Engineering a Self-Amplifying RNA Amplicon as a Vaccine or Therapeutic for Influenza
RNA-based vaccines and therapeutics are promising next generation alternatives to conventional methods of developing prophylactics. Compared to current available vaccines, nucleic acid-based prophylactics have several advantages. They are inexpensive, generally easy and faster to manufacture. The ease by which RNA platforms can be synthetically generated or modified provides great flexibility in the design of prophylactics for influenza A and B viruses. The speed at which nucleic acid-based vaccines can potentially be generated during a pandemic can be of significant impact in limiting transmission and decreasing deaths. Nucleic acid-based prophylactics can potentially mimic immune responses comparable to live attenuated vaccines or even natural infection – all without causing disease. While most work in the past decades have mostly focused on advancing DNA-based vaccines, RNA-based vaccines and therapeutics have lately attracted more research. Lastly, in contrast to DNA-based amplicons, which requires to bypass the plasma and the nuclear membranes before transcription is initiated, RNA-based platforms only require to bypass only the plasma membrane before translation of the gene of interest.
Here, we will investigate the viability of using a self-amplifying RNA amplicon expressing key antigens from influenza A or B viruses as a basis for an influenza vaccine. The idea is to generate a safe influenza vaccine that will elicit a robust and long-lasting immune response. In parallel, we will also explore the use of an RNA self-replicating amplicon expressing a broadly protective monoclonal antibody for use as a pre- and post-exposure prophylaxis against infection.
Amongst the challenges that hamper the development of nucleic acid-based vaccines and therapeutics are approaches that can efficiently deliver the platforms into target cells in vivo. To overcome this obstacle, we are collaborating with Dr. Michael Sailor (University of California San Diego), who will utilize nanoparticle approaches to encapsulate the RNA replicon. Fusogenic porous silicon nanoparticle (F-PSiNP) carrier will encapsulate the RNA replicon with a lipid shell that will allow fusion with the cellular membrane upon adsorption. This theoretically will insert its RNA replicon directly into the cytoplasm and bypass endocytosis. The fusion mechanism also provides a means to induce dissolution of the silicon nanoparticles, rapid releasing the nucleic acid into the cytoplasm. We hypothesize that self-amplifying RNA amplicons encapsulated in F-PSiNPs will provide a biosafe and effiacious approach for vaccination or therapeutics.