Engineering next-generation messenger RNA vaccines: Reinforcing the mucosal barriers by thermostable dry powder vaccines for inhalation

Vaccines based on messenger RNA (mRNA) have been shown to provide effective and safe protection against COVID-19, and many hundreds of millions of doses of mRNA vaccines have been administered worldwide. However, the current mRNA vaccine technology has some limitations e.g., limited durability and breadth of protective immunity, formulation and potential side effects, manufacturing capacity and cost, and cold chain requirements. WHO recognizes ultra-cold-chain requirement as one of major bottlenecks for the inequitable access and cost of mRNA vaccines in low- and middle-income countries and thus thermostability is one WHO's preferred product characteristics for future mRNA vaccines. The existing mRNA vaccines are given in the muscles and induce strong immunity in the blood but do not induce protective immunity in the lungs, which are the site of entry for many respiratory pathogens. This represents a great opportunity for the development of novel inhalable dry powder-based mRNA vaccines that are thermostable and can induce protective immunity in the lungs. However, inhalable mRNA vaccines must navigate through biological barriers in the lungs and overcome the challenge of stability at various temperatures before successful production of such vaccines can be realized. The overall purpose of this proposal is to investigate and improve the delivery of inhalable dry powder mRNA vaccines and evaluate their safety and ability to stimulate an immune response and protective efficacy, which in the short term will generate new knowledge on how to design and administer inhalable dry powder mRNA vaccines to induce local immunity in the lungs. In the long run, it will result in the development of new and improved inhalable dry powder-based mRNA vaccines against a range of respiratory pathogens.