The highly integrated INCENTIVE consortium represents true partnership between Indian and European/US groups that addresses the global health and economic challenge posed by influenza infections, to reduce the worldwide burden resulting from outbreaks. INCENTIVE’s strategic goals are to provide seminal knowledge on the underlying mechanisms of poor responsiveness to influenza vaccines in vulnerable individuals and advance the development of two next generation universal influenza vaccines. This is achieved by pursing the following specific objectives: 1) address the current knowledge gap by performing comprehensive immunome profiling of responders and non-responders to licensed influenza vaccines in infants, children, adults and elderly in parallel phase IV trials in Europe and India to identify the underlying mechanisms of vaccine responsiveness in different vulnerable populations and ethnical groups; 2) advance the development of two next generation universal vaccines, including an antigen presenting cell-targeted nucleic acid vaccine up to proof-of-concept for vaccine efficacy in non-human primates, and a computationally-derived second generation COBRA (Computationally-Optimized Broadly-Reactive Antigens) vaccine up to clinical development, comprising a phase I trial in Europe, a phase II trial in India and efficacy studies using an influenza controlled human challenge model; 3) identify predictive biomarkers of responsiveness to vaccination to develop new diagnostics; 4) implement comprehensive technology transfer and harmonization activities for immunological analysis and data integration; and 5) perform a health systems and investment analysis, and discrete choice experiments to assess the suitability of the developed technologies for low- and middle-income countries and to identify potential downstream constraints that might affect uptake by health care systems.

ENDFLU will develop three complementary next-generation influenza vaccination strategies for the world, fueled by the unique combined expertise of Indian and European partners in rational vaccine design and development: • Create a repository of pre-pandemic GMP-compliant MVA-based vaccine seeds, each encoding an influenza hemagglutinin (HA), based on European partners demonstration of clinical safety and cross-clade immunogenicity of MVA-H5. • Optimize and select protein- and MVA-based constructs developed by Indian and European ENDFLU partners, resulting in a rationally combined vaccine formulation that induces broadly protective humoral and cell-mediated immunity against all influenza manifestations. • Pre-clinically advance other promising protein- and MVA-based constructs toward future development beyond ENDFLU. Constructs to elicit humoral immunity build on rationally-designed and optimized conserved epitopes of influenza surface proteins, HA stem- and HA head-nanoparticles, and NA-M2e fusions either as proteins or MVA expressed. Other MVA-based constructs to elicit cell-mediated immunity will encode conserved internal protein T cell epitopes, as an artificial polyepitope. The best candidates will be selected based on biochemical, biophysical, functional and manufacturing criteria, and immunogenicity and protective efficacy in mice and ferrets. The selected protein-based construct will enter a Phase I clinical trial in Europe assessing safety, immunogenicity and optimal dose, to be combined with the selected MVA-based construct. This protein-MVA combination will be GMP produced and toxicologically tested, including in combination with the protein-based construct, for clinical readiness. A dissemination and exploitation plan, and collaboration with key scientific advocacy organizations will facilitate the adoption of ENDFLU achievements to combat influenza worldwide.

Despite the availability of flu vaccines for decades, influenza is still an important disease in both developing and developed countries with 500,000 casualties annually and many more people affected. From a global health perspective, the lack of effectivity, availability, affordability, and accessibility of flu vaccines significantly limits our ability to respond to the seasonal flu every year and in the event of a pandemic. Currently, a low vaccine effectivity of 40% implies that 60% of vaccinated people are not sufficiently protected, with low confidence further contributing to limited uptake/immunization. Within INDIGO, public and private R&D organizations in India, EU and US collaborate on the development of two novel influenza vaccine concepts that meet the requirements of global vaccination, aiming to achieve less non-responders, lower costs, and better accessibility: 1) TETRA-LITE, an affordable seasonal flu vaccine with high efficacy at low cost and possible exploitation within a few years after completion of the project; and 2) PANDEMIC-PLUS, a further improved flu vaccine concept dealing with technological shortcomings and challenges of wide-spread use. The first approach combines a low dose of a commercial, inactivated, seasonal flu vaccine with a novel, potent adjuvant CMS (LVA). The adjuvant was tested in humans for the first time within the INDIGO project and was proven safe and well tolerated. When combined with just one-fifth of the standard flu vaccine dose, CMS induced immune responses comparable to full-dose vaccines without adjuvants. This suggests significant potential for antigen sparing, which could lead to more cost-effective vaccine production. The second approach builds on three innovations: 1) a novel recombinant HA with increased immunogenicity, 2) novel adjuvants, and 3) an easy, needle-free delivery by intradermal patches. Contra-productive parts of HA have been removed to increase the immunogenicity of influenza epitopes. The adjuvants further stimulate protective immunity and immunological memory. The use of intradermal patches opens possibilities for self-administration, which will improve vaccine uptake in developing as well as developed countries. These plans differ in complexity and timelines but can all contribute to delivering next-generation flu vaccines for the globe.