Antiviral Susceptibility of Swine-Origin Influenza A Viruses Isolated from Humans, United States

Abstract

Since 2013, a total of 167 human infections with swine-origin (variant) influenza A viruses of A(H1N1)v, A(H1N2)v, and A(H3N2)v subtypes have been reported in the United States. Analysis of 147 genome sequences revealed that nearly all had S31N substitution, an M2 channel blocker-resistance marker, whereas neuraminidase inhibitor-resistance markers were not found. Two viruses had a polymerase acidic substitution (I38M or E199G) associated with decreased susceptibility to baloxavir, an inhibitor of viral cap-dependent endonuclease (CEN). Using phenotypic assays, we established subtype-specific susceptibility baselines for neuraminidase and CEN inhibitors. When compared with either baseline or CEN-sequence-matched controls, only the I38M substitution decreased baloxavir susceptibility, by 27-fold. Human monoclonal antibodies FI6v3 and CR9114 targeting the hemagglutinin's stem showed variable (0.03 to >10 µg/mL) neutralizing activity toward variant viruses, even within the same clade. Methodology and interpretation of laboratory data described in this study provide information for risk assessment and decision-making on therapeutic control measures.

Keywords: IRINA; United States; antimicrobial resistance; antivirals; baloxavir marboxil; hemagglutinin; human infections; influenza; monoclonal antibodies; pandemic risk assessment; swine-origin influenza A virus; viruses.

Figure

Susceptibility of variant viruses to NA inhibitors based on subtype and NA lineage in study of antiviral susceptibility of swine-origin influenza A viruses isolated from humans, United States. A) Susceptibility of A(H1N1)v (n = 15), A(H1N2)v (n = 14), and A(H3N2)v (n = 21) viruses to NA inhibitors determined in a fluorescence-based assay (29). The IC₅₀s of viruses lacking known or suspected molecular markers that reduce inhibition by NA inhibitors were used to calculate the subtype-specific median IC₅₀s (baseline susceptibility). B, C) Effect of NA lineage on inhibition by NA inhibitors. IC₅₀s obtained in NA inhibition assay were grouped according to their respective NA lineage: N1-classical (n = 7, closed diamond), N1-pdm09 (n = 8, open diamond), N2-1998 (n = 12, closed square), or N2-2002 (n = 23, open square). Horizontal bars and numbers indicate median IC₅₀s. IC₅₀, 50% inhibitory concentration; Lan, laninamivir; NA, neuraminidase; Ose, oseltamivir; Per, peramivir; Zan, zanamivir.