Passive Transfer of A Germline-like Neutralizing Human Monoclonal Antibody Protects Transgenic Mice Against Lethal Middle East Respiratory Syndrome Coronavirus Infection

Abstract

Middle East Respiratory Syndrome coronavirus (MERS-CoV) has repeatedly caused outbreaks in the Arabian Peninsula. To date, no approved medical countermeasures (MCM) are available to combat MERS-CoV infections. Several neutralizing human monoclonal antibodies (mAbs), including m336, a germline-like human mAb, have been chosen as promising MCM for MERS-CoV. However, their clinical development has been hindered by the lack of a robust animal model that recapitulate the morbidity and mortality of human infections. We assessed the prophylactic and therapeutic efficacy of m336 by using well-characterized transgenic mice shown to be highly sensitive to MERS-CoV infection and disease. We found that mice treated with m336 prior to or post lethal MERS-CoV challenging were fully protected, compared to control mice which sufferered from profound weight loss and uniform death within days after infection. Taken together, these results support further development of m336 and other human monoclonal antibodies as potential therapeutics for MERS-CoV infection.

Prophylactic and therapeutic efficacy of mAb treatment against MERS-CoV in common marmosets

“…However, despite promising results in mouse models, the high case-fatality rate in humans, low neutralizing antibody titers in survivors and the inability of many survivors to function as plasma donors due to underlying health issues are considerable hurdles in the implementation of convalescent plasma therapy for MERS patients (Arabi et al, 2016). Monoclonal antibody (mAb) treatment could provide an alternative for convalescent plasma, and several neutralizing monoclonal antibodies have been developed and tested in animal models (Agrawal et al, 2016; https://doi.org/10.1016/j.antiviral.2018.06.006 Received 2 April 2018; Received in revised form 4 June 2018; Accepted 5 June 2018 Corti et al, 2015;Houser et al, 2016;Johnson et al, 2016;Li et al, 2015;Pascal et al, 2015;Qiu et al, 2016).…”

Efficacy of antibody-based therapies against Middle East respiratory syndrome coronavirus (MERS-CoV) in common marmosets

“…In contrast, administration of m336 1 dpi via the same routes did not reduce viral RNA titers in the lungs of rabbits (Houser et al, 2016). Reduced mortality and morbidity was observed in a MERS-CoV mouse model upon intraperitoneal prophylactic and therapeutic treatment with m336, and therapeutic treatment resulted in a decrease in viral titer as well as viral RNA in lung tissue (Agrawal et al, 2016). It can be argued that neither the rabbit nor the mouse model have a high predictive value for potential MERS therapies in humans.…”

“…It has therefore been speculated that the potential for viral escape mutants might be limited by the requirement of the spike protein to bind to DPP4 (Ying et al, 2015). Prophylactic treatment with m336 resulted in significantly reduced viral titer in rabbit lung tissue (Houser et al, 2016) and both prophylactic and therapeutic treatment with m336 protected mice against lethality by MERS-CoV infection (Agrawal et al, 2016). Here we assess the effect of treatment with marmoset-derived hyperimmune plasma as well as the human mAb m336 on disease outcome in the recently developed marmoset MERS-CoV infection model, which recapitulates severe respiratory disease (Falzarano et al, 2014).…”

Detection of MERS-CoV antigen on formalin-fixed paraffin-embedded nasal tissue of alpacas by immunohistochemistry using human monoclonal antibodies directed against different epitopes of the spike protein

“…Similarly, minimal virus shedding was detected in goats, sheep, and horses after experimental infection, but only goats developed neutralizing antibodies (Adney et al, 2016b). Due to the close interactions of humans with potentially susceptible and contagious livestock species in certain parts of the world, the development of an effective vaccination strategy against MERS-CoV was proposed early after its initial discovery and was recently followed up by the development of protective antibodies by different protocols (Agrawal et al, 2016;Corti et al, 2015;Houser et al, 2016;Jiang et al, 2014;Johnson et al, 2016;Li et al, 2015;Pascal et al, 2015;Qiu et al, 2016;Tang et al, 2014;Widjaja et al, 2019). Widjaja and colleagues (2019) developed a set of protective neutralizing and non-neutralizing human monoclonal antibodies (mAbs) which target different epitopes of the MERS-CoV spike (MERS-S) protein.…”