mRNA COVID-19 Vaccines Delivered with Plant Virus/Polymer Devices

Summary The rapid development, distribution and administration of a COVID-19 vaccine to the global population is the most effective approach to quell this pandemic and future reoccurrence. Vaccination must occur broadly both in well-resourced and resource-poor areas of the world to be most effective. We propose a vaccine delivery device based on a plant virus/polymer blend. The manufacturing scheme proposed would allow for timely production at scale; most importantly, the vaccine delivery device would be stable outside of the cold- chain and only require a single-dose administration. We propose to package an mRNA vaccine encoding the SARS-CoV-2 S protein (and domains thereof) in virus-like particles (VLPs) derived from the plant virus Tobacco mosaic virus (TMV). TMV can be reconstituted in vitro or in plants to carry heterologous RNA and its utility in mRNA vaccine delivery has been demonstrated. Plant VLPs are highly visible to the immune system, these vaccine delivery agents boost immunity through signaling via multiple receptors of the innate immune system; therefore, the VLP serves as carrier and well-defined adjuvant. Furthermore, TMV offers high thermal stability - therefore overcoming cold chain requirements; but more importantly the mRNA-laden TMV vaccine candidates offer such a high degree of stability that they can withstand the rigors of melt-processed device manufacture, therefore allowing the formulation of slow-release implants or microneedle patches for single-administration. We will produce mRNA-laden TMV and then apply melt-processing tools manufacture the slow-release implants. We have developed a microextruder to manufacture protein/polymer blends that allows for the formulation of plant virus-based vaccines into slow-release devices. We have already demonstrated that plant virus-based vaccines can withstand the rigor of melt-processing. Under the tenure of this R21, we will package SARS-CoV-2 derived mRNA cassettes into TMV and verify mRNA delivery and protein expression in immune cells (Aim 1). We will formulate slow-release VLP/polymer (PLGA) blends and determine VLP (mRNA-laden TMV) release rates from the VLP/polymer blends (Aim 2). We will determine antibody titers and cellular anti-SARS-CoV-2 responses of the mRNA-laden TMV vaccine candidates in mice and compare soluble (prime-boost) vs. implant vaccine candidates (single administration). We will determine whether vaccination yields neutralizing SARS-CoV-2 sera and cellular responses; in vitro and in vivo SARD-CoV-2 challenge studies will be performed (Aim 3). Our technology brings unique attributes in that it does not require the cold chain for distribution and would enable vaccination upon single administration. Single- administration vaccines could also enable vaccination of livestock and this could be a step forward to meet the goals of the One Health Initiative to prevent future outbreaks.