Microneedle-based mRNA Flu Vaccine for Transcutaneous Immunization

Flu is a contagious respiratory disease caused by influenza viruses, which infect the nose, throat, and sometimes the lung. It can cause mild to severe illness and at times lead to death. The best way to prevent seasonal flu is by receiving a flu vaccine annually. Multivalent flu vaccines are designed to protect against the 3-4 influenza viruses that research predicts would be most common during the upcoming flu season, and due in part to having to guess next season’s strains, the CDC reported effectiveness of seasonal flu vaccine in the U.S. ranged between 19% and 60% over the past 15 years. For a flu pandemic that occurs occasionally, a new vaccine would be needed. Our long-term goal is to develop a universal influenza vaccine. A stable, microneedle-based, multivalent messenger RNA (mRNA) flu vaccine that allows non-invasive, patient-friendly intradermal administration would be an ideal candidate of such a vaccine, as there are many antigen-presenting cells in the dermis, and often a significantly lower dose of vaccine is needed when a vaccine is given intradermally as compared to the intramuscular injection. Our objective in this phase 1 STTR application is to develop a microneedle-based influenza virus hemagglutinin (HA) mRNA vaccine candidate by taking advantage of our proprietary thin-film freeze-drying technology and to evaluate the HA-specific immune responses induced in a mouse model. Our hypothesis is that transcutaneous immunization using HA-encoding mRNA-lipid nanoparticle (LNP)-carrying microneedles will induce strong specific humoral and cellular immune responses. To date, we have developed a prototype HA mRNA-LNP-carrying microneedle system. We have shown that the mRNA-LNPs released from the microneedles maintained their physicochemical properties as well as the mRNA encapsulation efficiency, and importantly the microneedles can successfully deliver the mRNA-LNPs into the pores created in mouse skin by applying the microneedles. To accomplish our objective and to test our hypothesis, we propose the following two specific aims: (1) to optimize the process of manufacturing the HA mRNA-LNP-carrying microneedles, and (2) to evaluate the immune responses induced by the HA mRNA-LNPs in mice that are transcutaneously immunized into the skin with the microneedles. To safeguard the success of the proposed project, we have assembled a team with extensive experience in microneedle-based immunization, mRNA vaccine, and vaccine development. Upon the completion of this phase 1 project, we expect to have optimized the mRNA-LNP-carrying microneedle manufacturing process and validated the immunogenicity of the mRNA- carrying microneedles in a mouse model for a phase 2 application to further optimize the design of the mRNA- LNP-carrying microneedles, scale up their manufacturing process, and test their safety and effectiveness in mouse and ferret models. Such an outcome would be highly impactful for the ultimate development of a stable, microneedle-based universal mRNA flu vaccine.