The coronavirus disease (COVID-19) pandemic caused by the global spread of the severe acute respiratory syndrome-2 (SARS-CoV-2) virus has led to a staggering number of deaths worldwide and significantly increased burden on healthcare as nations have scrambled to find mitigation strategies. Viral infections such as SARS-CoV-2 can also predispose patients to bacterial co-infections. In fact, at least one in seven patients who have tested positive for COVID-19 have developed bacterial co-infections which have increased the severity and mortality of the disease. Since antiviral drugs have no effect on bacterial infections, these co-infections are treated with antibiotics. This surge in the use of antibiotic use during the COVID-19 pandemic has a detrimental effect in terms of driving the global growth of antibiotic resistance. The goal of TRIAL is to design and test drug delivery vehicles tethered with antimicrobials to deliver the requisite therapeutic dose to tackle viral and bacterial infections in a controlled manner. The antimicrobials that are being developed in our laboratory have shown to have an effect on a wide range of respiratory viruses and bacterial pathogens. As we are using broad spectrum antimicrobials that are not antibiotics and we are therefore lowering the risk of developing antimicrobial resistance. The technology being developed here is highly novel and will be revolutionary in the treatment of respiratory infections including that of COVID-19. We have brought together a group of world-class scientists, a clinician and an industrial partner with over 20 years' experience in their respective fields who will work to achieve the ambitious goals of the proposed work. The long term goal is the acceleration of bench to clinic impact followed by the commercialisation of the technology.

Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Antibiotics constitute the standard of care but are faced with the emergence of antimicrobial resistance (AMR) and the curative failure. The FAIR consortium aims at assessing an adjunct to antibiotic therapy as an emerging concept of overcome AMR in pneumonia. The project leverages (i) a unique immunomodulatory flagellin that enhances airway epithelial innate immune defences and increases the therapeutic outcome relative to antibiotic alone, and (ii) airway-specific aerosol delivery by nebulization. FAIR's objectives are to: • develop nebulization modalities for optimal airway targeting and rapid action at the infection site • demonstrate that nebulized flagellin strengthens the response to antibiotics in relevant preclinical models of antibiotic-resistant pneumonia • identify host immune factors required for the gain of protection with systems biology • implement pharmacokinetics/pharmacodynamics model-based design and simulation for clinical validation • assess nebulized flagellin's safety in a Phase I clinical trial. • analyze the acceptability and economic relevance of the therapy • identify stratification markers that predict the course of pneumonia and treatment in antibiotic-treated cohorts. Expected outcomes include the enrichment of the pipeline of novel treatments against pneumonia, reinforcement of EU capacity to control AMR and infections, the Phase I safety report on nebulized flagellin, recommendations for future trials, and acceptability by the stakeholders and cost-effectiveness for public health. FAIR will develop new avenues of research on mechanisms of action of the adjunct flagellin, and will define (for future trials) the subpopulation of patients that might benefit most from this treatment. Our industrial partnerships and exploitation plan will enable straightforward development of drug and nebuliser device, and bring innovation to the patients.

Streptococcus pneumoniae is a bacterium that uses the lungs as a route of entry into the body causing community acquired-pneumonia (CAP). It is a leading cause of ill-health and death in children, elderly and immunocompromised worldwide. Moreover, amongst adults, it is the leading cause of CAP which is likely to rise with increasing life expectancy and escalating resistance towards antibiotics. Furthermore, if S. pneumoniae is not treated it can gain entry into the blood resulting in life-threatening septicaemia and meningitis. The health service costs associated with pneumococcal infection is £1 billion (UK), $5.5 billion (USA), 10 billion Euros (Europe) and $240 million (Brazil). The World Health Organization regards vaccination as an important public health strategy to combat infectious diseases. Vaccines should be safe, effective, practical and affordable. The current vaccine only offers protection against 13 most common strains of S. pneumoniae and has limited effectiveness against CAP. To be effective multiple vaccine candidates are required offering cross-protection against the many different strains. However, this is not practical due to high costs and lengthy timescale for production. Furthermore, it is administered via injection resulting in poor immune protection within the lungs. Therefore, there is a need for a more effective vaccine candidate that can be given safely and practically directly to the lungs providing better protection against S. pneumoniae. Vaccination via the lungs is an attractive avenue as it mimics the natural infection route of S. pneumoniae and can lead to immune protection over the whole body via other connected sites, such as nose and intestines. Inhalation offers the advantage of eliminating syringes and needles, removing the hazard of safe disposal and lowering the risk of blood-borne infections. Various parts of bacteria known as antigens can stimulate an immune response. Researchers in Institute Butantan, Brazil are proposing proteins common to all strains: PspA, from the surface of S. pneumoniae, genetically detoxified pneumolysin (PdT) and PspA-PdT fusion protein. The three proteins will be separately incorporated into small particles (nanoparticles, NPs) and compared to each other with regards to activity, immune response and aerosolisation efficiency into the lungs. The NPs are safe and have adjuvant properties which help activate an immune response, hence can result in a stronger immune response using lower protein concentrations. Moreover, due to the NPs size (~200nm) they can cross barriers in the lungs and promote the uptake of proteins by antigen presenting cells that can effectively initiate an immune response in the lungs. In order to increase delivery of NPs into the lungs, they are embedded within larger microparticle carriers prepared using pharmaceutically inert amino-acids or sugars, resulting in dry powder nanocomposite microparticle carriers (NCMPs) of suitable particle size (1-5micron) for deposition within the lung. In addition, we will also test the NCMPs via nebulisation, which is of benefit to children and elderly who have difficulty with using conventional dry powder inhalers. Furthermore, the formation of dry powder NCMPs will increase the stability of NPs and antigen, and eliminate cold temperature transport and storage. This project will evaluate vaccine delivery of NPs/NCMPs as carriers of PspA or PdT or PspA-PdT, for the prevention of pneumococcal diseases via inhalation enhancing immune response in mice compared to needle-based vaccination of free antigen as control. We will investigate the immune responses after single and booster injections through this route, and evaluate the protection against S. pneumoniae challenge in the lungs. If successful, our vaccine nanocarrier technology platform can be applied to a range of different infectious agents not only in human health but also for veterinary use.

Despite the widespread availability of antibiotics, infection deep in the lung (pneumonia) remains an important cause of death in older people, as well as in critically ill patients in intensive care units. Our lungs contain a population of cells that sit in the air pockets of the lung and sense the presence of bugs. These cells are called alveolar macrophages (AMs). When AMs sense bugs in the lung, they kill them and if necessary send signals to the wider immune system for more help. Our study wishes to find out if AMs work less well as we get older, or when we are critically ill, as this may explain why we become susceptible to pneumonia. We know that a natural chemical in the body, called granulocyte-macrophage colony-stimulating factor (GM-CSF), maintains the health of our AMs. A further aim of our study is to determine whether giving GM-CSF as an inhaled drug, directly into the lung, might boost the function of AMs. If it does, this would provide the impetus for further research to see if GM-CSF could be given to people at very high risk of pneumonia (for example those in intensive care units), to prevent infection. This may have great advantages, because GM-CSF is not an antibiotic. The very heavy use of antibiotics in intensive care units has led to the emergence of "superbugs" that are not killed by antibiotics, and there is an urgent need to develop safe treatments that might boost immune cells such as AMs, instead of relying entirely on antibiotics. Nearly all of our information on how GM-CSF improves the function of AMs comes from studies in mice. We need to understand better how human AMs kill bugs, we need to know if this goes wrong as we get older or become critically unwell, and we need to know if GM-CSF can improve things. These issues have driven the design of our study. We shall ask 20 young volunteers (aged 18-30) and 20 older volunteers (60 or over) to come to the hospital on three days. On day one and day two they will inhale GM-CSF or a placebo, but neither they nor the research team will know which they inhaled. Each session will last about an hour. On day three they will come back for a telescope test of the lungs (bronchoscopy), where they are closely monitored and fluid is instilled into the a small area of the lung and gently sucked back. The fluid sucked back contains millions of AMs. The test lasts about 20 minutes and the person rests in hospital afterwards for a few hours before going home. Separately, a group of critically ill patients in the ICU will have the same protocol, i.e. GM-CSF or placebo on days 1 and 2, and bronchoscopy on day 3. In a final variation, the young volunteers will come back at least one month later, and have the same procedures done again, except that if they received GM-CSF first time round they will receive placebo the second time, and vice versa. We can take the AMs to the lab and study how well they eat bugs. We can block the function of specific molecules in the AMs and if this prevents the anti-bug effects we can infer that these molecules must be important for AM function. This way we shall build up a profile of the key molecules at the surface of the AM ("receptors") or inside the AM. Once we have the results we can "unblind" ourselves to find out who had GM-CSF and who had placebo. In this way we can piece together the answers to our questions - how do human AMs get rid of bugs? Do ageing and critical illness reduce the function of AMs and, if so, how? Does GM-CSF restore good function to AMs? The study will generate entirely new information on the function of human AMs. If GM-CSF is safe and boosts AM function we shall take this information forward to work out if inhaled GM-CSF can effectively and safely prevent pneumonia in patients who are at highest risk.

Lung cancer (LC) treatments have advanced in recent years with the advent of genetic profiling and immunotherapy. However, LC is a complex heterogeneous disease and survival rates remain poor. RNA (mRNA, microRNA, other non-coding RNAs and nucleic acid based modulators of same) and gene therapies (DNA or gene editing) for delivering nucleic acid-based therapeutics have curative potential for a host of indications previously untreatable. They have yet to enter the mainstream, due to safety concerns and difficulties delivering them efficiently to areas other than the liver, kidney and circulatory system. Aerosol delivery allows direct targeting of lung tissues but viscous mucus in the lung is a significant barrier to gene transfer to the target cells of the lungs. Even if the mucus layer can be penetrated, inefficient penetration through the cell membrane further impedes access of these vectors to the underlying target cells, thus preventing successful gene transfer. Delivery is a major barrier to successful pulmonary gene therapy for competing viral and non-viral gene transfer vectors and the vast promise of gene therapy has many challenges to overcome. OMNI's novel solution is pioneering the use of genetically modified MSC EVs with a proprietary surface engineering technology to further enhance delivery through the mucus barrier and into the targeted lung cells. This platform technology also combines efficient aerosol delivery of the EVs via AERO's proprietary state of the art vibrating mesh nebulizer technology. This unique solution solves the problems associated with lung targeted delivery of RNA based advanced therapies.