Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice

Abstract

Prolonged treatment of immunocompromised influenza patients with viral neuraminidase (NA) inhibitors is required, because the immune system of such patients fails to eradicate the viruses. Here, we attempted to eradicate influenza virus from the respiratory organs of nude mice, which is a model of immunocompromised hosts, by using combination therapy of the viral polymerase inhibitor favipiravir and monoclonal antibodies (mAbs) against the receptorbinding site (RBS) and stem of viral hemagglutinin (HA). Although monotherapy or combination therapy of two antivirals (two mAbs or favipiravir plus a mAb) suppressed virus replication, they failed to eradicate viruses from nude mice. In contrast, the triple combination therapy of favipiravir plus anti-Stem and anti-RBS mAbs completely stopped virus replication in nude mice, resulting in virus clearance. Triple combination approaches should be considered for the treatment of human immunocompromised patients with severe influenza.

Low Dose Pig Anti-Influenza Virus Monoclonal Antibodies Reduce Lung Pathology but Do Not Prevent Virus Shedding

“…In particular there was no evidence of a synergistic or additive effect of the pb18 and pb27 cocktail, although the mAbs targeted different epitopes. This is in agreement with other studies on the use of mAb cocktails alone in influenza infection although combination therapy with the viral polymerase inhibitor favipiravir and mAbs against the receptor-binding site and stem of virus HA completely stopped virus replication in nude mice, resulting in virus clearance ( 3 , 34 , 35 ). Administration of both anti-HA and anti-NA antibodies might also be effective and further studies to define whether the pigs generate broadly inhibiting anti-NA antibodies as has been shown in humans, would allow us to test how protective these are in vivo ( 36 ).…”

Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro

“…The combination of antivirals with host-directed drugs makes it much more unlikely that a virus can overcome the antiviral barrier and emerge resistances. Thus, the combination of both is routinely explored for enhanced treatment success [42][43][44].…”

Low dose pig anti-influenza virus monoclonal antibodies reduce lung pathology but do not prevent virus shedding

“…There is already a large literature on attempts to improve efficacy of mAbs by administering them as cocktails, which may result in lowered infection rates and virus loads, thereby reducing the probability of neutralizationescape variants emerging (33)(34)(35)(36). While mAb cocktails alone have not proved effective in influenza, combination therapy with the viral polymerase inhibitor favipiravir and mAbs against the receptor-binding site and stem of virus HA completely stopped virus replication in nude mice, resulting in virus clearance (6,37,38). Administration of both anti-HA and anti-NA antibodies might also be effective and further studies to define whether the pigs generate broadly inhibiting anti-NA antibodies as has been shown in humans would allow us to test how protective these are in vivo (39).…”