Periodic Reporting for period 5 - OptiMalVax (Optimizing a deployable high efficacy malaria vaccine)
Periodo di rendicontazione: 2022-07-01 al 2022-12-31
A highly effective malaria vaccine against Plasmodium falciparum should help prevent half a million deaths from malaria each year.
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.
This ambitious and exciting programme should have a high chance of success in tackling the major global health problem posed by malaria.
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.
This ambitious and exciting programme should have a high chance of success in tackling the major global health problem posed by malaria.
We have identified new antigens that are potential vaccine candidates for all stages of the malaria parasite (Plasmodium) lifecycle. A particularly exciting new family of antigens acting at liver-stage and blood-stage has been discovered. Furthermore, we have generated a prioritised list of candidate antigens from the sporozoite stage. Screening of these candidates highlighted some promising novel antigens, which will proceed to immunogenicity studies for further selection of the most promising vaccine targets.
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. 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.
Structural studies have revealed insight into the neutralising and growth inhibitory epitopes on the essential and conserved leading blood-stage antigens PfRH5, PfCyRPA and PfRIPR that together form the RCR invasion complex. They have also revealed two distinct mechanisms of synergy: slowing parasite invasion and heterotypic lateral fab-fab interactions. PfRIPR has been largely refractory to structural studies so far, however newer technologies and computational approaches, such as AlphaFold, are aiding investigations of this difficult protein. We also assessed the immuno-efficacy of new candidate blood-stage antigens associated with the PfRH5 (RCR) invasion complex. Antibodies against PfCyRPA and PfRIPR elicit functional, growth inhibitory antibodies against the blood-stage merozoite, whereas antibodies against PfP113 do not. However, when immunising with a mixture of full-length PfRH5, PfCyRPA and PfRIPR we observed that PfRIPR is immuno-dominant and responses to PfRH5 and PfCyRPA are reduced. To circumvent this problem, we proceeded to define only the regions of PfRIPR that elicit growth inhibitory antibodies using antigen-reversal methodology, specifically these regions included the C-terminal EGF domains. We thus made a novel bivalent vaccine targeting PfCyRPA and PfRIPR EGF domains (7-8) called “R78C”. This new bivalent blood-stage antigen vaccine has now been manufactured to GMP using a stable Drosophila S2 cell platform and entered the VAC089 Phase I clinical trial, combined with Matrix-M™ adjuvant, to assess the safety, immunogenicity and immuno-efficacy in healthy UK adults (ClinicalTrials.gov NCT05385471).
For transmission stages two promising candidate vaccines were selected for GMP manufacture and successfully produced for clinical trials. R0.6C has now completed a phase I trial, using the Matrix-M(TM) adjuvant in combination with Alhydrogel®. The two R0.6C vaccine formulations were safe and well tolerated with no serious adverse events reported and induces antibodies against the full-length R0.6 vaccine construct, as well as against specifically the (transmission-associated) 6C fragment. An in-depth analysis of the immunogenicity and transmission-blocking activity data from the trial is underway. The second, Pfs48/45, is now also in clinical testing with Matrix-M(TM) to demonstrate safety and immunogenicity. We have also resolved the protein structure of Pfs48/45 at the atomic level, this will help us to understand how this protein works in the parasite allowing us to better comprehend how our vaccines work in humans and how to improve them in the future.
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.
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.
An in vitro miniaturized platform has been established to assess for presentation of liver-stage antigens by infected human hepatocytes to human CD8 T lymphocytes. We showed that liver stage parasites could be eliminated through IFN-dependent and independent effector mechanisms (Bigeard et al, in prep).
An adjuvant suitable for use in toxicology studies and human clinical trials has been developed. LMQ is a liposomal adjuvant containing cholesterol, DOPC, a saponin (QS21), and TLR4 ligand. Methods for the production and quality control of LMQ were established, and LMQ’s physico-chemical, stability and immunostimulatory properties evaluated. LMQ was demonstrated to be compatible in formulation with several malaria antigens provided by the project’s partners and to have a clear adjuvant effect in pre-clinical studies. VFI has provided the consortium with access to its portfolio of adjuvants for testing with the consortium’s malaria antigens. Each of the various adjuvants within the portfolio were compatible in formulation with malaria antigens. Subsequent immunogenicity studies showed a clear adjuvant effect in pre-clinical mouse studies.
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. 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.
Structural studies have revealed insight into the neutralising and growth inhibitory epitopes on the essential and conserved leading blood-stage antigens PfRH5, PfCyRPA and PfRIPR that together form the RCR invasion complex. They have also revealed two distinct mechanisms of synergy: slowing parasite invasion and heterotypic lateral fab-fab interactions. PfRIPR has been largely refractory to structural studies so far, however newer technologies and computational approaches, such as AlphaFold, are aiding investigations of this difficult protein. We also assessed the immuno-efficacy of new candidate blood-stage antigens associated with the PfRH5 (RCR) invasion complex. Antibodies against PfCyRPA and PfRIPR elicit functional, growth inhibitory antibodies against the blood-stage merozoite, whereas antibodies against PfP113 do not. However, when immunising with a mixture of full-length PfRH5, PfCyRPA and PfRIPR we observed that PfRIPR is immuno-dominant and responses to PfRH5 and PfCyRPA are reduced. To circumvent this problem, we proceeded to define only the regions of PfRIPR that elicit growth inhibitory antibodies using antigen-reversal methodology, specifically these regions included the C-terminal EGF domains. We thus made a novel bivalent vaccine targeting PfCyRPA and PfRIPR EGF domains (7-8) called “R78C”. This new bivalent blood-stage antigen vaccine has now been manufactured to GMP using a stable Drosophila S2 cell platform and entered the VAC089 Phase I clinical trial, combined with Matrix-M™ adjuvant, to assess the safety, immunogenicity and immuno-efficacy in healthy UK adults (ClinicalTrials.gov NCT05385471).
For transmission stages two promising candidate vaccines were selected for GMP manufacture and successfully produced for clinical trials. R0.6C has now completed a phase I trial, using the Matrix-M(TM) adjuvant in combination with Alhydrogel®. The two R0.6C vaccine formulations were safe and well tolerated with no serious adverse events reported and induces antibodies against the full-length R0.6 vaccine construct, as well as against specifically the (transmission-associated) 6C fragment. An in-depth analysis of the immunogenicity and transmission-blocking activity data from the trial is underway. The second, Pfs48/45, is now also in clinical testing with Matrix-M(TM) to demonstrate safety and immunogenicity. We have also resolved the protein structure of Pfs48/45 at the atomic level, this will help us to understand how this protein works in the parasite allowing us to better comprehend how our vaccines work in humans and how to improve them in the future.
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.
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.
An in vitro miniaturized platform has been established to assess for presentation of liver-stage antigens by infected human hepatocytes to human CD8 T lymphocytes. We showed that liver stage parasites could be eliminated through IFN-dependent and independent effector mechanisms (Bigeard et al, in prep).
An adjuvant suitable for use in toxicology studies and human clinical trials has been developed. LMQ is a liposomal adjuvant containing cholesterol, DOPC, a saponin (QS21), and TLR4 ligand. Methods for the production and quality control of LMQ were established, and LMQ’s physico-chemical, stability and immunostimulatory properties evaluated. LMQ was demonstrated to be compatible in formulation with several malaria antigens provided by the project’s partners and to have a clear adjuvant effect in pre-clinical studies. VFI has provided the consortium with access to its portfolio of adjuvants for testing with the consortium’s malaria antigens. Each of the various adjuvants within the portfolio were compatible in formulation with malaria antigens. Subsequent immunogenicity studies showed a clear adjuvant effect in pre-clinical mouse studies.
Thus far this project has progressed beyond state of the art in identifying and evaluating potential vaccine candidates for all stages of the malaria parasite (Plasmodium) lifecycle. It is expected that we will in future be able to combine the best of these malaria vaccine candidates from each lifecycle stage into a single multivalent malaria vaccine that will be able to prevent both clinical disease and onward transmission of the parasite. The socio-economic impact of an effective malaria vaccine would be very considerable leading to fewer deaths, lower malaria control costs, reduced health-care burden, and fewer work hours lost to sickness. The cost-effectiveness of this planned vaccine would mean it can be deployed in the poorest countries that are most in need of it. The availability of an effective malaria vaccine should have a substantial positive impact on the future economic development of countries currently afflicted by a high malaria disease burden.