MICA VACCINE FAPESP MICA: Pulmonary Delivery of a Targeted Mucosal Nanocarrier Vaccine for Pneumonia 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. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.