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. This will be advanced in a Phase I clinical trial and Controlled Human Infection Model (CHIM) study. • 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 Part A Phase I clinical trial in India assessing safety, immunogenicity and optimal dose, to be combined with the selected MVA-based construct. This protein-MVA combination will enter a Part B Phase I clinical trial in the EU, assessing safety and immunogenicity, followed by the CHIM study. A dissemination and exploitation plan, and collaboration with key scientific advocacy organizations will facilitate the adoption of ENDFLU achievements to combat influenza worldwide.

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.

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. In this project, 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 <10% instead of 60% non-responders, lower costs, and better accessibility. The first approach combines a low dose of a commercial, inactivated, seasonal flu vaccine with a novel, potent adjuvant, and will deliver proof-of-concept in Phase I and IIa trials within 5 years. The second approach builds on three innovations: 1) a novel recombinant HA with increased immunogenicity, 2) a potent adjuvant, and 3) an easy, needle-free delivery by intradermal patches. Contra-productive parts of HA will be removed to increase the immunogenicity of neutralizing epitopes. The adjuvant further stimulates 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. With proven nonclinical immunogenicity and safety, we will embark on clinical development of this concept after completion of the project. These plans differ in complexity and timelines but are realistic with chances to deliver next-generation flu vaccines for the globe.