Last Updated: 02/12/2024
Development and delivery of novel biologics that block red blood cell invasion by the human malaria parasite
Objectives
The project aims to provide significant information to develop new biologics that block red blood cell invasion by the human malaria parasite.
The specific objects are:
- To identify other protein component(s) of the RH5 invasion complex, and develop monoclonal antibodies (mAbs) against these protein targets. These will be screened for functional anti-parasitic activity and combined with leading mAbs against RH5 to identify a highly inhibitory mAb cocktail.
- To develop and optimise an AAV-delivery platform to deliver the mAbs identified in aim 1. Novel AAV vectors will be designed, tested in vitro and screened in animal models. Serum will be tested for anti-malarial activity following immunisation.
The mainstay approach to vaccination against the blood-stage of malaria infection is to induce antibodies against the merozoite form of the parasite that invades red blood cells (RBC). Such a vaccine would protect against disease severity and could reduce transmission. A major recent advance has been the identification of a critical non-redundant interaction during RBC invasion – mediated between basigin (CD147) on the RBC surface and the parasite protein RH5. New data suggest RH5 is delivered to the parasite’s surface in a protein complex whose components are not fully elucidated. All known components of the complex are essential and need to be investigated as vaccine targets to complement on-going approaches against RH5.
In parallel, a second challenge facing current malaria vaccine strategies is the inability to induce durable immunity by conventional vaccination. High and sustained levels of serum antibody are required to protect, and these cannot be maintained once the immune response contracts into the memory phase. An alternative approach is to use adeno-associated virus (AAV) vectors to deliver antibody genes. Following administration of the AAV vector by intramuscular injection, the virus expresses antibody into the serum – effectively delivering sustained passive immunity against malaria. Moreover, this approach circumvents the need to manufacture recombinant antibody as a biological drug – a costly process that has prevented such therapies being developed for diseases of the developing world.
Oct 2016 — Sep 2020
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