Human convalescent plasma protects K18-hACE2 mice against severe respiratory disease

Abstract

SARS-CoV-2 is the causative agent of COVID-19 and human infections have resulted in a global health emergency. Small animal models that reproduce key elements of SARS-CoV-2 human infections are needed to rigorously screen candidate drugs to mitigate severe disease and prevent the spread of SARS-CoV-2. We and others have reported that transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) viral receptor under the control of the Keratin 18 (K18) promoter develop severe and lethal respiratory disease subsequent to SARS-CoV-2 intranasal challenge. Here we report that some infected mice that survive challenge have residual pulmonary damages and persistent brain infection on day 28 post-infection despite the presence of anti-SARS-COV-2 neutralizing antibodies. Because of the hypersensitivity of K18-hACE2 mice to SARS-CoV-2 and the propensity of virus to infect the brain, we sought to determine if anti-infective biologics could protect against disease in this model system. We demonstrate that anti-SARS-CoV-2 human convalescent plasma protects K18-hACE2 against severe disease. All control mice succumbed to disease by day 7; however, all treated mice survived infection without observable signs of disease. In marked contrast to control mice, viral antigen and lesions were reduced or absent from lungs and absent in brains of antibody-treated mice. Our findings support the use of K18-hACE2 mice for protective efficacy studies of anti-SARS-CoV-2 medical countermeasures (MCMs). They also support the use of this system to study SARS-CoV-2 persistence and host recovery.

Outpatient treatment with concomitant vaccine-boosted convalescent plasma for patients with immunosuppression and COVID-19

“…There is consensus that the primary mechanism of action of vax-plasma is through viral neutralization ( 19 )—a finding established among humans early during the COVID-19 pandemic ( 22 ) and supported by several preclinical models including mice ( 23 , 24 ), hamsters ( 25 ), and macaques ( 26 ). Because the neutralizing capacity of vax-plasma can evolve with emerging variants, issues related to escape by new variants that have time limited the efficacy of monoclonal antibodies can potentially be avoided.…”

Outpatient treatment with concomitant vaccine-boosted convalescent plasma for patients with immunosuppression and COVID-19

“…There is consensus that the primary mechanism of action of vax-plasma is through viral neutralization 19 —a finding established among humans early during the COVID-19 pandemic 22 and supported by several preclinical models including mice, 23,24 hamsters, 25 and macaques. 26 Because the neutralizing capacity of vax-plasma can evolve with emerging variants, issues related to escape by new variants that have time limited the efficacy of monoclonal antibodies can potentially be avoided.…”

Preliminary nonclinical safety and immunogenicity of an rVSV-ΔG-SARS-CoV-2-S vaccine in mice, hamsters, rabbits and pigs

“…To further evaluate the safety of rVSV-ΔG-SARS-CoV-2-S vaccine, the ability of the vaccine to propagate at the site of injection and to spread to the lungs was assessed in K18-hACE2 transgenic mice in which the human ACE-2 receptor (hACE2) is expressed under the K18 promotor in all epithelial cells. K18-hACE2 transgenic mice are considered to be a highly sensitive animal model for SARS-CoV-2 (Golden et al 2021 ; Yinda et al 2021 ; Zheng et al 2021 ), and were also shown to induce neutralizing antibodies in response to rVSV-ΔG-SARS-CoV-2-S vaccination (manuscript in preparation). Mice were vaccinated i.m.…”