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Review
. 2021 Feb;36(1):13-24.
doi: 10.1007/s12250-020-00283-6. Epub 2020 Sep 1.

Flu Universal Vaccines: New Tricks on an Old Virus

Ruikun Du  1   2   3 , Qinghua Cui  4   5   6 , Lijun Rong  7
Affiliations
Review

Flu Universal Vaccines: New Tricks on an Old Virus

Ruikun Du et al. Virol Sin. 2021 Feb.

Abstract

Conventional influenza vaccines are based on predicting the circulating viruses year by year, conferring limited effectiveness since the antigenicity of vaccine strains does not always match the circulating viruses. This necessitates development of universal influenza vaccines that provide broader and lasting protection against pan-influenza viruses. The discovery of the highly conserved immunogens (epitopes) of influenza viruses provides attractive targets for universal vaccine design. Here we review the current understanding with broadly protective immunogens (epitopes) and discuss several important considerations to achieve the goal of universal influenza vaccines.

Keywords: Broadly protection; Conserved epitopes; Influenza virus; Universal vaccine.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Influenza virus surface proteins. A A model of influenza viral particle with surface proteins. B Structures of the surface proteins. HA, Hemagglutinin; NA, neuraminidase; M2, matrix protein 2; M2e, extracellular region of M2.
Fig. 2
Fig. 2
T-cell response and influenza viral internal proteins. A CD8+ T cell response. Virus-derived peptide antigens presented by major histocompatibility complex-I (MHC-1) at surface of virus infected cells can be recognized by CD8+ T cells through specific T cell receptors (TCRs), resulting in lysis of target cells. B A model of influenza viral particle with internal proteins. M1, Matrix protein 1; NP, nucleoprotein; PB1, polymerase basic-1. *, CD8+ T cell targets from IBV HA and NS (nonstructural protein 1) proteins also have been reported.
Fig. 3
Fig. 3
Immunofocusing approaches for a universal flu vaccine. A Head masking. The “Head” region of trimeric HA was hyperglycosylated, leaving only the HA stalk immunogenic. B Mini-HA. The “Head” region of trimeric HA was removed completely, while the conformation of the stalk domain maintains well. C Schematic of the PMD strategy. First, the epitope of interest is protected by binding of specific mAb. Then the surface of the protein·mAb complex is modified and rendered nonimmunogenic (shown as grey). By removal of the mAb, the epitope is deprotected and exposed as PMD antigen.
Fig. 4
Fig. 4
immunosubversion strategies for a universal flu vaccine. A Chimeric hemagglutinin (cHA) constructs and vaccination strategy. The cHAs consist of a conserved stalk domain in combination with “heads” from different avian influenza virus HA subtypes. Vaccination with the first cHA leads to primary antibody responses mainly targeting the immunodominant head domain and low-level priming against the stalk domain. Upon boosting with a second cHA that has the same stalk domain but a completely different head domain, the immune system induces a primary response against the novel head domain and a strong memory response against the stalk domain. B Mosaic hemagglutinin (mHA) constructs and vaccination strategy. Only the variable immunodominant antigenic sites in mHAs are replaced with antigenic site equivalents from different influenza virus HA subtypes, and the resulting mHA displays conserved epitopes in both the stalk and head domains. Vaccination with the first mHA likely induces a strong primary response against the grafted antigenic sites and low-level priming for conserved epitopes in the stalk and head domains. Revaccination with a second mHA with antigenic sites that have been grafted from a different subtype might result in a primary response against the antigenic sites and a strong recall response against conserved epitopes in both the head and stalk domains. C Model of immunosubversion approach with mosaic antigen array. Colored and black simbols indicates strain specific and conserved antigens respectivley. B cells possessing BCRs specific to multiple antigenic variants are colored accordingly. The avidity advantage of the mosaic antigen to cross-reactive B cells over mono-specific B cells is anticipated, promoting proliferation of cross-reactive B cells.
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