Design of Human Influenza vaccines using multifunctional micelles harnessing innate immunity (FluNanoAir)

Influenza viruses remain a substantial public health burden with seasonal epidemics resulting in significant morbidity, mortality and economic loss. Vaccination is the main method of prophylaxis but requires regular annual updating of seasonal influenza vaccine strains to match the circulating epidemic viruses. Inactivated vaccines act mainly through the induction of neutralizing serum IgG antibodies, and a major limitation of current vaccines is their failure to protect against new emerging strains as witnessed by the high number of cases in 2017/18 season. The objective of FluNanoAir is to develop a cross-reactive influenza vaccine, able to induce both mucosal and systemic responses, including a strong influenza-specific T cell response, with broad and long lasting properties using multifunctional micelles harnessing innate immunity. Partners in France have developed a novel micelle nanoparticle vaccine coupled with the influenza surface glycoprotein haemagglutinin as a potential platform for cross reactive influenza vaccines and tested them in the laboratory. We have focused our work on the use of surface glycoprotein neuraminidase (NA). We have studied health care workers who were vaccinated with AS03 adjuvanted influenza A H1N1 vaccine and subsequent influenza vaccination as the NA component remained unchanged for another 4 years. We found that annual vaccination boosted anti-NA antibodies and showed a slow decline if no revaccination occurred. We further generated human monoclonal antibodies from an influenza-infected patient during the 2009 pandemic to understand the role of broadly protective antibodies to the pandemic H1N1 virus. These monoclonal antibodies have been tested in vitro and in vivo and shown broad reactivity, these findings will guide our development of generating the next generation universal influenza vaccines providing broad protection.

We have demonstrated in man that use of a suitably aduvanted vaccine can induce persistent antibody responses and by generating human monoclonal antibodies we could show that these were broadly reactive against a range of influenza A H1N1 strains. Our work has focused on using neuraminidase as a candidate for next generation influenza vaccines.

Influenza viruses remain a substantial public health burden with seasonal epidemics resulting in significant morbidity, mortality and economic loss. Vaccination is the main method of prophylaxis but requires regular annual updating of seasonal influenza vaccine strains to match the circulating viruses. Inactivated vaccines act mainly through the induction of neutralizing serum IgG antibodies, and a major limitation of current vaccines is failure to protect against new emerging strains. The objective of FluNanoAir is to develop a cross-reactive influenza vaccine, able to induce both mucosal and systemic responses, including a strong influenza-specific T cell response, with broad and long lasting properties using multifunctional micelles harnessing innate immunity. To address this aim, we will: 1) Design micelles based vaccine candidates, using amphiphilic block copolymer of poly(D,Llactide)- b-poly(N-acryloxysuccinimide-co-N-vinylpyrrolidone) (PLA-NVP). They will carry at their corona surface, either outer surface (Hemagglutinin/Neuraminidase) or membrane protein (M2e proteins). Furthermore, hydrophobic TLR ligands encapsulated in the PLA core will amplify and redirect immune responses to the site of viral entry the mucosal compartment. 2) Compare two routes of administration, sub-cutaneous and tracheal routes, to study their biodistribution by whole imaging studies using tomography and their uptake by pulmonary or skin dendritic cells using transgenic mice models. 3) Analyze their immunogenicity properties, both ex vivo using human samples from influenza infected patients and in vivo comparing two routes of administration in Non-Human Primates and extensive immune monitoring of T and B cell responses through FACS analysis and T bioassays harmonized between human and NHP species. 4) Test the efficacy of such vaccine candidates through a challenge model in mice, assessing cross protection through the use of recent strains of influenza.