Introduction and Background of the Project

Introduction

Vivax malaria is recognized as a leading neglected tropical disease worldwide. Plasmodium vivax parasite poses a major challenge to malaria elimination due to its ability to cause recurring blood infections. These ‘relapses’ of malaria are caused by hypnozoites, the dormant form of the parasite in the liver. Therefore, hypnozoites is considered as the major challenge towards malaria elimination in vivax endemic countries. The only drugs available to clear hypnozoites are primaquine and tafenoquine. However, these drugs cause severe hemolysis in people with G6PD deficiency and are difficult to deploy in large scale to drive vivax malaria elimination. Vaccination is an alternative and the most cost-effective way to control malaria, however, malaria vaccine which target P. vivax has not been developed.

Project objective

The goal of this project is to develop a novel nucleoside-modified mRNA vaccine targeting Pvs25 protein that induces potent and long-lasting transmission blocking immunity and is able to interrupt transmission of P. vivax from human to mosquito.

Project design

To achieve our objective, we will combine our experiences in malaria vaccine development (Mahidol and Ehime Universities) and mRNA vaccine technology (the University of Pennsylvania) to develop nucleoside-modified mRNA vaccines that block transmission of P. vivax, a major malaria parasite outside Africa. The vaccine target is the protein Pvs25 which is expressed on the surface of the transmission-stage parasite, a well-validated target. In our vaccines, nucleoside-modified mRNA encoding Pvs25 will be delivered by lipid nanoparticles (LNP), an approach which has been shown to be highly effective in other vaccines. Several mRNA-LNP formulations will be tested in animals to identify the best candidate. Several routes of administrations and immunization schedules will also be explored. Vaccine efficacy will be determined by the ability of the immune sera of immunized animals to block mosquito infection using membrane feeding assay with P. vivax parasites isolated in Thailand. In addition to developing a new transmission blocking vaccine, we will also investigate the immune mechanism that results in transmission blocking activity.

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

Malaria continues to place a heavy toll on human health and economic burden in low and middle-income countries. The WHO’s Global Technical Strategy for Malaria (2016–2030) aims to eliminate malaria in a further 35 countries by 2030 compared to 2015. P. vivax can cause relapses which make it difficult to cure or control. A vaccine that interrupts parasite transmission will contribute to the elimination of malaria but no such vaccine has been developed to date.

Short-term Impact: To develop a Pvs25 mRNA-LNP vaccine that elicits robust and long-lasting transmission blocking immunity in mice. The vaccine could be further evaluated in nonhuman primates and humans. A controlled human malaria infection model of P. vivax has recently been established at Mahidol University to test new vivax malaria vaccines.

Long-term Impact: The Pvs25 mRNA-LNP vaccine will be combined with Pre-erythrocytic vaccine (PvCSP mRNA-LNP vaccines have recently been developed by our collaborators). This combined vaccine approach will serve as an essential tool in P. vivax elimination. It is expected to reduce both the number of infected patients and the number of asymptomatic hypnozoite carriers in the endemic communities.

What sort of innovation are you bringing in your project?

To date, two most advanced transmission blocking vaccines for P. vivax utilized Pvs25 protein to immunize human volunteers, but the results were disappointing due to low immune response and adverse reactions from adjuvant in the vaccine formulation. Thus, there is a need to develop/test more effective vaccine platforms and/or immunization schemes. Nucleoside-modified mRNA formulated with lipid nanoparticle (mRNA-LNP) has recently emerged as a promising vaccine platform against other infectious diseases. Therefore, we propose to develop a mRNA-LNP vaccine targeting a prime P. vivax transmission blocking vaccine candidate, Pvs25. Pvs25-encoding nucleoside-modified mRNA-LNP vaccines will be engineered to induce potent and long-lasting transmission blocking immunity with the potential to interrupt transmission from human to mosquito.

Role and Responsibility of Each Partner

This research collaborative partnership comprises three academic institutes: Mahidol University, Thailand, the University of Pennsylvania, USA, and Ehime University, Japan. Mahidol University will be responsible for overall project administration, conducting immunization and transmission blocking experiments, data analyses, and reporting. The University of Pennsylvania will be responsible for designing and producing Pvs25 nucleoside-modified mRNA-LNP vaccines, and conducting in-vitro cell transfection studies to confirm protein production from Pvs25 mRNA. Ehime University will be responsible for the production of Pvs25 protein antigen using their wheat germ cell-free protein synthesis technology for protein/adjuvant immunization, transmission blocking experiments with Mahidol group.

Others (including references if necessary)

WHO Global Technical Strategy for Malaria 2016-2030.

https://www.who.int/malaria/publications/atoz/9789241564991/en/