Project Background
UltiMalVax consortium members at the project Kick-off meeting, in Heidelberg, Germany (June 2023).
From left: Adrian Hill, University of Oxford; Geraldine Frank, Vaccine Formulation Institute (VFI); Ole Olesen, European Vaccine Initiative (EVI); Raquel Fortunato, GenIbet Biopharmaceuticals SA, Mariana Almeida, GenIbet Biopharmaceuticals SA; Dalit Landesman Milo, NeoVac LTD; Jenny Reimer, Novavax AB; Tova Sharon, NeoVac LTD; Sumi Biswas, University of Oxford; Cecilia Carnrot, Novavax AB; Roland Ventura, Global malaria vaccines (GMV); Irene Nkumama, European Vaccine Initiative (EVI).
The consortium brings together not-for-profit organisations leading in malaria vaccine development, renown malaria vaccine developers who also developed R21/Matrix-M vaccine, the developers of potent adjuvants, biotechnology companies with cutting edge thermostable mRNA technology and VLP design technology, and leading vaccine manufacturers, including the world largest vaccine manufacturer, to develop the ultimate vaccine targeting malaria elimination.
Malaria,
a deadly disease
Malaria is a deadly disease that has been with us for millions of years resulting in countless loss of life. Though once more widespread, it has been eliminated in several countries and has now retreated to the tropics. However, progress has stalled.
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WHO estimates that in 2021 there were about 247 million clinical cases and 619,000 malaria deaths globally, with the great majority of these in Africa. Insecticide and drug resistance as well as the effects of COVID have contributed to this stalling of progress.
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Malaria is both a cause and consequence of poverty as it predominantly affects the most vulnerable populations (young children and pregnant women) in rural areas of low-income countries. This impact of malaria occurs despite billion dollars being spent annually on malaria control. Vaccines are a necessary tool in a comprehensive effort towards malaria elimination and eventual eradication.
Malaria elimination status by country from 2000 to 2021. Countries with zero indigenous cases for at least 3 consecutive years are considered to have eliminated malaria. Malaria has been eliminated in several countries since 2000, however, it remains endemic in sub-Saharan Africa, parts of South America, and South-East Asia.
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Source: WHO world malaria report 2022.
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Plasmodium life cycle and malaria vaccines: Plasmodium parasites have a complex life cycle with developmental stages in the mosquito vector and in the human host. Notably P. vivax can form dormant liver hypnozoites that cause relapsing disease. Malaria vaccines can be grouped based on the parasite stage targeted the UltiMalVax project will focus on pre-erythrocytic vaccines that target sporozoites to prevent infection of the liver (as do R21 and RTS,S malaria vaccines) and transmission blocking vaccines that prevent parasite development in the mosquito vector.
Modified from Bousema & Drakeley 2011 Clinical Microbiology Reviews
Strategy
Building on past successes
There are several very encouraging steps for malaria vaccines:
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RTS,S/AS01 vaccine (MosquirixTM) by GSK became the first malaria vaccine to receive a recommendation for wider use by WHO policy committee
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R21/Matrix-M vaccine (still in Phase III trials) is the first malaria vaccine to achieve >75% vaccine efficacy against malaria in children and has already received regulatory approval in Ghana and Nigeria. It was developed by Oxford University and the Serum Institute of India using proprietary adjuvant from Novavax
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Some vaccines are blocking malaria transmission while other is leading to substantial efficacy in a clinical trials
Our aim is not just to develop another malaria vaccine, but rather to create the ultimate vaccine for malaria elimination.
The UltiMalVax Consortium
R21/Matrix M showed 77% vaccine efficacy in a phase II trial children after 1 year follow up. The primary case definition of clinical malaria in this study was the presence of an axillary temperature of 37·5°C or greater and Plasmodium falciparum parasite density greater than 5000 asexual forms per μL. Group 1 received 5 μg R21/25 μg Matrix-M, group 2 received 5 μg R21/50 μg Matrix-M, and group 3, the control group, received the Rabivax-S rabies vaccine.
Adopted from Datoo et al., 2022 Lancet.
How transmission-blocking vaccines (TBV) work:
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TBVs activate the host immune response to generate antibodies against sexual stage parasites.
These antibodies prevent parasite development in the mosquito thereby reducing malaria transmission.
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Adopted from Coelho et al., 2019 Trends in Parasitology
These achievements open the prospect of a two-stage vaccine that would prevent malaria infection and also have a major impact on malaria transmission, thereby enabling regional elimination and ultimate eradication. There are 2 major malaria parasite species, P. falciparum, the deadliest species, and P. vivax, the most geographically widespread species that causes relapsing malaria.
A vaccine for malaria elimination would need to target both parasite species.
Technology
The UltiMalVax consortium will develop and assess both established virus-like particle (VLP) vaccines in potent saponin adjuvants and exciting new thermostable mRNA vaccines expressing the parasite antigens that have shown high efficacy.
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We will adopt new VLP design technologies, e.g., SpyCatcher bonding, that allow display of 2 different antigens on each VLP. This will enable a single vaccine to protect against the two parasite species. A lead vaccine candidate will be down-selected based on well-studied pre-clinical efficacy models and induction of functional transmission-blocking antibodies, prior to GMP manufacture and a clinical trial in year 4.
mRNA vaccine production pipeline:
The mRNA vaccine development process starts from design of the antigen sequence and insertion into a plasmid DNA which is then transcribed into mRNA in vitro. The transcripts are then purified mixed with lipids to form lipid nanoparticles. Lipids encapsulate mRNA to generate self-assembled nanoparticles. The mRNA containing lipid nanoparticles are then purified to generate mRNA vaccine.
Adopted from Chaudhary, Weissman & Whitehead, 2021, Nature Reviews Drug Discovery.
An overview of SpyCatcher VLPs development process.
SpyCatcher is genetically fused to the AP205 phage coat protein (AP205 CP3) and expressed in E. coli. Self-assembly of monomers generates SpyCatcher-VLPs. Upon mixing, SpyTag-antigen forms a spontaneous isopeptide bond with SpyCatcher-VLPs, yielding decorated particles for immunisation.
Adopted from Brune et al., 2016 Scientific Reports.