Parasitic worms use their own RNA molecules to manipulate the immune systems of their hosts, and this project aims to block that communication with a new type of vaccine. Around 1.3 billion people worldwide are infected with soil-transmitted parasitic worms, and no licensed human vaccine exists. Livestock infections also cause huge economic losses and threaten food security. The parasites are remarkably good at evading host immunity, partly by exporting RNA that alters the host’s biology. The researchers have identified two key proteins—exWAGO and SID-2—that the worms need to send these RNA signals. They plan to create a bivalent RNA vaccine that targets both proteins, effectively jamming the parasite’s messaging system. If successful, this would be the first real-world test of an RNA vaccine against a parasitic worm. The team will test the vaccine first in lab mice, then in wild wood mice infected with a natural parasite, to see whether genetic and environmental variation—conditions that often cause lab vaccines to fail—undermine protection. The work is fundamental bioscience: it asks how parasites sense and adapt to their hosts via RNA, and whether cutting that link can force the worms to lose their survival advantage.
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The goal of this proposal is to develop and apply cutting-edge RNA technologies to test new vaccine strategies against gastrointestinal nematodes, while advancing frontier bioscience on how these parasites use their own RNAs to modulate the host environment to increase survival and transmission. Vaccines are the most cost-effective method to combat infectious disease in humans and animals. Currently, there are no vaccines licensed for soil-transmitted helminths in humans, even though ~1.3 billion humans suffer morbidity due to infection. There are also no vaccines licensed for gastrointestinal nematodes that are suitable for scalable commercial production in livestock, despite the significant impact on food security and the huge economic losses associated with infections. Our approach addresses two potential causes of this gap: (i) the striking ability of gastrointestinal nematodes to manipulate and evade host immunity and (ii) the substantial effects of genetically and ecologically diverse host and parasite populations that exist outside of the lab on vaccine responsiveness. We discovered that gastrointestinal nematodes have evolved novel RNA interference and RNA export pathways that enable them to evade host immunity and survive in the host. Our data suggest that parasites use a diverse suite of RNAs to alter the host environment. We have developed a vaccine strategy to target an Argonaute protein (exWAGO) that is required for parasite RNAs function. Our preliminary data indicate that this is the Achilles heel of the RNA transport mechanism and we predict that targeting exWAGO in combination with extracellular vesicles will provide a robust strategy to block all nematode RNA transmission to the host. Our goal is to generate a bivalent vaccine with exWAGO and SID-2, a membrane protein expressed on the surfaces of extracellular vesicles, using RNA technologies that are amenable to multiplexing and future scale up in manufacturing. The proposed research will provide the first real-world test of an RNA vaccine against a helminth. We will test the immunogenicity of exWAGO and SID-2 RNA vaccine constructs in C57BL/6 mice (Aim 1) and their protective capacity when administered individually or in combination followed by parasite challenge (Aim 2). Once we have optimised the bivalent vaccine in the laboratory model, we will then move to testing vaccine efficacy and the consequence of blocking RNA transmission in real-world conditions of H. polygyrus infecting Apodemus sylvaticus (wood mice; Aim 3). This model allows us to address the second gap: the impact of host, parasite and environmental variation on vaccine responsiveness. We hypothesise that parasites sense and respond with transmitted RNA to variable host/environmental conditions and that, by blocking all RNAs that the parasite transmit, this vaccine approach may prevent the parasite from modulating the host for its own adaptation/survival. We will employ both controlled laboratory and field studies and in parallel use small RNA sequencing analysis to directly test whether and how vaccination blocks parasite RNA trafficking to host cells in vivo. This project integrates three BBSRC priority areas: we will develop and implement transformative RNA technologies to advance understanding of the rules of life using a unique animal model to understand the role of RNA communication in a natural ecological system. We use these advances in bioscience to develop new vaccine strategies for sustainable agriculture and food.
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