• Reduce text

    Reduce text
  • Restore text size

    Restore text size
  • Increase the text

    Increase the text
  • Print

    Print

Towards a new universal influenza vaccine

The insertion of conserved epitopes of influenza virus hemagglutinin into nanostructures of the N protein of syncytial respiratory virus (N-SRS) has displayed considerable potential regarding the development of a universal influenza vaccine. Development of this novel approach is currently receiving support as a “pre-maturation” project

Les N-SRS, des vecteurs antigéniques innovants
Updated on 06/21/2018
Published on 03/29/2018

A major problem with respect to vaccination against the influenza virus is the natural and rapid evolution of this virus from one year to another. This evolution sometimes leads to the abrupt emergence of new viral strains that are created as a result of mutations and genetic rearrangements. In many cases, the protection generated by vaccination against seasonal influenza therefore becomes ineffective during the next season. For this reason, standard vaccine development anticipates changes to the virus thanks to surveillance systems and the viruses in circulation the previous year. Inadequate anticipation can lead to a weakly effective vaccine. The recent discovery of conserved epitopes on the stem of hemagglutinin A (HA) offers new opportunities to create a universal influenza vaccine that would protect against any variant of the virus and thus constitute a major advance in public health.

N-SRS, innovative antigenic vectors

In the context of developing new vaccination strategies against human syncytial respiratory virus (RSV), scientists in the Molecular Virology and Immunology Research Unit (VIM) have developed a new antigenic substrate made up of RSV N proteins polymerised in the form of nanorings, referred to as “N subnucleocapsid ring structures” (or N-SRS). These structures are endowed with antigenic properties (via the intranasal or subcutaneous routes) that are sufficiently strong not to require an adjuvant. They support the insertion of exogenous antigens at precise sites (patented). The recombinant proteins can be produced in large quantities using a prokaryote system (for more information, see insert).

A novel vaccination approach to the influenza virus

An initial antigenic structure made up of N-SRS hybrids directed against the influenza virus has already been tested with success. Injections in the mouse of an N-SRS protein carrying a fragment of the M2 protein (a conserved but weakly antigenic epitope of the influenza virus) demonstrated its efficacy against a lethal challenge with the influenza virus.  The next step is to verify whether it is possible to graft the conserved hemagglutinin A epitopes on N-SRS to produce a universal influenza vaccine. This novel approach is receiving support as a pre-maturation project funded by INRA and Université Paris-Saclay.

Several N-HA antigenic constructs carrying HA epitopes of circulating influenza viral strains are currently being produced. Conservation of the three-dimensional structure of the N-HA rings, and the antigenic properties of HA epitopes, are being evaluated in vitro in order to select candidate vaccines. The protection they confer will then be assessed in a mouse model. The ability of these rings to induce a serological response will be analysed in animal species that are targets of the influenza virus at the Experimental Infectiology Platform (PFIE) based in the INRA Val-de-Loire Research Centre.
The aim is to show that these N-HA rings induce the production of antibodies directed against the majority of circulating influenza strains and protect against viral challenge using different strains. If this is achieved, the prospect of one day seeing a universal vaccination against influenza for use in both humans and animals (poultry, pigs, horses) will become more of a reality.

Contact(s)
Scientific contact(s):

  • Jean-François ELEOUET Molecular Virology and Immunology Research Unit (UR 892, VIM), Inra, Domaine de Vilvert, 78352 JOUY-EN-JOSAS CEDEX

N-SRS nanorings: an innovative antigen vector

This vector is composed of nanorings carrying 10 to 11 molecules of the N protein of syncytial respiratory virus, the agent that causes bronchiolitis in young infants (in green, the C-terminal part of the N protein).  The use of N-SRS nanorings has several advantages:

  • The structure is itself highly antigenic and chemical adjuvants such as aluminium in the vaccines can be reduced or even eliminated;
  • N-SRS support the insertion of exogenous antigenic sequences at two precise sites and the chimeric proteins ensure efficient stimulation of the immune system in a mouse model. The insertions at these two sites are protected by patents.
  • N-SRS and their derivatives carrying exogenous antigens will be produced by E. coli bacteria, an expression system that is less expensive than the eukaryote cells or poultry eggs currently used to produce influenza vaccines.

These N-SRS have already been tested with success in the development of vaccines against bronchiolitis in animal models (see article: “Vaccine nanostructures to fight bronchiolitis”). Additional studies to develop a vaccine against bronchiolitis in bovines are currently under way in the context of the H2020 SAPHIR project.

For more information

Patents:

  • WO2006/117456 "Preparation of soluble N-Protein Truncated P-Protein complexes or N-Proteins soluble in a virus of the Paramyxoviridae family and use thereof in vaccines”.
  • WO2007/119011 "N Protein fusion Proteins of a virus in the Paramyxoviridae-Protein of interest family”
  • PCT/EP2017/052342  "Fusion protein comprising the N protein of a virus of the Pneumovirinae subfamily”.

Publications:

  • Hervé, P.-L., et al. A Novel Subnucleocapsid Nanoplatform for Mucosal Vaccination against Influenza Virus That Targets the Ectodomain of Matrix Protein 2. Journal of Virology. 2014  88 (1), 325-338.
  • Hägglund S et al., Characterization of an experimental vaccine for bovine respiratory syncytial virus. Clin Vaccine Immunol. 2014 Jul; 21(7):997-1004.
  • Hervé PL et al., Non-invasive epicutaneous vaccine against Respiratory Syncytial Virus: Preclinical proof of concept. J Control Release. 2016 Dec 10; 243:146-159.
  • Bernelin-Cottet C et al., A Universal Influenza Vaccine Can Lead to Disease Exacerbation or Viral Control Depending on Delivery Strategies. Front Immunol. 2016 Dec 26;7:641.
  • Meyer L et al., Codon Deletions in the Influenza A Virus PA Gene Generate Temperature-Sensitive Viruses. J Virol. 2016 Jan 20; 90(7):3684-93.
  • Hervé PL et al., RSV N-nanorings fused to palivizumab-targeted neutralizing epitope as a nanoparticle RSV vaccine. Nanomedicine. 2017 Feb; 13(2):411-420.