Periodic Reporting for period 2 - INCENTIVE (Indo-European Consortium for Next Generation Influenza Vaccine Innovation)
Okres sprawozdawczy: 2022-02-01 do 2023-07-31
The highly integrated INCENTIVE consortium is a 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 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 mucosal 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.
1) address the current knowledge gap by performing comprehensive immunome profiling of responders and non-responders to licensed influenza vaccines in infants, children 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 mucosal 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.
The INCENTIVE management and coordination framework continues to be operational (WP1). Two vaccine strategies (COBRA vaccine adjuvanted with c-di-AMP and APC-MIX DNA Vaccine) have advanced in pre-clinical evaluation. The immunological and efficacy evaluations of the APC-MIX vaccine in mice have been finalised. Vaccine constructs to be used for vaccination of Non-human Primates (NHP) are prepared. For the COBRA vaccine, we have identified c-di-AMP as a highly effective adjuvant for raising both humoral and cellular immunity when delivered intramuscularly (i.m.) or intranasally (i.n.) in mice. Based on preclinical results in mice, studies in ferrets were carried out that demonstrate the immunogenicity and efficacy of the formulations in näive and preimmune animals, allowing to down select the candiate COBRA vaccine for GMP manufacturing and clinical development (WP3).
The GMP manufacturing of the COBRA vaccine candidate will be tendered through a Request for Proposal (RFP) document prepared with the input from Indian, European and US project partners as well as Indian experts. With respect to the adjuvant, the production process for manufacturing the GMP-grade CDA was optimized and validated as well the production process for the CDA injection solution, suitable for the bedside mixing in the clinical Phase 1 was developed (WP2).
Phase IV clinical trials with a commercially available influenza vaccine (QIV) include three age groups: 1) elderly ≥ 60 years (QIV-1); 2) children 3-11 years (QIV-2); and 3) infants 6-8 months (QIV-3). The trials have been completed in Europe. In India, QIV-1 has been completed, whereas QIV-2 and QIV-3 are planned to start in Sept/Oct 2023 (WP4).
Samples collected from the Phase IV QIV trials were shipped to the respective immunological labs in Europe and India. Immunological analysis is ongoing. Preliminary analysis are already revealing important quantitative and qualitative differences in immune responses to influenza vaccination between different age groups (WP5).
The “data warehouse” in Europe and India is established. It is implemented as FAIR Data Points (FDPs) distributed across the sites generating the data. All the FDPs have been deployed in Europe/India and await the availability of data to load (WP6).
The standardization and harmonization of immunological readouts, such as serology, T- and B-cell responses, etc. between the European and Indian partners was successfully carried out. Harmonization of the clinical trials and procedures was also successfully managed (WP7).
For the study for eliciting preferences towards influenza vaccines and vaccination amongst the phase IV QIV trial participants in India, a Discrete Choice Experiment (DCE) was performed with QIV-1 cohort. First analyses of the data have been performed and preliminary results are available. Health system and needs assessment for vaccine implementation & community mobilization has started in India. The first version of software for influenza like illness (ILI) surveillance has been developed and piloting for DCE tool has also been completed. Additionally, in-depth documentation related to the barriers to vaccination coverage within the European Union (EU) as well as an online survey across all 27 member states of the European Union for assessement of pandemic preparedeness was developed (WP8).
The GMP manufacturing of the COBRA vaccine candidate will be tendered through a Request for Proposal (RFP) document prepared with the input from Indian, European and US project partners as well as Indian experts. With respect to the adjuvant, the production process for manufacturing the GMP-grade CDA was optimized and validated as well the production process for the CDA injection solution, suitable for the bedside mixing in the clinical Phase 1 was developed (WP2).
Phase IV clinical trials with a commercially available influenza vaccine (QIV) include three age groups: 1) elderly ≥ 60 years (QIV-1); 2) children 3-11 years (QIV-2); and 3) infants 6-8 months (QIV-3). The trials have been completed in Europe. In India, QIV-1 has been completed, whereas QIV-2 and QIV-3 are planned to start in Sept/Oct 2023 (WP4).
Samples collected from the Phase IV QIV trials were shipped to the respective immunological labs in Europe and India. Immunological analysis is ongoing. Preliminary analysis are already revealing important quantitative and qualitative differences in immune responses to influenza vaccination between different age groups (WP5).
The “data warehouse” in Europe and India is established. It is implemented as FAIR Data Points (FDPs) distributed across the sites generating the data. All the FDPs have been deployed in Europe/India and await the availability of data to load (WP6).
The standardization and harmonization of immunological readouts, such as serology, T- and B-cell responses, etc. between the European and Indian partners was successfully carried out. Harmonization of the clinical trials and procedures was also successfully managed (WP7).
For the study for eliciting preferences towards influenza vaccines and vaccination amongst the phase IV QIV trial participants in India, a Discrete Choice Experiment (DCE) was performed with QIV-1 cohort. First analyses of the data have been performed and preliminary results are available. Health system and needs assessment for vaccine implementation & community mobilization has started in India. The first version of software for influenza like illness (ILI) surveillance has been developed and piloting for DCE tool has also been completed. Additionally, in-depth documentation related to the barriers to vaccination coverage within the European Union (EU) as well as an online survey across all 27 member states of the European Union for assessement of pandemic preparedeness was developed (WP8).
INCENTIVE will develop a novel next generation universal vaccines that will provide a considerable broader protection against both co-circulating seasonal influenza strains over multiple seasons, as well as against pre-pandemic strains from subtypes that do not currently circulate in the human population. The safety, immunogenicity and efficacy studies for COBRA vaccine and APC-MIX in Non-Human Primates (NHPs) would be a proof-of-concept for the employment of these experimental vaccines for the protection against seasonal and pandemic influenza. Furthermore, INCENTIVE will develop and validate the safety and immunogenicity of the COBRA mucosal vaccine candidate (in combination with the adjuvant CDA) in a phase I trial in Europe and a phase II trial in India, as well as its efficacy in a controlled human challenge. INCENTIVE will also perform phase IV clinical studies in vulnerable populations in Europe and India, and the comprehensive immune monitoring and profiling data obtained will contribute towards the identification of biomarkers and correlates of protection, which can facilitate the development of diagnostics for stratification and follow-up of vaccines, as well as the establishment of tailored vaccination strategies for poor responders. In summary, the development of knowledge and technologies for innovative next generation vaccines against influenza across European and Indian sites will have a significant impact on morbidity and mortality, human suffering and disability, and associated care costs. It will impact the quality of life of families, communities and nations. The development of cost- and time-efficient GMP manufacturing of vaccine components in India, and the inclusion of influenza vaccination in national programs will also facilitate effective implementation and quicker uptake by health systems with limited resources.