Targeting B cell responses in universal influenza vaccine design

Abstract

Since its first administration in the 1940s, the influenza vaccine has provided tremendous relief against influenza infections. However, time has revealed the ultimate limit of the vaccine and the call for its reinvention has now come, just as we are beginning to appreciate the antibody immune responses vital in preventing infections. New strategies to design the influenza vaccine rely on selectively inducing broadly neutralizing antibodies that are specific for highly conserved viral epitopes. Such approaches take us away from the limited range of protection provided by current seasonal influenza vaccines and towards a future with a pan-influenza vaccine capable of providing universal strain coverage.

Figure 1

a) Mode of action of neutralizing antibodies against influenza virus. The influenza viral life cycle is depicted with magnification of critical steps in infection: HA mediated cell entry and NA mediated release. Neutralizing antibodies against influenza virus prevent infections by inhibiting either viral entry into host cells or release of virions from infected cells. HA-specific antibodies are responsible for preventing viral entry into host cells by binding two regions on HA: the head region and the stalk region. HA-head reactive antibodies block binding of the HA head region to sialic acids on host cells thus preventing attachment of virus to host cells while HA-stalk reactive antibodies inhibit conformational changes required in HA for fusion of the virus with host cell membrane. Generally, HA-head reactive antibodies are strain specific since the head region is mostly variable while some HA-stalk reactive antibodies can be broadly neutralizing if they bind a highly conserved and vital region of HA. NA-reactive antibodies block the later stages of the virus replication cycle by inhibiting the cleavage of sialic acids by NA and the release of new virions. This then prevents further infection of other cells. b) Structure of Hemagglutinin. A space-filling model of a trimer of HA is shown (PDB ID: 3LZG) [35]. One of the HA monomers is illustrated in Ribbons representation with HA1 colored in red and HA2 colored in green. The region of HA2, which is colored in darker green and shown as an alpha helix, is representative of the LAH construct used in designing a minimal immunogen for vaccination [40]. Antibodies that are hemagglutinin inhibiting (HAI) most commonly bind to the antigenic Sa and Sb sites on the receptor-binding domain of the globular head region. Broadly neutralizing antibodies typically bind critical conserved epitopes in the stalk region of HA and two examples of such epitopes are shown in blue [25] and in yellow [26].