Targeting Antigens for Universal Influenza Vaccine Development

Abstract

Traditional influenza vaccines generate strain-specific antibodies which cannot provide protection against divergent influenza virus strains. Further, due to frequent antigenic shifts and drift of influenza viruses, annual reformulation and revaccination are required in order to match circulating strains. Thus, the development of a universal influenza vaccine (UIV) is critical for long-term protection against all seasonal influenza virus strains, as well as to provide protection against a potential pandemic virus. One of the most important strategies in the development of UIVs is the selection of optimal targeting antigens to generate broadly cross-reactive neutralizing antibodies or cross-reactive T cell responses against divergent influenza virus strains. However, each type of target antigen for UIVs has advantages and limitations for the generation of sufficient immune responses against divergent influenza viruses. Herein, we review current strategies and perspectives regarding the use of antigens, including hemagglutinin, neuraminidase, matrix proteins, and internal proteins, for universal influenza vaccine development.

Protective Efficacy of Recombinant Influenza Hemagglutinin Ectodomain Fusions

“…These HA ectofusion molecules will likely provide only sub-type or strain-specific protection [ 41 ]. Given the requirement to provide broad protection, the focus of immunogen design in recent years has been to include conserved epitopes in the hemagglutinin stem, hemagglutinin receptor binding site, and to alternative immunogens, such as neuraminidase (NA), M2 extracellular domain (M2e), and internal proteins (PB1, NP, and M1) [ 15 , 42 , 43 , 44 ]. Antibodies against neuraminidase, the other major surface glycoprotein of influenza, are also known to protect against influenza virus infection [ 45 ].…”

“…Recently broadly protective anti-NA antibodies have been identified against influenza A and B viruses [ 18 , 19 , 46 ]. Antibodies to M2e, the terminal extracellular domain of the M2 protein, are also known to confer broad protection [ 15 , 20 , 21 , 22 , 47 ]. These conserved antigens are promising candidates for vaccine design, but likely cannot be used as stand-alone vaccines [ 15 ].…”

“…Antibodies to M2e, the terminal extracellular domain of the M2 protein, are also known to confer broad protection [ 15 , 20 , 21 , 22 , 47 ]. These conserved antigens are promising candidates for vaccine design, but likely cannot be used as stand-alone vaccines [ 15 ]. However, these antigens can be used in combination with HA to potentially improve and broaden protection against influenza [ 43 , 48 ].…”

“…Furthermore, vaccine strains need to be updated every year [ 14 ]. Thus, to improve immunogenicity and provide broad-range, long-lasting protection, conserved antigens of influenza viruses, such as the hemagglutinin stem, neuraminidase, matrix, and internal proteins, have been explored to develop a ‘universal influenza vaccine’ [ 15 ]. Antibodies against neuraminidase (NA), the other major surface glycoprotein which mediates viral egress, are known to protect against influenza virus infection, and neuraminidase inhibition (NAI) titers have been identified as a correlate of protection [ 16 , 17 ].…”

“…Recently, neutralizing anti-NA antibodies against influenza A and B viruses have been identified, suggesting, correctly folded and immunologically relevant NA antigens can induce broadly protective antibody responses [ 18 , 19 ]. In addition, the N-terminal extracellular domain of matrix protein 2 (M2e) reduces viral replication in infected cells and confers cross-protection against different strains of influenza viruses [ 15 , 20 , 21 , 22 ]. Vaccines derived from egg grown, inactivated virus constitute the bulk of current influenza virus vaccines.…”