Targeting M2e to DEC-205 induces an enhanced serum antibody-dependent heterosubtypic protection against influenza A virus infection.

The ectodomain of the influenza A virus (IAV) M2 protein (M2e) is highly conserved, and it represents a promising candidate for the development of an "universal vaccine". However, the low immunogenicity associated to M2e in a natural infection or in response to seasonal vaccines has led to explore new approaches to enhance it. In recent years, it has become clear that targeting antigens to dendritic cells (DC) is an efficient way to enhance immune responses against pathogens. In this work, the M2e peptide was chemically cross-linked to a monoclonal antibody (mAb) specific for DEC-205 (α-DEC-205:M2e), present on DC. BALB/c mice were inoculated subcutaneously (s.c.) three times with the conjugate equivalent to 1 µg of M2e, in the presence of polyinosinic-polycytidylic acid (poly I:C) as adjuvant. As controls, other groups of mice were inoculated under the same conditions with M2e cross-linked to an isotype control mAb (isotype:M2e), 5 µg of free M2e peptide, ovalbumin (OVA) cross-linked to the α-DEC-205 mAb (α-DEC-205:OVA) or poly I:C alone. Immunization with α-DEC-205-M2e induced high levels of serum antibodies (Abs) compared to isotype:M2e or to free M2e peptide, and in all cases IgG1 was predominant over IgG2a Abs. Furthermore, immunization with the α-DEC-205:M2e conjugate did not prevent morbidity, but it induced up to 76% protection against a heterosubtypic IAV lethal challenge. Contrasting with the 20 to 40% protection induced by isotype:M2e or by free M2e peptide. The protection induced by α-DEC-205:M2e conjugate was dependent on non-neutralizing serum Abs and independent of effector CD4+ T cells. These results show that targeting M2e to DEC-205 is a very effective alternative to induce strong heterosubtypic protection against an IAV infection.