Progress in the Development of Universal Influenza Vaccines

Abstract

Influenza viruses pose a significant threat to human health. They are responsible for a large number of deaths annually and have a serious impact on the global economy. There are numerous influenza virus subtypes, antigenic variations occur continuously, and epidemic trends are difficult to predict-all of which lead to poor outcomes of routine vaccination against targeted strain subtypes. Therefore, the development of universal influenza vaccines still constitutes the ideal strategy for controlling influenza. This article reviews the progress in development of universal vaccines directed against the conserved regions of hemagglutinin (HA), neuraminidase (NA), and other structural proteins of influenza viruses using new technologies and strategies with the goals of enhancing our understanding of universal influenza vaccines and providing a reference for research into the exploitation of natural immunity against influenza viruses.

Keywords: antigenic variation; cellular immunity; cross-protection; influenza virus; universal vaccine.

Figure 1

Mutation frequency of different antigenic regions and surface amino acids in the hemagglutinin (HA) protein of influenza viruses. H1 represents the 3D structure of A/Puerto Rico/8/34 (H1N1) HA protein (PDB ID: 1RU7) on which the location and distribution of different antigenic regions (Ca1, Ca2, Sa, Sb, Cb, and H1C) are indicated. H3 represents the 3D structure of A/X-31 H3 subtype HA protein (PBD ID: 2VIU) illustrating the location and distribution of different antigenic regions (A, B, C, D, and E). B represents the 3D structure of B/Lee/40 B subtype HA protein (PDB ID: 1RFT) highlighting the location and distribution of different antigenic regions (A, B, C, D, and E). H1 abs, H3 abs, and B abs illustrate the mutation frequency of surface amino acids on the respective HA proteins, with their color representing the intensity of mutation frequency based on H1N1 (n = 531, isolated between 1918–2008), H3N2 (n = 968, 1968–2005), and flu B (n = 209, 1940–2007).

Figure 2

Phylogenetic tree of HAs of different subtypes (H1–H16) of influenza viruses. The phylogenetic tree was constructed using the neighbor-joining (NJ) method within MEGA software (version 7.0). The colors of the trees are edited using Adobe Illustrator software. The scale bar indicates the average number of amino acid substitutions per site.

Figure 3

Schematic diagram of immune responses activated by different types of potential universal influenza vaccines. Universal influenza vaccines developed using different strategies involving different target proteins are administered by subcutaneous, intranasal, and intramuscular routes. The antigen is phagocytosed and processed by macrophages and other APC cells. Subsequently, B cell epitopes form a complex with MHC-II and are presented to the cell surface. Under the combined action of CD4 cells, B cells are activated to differentiate into plasma cells and secrete antibodies—e.g., anti-HA, anti-NA, anti-NP, anti-M2e, and anti-HA stem–to neutralize the virus. T cell epitopes—mainly, NP, M1, and HA stem—form a complex with MHC-I and are presented to the cell surface, under the action of CD8 cells and activate T cells to differentiate into CTLs to kill virus-infected cells.