs, only Plasmodium falciparum surface protein 25 (Pfs25) and the P. vivax homolog Pvs25 have been tested in Phase 1 clinical trials. Existing TBV candidates and formulations have not been optimized for expression, scalability, or the induction of high-titer functional antibodies in humans. As a result, the transmission-blocking pipeline is small and immature. The identification and rigorous testing of novel antigens is needed to expand the diversity of approaches under development.
How can your partnership (project) address global health challenges?
Vaccines that can induce immunity to break the cycle of malaria parasite transmission are viewed as an important intervention to support future elimination and eradication efforts. The PATH Malaria Vaccine Initiative (MVI) has partnered with Ehime University to accelerate the development of a novel (Pf75) vaccine candidate. This project will need to meet predefined development stage-gates to determine whether Pf75 is a suitable candidate that meets the requirement for function (blocking parasite development in standard membrane feeding assays [SMFAs]), manufacture through identification of scalable expression systems, and suitability of process development and adjuvant formulation.
This proposal aims at fast-tracking Pf75, which targets a different mode of action from the present TBV candidates, such as Pfs25, once proof of principle is demonstrated and stage-gate requirements are met. MVI will streamline development efforts in manufacture through identification of scalable expression systems; assess the functionality of the Pf75 novel TBV candidate through qualified SMFA, and suitability of process development and adjuvant formulation; and examine ways to evaluate combinations with existing target antigens, such as Pfs25, resulting in acting alone or synergistic enhancement of transmission-blocking activity. These activities will add value and benefits to the existing small and immature pipeline of TBVs.
What sort of innovation are you bringing in your project?
Ehime University researchers used innovative approaches to select the Pf75 antigen using bioinformatic analyses from gametocyte protein database, a surface protein algorithm, and knowledge of orthologs in human P. falciparum and P. vivax. Next, they used proprietary WGCFS to express candidate antigens and induce antibodies that were subsequently tested by membrane-feeding assay. The identified homolog (Pf75 in P. falciparum) will be expressed using WGCFS to produce milligram quantities of soluble protein within a very short time, with proper conformation similar to that of native Plasmodium proteins, and hence, formation and exposure of relevant antigenic epitopes of the target proteins. As a result, we can obtain high-quality antibodies that can be used for functional assays toward early decision of stage-gating (i.e. Target Identification). In the following antigen production phase, MVI will fast-track development efforts in manufacture through leveraging expertise and existing partnership in the state-of-the-art scalable expression systems; assess the functionality of Pf75 through qualified SMFA, and suitability of process development and clinical compatible adjuvant formulation; and examine ways to evaluate combinations with existing target antigens, such as Pfs25, resulting in new vaccine products that can have increased likelihood and efficacy of blocking the parasite transmission.
Others (including references if necessary)
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 (VIMTs) are urgently needed to help control malaria and support future elimination and eventual eradication efforts.
Despite vast interest in the development of VIMTs from major stakeholders, only a handful of antigens have been identified and only Plasmodium falciparum surface protein 25 (Pfs25) have been tested in Phase 1 clinical trials.
2. Project design
Ehime University previously identified a novel antigen Py75 of rodent malaria parasite P. yoelii. Mosquitoes that fed on the mice immunized with Py75 blocked completely parasite development. With the financial support from GHIT, PATH MVI has collaborated with Ehime University on expression and validation of P. falciparum version of target antigen Pf75. The stage-gate to determine whether Pf75 is a suitable candidate is the functionality requirement - blocking parasite development in standard membrane feeding assay (SMFA), before developing scale-up process development.
3. Results, lessons learned
The project achieved positive outcomes of Milestone 1, producing 1 mg of 12 different domain constructs of recombinant Pf75 in wheat germ cell-free system, and of Milestone 2, anti-Pf75 antibodies reacting with native antigen in gametocyte/gamete IFAs and the ability to restrict parasite motility in exflagellation assay. However, anti-Pf75 antibodies tested in SMFA thus far showed only marginal blocking activity, around 50% of blocking activity, unable to meet the stage-gate criteria which is 80% of blocking activity. Despite anti-Pf75 antibodies were produced from a comprehensive list of Pf75 constructs aimed to improve the yield, solubility and domain coverage, only limited increase of blocking activity was demonstrated.
To conserve the endowment of GHIT fund, Ehime and PATH MVI decided to terminate the current project effort and return the unused fund to GHIT, with great appreciation. The project team will continue its endeavor improving this novel antigen to its ultimate success and we hope in the future to come back to GHIT Fund with confident results.