Broadly neutralizing antibodies against influenza virus and prospects for universal therapies

Abstract

Vaccines are the gold standard for the control and prevention of infectious diseases, but a number of important human diseases remain challenging targets for vaccine development. An influenza vaccine that confers broad spectrum, long-term protection remains elusive. Several broadly neutralizing antibodies have been identified that protect against multiple subtypes of influenza A viruses, and crystal structures of several neutralizing antibodies in complex with the major influenza surface antigen, hemagglutinin, have revealed at least 3 highly conserved epitopes. Our understanding of the molecular details of these antibody-antigen interactions has suggested new strategies for the rational design of improved influenza vaccines, and has inspired the development of new antivirals for the treatment of influenza infections.

Figure 1. Structure of the major influenza viruses surface glycoprotein, hemagglutinin

HA is a trimer consisting of three identical copies of the HA protein (one protomer is colored, the other two are in gray). Each protomer contains two subunits, HA1 (red) and HA2 (blue). HA1 is the receptor binding domain and contains the sialic acid binding pocket. A human α(2,6) sialoglycan receptor is depicted (yellow spheres). HA2 contains the membrane fusion machinery. Broadly neutralizing antibodies can block receptor engagement and virus attachment or they can block membrane fusion.

Figure 2. V_H1-69 mAbs, such as CR6261 and F10, have broad activity against group 1 influenza

(A) Phylogenetic tree of the 16 influenza A virus subtypes, classified into two major groups (1 and 2). Subtypes bound or neutralized by CR6261 or F10 are highlighted in red, and include most group 1, but no group 2 subtypes. (B) CR6261 and F10 recognize essentially identical epitopes on the HA stem. HA is depicted as a molecular surface, with the HA1 and HA2 subunits from one protomer highlighted in pink and cyan, respectively. CR6261 is shown as red and yellow ribbons (heavy chain and light chain, respectively).

Figure 3. CR8020 has broad activity against group 2 influenza A

(A) Phylogenetic tree of the 16 influenza A virus subtypes, classified into two major groups (1 and 2). Subtypes bound or neutralized by CR8020 are highlighted in red, and include all group 2, but no group 1 subtypes. (B) CR8020 recognizes an epitope on the HA stem proximal to the viral membrane. HA is depicted as a molecular surface, with the HA1 and HA2 subunits from one protomer highlighted in pink and cyan, respectively. CR8020 is shown as red and yellow ribbons (heavy chain and light chain, respectively). (C) The CR8020 epitope (green surface) is largely distinct from the CR6261/F10 epitope (lilac surface), but overlaps slightly with two residues shared between the two sites (orange surface).

Figure 4. Cross-group neutralization by FI6 and S139/1

Phylogenetic trees with subtypes bound or neutralized by FI6 (A) or S139/1 (B) highlighted in red. Note that both antibodies neutralize subtypes from both major virus groups (1 and 2). (C) Like CR6261 and CR8020, FI6 also recognizes an epitope on the HA stem. HA is depicted as a molecular surface, with the HA1 and HA2 subunits from one protomer highlighted in pink and cyan, respectively. FI6 is shown as red and yellow ribbons (heavy chain and light chain, respectively). While the precise location of its epitope is unknown, escape mutations suggest that S139/1 recognizes the HA1 “head”. (D) The FI6 and CR6261/F10 epitopes overlap extensively (orange surface), with only a small number of HA residues being recognized by FI6 only (green surface) or CR6261 only (lilac surface).