RAVEN (Rapid Attenuated Virus EvolutioN) Surveils and Estimates Risks from Animal-Borne Pathogens

**Curt Hewitt**
*Senior Molecular Biologist*

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The Intelligence Advanced Research Projects Activity (IARPA) funded the development a laboratory-based model of viral evolution of pandemic viruses as a part of the COVID-19 Seedling Research program. The COVID Seedling Research program was created under the unique circumstances of the COVID-19 pandemic to solicit short-term, limited scope research in topic areas that are not addressed by emerging or ongoing IARPA programs. One such topic was the development of tools for widespread surveillance and risk estimation of animal-borne pathogens (before they ever come into contact with humans). more dangerous strains and investigate prophylactic measures or treatments for these novel viruses before they reach pandemic levels.

Figure 1: RAVEN Directed Evolution. Libraries of genetically variant CoV genomes can be produced to accelerate the process of evolution. Individual viral genomes are then transfected into helper cells, resulting in a library of variant virions containing their corresponding genome. These virions are then challenged to infect a reporter cell line under stringent conditions. Vector RNA from successful infection is recovered, sequenced, and may be used to for iterative rounds of directed evolution to identify the variants that provide the greatest fitness advantage to the virus.

This risk estimation was to include potential to cross species barriers, transmission mechanisms, reproduction numbers, incubation times, duration of infectivity, virulence, mechanisms of human immune evasion and modification, pathogenetic mechanisms, and/or lethality. Signature Science was initially selected to receive Phase A funding, under which our synthetic biologists engineered non-replication competent SARS-CoV-2 vectors as proof-of-concept. After successfully demonstrating proof-of-concept in Phase A, IARPA awarded a second-phase contract extension to continue the development the model, shifting focus to the study of viral variants which were directly relevant to the state of the COVID-19 pandemic. With the additional funding, Signature Science employed synthetic biology techniques common in the field of viral vectorology to deliver an accurate and safe laboratory alternative to in silico modeling, which can be limited by a lack of empirical data. In doing so, Signature Science produced a catalog of dangerous viral variation to compare to emerging epidemiological data. Should critical variants begin to arise in human or animal populations, IARPA and the U.S. Intelligence Community will be positioned to act, informing public health response to restrict transmission of the more dangerous strains and investigate prophylactic measures or treatments for these novel viruses before they reach pandemic levels

Figure 2: SigSci’s RAVEN Concept. During Phase A, SigSci performed the genetic engineering necessary to build a safe, BSL-2-suitable method to produce SARS-CoV-2 vectors. Following this proof of concept, Phase B focused on rapid, directed evolution of viral genomes to identify high-risk variants in vivo. This data will support the future creation of programs that aim to meld empirical data with modeling systems to achieve heretofore unprecedented predictive analytics of zoonotic viral threats.

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