Rapid generation and testing of live-attenuated vaccines against SARS-CoV-2

There is a clear unmet need for a vaccine against the ongoing epidemic of coronavirus disease 2019 (COVID19) caused by SARS-CoV-2. SARS-CoV-2 was initially detected in the Hubei Province of China late in 2019.SARS-CoV-2 is highly contagious (R0 of 1.4-3.9, greater than seasonal influenza), and presents with fever,cough, fatigue, and shortness of breath. Older patients and those with underlying health conditions may be ata higher risk of severe illness, with most reported cases having occurred in adults (median 59 years of age).There are no vaccines or other medical countermeasures available against SARS-CoV-2. This submission is anAdministrative Supplement to 1R44AI131756-01 in response to NOT-AI-20-030, where we describe ourapproach to pre-clinical testing of our SARS-CoV-2 vaccine candidates. In the parent grant application,Codagenix is developing a safe and effective RSV vaccine based on Codagenix's algorithm-based platform forrapid generation of vaccines. Together, the respiratory illnesses caused by RSV and SARS-CoV-2 present majorpublic health threats. In this administrative supplement, we seek to apply our "synthetic attenuated virusengineering' (SAVE) platform to design and develop a live-attenuated vaccine (LAV) against SARS-CoV-2.SAVE relies on large-scale DNA synthesis and rational re-design of a target virus to construct a vaccine that is"deoptimized" for protein expression in human cells. The SAVE platform has been used to generate vaccinesagainst multiple viruses including influenza, Zika, dengue, RSV, and others. One SAVE-based vaccine iscurrently in the clinic in Phase I trials under a US IND, and another entering clinical trials in Q1-20,demonstrating the proof of principle behind SAVE. We already initiated the SARS-CoV-2 vaccine developmentin a real-time response to the ongoing epidemic of SARS-CoV-2. Using our SAVE platform, we designed sixvaccine candidates that are deoptimized to varying extents across the RdRp and Spike genes, along with asynthetic wt SARS-CoV-2. These genomes were synthesized de novo, assembled, sequenced, and are nowready for recovery following transfection in cell culture. Candidate vaccine viruses will be recovered underBSL-3 containment, passaged, deep sequenced, and screened for attenuation, immunogenicity and efficacy in aprimate model. We expect at least one, but likely 4 viruses will be recovered from transfection. Three of thebest-growing viruses (growing to >104 TCID50/ml) will be tested for safety, immunogenicity and efficacy inAfrican green monkeys, previously used for SARS studies. Following the completion of the work describedhere, using non-grant funding, two of the viruses that perform best in primate studies will be put through GLPtoxicity screening, GMP manufacturing and a Phase I clinical trials.