leveraging On t-cell immune resPonse To Improve influenza VACcines. – OPTIVAC

The influenza nucleoprotein antigen, NP, is the most conserved influenza antigen; therefore immunizing humans against this antigen may protect them against various strains of influenza. However, by itself, NP’s vaccine response is not sufficient enough. IMX313 is a technology dedicated to improve the immunogenicity of various antigens; therefore fusing NP and IMX313 may increase the efficacy of NP in humans. For all these reasons, adding NP-IMX313 to annual influenza vaccines may improve their efficacy, especially in the elderly.

The efficacy of the add-on NP-IMX313P, so as its safety, will be tested in the standard preclinical model, recommended by the regulatory agencies. Simultaneously, in vitro analysis will be performed to better understand its mechanism of action in order to explain why the use of this add-on will be necessary in case of success.

In order to produce the vaccine candidate in a pharmaceutic form compatible with an administration in human, IMAXIO have developed its manufacturing process, and started its scale-up toward an industrial process.

Also, to evaluate the candidate efficacy, le preclinical model required for the protection test was set up by VIRPATH

Finally, since understanding the mechanisms of action of the candidate is important, the ICL team from the CIRI has demonstrated its activator effect on key actors of the immunological and vaccine response (T lymphocytes and dendritic cells).

Improved annual influenza vaccines could have a major impact on healthcare, especially for the elderly, and significantly reduce healthcare costs. All vaccinated persons could benefit from an improved vaccine in years when there is a mismatch between the vaccine strains and the circulating strains of influenza: this should improve public acceptance of influenza vaccination.

To date (18 months), the patent application «Influenza nucleoprotein vaccines« submitted by Imaxio, has led to a patent delivery in the United States of America. This application is in examination in other countries.
Furthermore, an article is in preparation.

Today, Influenza vaccines are a cornerstone of influenza prevention with roughly 500 million doses administered every year. However, with more than 250 000 deaths annually, influenza remains a heavy medical burden and there are still high unmet medical needs for Influenza vaccines, with two key elements: 1) protection of elderly populations who do not respond well to vaccines, and 2) cross-protection against modified influenza viruses as a result of antigenic drift (incremental changes observed during seasonal variations) or antigenic shift (profound changes due to the emergence of a new pandemic virus).

The project “OPTIVAC” (leveraging On cellular immune resPonse To Improve flu VACcines) aims to improve current Influenza seasonal vaccines, paving the way towards the clinical development of a vaccine candidate. This vaccine should elicit, in addition to the humoral response brought by regular seasonal Influenza vaccine, strong, protective and long-lasting T-cell responses against the most conserved influenza antigen: the nucleoprotein NP. The vaccine candidate to be tested will be comprised of a regular seasonal Influenza vaccine formulated with a recombinant form of NP fused to the pro-immunogenic tag IMX313T (which will be named NPm-IMX313T).

The project is based on highly synergistic innovations and expertise brought by each partner:
- A detailed understanding of the evolution of Influenza viruses
- A highly-immunogenic, proprietary version of the nucleoprotein NP which, when formulated with the seasonal vaccine, triggers strong anti-NP CD8 T-cell responses in mice, without being deleterious to the humoral response to the seasonal vaccine
- A recognized expertise in preclinical Influenza challenge models

The scientific bottlenecks which will be confronted during the project are:
- prove that NPm-IMX313T can protect ferrets, alone and when formulated with regular seasonal vaccines, against homosubtypic and drifted strains
- understand the mechanisms by which immunogenicity is improved;
- characterize and validate the responses induced by the fusion of NP to IMX313T;
- optimize the production process (yield) to produce pilot GMP-batches (Good Manufacturing Practices) at a cost that is compatible with improved seasonal Flu vaccines;
- prove that the vaccine candidate is safe in preclinical toxicology studies.

The initial work-packages in this program will demonstrate that improved protection against influenza can be obtained by adding NPm-IMX313T to the seasonal influenza vaccine in ferrets, an established pre-clinical animal model. In parallel, detailed characterization of immune responses to both the nucleoprotein antigen and the IMX313T protein to which it is fused will be conducted, along with detailed mechanism of action studies to confirm hypotheses on the way the IMX313T protein works.

Thereafter, the groundwork for a Phase I trial will be carried out. This will involve the production of cGMP lots of the recombinant NPm-IMX313T protein, toxicology studies, and the preparation of a Clinical Trial Application (CTA) request for the Phase I trial, which will take place after the completion of the OPTIVAC program.

The consortium unites 3 partners: 1 SME, 1 academic immunology laboratory and 1 academic laboratory specialist of Flu:
1. IMAXIO (IMA) is a biotechnology company based in Lyon employing 19 people. R&D of pro-immunogenic tags is an important pillar of the company. They have invented and patented both the pro-immunogenic tag IMX313T, and its use with NP
2. Bruno Lina (CNR Lyon), CNR Flu – VirPatH, CNR grade: A, and his team, have recently focused their research objectives on the pathogenicity and mechanisms of emergence of Influenza viruses.
3. Jacqueline Marvel (ICL-JM) directs the team “Immunity and Cytotoxic Lymphocytes”. -AERES grade: A. The NP antigen has long been a model antigen for her immunological research.