Neuraminidase inhibitors including oseltamivir, zanamivir, laninamivir, and peramivir have been approved for treatment of uncomplicated influenza, and have also become de facto ‘standard of care’ therapy for hospitalized patients
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412085/
Annual influenza epidemics cause significant world-wide morbidity and mortality despite vaccine and antiviral drug development efforts, with an ever-present risk of emergent or zoonotic virus pandemics. Neuraminidase inhibitors including oseltamivir, zanamivir, laninamivir, and peramivir have been approved for treatment of uncomplicated influenza, and have also become de facto ‘standard of care’ therapy for hospitalized patients [1]. The cap-dependent endonuclease inhibitor, baloxavir marboxil, is a potent inhibitor of influenza A virus replication [2] and has been approved for use in uncomplicated influenza patients in Japan and the U.S., with application for approval pending in Europe. Despite these advances, no influenza antiviral has been approved to date for treatment of hospitalized patients with severe disease. In the U. S., it is estimated that up to 600,000 seasonal influenza patients may be hospitalized each year, with up to 27,000 deaths [3].
There is a long history of therapeutic antibody treatment for influenza, particularly in high-mortality pandemics. During the 1918 influenza pandemic, physicians resorted to administration of convalescent blood products (serum, plasma, or whole blood), interventions that a modern meta-analysis of 8 published studies involving 1074 patients suggests may have halved mortality rates [4]. During the 2009/2010 H1N1 pandemic, investigators in Hong Kong treated patients requiring intensive care with convalescent plasma containing a neutralizing H1N1 titer of 1:160, and observed lower mortality rates as well as lower influenza viral loads [5]. The investigators continued these studies over the following years using fractionated IVIG from H1N1 convalescent patients, again reporting a mortality benefit [6]. In an open-label Phase 2 randomized and controlled trial, Beigel and colleagues treated hospitalized patients in the U.S. with severe influenza A (principally H1N1) or influenza B with anti-influenza plasma containing hemagglutination inhibition (HAI) titers of 1:80 to the infecting strain [7]. In that study, 61% of patients had received neuraminidase inhibitor therapy prior to randomization (increasing to 99%, post-randomization); 58% of participants were in the Intensive Care Unit and 43% were already on mechanical ventilation at enrolment. This small study did not demonstrate significant benefits of plasma treatment, but the investigators reported encouraging trends in reduction in mortality and days on mechanical ventilation. Operational challenges to the use of patient-derived convalescent blood products in these trials were addressed, but clearly limit the scalability of this approach. Monoclonal antibody therapy has the potential to address the scalability challenge.