Epistasis reduces fitness costs of influenza A virus escape from stem-binding antibodies

Abstract

The hemagglutinin (HA) stem region is a major target of universal influenza vaccine efforts owing to the presence of highly conserved epitopes across multiple influenza A virus strains and subtypes. To explore the potential impact of vaccine-induced immunity targeting the HA stem, we examined the fitness effects of viral escape from stem-binding broadly neutralizing antibodies (stem-bnAbs). Recombinant viruses containing each individual antibody escape substitution showed diminished replication compared to wild-type virus, indicating that stem-bnAb escape incurred fitness costs. A second-site mutation in the HA head domain (N133D) reduced the fitness effects observed in primary cell cultures and likely enabled the selection of escape mutations. This putative permissive mutation was not, however, sufficient to ease fitness costs in a ferret transmission model. Taken together, these data suggest that viral escape from stem-bnAbs is costly but highlight the potential for epistatic interactions to enable evolution within the functionally constrained HA stem domain.

C1q enables influenza hemagglutinin stem binding antibodies to block viral attachment and broadens the antibody escape repertoire

“…Lee et al ( 52 ) recently reported that adsorptive mutations restore fitness to anti-stem mAb escape mutations localized in the selecting Ab epitope. Presumably, epistasis, in this case, is caused by alterations in HA receptor binding due to long-range conformational effects.…”