RNA therapeutics have emerged as a revolutionary approach to treating diseases, offering a powerful platform for delivering therapeutic RNA molecules encapsulated in lipid nanoparticles (LNPs). These LNPs protect the RNA in the bloodstream, enhancing its stability and ensuring it reaches its target cells. The recent success of mRNA-based COVID-19 vaccines has demonstrated the immense potential of RNA therapeutics, showing their capacity to respond quickly to emerging health threats and provide effective treatments for previously difficult-to-treat diseases. Despite these advancements, a significant challenge remains: delivering these therapies efficiently and precisely to the correct cells to maximize therapeutic benefit while minimizing off-target effects. This project aims to address this challenge by using glycoscience through the application of glycan-targeted LNPs, a novel approach that leverages specially designed sugar molecules (glycans) to direct the LNPs to specific cell types. Glycans naturally interact with proteins on the surfaces of cells, making them ideal for targeting immune cells or inflamed endothelial cells, both of which play critical roles in immune responses and disease progression. The collaboration between NeoVac, a leader in LNP technology, and Sussex Research Laboratories (SRL), a leader in glycan chemistry and the development of glycan targeting ligands, will drive the development of LNPs that can deliver RNA therapies with greater precision. Our project will focus on synthesizing and screening various glycan ligands that bind to target cells. These ligands will then be incorporated into LNPs and evaluated for their ability to effectively deliver RNA to specific cell types. Successful outcomes will be validated using disease models to ensure therapeutic relevance. The development of glycan-targeted LNPs has the potential to transform RNA therapy delivery, enhancing precision and reducing the risk of side effects, the result of commonly encountered off-target effects. This project could pave the way for new therapeutic approaches to diseases such as cancer, autoimmune disorders, and infectious diseases. Ultimately, the goal is to create a scalable and adaptable platform for targeted RNA delivery, offering a safer and more efficient method for treating complex diseases. If successful, this technology could significantly advance the field of precision medicine and improve outcomes in RNA-based therapies.

The purpose of this project is to develop a mRNA vaccine against the Plague that is easy and suitable for distribution and use in lower- and middle-income countries (LMICs). Plague is a deadly disease caused by bacteria called _Yersinia pestis_(_Y. pestis_). Plague has caused millions of deaths throughout recorded history, most notoriously in the 1300s the 'Black Death' Pandemic that ravaged in western Eurasia killing up to 60% of the population., Nowadays endemic outbreaks are still experienced in many LMICs today. _Y. pestis_ is also recognised as a serious bioterrorism threat. Only if diagnosed early, plague can be effectively treated with antibiotics. However, antibiotic-resistant strains of _Y. pestis_ have emerged and human to-human transmission of such strains was recently reported in the 2017 Madagascar outbreak raising concerns about the future effectiveness of antibiotics against plague. Therefore, a plague vaccine could be very useful in preventing future endemic/epidemic outbreaks in LMICs. The Pfizer/BioNTech and Moderna COVID-19 LNP-mRNA vaccines demonstrated effective vaccines against contagious viruses, but mRNA is yet to be used in as antibacterial vaccine in humans. The first report of full protection against a highly lethal bacteria by a single dose of mRNA-LNP vaccine, has been recently published by NeoVac Co-founder Professor Peer and IIBR with the study demonstrating that one dose of a novel mRNA-LNP vaccine in mice provided full protection against plague. Current problem with existing mRNA-LNP vaccines is long-term storage and transportation at below-freezing temperatures. This makes their distribution and use in LMICs very challenging and expensive. To tackle this, NeoVac has developed a large library of proprietary LNPs which are designed to be stable at fridge temperatures (2-8 oC), that can be easily distribute and reduce the cost of vaccines for LMICs. In this project, NeoVac will employ Prof. Peer group's published mRNA encoding for _Y. pestis_ antigens, which have recently been demonstrated as effective in a preclinical plague model. The mRNA will be used to produce a thermostable mRNA-LNP vaccine that can be stored in the fridge. The project will start with the manufacturing of mRNA sequences followed by encapsulation in to the LNPs and efficacy studies both in vitro and in vivo. The vaccine will then be manufactured on a larger scale sufficient for first-in-human clinical trials. The large-scale batch will be further evaluated for stability, toxicity and immunogenicity required to support a clinical trial application.

Malaria killed about 640 thousand people in 2020, largely young children in Africa. Rapid recent progress has led to two anti-sporozoite vaccine developers planning WHO prequalification applications in 2022. These include the new high efficacy R21/Matrix-M vaccine, to be supplied at the required large scale, and led by partners in this consortium. In parallel, recent progress with transmission-blocking malaria vaccines has led to substantial efficacy in a first direct skin feeding field trial. This opens up the prospect of a two-stage vaccine targeting both sporozoites and sexual-stage parasites that should have a major impact on malaria transmission, thereby enabling regional elimination and ultimate eradication. We propose here to develop such a vaccine assessing both established virus-like particle (VLP) vaccines in potent saponin adjuvants and also exciting new thermostable mRNA vaccines expressing the parasite antigens now showing high efficacy. Importantly, we will adopt new VLP design technologies, e.g. SpyCatcher bonding, that allow bivalent antigen display, to enable a single vaccine to protect against both the Plasmodium falciparum parasite, which causes most deaths, and the more widespread Plasmodium vivax parasite. 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. The consortium brings together academics, non-profits and a wide range of companies with both leading technologies and access to small and very large scale GMP manufacturing capacity. This programme builds on the recent success of several partners in the R21/Matrix-M programme and aims to accelerate the malaria eradication agenda by providing the first vaccine to tackle both major malaria parasite species, and confer both individual and community protection on the way to eradication.