Periodic Reporting for period 1 - INCENTIVE (Indo-European Consortium for Next Generation Influenza Vaccine Innovation)
Período documentado: 2020-08-01 hasta 2022-01-31
The highly integrated INCENTIVE consortium represents a 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 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.
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 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 (WP1) is operational. Two vaccine strategies aiming for broad protection against different influenza viruses are advanced in pre-clinical evaluation (WP3). Vaccination with DNA plasmids encoding the APC-MIX antigens raised cross-reactive immune responses, as well as protection against different influenza subtypes in mice. For the COBRA vaccine, we have identified c-di-AMP (CDA) as a highly effective adjuvant, and particularly for raising both humoral and cellular immunity when delivered intramuscularly (i.m.) or intranasally (i.n.) in mice. A candidate COBRA vaccine, in combination with the adjuvant CDA, has progressed to ferrets for assessment of immunogenicity and protective efficacy in this gold standard animal model for influenza. Data demonstrate promise, and we have selected a candidate vaccine for further progression towards clinical evaluation.
The GMP manufacturing of the COBRA vaccine candidate is being tendered through a request for proposal (RFP) document with the input from Indian, European and US project partners as well as Indian experts (WP2). With respect to the adjuvant, the production process for manufacturing the GMP-grade CDA was optimized and validated (WP2).
Phase IV clinical trials with a commercially available influenza vaccine (QIV) in vulnerable individuals have commenced in Europe and India (WP4). The phase IV QIV trials include three age groups: 1) elderly ≥ 60 years (QIV-1); 2) children 3-8 years (QIV-2); and 3) infants 6 months (QIV-3). All approvals (ethics committee and national regulatory authorities) have been received and the studies have been registered with an appropriate open access database. Currently, for Europe, QIV-1 and QIV-2 are fully enrolled, and the enrolment of QIV-3 is ongoing. In India, QIV-1 are fully enrolled whereas QIV-2 and QIV-3 are planned to start in April/May 2022.
Phase IV QIV trials were supported by development of a master Laboratory Manual that was adapted to the three clinical studies and to specific constraints of sites in Europe and India (WP5). As well, the influenza virus strains and proteins to be used in the immunological assays at the different laboratories in Europe and India were defined. Subsequently, high quality hemagglutinin (HA) and neuraminidase (NA) antigens as well as virus stocks have been produced.
A data infrastructure based on the FAIR data principles will be implemented in Europe (WP6). For this purpose, FAIR SOLUTIONS has been subcontracted. For a data warehouse in India, a tender has been placed for procuring FAIR-enabled compute and storage hardware (WP6).
To strengthen the partnership between Indian, European and US partners, a common framework was build for a coordinated assay transfer and qualification of procedures across sites (WP7). Furthermore, capacity building was advanced through scientific discussions during online meetings and by scheduling intensive online training sessions for the technology transfer between European and Indian partners.
With respect to the study for eliciting preferences towards influenza vaccines and vaccination amongst the Phase IV QIV trial participants in India, a Discrete Choice Experiment (DCE) protocol was developed and submitted for ethical and regulatory approvals. Additionally, the DCE protocol for two cohort studies in India has also been developed. Questionnaires and semi-structured interviews around pandemic preparedness have been prepared. Experts in Europe and India that can advise on related research activities have also been identified (WP8).
The GMP manufacturing of the COBRA vaccine candidate is being tendered through a request for proposal (RFP) document with the input from Indian, European and US project partners as well as Indian experts (WP2). With respect to the adjuvant, the production process for manufacturing the GMP-grade CDA was optimized and validated (WP2).
Phase IV clinical trials with a commercially available influenza vaccine (QIV) in vulnerable individuals have commenced in Europe and India (WP4). The phase IV QIV trials include three age groups: 1) elderly ≥ 60 years (QIV-1); 2) children 3-8 years (QIV-2); and 3) infants 6 months (QIV-3). All approvals (ethics committee and national regulatory authorities) have been received and the studies have been registered with an appropriate open access database. Currently, for Europe, QIV-1 and QIV-2 are fully enrolled, and the enrolment of QIV-3 is ongoing. In India, QIV-1 are fully enrolled whereas QIV-2 and QIV-3 are planned to start in April/May 2022.
Phase IV QIV trials were supported by development of a master Laboratory Manual that was adapted to the three clinical studies and to specific constraints of sites in Europe and India (WP5). As well, the influenza virus strains and proteins to be used in the immunological assays at the different laboratories in Europe and India were defined. Subsequently, high quality hemagglutinin (HA) and neuraminidase (NA) antigens as well as virus stocks have been produced.
A data infrastructure based on the FAIR data principles will be implemented in Europe (WP6). For this purpose, FAIR SOLUTIONS has been subcontracted. For a data warehouse in India, a tender has been placed for procuring FAIR-enabled compute and storage hardware (WP6).
To strengthen the partnership between Indian, European and US partners, a common framework was build for a coordinated assay transfer and qualification of procedures across sites (WP7). Furthermore, capacity building was advanced through scientific discussions during online meetings and by scheduling intensive online training sessions for the technology transfer between European and Indian partners.
With respect to the study for eliciting preferences towards influenza vaccines and vaccination amongst the Phase IV QIV trial participants in India, a Discrete Choice Experiment (DCE) protocol was developed and submitted for ethical and regulatory approvals. Additionally, the DCE protocol for two cohort studies in India has also been developed. Questionnaires and semi-structured interviews around pandemic preparedness have been prepared. Experts in Europe and India that can advise on related research activities have also been identified (WP8).
INCENTIVE will develop for the first time 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 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.