Conserved epitopes of influenza A virus inducing protective immunity and their prospects for universal vaccine development

Abstract

Influenza A viruses belong to the best studied viruses, however no effective prevention against influenza infection has been developed. The emerging of still new escape variants of influenza A viruses causing epidemics and periodic worldwide pandemics represents a threat for human population. Therefore, current, hot task of influenza virus research is to look for a way how to get us closer to a universal vaccine. Combination of chosen conserved antigens inducing cross-protective antibody response with epitopes activating also cross-protective cytotoxic T-cells would offer an attractive strategy for improving protection against drift variants of seasonal influenza viruses and reduces the impact of future pandemic strains. Antigenically conserved fusion-active subunit of hemagglutinin (HA2 gp) and ectodomain of matrix protein 2 (eM2) are promising candidates for preparation of broadly protective HA2- or eM2-based vaccine that may aid in pandemic preparedness. Overall protective effect could be achieved by contribution of epitopes recognized by cytotoxic T-lymphocytes (CTL) that have been studied extensively to reach much broader control of influenza infection. In this review we present the state-of-art in this field. We describe known adaptive immune mechanisms mediated by influenza specific B- and T-cells involved in the anti-influenza immune defense together with the contribution of innate immunity. We discuss the mechanisms of neutralization of influenza infection mediated by antibodies, the role of CTL in viral elimination and new approaches to develop epitope based vaccine inducing cross-protective influenza virus-specific immune response.

Figure 1

Humoral and cellular immunity induced by influenza virus infection. (1) Influenza virus binds to the receptor on the host cell and entry the cell by receptor-mediated endocytosis. (2) The endosomal acidification permits fusion of the host and viral membranes by altering the conformation of hemagglutinin. (3) Upon the fusion, viral ribonucleoprotein complexes (RNP complex) are released into the cytoplasm and (4) transported to the nucleus, where the viral RNAs (vRNA) are transcribed into messenger RNAs (mRNA) and replicated by the viral RNA-dependent RNA polymerase complex into complementary RNA (cRNA). (5) mRNA are exported to the cytoplasm for translation of structural proteins. (6) Synthesis of envelope proteins take place on ribosomes of endoplasmic reticulum. (7) The newly synthesized viral RNPs are exported from the nucleus to the assembly site at the apical plasma membrane, where (8) new virus particles are budding and release out of host cells. Influenza virus infection triggers innate (not shown) and adaptive immune response where the effector cells and molecules are involved in restriction of viral spread, as follows: The cellular immune response (right) is initiated after recognition of viral antigens presented via MHCI and MHC II molecules by antigen presenting cells (APC), which then leads to activation, proliferation and differentiation of antigen-specific CD8+ T or CD4+ cells. These cells gain effector cell function and either they help directly (Th1 or Th2 cell) to produce antibodies or, CTL effector cells recognize antigen peptides presented by MHCI on APC and kill the virus infected cells by exocytosis of cytolytic granules. The humoral immune response (left)is mediated by specific antibodies (e.g IgG, IgA) produced by antibody secreting plasma cells (ASC) which are the final stage of B cell development. This process is aided by CD4+ T helper and T cell-derived cytokines essential for the activation and differentiation of both B-cell responses and CD8+ T cell responses.

Figure 2

Mechanisms of antibody-mediated neutralization during influenza infection. A. Serum IgG or B. mucosal IgA antibodies specific to hemagglutinin prevent influenza infection by blocking attachment to host cell receptors. C. After binding, the virus is internalized by receptor mediated endocytosis. The low pH in the endosome triggers conformational changes in hemagglutinin that expose fusion peptide located in HA2 required for membrane fusion. In this step, antibodies bound to HA2 block the fusion of viral and endosomal membranes and prevent release of ribonucleoprotein complex into the cytoplasm of target cell. D. Intracellular neutralization of influenza virus through transcytotic pathway of IgA that complex with viral proteins and inhibit assembly of progeny virions. E. Antibodies specific to neuraminidase inhibit release of budding viral particles and further spread of influenza infection by inhibition of neuraminidase activity.

Figure 3

Indirect anti-influenza mechanisms of protection via Fc region of antibodies. Infected cells are killed via antibody-dependent cell-mediated cytotoxicity (ADCC) after activation of natural killer cells (NK cell) by Fc region of IgG (red arrow). Phagocytosis of viral particles or infected cells (not shown) is mediated through recognition of Fc region of IgG by macrophages (green arrows) or by interaction of complement with complement receptor on macrophages (CR) (blue arrow).