Development of microneedle-based vaccine delivery systems and mRNA-based vaccines

Abstract

The emergence of the COVID-19 pandemic has accelerated the clinical development of novel mRNA-based vaccines, such as Comirnaty and Spikevax. These vaccines elicit potent efficacy in human patients, supporting the impactful development of mRNA therapeutics in the recent years. The thesis includes two complementary parts. The first part of the research uniquely develops an in-house mRNA platform to generate various treatments for cancer and COVID-19. Cationic InstantFECT-liposomes are selected for the mRNA formulation by comparing different transfection vectors, such as liposomes, PEI, protamine and silica nanoparticles. A cocktail of different cytokine-encoding mRNAs (i-cocktail a vaccine: IL-2, IL-15, GM-CSF and IFN-gamma) is developed for the effective localized treatment of several cancer types. The i-cocktail a vaccine works by activating the host immunity to stimulate anti-cancer immune cells in the local tumor microenvironment. The i-cocktail a vaccine prolongs the tumor-bearing mice survival and enhances T cell antigen-recognition. Alternatively, mRNAs encoding for various SARS-CoV-2 immunogenic antigens are produced against COVID-19. The ultimate objective of investigating the preclinical efficacy of various mRNA vaccines is to produce novel and clinically-translatable treatments. The second part of the research is to develop microneedle-based delivery of mRNA and proteins. Interestingly, current nucleic acid-based vaccines are administered to patients solely by traditional bolus injection. This poses certain limitations such as, pain, injection-site inflammation, inconvenient needle disposal and the requirement of trained health providers to perform the injection. To transcend these limitations, this research investigates the delivery of various mRNA and protein vaccines by using dissolvable microneedles. The micro-molding technique is used for the cost-effective fabrication of microneedles. Hyaluronic acid-based microneedles (MN) delivering SARS-CoV-2 proteins (spike receptor-binding domain protein and nucleocapsid protein) and adjuvants induce robust humoral and cellular immunity in mice after simple patch-and-peel administration. Hyaluronic acid is a naturally-occurring substance in the skin and is highly biodegradable. Importantly, MN patches possess the future potential to be self-applied painlessly which may enhance global compliance towards vaccinations. Furthermore, cryogenic MNs that are fabricated under ultra-low temperatures could be used to deliver temperature-sensitive mRNA vaccines, such as Comirnaty. This supports the future possibility of using non-invasive MN devices to administer commercial vaccines in clinics. Together, the development of novel mRNA therapies and microneedle vaccine delivery devices provide the promising opportunity for clinical therapeutics translation.