Cross-clade antibody reactivity may attenuate the ability of influenza virus to evade the immune response

Abstract

Vaccines developed against influenza lose efficacy primarily due to the ability of the virus to generate variants that escape recognition of the immune system. Frequent accumulation of mutations in the virus surface proteins is believed to be responsible for immune evasion. Surprisingly, despite the high mutation rate, the appearance of new viral strains through antigenic drift is slow. This delay in the emergence of new strains has been explained by several different hypotheses over the past decade. In the present study, we have probed the antibody response against multiple clades of influenza neutralizing epitope in the context of antigenic drift. Both, the serum IgG and the monoclonal antibodies raised against the epitope showed strong predisposition against different variants even with non-conservative mutations. The physiologically relevant binding with hemagglutinin protein and its variants revealed multi-reactive recognition potential of human single-chain variable fragments (scFvs). Differential scope for antibody cross-reactivity was evident among different clades that could counterbalance the effect of antigenic drift. Our findings reveal that the majority of epitope variants, which could manifest as single or double amino acid substitutions, would not escape immune surveillance. However, mutations beneficial for the virus do appear causing effective antigenic changes. It is suggested that inherent antibody promiscuity could reduce the deleterious effects of natural mutations on antigen recognition and may be responsible for the delay in the appearance of new antigenic variants of the fast-mutating viruses.