Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza

The immune responses to influenza, a virus that exhibits strain variation, show complex dynamics where prior immunity shapes the response to the subsequent infecting strains. Original antigenic sin (OAS) describes the observation that antibodies to the first encountered influenza strain, specifically antibodies to the epitopes on the head of influenza’s main surface glycoprotein, haemagglutinin (HA), dominate following infection with new drifted strains. OAS suggests that responses to the original strain are preferentially boosted. Recent studies also show limited boosting of the antibodies to conserved epitopes on the stemofHA,which are attractive targets for a ‘universal vaccine’. We developmulti-epitopemodels to explore howpre-existing immunitymodulates the immune response to newstrains following immunization.Our models suggest that the masking of antigenic epitopes by antibodies may play an important role in describing the complex dynamics ofOASandlimited boosting of antibodies to the stem of HA. Analysis of recently published data confirms model predictions for howpre-existing antibodies to an epitope onHAdecrease the magnitude of boosting of the antibody response to this epitope following immunization. We explore strategies for boosting of antibodies to conserved epitopes and generating broadly protective immunity to multiple strains.