Universal M2 ectodomain-based influenza A vaccines: preclinical and clinical developments

Abstract

Influenza vaccines used today are strain specific and need to be adapted every year to try and match the antigenicity of the virus strains that are predicted to cause the next epidemic. The strain specificity of the next pandemic is unpredictable. An attractive alternative approach would be to use a vaccine that matches multiple influenza virus strains, including multiple subtypes. In this review, we focus on the development and clinical potential of a vaccine that is based on the conserved ectodomain of matrix protein 2 (M2) of influenza A virus. Since 1999, a number of studies have demonstrated protection against influenza A virus challenge in animal models using chemical or genetic M2 external domain (M2e) fusion constructs. More recently, Phase I clinical studies have been conducted with M2e vaccine candidates, demonstrating their safety and immunogenicity in humans. Ultimately, and possibly in the near future, efficacy studies in humans should provide proof that this novel vaccine concept can mitigate epidemic and even pandemic influenza A virus infections.

Figure 1. Influenza A virion

There are three proteins embedded in the influenza A virion envelope: hemagglutinin, neuraminidase and matrix protein 2. Below the envelope is the matrix, composed of matrix protein 1, which surrounds the segmented negative-stranded RNA genome. The genome consists of eight segments that are packed into ribonucleoprotein complexes, with the three polymerase subunits (turquoise, teal and orange) assembled at the genomic RNA termini. Nonstructural protein 2 is also incorporated in the virion.

Figure 2. The M2e consensus sequences of human (top) and avian (bottom) influenza A viruses

Amino acid differences between the two sequences are highlighted in bold. The consensus human and avian M2e sequences were obtained by aligning 3913 human and 2994 avian M2 amino acid sequences, respectively, as present in the Influenza Virus Resource database (National Center for Biotechnology Information) on 3 February 2009, using MUSCLE version 3.6 [76].

Figure 3. Proposed in vivo immune mechanism of action of anti-M2e and anti-HA antibodies

Infected epithelial cells display hemagglutinin, neuraminidase and matrix protein 2 (M2) on the cell membrane in the course of infection. Anti-M2 external domain (M2e) antibodies can bind to M2 present on infected cells and the resulting immune complexes can be recognized by Fc-receptor bearing effecter cells, such as natural killer cells, leading to killing of the infected cell by antibody-dependent cellular cytotoxicity (right). Alternatively, anti-M2e opsonized infected cells can be taken up by phagocytes in a Fc-receptor-dependent way. The canonical mode of action of anti-hemagglutinin (HA) antibodies is through the direct neutralization of virions (left). In addition, anti-HA antibodies can promote uptake of virions by phagocytes and bind to HA on infected cells followed by removal of infected cells by phagocytes.