A novel mouse AAV6 hACE2 transduction model of wild-type SARS-CoV-2 infection studied using synDNA immunogens

Gary, Ebony N.; Warner, Bryce M.; Parzych, Elizabeth M.; Griffin, Bryan D.; Zhu, Xizhou; Tailor, Nikesh; Tursi, Nicholas J.; Chan, Mable; Purwar, Mansi; Vendramelli, Robert; Choi, Jihae; Frost, Kathy L.; Reeder, Sophia; Liaw, Kevin; Tello, Edgar; Ali, Ali R.; Yun, Kun; Pei, Yanlong; Thomas, Sylvia P.; Rghei, Amira D.; Guilleman, Matthew M.; Muthumani, Kar; Smith, Trevor; Wootton, Sarah K.; Patel, Ami; Weiner, David B.; Kobasa, Darwyn

More than 100 million people have been infected with SARS-CoV-2. Common laboratory mice are not susceptible to wild-type SARS-CoV-2 infection, challenging the development and testing of effective interventions. Here, we describe the development and testing of a mouse model for SARS-CoV-2 infection based on transduction of the respiratory tract of laboratory mice with an adeno-associated virus vector (AAV6.2FF) expressing human ACE-2 (AAV6.2FF-hACE2). We validated this model using a previously described synthetic DNA vaccine plasmid, INO-4800 (pS). Intranasal instillation of AAV6.2FF-hACE2 resulted in robust hACE2 expression in the respiratory tract. pS induced robust cellular and humoral responses. Vaccinated animals were challenged with 105 TCID50 SARS-CoV-2 (hCoV-19/Canada/ON-VIDO-01/2020) and euthanized four days post-challenge to assess viral load. One immunization resulted in 50% protection and two immunizations were completely protective. Overall, the AAV6.2FF-hACE2 mouse transduction model represents an easily accessible, genetically diverse mouse model for wild-type SARS-CoV-2 infection and preclinical evaluation of potential interventions.