Is It Possible to Develop a "Universal" Influenza Virus Vaccine? Outflanking Antibody Immunodominance on the Road to Universal Influenza Vaccination

Abstract

Influenza remains a major human pathogen despite seasonal vaccination. At long last, there is energy and resources to develop influenza vaccines that provide more predictable and durable protection. Vaccines based on inducing antibodies to the conserved stem of the viral hemagglutinin (HA) have emerged as leading candidates for broadening population immunity and ultimately limiting antigenic drift. Here, we discuss the knowns and unknowns of HA-specific B-cell and antibody responses. In particular, we focus on how immunodominance sculpts antibody responses and drives antigenic drift. We propose a number of strategies to overcome immunodominance and improve the breadth and efficacy of antibody responses.

Figure 1.

Cartoon representing the hemagglutinin (HA) trimer. The head (highlighted in orange) and the stem (highlighted in blue) domains of one monomer are shown with the amount of specific binding Abs present in human sera (Fazekas de St. Groth and Webster 1966; Sui et al. 2011). Stem-Abs are present at levels too low to confer in vivo protection (PDB: 1RVZ).

Figure 2.

Pattern of immunodominance (ID) to influenza A virus (IAV) virion. Cartoon of a virion depicting hemagglutinin (HA) (blue), neuraminidase (NA) (red), M2 (violet), and ribonucleoproteins (green) (courtesy of the Centers for Disease Control website). Indicated is the relative abundance of surface and internal proteins (Hutchinson et al. 2014). The relative ID of serum Abs in response to infection (Altman et al. 2015) and immunization is not dependent on the number of proteins presented on the virion. n.d., not determined.