Table 1.

Biological response modifiers discussed.

BRM class	Target	Therapy	Activity	IAV strain	References
Therapeutic antibodies	HA	MHAA4549A, MEDI8852 and VIS410	– Reduced viral replication. – Improved symptoms of human patients in phase 2 clinical trials	– Circulating seasonal (2015/16) IAV; Seasonal IAV (H3N2) challenge	(13–15)
	ANGPTL4	Anti-ANGPTL4	– Reduced pulmonary tissue leakiness, significantly accelerated lung recovery and improved lung tissue integrity in mice.	– Mouse-adapted laboratory IAV (H1N1)	(16)
	C5a	IFX-1 antibody	– Reduced viral load and virus-induced ALI due to reduced infiltration of lung macrophages and neutrophils in IAV-infected African green monkeys.	– Highly-pathogenic avian IAV (H7N9)	(17)
	TRAIL	Anti-Trail	– Increased survival rate following IAV infections in mouse studies.	– Mouse-adapted laboratory IAV (H1N1 and its derivative H3N2)	(18, 19)
	TNFα	Anti-TNFα	– Reduced disease burden in mouse studies. – No effect on viral replication.	– Mouse-adapted laboratory IAV (H1N1-derived H3N2)	(20)
Therapeutic peptides	AMP	LL-37	– Reduced morbidity and mortality to similar levels as zanamivir in mice.	– Mouse-adapted laboratory IAV (H1N1)	(21)
	Influenza A virus	TAT-Kα2	– Complete protection of infected mice. – Direct virocidal activity.	– Highly-pathogenic avian IAV (H5N1)	(22)
Therapeutic small molecules	JNK1/JNK2	SP600125, AS601245	– Reduced levels of pro-inflammatory cytokines and reduced viral titers in mice.	– Highly-pathogenic avian IAV (H7N7); 2009 pandemic IAV (H1N1)	(23, 24)
	p38	SB202190, SB203580	– Mice were protected from lethal H5N1 infection exhibiting reduced mortality and pro-inflammatory responses.	– Highly-pathogenic avian IAV (H5N1)	(25)
	MEK	CI-1040	– Reduced lung viral load and mortality of IAV-infected mice.	– 2009 pandemic IAV (H1N1)	(26)
	NFkB	SC75741	– Reduced mortality and morbidity in mice following highly pathogenic IAV infections. – Similar results prophylactically.	– Highly-pathogenic avian IAV (H7N7 and H5N1)	(27)
	GRK2	Paroxetine	– Reduced viral load. – No effect on mortality in IAV-infected mice.	– 2009 Pandemic IAV (H1N1)	(28)
	SphK1/SphK2	SK-1I, SK-2I, and Pan-SKI	– Prolonged survival of mice following lethal IAV infection.	– Mouse-adapted laboratory IAV (H1N1)	(29)
	PAR1	SCH79797	– Increased survival and a decrease in inflammatory responses in H5N1 or H1N1 infected mice. – Similar effect when administered 48–72 h after infection.	– Mouse-adapted IAVs (H1N1 and H3N2); Oseltamivir-resistant 2009 pandemic IAV isolate (H1N1); highly-pathogenic avian IAV (H5N1)	(30)
	PPARα/PPARγ	Gemfibrozil (PPARα), Pioglitazone (PPARγ)	– Improved symptoms and increased survival of IAV infected mice. ed survival after H1N1 or H5N1 mouse infections.	– 1957 Pandemic IAV (H2N2); mouse-adapted laboratory IAV (H1N1); 2009 pandemic IAV (H1N1)	(31–33)