Monoclonal antibodies recognizing a putative immunodominant epitope in the hemagglutinin stalk do not enhance influenza A virus mediated fusion activity (VIR5P.1156)

Abstract The discovery of broadly neutralizing antibodies (Abs) which bind to the conserved hemagglutinin (HA) stalk has led to renewed interest in the development of a universal influenza virus vaccine. In swine, there have been isolated reports of vaccine-induced enhancement of disease in heterologous vaccination and challenge studies. It has been suggested that Abs recognizing the HA stalk promote virus fusion activity, contributing to pathology in pigs. Given that robust data in mouse and ferret models suggests a protective role for stalk Abs, here we examined the relationship between HA-stalk binding Abs and fusion. We generated mouse monoclonal Abs C4 and C6, which recognize a previously identified minimal epitope in the HA stalk. These Abs lack hemagglutination inhibition activity and did not inhibit or enhance virus-mediated fusion in vitro.In a mouse challenge model, we assessed the consequences of pre-exposure administration of a C4/C6 cocktail. No significant differences were observed in animals receiving C4/C6 in morbidity and mortality relative to naïve and isotype controls. We also probed the sera from a cohort of individuals who received an H5N1 vaccine. Although we detected baseline levels of Abs to the minimal stalk epitope associated with increased fusion activity in swine, titers did not increase post-vaccination. Together, our data suggests that stalk Abs do not enhance virus-mediated fusion and thus should not impede progress toward a universal influenza vaccine.