The impact of egg adaptation and immune imprinting on influenza vaccine effectiveness

Most influenza vaccines are produced in hens' eggs and may undergo 'egg adaptation', whereby mutations within the haemagglutinin protein that result in adaptation to the avian cells undergo positive selection. It is well established that egg adaptation can impact antigenicity and vaccine effectiveness (VE) by causing mismatches between the vaccine virus and circulating viruses. However, few studies have investigated the potentially long-lasting impact of childhood vaccination with an egg-adapted vaccine on the immunological memory. Prior exposure history shapes subsequent immune responses, such that memory responses to previously encountered antigens trigger stronger immune responses than those elicited by de novo antigen exposure. This phenomenon is called immune imprinting, when referring specifically to the impact of the first lifetime exposure, and antigenic seniority, when referring to exposures after the first, which also shape an individual's antibody repertoire according to how early and how often they are encountered. Crucially, if an individual's first influenza exposure is via an egg-adapted vaccine, this imprinting event could adversely affect antibody responses to circulating viruses in future seasons, reducing the benefit of influenza vaccination. Using alternative types of vaccines that avoid egg adaptation is particularly important now that the World Health Organization (WHO) recommend immunising children aged ≥6 months against influenza. In this review, we cover the historical frequency and nature of egg adaptations and the impact of egg adaptation, immune imprinting and antigenic seniority on the clinical effectiveness of seasonal influenza vaccinations. We discuss the impact of interactions between egg adaptation and immune imprinting, examine how egg-adapted vaccines can lead to suboptimal imprinting and potentially reduce VE throughout an individual's lifetime, and identify how we can address this issue in future.