Last Updated: 16/06/2015
Defining epitopes of Plasmodium vivax RBP that are potential vaccine targets
Objectives
This project aims to define the immunological properties of P. vivax reticulocyte protein 1 (PvRBP1), and identify functionally conserved epitopes that are correlates of protective immunity.
This objective will be achieved through specific objectives:
- In vitro recreation of the native conformation of RBP1 epitopes from the P. vivax Sal1 strain as recombinant proteins expressed by virus-like particles (VLPs) of the RNA bacteriophage MS2.
- Broadly neutralizing anti-RBP inhibitory immune sera and/or monoclonal antibodies raised against recombinant fragments of RBP1 will be used to screen MS2 phage libraries displaying fragments of RBP1 or random peptides on VLPs to define target epitopes of these neutralizing antibodies.
- The immunogenicity of the selected VLP targets will be evaluated by immunization of laboratory animals and the vaccine potential of these targets will be evaluated by the ability of epitope-specific antibodies to inhibit RBP-reticulocyte binding of allelic RBP variants, recognition of the native protein on the parasite by IFA and immunoblot and anti-parasite activity in short-term in vitro cultures. It is expected that a sub-unit vaccine based on defined protective epitopes expressed on the VLP surface will induce a stronger immune response to potential neutralizing epitopes on RBP than recombinant antigens.
Plasmodium vivax is the leading cause of malaria outside of Africa, with over 100 million clinical cases annually. Increasing reports of clinical severity of vivax malaria due to emergence of more virulent and drug resistance forms of the parasite, the ability of the parasite to undergo relapse in the liver and the strain specific nature of the immunity to P. vivax infections has contributed in making control more difficult. There is therefore an urgent need for a vaccine to control the disease. Merozoite invasion of human erythrocytes is essential for blood stage development of malaria parasites. P. vivax has a selective preference for infecting reticulocytes, a process mediated by the reticulocyte binding proteins (RBPs), which target reticulocytes for invasion. This essential role in the invasion process makes RBPs ideal targets for vaccine development induced against blood stage P. vivax. We hypothesize that an effective RBP based vaccine will require targeting the functionally conserved receptor-binding domains of multiple RBPs. The large size of the RBPs makes it difficult to produce correctly refolded recombinant proteins using the traditional expression systems. Refolded proteins may surfer from poor immunogenicity due to ineffective presentation of protective epitopes. Thus, it is difficult to induce a strong, high-titer response to all potential epitopes. Usually, immunodominant epitopes, which in most part are polymorphic, do not necessarily correspond to the most effective neutralizing epitopes.
Enabling Technologies & Assays
P. vivax
Vaccines (Immune Correlates)
Aug 2014 — Jul 2016
$411,125
