The Tetra-M2e vaccine construct provided a significant viral load reduction at the peak of viral shedding in immunized chickens. Chickens immunized with Tetra-M2e that harbors the tetrameric M2e with Freund's adjuvant showed a clear reduction in cloacal and tracheal excretion of LPAI compared to challenge control groups. The results of immunization with Mono-M2e with adjuvant and Tetra-M2e without adjuvant were also promising and by improving both B-and T-cell epitopes of those constructs, desirable results may be obtained. In vaccine design, repetitive Bcell epitope display is considered a strategy for improving the humoral immune response [33, 34] . In addition to repetitive antigen display on the nanoparticle, we were able to present M2e in its native tetrameric conformation. The correlation between high protection and antibody response specific for tetrameric M2e elicited by Tetra-M2e supports our assumption of tetrameric M2e presentation. The results of our studies show that tetrameric M2e stimulates a more specific immune response compared to the monomeric presentation and induces a significant protection against homologous virus challenge. The fact that a large portion of the antibody response is directed against the carrier and not only against the epitope(s) (Figures 7 and 8) can be explained by the fact that significant portions of the core of the nanoparticles are also exposed to the immune system (compare Figure 1) and hence, these portions will also induce a significant immune response.