Next-Generation Influenza HA Immunogens and Adjuvants in Pursuit of a Broadly Protective Vaccine

Abstract

Influenza virus, a highly mutable respiratory pathogen, causes significant disease nearly every year. Current vaccines are designed to protect against circulating influenza strains of a given season. However, mismatches between vaccine strains and circulating strains, as well as inferior vaccine effectiveness in immunodeficient populations, represent major obstacles. In an effort to expand the breadth of protection elicited by influenza vaccination, one of the major surface glycoproteins, hemagglutinin (HA), has been modified to develop immunogens that display conserved regions from multiple viruses or elicit a highly polyclonal antibody response to broaden protection. These approaches, which target either the head or the stalk domain of HA, or both domains, have shown promise in recent preclinical and clinical studies. Furthermore, the role of adjuvants in bolstering the robustness of the humoral response has been studied, and their effects on the vaccine-elicited antibody repertoire are currently being investigated. This review will discuss the progress made in the universal influenza vaccine field with respect to influenza A viruses from the perspectives of both antigen and adjuvant, with a focus on the elicitation of broadly neutralizing antibodies.

Keywords: adjuvant; antibodies; broadly neutralizing antibodies; hemagglutinin; influenza; universal influenza vaccine; vaccine.

Figure 1

Antigenic sites and epitopes on H1 and H3 hemagglutinins (HAs). (A) H1 antigenic sites and antibody epitopes labeled on the A/California/04/2009 HA (gray). Antigenic sites Sa (light blue), Sb (magenta), Ca1 (dark yellow), Ca2 (green), and Cb (red) are located on the globular head domain. The intratrimeric epitope, represented by the FluA-20 antibody epitope (purple), is present on the interface between HA protomers in the trimer. Residues overlapping the intratrimeric epitope and the Ca2 antigenic site are in sky blue. Sa, Sb, and Ca2 comprise the periphery of the receptor-binding site (RBS). The epitope of a H1 stem-reactive antibody, CR6261, is shown in orange. (B) H3 antigenic sites and antibody epitopes on the A/Hong Kong/1/1968 HA (gray). Antigenic sites A (light blue), B (magenta), C (dark yellow), D (green), and E (red) are present on the head, as is the intratrimeric epitope (purple), shown as the epitope of FluA-20. Residues in both antigenic site D and the intratrimeric epitope are shown in sky blue. Antigenic sites A, B, and D comprise the RBS. The epitope of a stem antibody reactive to H3 viruses, CR9114, is labeled in orange. A/California/04/2009 HA taken from PDB structure 5GJS. A/Hong Kong/1/1968 HA taken from PDB structure 4FQY. Epitopes were labeled based on the interacting residues of monoclonal antibodies (mAbs) CR6261, CR9114, and FluA-20 with HA.

Figure 2

HA-based universal influenza vaccine designs. COBRA (computationally optimized broadly reactive antigen)-based HAs are head-focused HA immunogens incorporating multiple HA sequences of distinct virus strains (shown as HAs of different colors) of a particular subtype into a consensus COBRA HA (shown as a merged HA of multiple colors) that elicit mainly head-targeting antibodies. Headless HAs lack the globular head domain and are comprised solely of the stem domain to focus antibody responses to the otherwise immunosubdominant, but conserved, stem. Chimeric HAs (cHAs) consist of the globular head domain of one subtype (shown in green) and the stem domain of another subtype (shown in cyan) to be targeted, more closely mimicking a native HA molecule while focusing antibody responses to the conserved stem through exposure to multiple cHA immunogens. Mosaic HAs (mHAs), which can be seen as a refinement of cHAs, consist of the majority of the head domain and the entire stem domain of one subtype (shown as a blue HA trimer), but the head antigenic sites of another subtype (shown as green regions in the HA head), eliciting both head- and stem-directed antibodies.