Towards a universal influenza vaccine: different approaches for one goal

Abstract

Influenza virus infection is an ongoing health and economic burden causing epidemics with pandemic potential, affecting 5-30% of the global population annually, and is responsible for millions of hospitalizations and thousands of deaths each year. Annual influenza vaccination is the primary prophylactic countermeasure aimed at limiting influenza burden. However, the effectiveness of current influenza vaccines are limited because they only confer protective immunity when there is antigenic similarity between the selected vaccine strains and circulating influenza isolates. The major targets of the antibody response against influenza virus are the surface glycoprotein antigens hemagglutinin (HA) and neuraminidase (NA). Hypervariability of the amino acid sequences encoding HA and NA is largely responsible for epidemic and pandemic influenza outbreaks, and are the consequence of antigenic drift or shift, respectively. For this reason, if an antigenic mismatch exists between the current vaccine and circulating influenza isolates, vaccinated people may not be afforded complete protection. There is currently an unmet need to develop an effective "broadly-reactive" or "universal" influenza vaccine capable of conferring protection against both seasonal and newly emerging pre-pandemic strains. A number of novel influenza vaccine approaches are currently under evaluation. One approach is the elicitation of an immune response against the "Achille's heel" of the virus, i.e. conserved viral proteins or protein regions shared amongst seasonal and pre-pandemic strains. Alternatively, other approaches aim toward eliciting a broader immune response capable of conferring protection against the diversity of currently circulating seasonal influenza strains.In this review, the most promising under-development universal vaccine approaches are discussed with an emphasis on those targeting the HA glycoprotein. In particular, their strengths and potential short-comings are discussed. Ultimately, the upcoming clinical evaluation of these universal vaccine approaches will be fundamental to determine their effectiveness against preventing influenza virus infection and/or reducing transmission and disease severity.

Keywords: HA head; HA stem; Hemagglutinin (HA); Influenza virus; Monoclonal antibodies (mAbs); Vaccine.

Fig. 1

Representation of ‘universal’ vaccine approaches under development. Top panel: schematic representation of COBRA-based approach. A phylogenetic tree is inferred based on hemagglutinin (HA) amino acid sequences. Primary and secondary consensus sequences are thus generated. Finally, the secondary consensus sequences are then aligned and the resulting consensus, designated COBRA, is generated. Central panel: schematic representation of approaches aimed at eliciting/boosting an antibody response against the HA stem region. These strategies rely on the chimerization of the HA molecule in order to direct the antibody response towards the stem region or on the masking of the head region (i.e. through the hyperglycosylation of the HA head). Bottom panel: schematic representation of anti-idiotype based approaches. As an example, a monoclonal antibody (mAb #1) recognizing a conserved and protective/neutralizing epitope of the HA molecule is used as a footprint antigen to elicit antibodies recognizing the idiotype of the original antibody (mAb #1). The best candidate anti-idiotype antibody able to elicit antibodies having similar binding and neutralizing characteristics of mAb #1 is then selected as immunizing antigen to develop epitope-based vaccine approaches