Periodic Reporting for period 4 - OptiMalVax (Optimizing a deployable high efficacy malaria vaccine)
Periodo di rendicontazione: 2021-07-01 al 2022-06-30
Our approach tackles the toughest problems in malaria vaccine design: choice of the best antigens, attaining high immunogenicity, avoiding polymorphic antigens and increasing the durability of vaccine immunogenicity and efficacy.
We take advantage of several recent advances in vaccinology and adopt some very new technologies: sequencing malaria peptides eluted from the HLA molecules, parasites expressing multiple transgenes, multi-antigen virus-like particles constructed with new bonding technologies, delayed release microcapsules, and liver-targeted immunisation with vaccine vectors.
We enhance our chances of success by using a multi-stage multi-antigen approach, by optimising the magnitude and durability of well-characterised immune responses to key antigens, and using stringent infectious challenges and functional assays as established criteria for progression at each stage.
The consortium comprises many of the foremost researchers in this field in Europe with leading groups in the USA, Australia and Africa. We link to EDCTP programmes and harmonise our timeline to fit with the recent roadmaps for malaria vaccine development. We include a major pharma partner and several excellent European biotech companies helping enhance Europe’s leading position in the commercial development of vaccines.
This ambitious and exciting programme should have a high chance of success in tackling the major global health problem posed by malaria.
Exploration of fusion (or chimeric) antigens and other dual antigen constructs has been conducted combining different pre-erythrocytic, blood stage and Transmission blocking vaccine candidates. We have also been evaluating the immune stimulatory ability of different virus-like particle (VLP) or "nanoparticle" constructs. These VLPs stimulate the immune system very potently as they are something the immune system recognises well as a target, and valuably they also provide a backbone structure that different antigens can be attached to. VLPs can be coated with more than one antigen to give increased stimulation of the immune system. In this project we have developed an antigen presenting VLP for each stage of malaria parasite’s life cycle. In addition, there has been evaluation of microparticles which can encapsulate vaccines and enhance durability of response. A new formulation for these microparticles has been assessed and showed promising results.
A new bivalent blood-stage antigen has been progressed through GMP manufacture and has proceeded to early clinical testing. For transmission stages two promising candidate vaccines have been down-selected for GMP manufacture. One of these transmission stage vaccine candidates, R0.6C has now completed a phase I trial in Nijmegen, The Netherlands. The vaccine was safe and well tolerated with no serious adverse events reported. An in-depth analysis of the immunogenicity data from the trial is underway. The second transmission blocking vaccine, Pfs48/45, is now also in clinical testing seek to show safety and potent immunogenicity.
From a clinical perspective we have determined that an initial two antigen vaccine candidate (termed LS2), which targeted the liver-stage of the Plasmodium lifecycle is outperformed by a well- studied existing candidate vaccine (ME-TRAP), but a new “prime-target” vaccine administration strategy has been developed with ME-TRAP that has the potential to target immune responses very well to the liver and provide protection at that stage of the parasite’s life cycle. A clinical trial using this approach has been conducted with promising results. We performed experiments to compare the impact of sporozoite exposure on maintenance of tissue-resident T cells (T cells are a part of the immune system that focuses on specific antigens). A slightly higher frequency of previously exposed mice were still protected from malaria 9 months after initial exposure. This data is encouraging and would suggest that in the field seasonal sporozoite exposure could promote the maintenance of malaria specific T cells and prolonged protection from malaria.
We have also assessed the safety and immunogenicity of a range of new vectored vaccines encoding parasite ribosomal proteins aiming to generate better protection at the liver-stage. These antigens were identified by the novel approach of sequencing the predominant displayed peptide epitopes eluted from the HLA molecules of parasite infected cells and new vaccines encoding these epitopes and antigens are being assessed for efficacy in vivo in pre-clinical challenge studies.