Extra-Neutralizing FcR-Mediated Antibody Functions for a Universal Influenza Vaccine

Abstract

While neutralizing antibody titers measured by hemagglutination inhibition have been proposed as a correlate of protection following influenza vaccination, neutralization alone is a modest predictor of protection against seasonal influenza. Instead, emerging data point to a critical role for additional extra-neutralizing functions of antibodies in protection from infection. Specifically, beyond binding and neutralization, antibodies mediate a variety of additional immune functions via their ability to recruit and deploy innate immune effector function. Along these lines, antibody-dependent cellular cytotoxicity, antibody-mediated macrophage phagocytosis and activation, antibody-driven neutrophil activation, antibody-dependent complement deposition, and non-classical Fc-receptor antibody trafficking have all been implicated in protection from influenza infection. However, the precise mechanism(s) by which the immune system actively tunes antibody functionality to drive protective immunity has been poorly characterized. Here we review the data related to Fc-effector functional protection from influenza and discuss prospects to leverage this humoral immune activity for the development of a universal influenza vaccine.

Keywords: ADCC; Fc receptor; adjuvant; antibody; glycosylation; influenza; vaccine.

Figure 1

Schematic structure of influenza virion. Surface proteins hemagglutinin (HA) and neuraminidase (NA) are present on the surface at an approximate 3:1 ratio. The M2 ion channel also spans the envelope. M1 matrix protein forms the inner capsid, which surrounds the segmented RNA genome coated in nucleoprotein (NP).

Figure 2

Antibody structure highlighting functions of both the Fab and Fc regions. Antibody image shows heavy chain in dark blue, light chain in light blue, and glycan in magenta. Antibody structure: PDB 1IGY.

Figure 3

Known FcR-dependent innate immune effector functions acting in influenza infection. (A) Clearance of virions and infected cells by macrophage phagocytosis. (B) Clearance of virions and infected cells by neutrophil phagocytosis, and the release of cytokines and reactive oxygen species. (C) Clearance of infected lung epithelial cells and activation of the adaptive immune system by antibody interaction with C1Q. (D) Clearance of infected lung epithelial cells by ADCC. (E) Neutralization of virus by FcRn-bound HA-specific antibodies.

Figure 4

Structures of antibody isotypes and subclasses. Fc domains are in color while Fab domains are in gray. Stars indicate N-linked Fc glycans. IgA isotypes are shown as both monomers (predominant in serum) and dimers (predominant at mucosal surfaces).

Figure 5

Structure of antibody glycan. Antibody image shows heavy chain in dark blue, light chain in light blue, and glycan in magenta. In glycan schematic, solid lines indicate core glycan consisting of two-branched linked N-acetylglucosamine (GlcNAc; blue rectangle), a mannose (green circle), followed by 2 branched mannoses, each followed by an additional GlcNAc on each mannose. Dotted lines indicate additional sugars that can be added at variable levels, including a core fucose on the first GlcNAc (red triangle), galactoses (yellow circle) to each terminal GlcNAc, sialic acids (pink diamond) to the each galactose, and a bisecting GlcNAc to the core mannose. Antibody structure: PDB 1IGY.