Periodic Reporting for period 4 - MultiViVax (Development of Effective Vaccines against Multiple Lifecycle Stages of Plasmodium vivax malaria)
Berichtszeitraum: 2021-07-01 bis 2022-12-31
Plasmodium vivax accounts for 100-400 million clinical malaria cases each year among 2.5 billion people living at risk. The Malaria Vaccine Technology Roadmap to 2030 recognises the severity of P. vivax malaria and calls for a vaccine intervention to achieve 75% efficacy over two years. Despite this global need, efforts to develop interventions against this parasite have lagged extremely far behind those for P. falciparum, in large part because of critical bottlenecks in the vaccine development process. These include; lack of assays to prioritise and downselect new vaccine candidates due to lack of an in vitro long-term culture system and lack of easy access to a safe controlled human malaria infection (CHMI) model to provide an early indication of vaccine efficacy in humans. Consequently, few novel candidate vaccines are in the pipeline or have progressed to the clinic.
MultiViVax aims to develop effective vaccines for P. vivax malaria, which will have massive impact in countries where the disease is prevalent. A highly effective vaccine against P. vivax will reduce the burden of morbidity and mortality associated with the disease. Additional impacts on public health in Europe and worldwide would be made by development and licensure of vaccines for military personnel and travellers.
As part of the MultiViVax project, we have successfully established a P.vivax CHMI model in Europe and this model is being used already to understand the basic of host-parasite interaction and also test blood-stage vaccine candidates. The CHMI re infection studies gave us insights into the safety and efficacy of repeated homologous P.vivax infection and also heterlogous P. falciparum infection. These studies also investigated the gametocytaemia and P. vivax transmissibility following repeated homologous blood-stage P. vivax CHMI.
Two vaccine candidates were tested as part of the MultiViVax project. This included a blood-stage and a transmission-blocking vaccine candidate. Safety, immunogenicity and efficacy data have been generated.
Several candidate antigens have been produced and selected for immunoprofiling studies and these analysis are ongoing. Parasite RNAseq data analysis is also ongoing from the CHMI studies.
Novel transgenic parasites for blood-stage antigen have been successfully generated and used to test serum and monoclonal antibodies.
MultiViVax aims to develop effective vaccines for P. vivax malaria, which will have massive impact in countries where the disease is prevalent. A highly effective vaccine against P. vivax will reduce the burden of morbidity and mortality associated with the disease. Additional impacts on public health in Europe and worldwide would be made by development and licensure of vaccines for military personnel and travellers.
As part of the MultiViVax project, we have successfully established a P.vivax CHMI model in Europe and this model is being used already to understand the basic of host-parasite interaction and also test blood-stage vaccine candidates. The CHMI re infection studies gave us insights into the safety and efficacy of repeated homologous P.vivax infection and also heterlogous P. falciparum infection. These studies also investigated the gametocytaemia and P. vivax transmissibility following repeated homologous blood-stage P. vivax CHMI.
Two vaccine candidates were tested as part of the MultiViVax project. This included a blood-stage and a transmission-blocking vaccine candidate. Safety, immunogenicity and efficacy data have been generated.
Several candidate antigens have been produced and selected for immunoprofiling studies and these analysis are ongoing. Parasite RNAseq data analysis is also ongoing from the CHMI studies.
Novel transgenic parasites for blood-stage antigen have been successfully generated and used to test serum and monoclonal antibodies.
The MultiViVax project has successfully established a blood-stage CHMI with P. vivax. Initially a pilot study was conducted whereby P. vivax sporozoites were delivered by mosquito bite to two healthy, malaria-naive adults. Blood was taken from both successfully infected volunteers and frozen down for future use in CHMI studies to assess vaccine efficacy and reinfection studies. A study, conducted in Q1 2019, assessed the optimum dose of the banked parasite inoculum required to successfully carry out CHMI trials. The optimised dose was subsequently administered to volunteers who had been vaccinated with the blood-stage vaccine. A total of 8 volunteers completed vaccinations with ChAd63 and MVA PvDBP_RII. Vaccinations caused predominantly mild to moderate, expected side effects with no safety concerns. Antibody responses following the final vaccination were relatively low. There was no significant efficacy seen on blood-stage malaria challenge conducted at 2-4 weeks following the final vaccination.
The first study of repeat homologous blood-stage P. vivax CHMI and commenced in January 2019. Five phases of the study were completed, followed by a final phase involving heterologous CHMI with P. falciparum. A total of 19 participants completed primary P. vivax CHMI, 12 completed secondary CHMI and 2 completed tertiary CHMI. No serious or unexpected safety concerns have been identified. Upon repeat P. vivax CHMI, symptoms and laboratory abnormalities occurred less frequently and were of milder severity compared to primary CHMI. Parasite growth, however, was similar between primary and repeat CHMI with no evidence of development of anti-parasitic immunity upon repeat homologous CHMI. Further work is underway to try and further characterise this phenomenon of clinical immunity following repeat homologous CHMI in humans. Samples collected during the CHMI re-infection trials will be used for parasite RNAseq and immuno-screening analysis. In preparation for these assays, a P.vivax protein expression library was developed. A number of proteins have been successfully produced and selected for immuno-screening.
The leading P. vivax transmission-blocking antigen has been evaluated preclinically in the form of two different vaccine candidates. The leading preclinical candidate has undergone cGMP manufacture during 2019/2020 in preparation for Phase I clinical testing. Volunteers were vaccinated with different doses of the vaccine in Matrix-M adjuvant. Safety and immunogenicity data from this study is available. As part of this trial, the functional impact of antibodies induced by vaccination will be assessed using a direct membrane feeding assay. Several transgenic P.falciparum line were also generated but these were not suitable to establish and qualify an SMFA to test vaccine induced antibodies.
Transgenic P. knowlesi parasites have been edited to replace endogenous PkDBP and replace this with PvDBP. These parasites have been used to validate GIA methodology for P.knowlesi. The serum samples from the blood-stage vaccine clinical trial were tested for GIA and published here: https://pubmed.ncbi.nlm.nih.gov/35664997/.
The first study of repeat homologous blood-stage P. vivax CHMI and commenced in January 2019. Five phases of the study were completed, followed by a final phase involving heterologous CHMI with P. falciparum. A total of 19 participants completed primary P. vivax CHMI, 12 completed secondary CHMI and 2 completed tertiary CHMI. No serious or unexpected safety concerns have been identified. Upon repeat P. vivax CHMI, symptoms and laboratory abnormalities occurred less frequently and were of milder severity compared to primary CHMI. Parasite growth, however, was similar between primary and repeat CHMI with no evidence of development of anti-parasitic immunity upon repeat homologous CHMI. Further work is underway to try and further characterise this phenomenon of clinical immunity following repeat homologous CHMI in humans. Samples collected during the CHMI re-infection trials will be used for parasite RNAseq and immuno-screening analysis. In preparation for these assays, a P.vivax protein expression library was developed. A number of proteins have been successfully produced and selected for immuno-screening.
The leading P. vivax transmission-blocking antigen has been evaluated preclinically in the form of two different vaccine candidates. The leading preclinical candidate has undergone cGMP manufacture during 2019/2020 in preparation for Phase I clinical testing. Volunteers were vaccinated with different doses of the vaccine in Matrix-M adjuvant. Safety and immunogenicity data from this study is available. As part of this trial, the functional impact of antibodies induced by vaccination will be assessed using a direct membrane feeding assay. Several transgenic P.falciparum line were also generated but these were not suitable to establish and qualify an SMFA to test vaccine induced antibodies.
Transgenic P. knowlesi parasites have been edited to replace endogenous PkDBP and replace this with PvDBP. These parasites have been used to validate GIA methodology for P.knowlesi. The serum samples from the blood-stage vaccine clinical trial were tested for GIA and published here: https://pubmed.ncbi.nlm.nih.gov/35664997/.
There is no licensed vaccine for P. vivax, so we aim to progress existing P. vivax malaria vaccines candidates along the development pipeline. The long-term output of the research may contribute effective component(s) to a P. vivax vaccine formulation. The end users would be infants in endemic areas vaccinated against malaria in the first year of life, potentially adults as part of elimination campaigns, travellers and military. If sufficiently effective, a vaccine will provide a key milestone towards malaria eradication.
Development of a CHMI model and in vitro assays will remove bottlenecks that have hindered P. vivax research and will be made available to others developing vaccines for P. vivax malaria. This will accelerate the clinical development and testing of a range of novel second-generation vaccine candidates in the future by establishing the first blood-stage and transmission-stage P. vivax CHMI models in Europe.
The homologous and heterlogous CHMI studies conducted as part of this project, the methods developed and the samples generated will help us dissect the human immune response to identify P. vivax antigens associated with protection using the latest advances in protein expression, immunomonitoring and parasite RNAseq technologies, paired with assays using novel transgenic parasites in related human Plasmodium species.
The expansion of vaccine research will result in higher employment through academic research and the private sector and strengthen the growth of both academia and industry in Europe by increasing the competitive advantage and attractiveness as a location-of-choice to carry out advanced medical research.
Throughout the project we have used state of the art technolgoies for generating the vaccine candidates which are more environment friendly for eg, use of alternative chromatography techniques rather than cobalt and nickel ions.
Development of a CHMI model and in vitro assays will remove bottlenecks that have hindered P. vivax research and will be made available to others developing vaccines for P. vivax malaria. This will accelerate the clinical development and testing of a range of novel second-generation vaccine candidates in the future by establishing the first blood-stage and transmission-stage P. vivax CHMI models in Europe.
The homologous and heterlogous CHMI studies conducted as part of this project, the methods developed and the samples generated will help us dissect the human immune response to identify P. vivax antigens associated with protection using the latest advances in protein expression, immunomonitoring and parasite RNAseq technologies, paired with assays using novel transgenic parasites in related human Plasmodium species.
The expansion of vaccine research will result in higher employment through academic research and the private sector and strengthen the growth of both academia and industry in Europe by increasing the competitive advantage and attractiveness as a location-of-choice to carry out advanced medical research.
Throughout the project we have used state of the art technolgoies for generating the vaccine candidates which are more environment friendly for eg, use of alternative chromatography techniques rather than cobalt and nickel ions.