Prophylactic and therapeutic efficacy of monoclonal antibodies against H5N1 influenza virus

• mAbs could enhance our armamentarium against H5N1 in support of pandemic preparedness • Several mAbs have shown prophylactic and therapeutic efficacy against H5N1 in animal models • Anti-IAV mAbs that have advanced in clinical trials could be evaluated against H5N1 • Resistance emergence during mAb treatment was infrequent in pre- and clinical studies Highly pathogenic avian influenza H5N1 continues to pose a serious zoonotic and pandemic threat due to its increasing cross-species transmission and high virulence in humans. Despite the availability of vaccines and antivirals for seasonal influenza, effective prophylactic and treatment options for H5N1 remain limited. Herein we explore the potential action of monoclonal antibodies (mAbs) against H5N1, focusing on those with demonstrated efficacy in animal models. Most of these mAbs target conserved hemagglutinin epitopes and function as broad neutralizing fusion/entry inhibitors; notably, CR9114 targets both groups 1 and 2 influenza A strains as well as B lineages. Other mAbs prevent viral release by targeting neuraminidase, and those directed against the M2 ectodomain and nucleoprotein function through Fc receptor-mediated pathways. These mAbs have shown robust protection against lethal H5N1 challenge in mice, ferrets, and/or non-human primates. Compounds such as CR6261, MEDI8852, and TCN-032 have been evaluated in clinical trials for seasonal influenza, yielding encouraging safety and pharmacokinetics results and notably, no reported emergence of resistance. Despite these positive results their clinical development was prematurely discontinued. Integrating these highly effective mAbs into our H5N1 pandemic preparedness arsenal is a logical next step to provide a robust prophylactic and therapeutic option at the early stages of an outbreak. Future efforts must address regulatory and logistical barriers, invest in stockpiling and emergency use protocols, and support adaptive clinical trial frameworks to ensure rapid deployment when needed.