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Development of Effective Vaccines against Multiple Lifecycle Stages of Plasmodium vivax malaria

Periodic Reporting for period 3 - MultiViVax (Development of Effective Vaccines against Multiple Lifecycle Stages of Plasmodium vivax malaria)

Reporting period: 2020-01-01 to 2021-06-30

Plasmodium vivax accounts for 100-400 million clinical malaria cases each year among 2.5 billion people living at risk in Latin America, Oceania and Asia. Recent data demonstrate that the infection brings a significant burden of morbidity and associated mortality which has been largely under-appreciated in the past. 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.
We have laid out four objectives to enable us to address the critical bottlenecks in P. vivax vaccine development:
1. Establish a P. vivax CHMI model in Europe for the first time to facilitate better selection of effective vaccines and remove the current bottleneck for early-phase clinical testing.
2. Utilise the CHMI model to identify novel antigens associated with protective blood-stage immunity in humans by taking advantage of recent advances in immuno-screening and parasite RNASeq.
3. Progress existing vaccines targeting the current leading antigens for both the blood- and transmission-stages along the clinical development pipeline.
4. Develop novel transgenic parasites for use in assays, to overcome the current bottleneck in vaccine down-selection caused by the inability to culture P. vivax parasites.
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. Three of the volunteers who participated in the pilot blood-stage CHMI also returned to undergo a secondary challenge. Ongoing clinical trials were halted in early 2020 due to the Covid-19 pandemic. After extensive safety assessments, trials were restarted in 2021, where volunteers successfully underwent CHMI; 7 primary, 2 secondary and 1 tertiary. The vaccination study CHMI will start later in the year.
Samples collected during the CHMI re-infection trials will also be used for parasite RNAseq and immuno-screening analysis. In preparation for these assays a P.vivax protein expression library is currently under development.
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 which will commence in 2021.
As part of this trial the functional impact of antibodies induced by vaccination will be assessed using a standard membrane feeding assay using a transgenic P. falciparum line. The generation of this transgenic parasite is underway and constructs are being generated while viability testing of the parasite is ongoing.
An in vitro culture is being established and growth inhibition assay (GIA) methodology using a P. knowlesi strain adapted to continuous growth in human red blood cells. Development of GIA methodology with wild-type and transgenic P. knowlesi parasite lines is now underway. These parasites will be used to test for GIA in the serum of vaccinees from the clinical trials.
MultiViVax has established governance with a Project Steering Committee, Independent Scientific Advisory Committee and Local Safety Committee to oversee the progression of work throughout the project.
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. If the blood-stage and transmission-blocking vaccines developed by this programme show significant immuno-efficacy in clinical trials, we are well placed to develop them and progress to Phase I/IIb field. 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.
We will extend the CHMI model to induce acquired immunity against P. vivax blood-stage by re-infection of volunteers with homologous parasites. This 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 achieved throughout the project 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. Opportunity for a malaria vaccines is divided into the public (population of malaria endemic countries) and private (military and travellers) markets, both of which are sensitive to the efficacy of the vaccine, its price and availability of public funding to subsidise its cost and support deployment.
During production of the transmission-blocking vaccine candidate we will produce single subunit vaccines, as opposed to the more traditional approach of attenuating or inactivating live organisms. We also use affinity processes which utilise non-toxic reagents. The process is therefore less environmentally harmful than other affinity chromatography techniques, which use a column containing cobalt or nickel ions.
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