Periodic Reporting for period 2 - INDIGO (Effective and Affordable Flu Vaccines for the World)
Periodo di rendicontazione: 2021-10-01 al 2023-03-31
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 <10% instead of 60% non-responders, lower costs, and better accessibility:
1) 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) 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 (LVA), 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 (HADEL), 2) a potent adjuvant (MDPA), 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, INDIGO 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.
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 <10% instead of 60% non-responders, lower costs, and better accessibility:
1) 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) 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 (LVA), 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 (HADEL), 2) a potent adjuvant (MDPA), 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, INDIGO 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.
The first in person consortium meeting could be held in Amsterdam in June 2022. This was a great landmark for collaborative evaluation of the project and the start of more intensive interaction between different Indian and EU partners, with a clinical EU delegation visiting India for harmonization of the clinical studies and training of procedures and India visiting Europe for technology transfer with respect to LVA adjuvant technology.
Within the second project period (18-36 months) the TETRALITE concept, the combination of the seasonal flu vaccine with a novel, potent adjuvant (LVA), was tested in a first-in-human trial. The research on the immunostimulatory role of LVA on human PBMC and dendritic cells has been published. LVA for clinical studies was produced under GMP, tested and released and long-term stability studies are ongoing. Required in vitro as well as in vivo toxicity studies were performed. The latter included acute toxicity studies in rabbits as well as a GLP repeated-dose toxicity study in rabbits. The efficacy of influenza vaccination with the projects’ innovative adjuvants LVA and MDPA, was investigated in the ferret model. The documents for clinical trial application (IB, IMPD) for TETRALITE were written, submitted to and approved by the regulatory authorities and enabled a successful start of the phase I clinical trial in Ghent in October. Preliminary results indicate TETRALITE is safe. Interim immunogenicity analyses of samples was performed in February, full analysis will start in June, when all samples are available. In the meantime preparation of the Phase I study in India as well as the Phase II study in Ghent are ongoing. Exchange of knowledge and know-how as well as harmonization is taking place between all European and Indian partners and collaborators involved, including sponsors, CRO’s, clinical trial sites and laboratories that are involved in humoral and cellular immunogenicity testing.
Also, results in realizing the further improved flu concept PANDEMICPLUS were generated. In silico design and stability were performed for H7, H5 and seasonal strains. Expression (both transient and stable) and purification of all H7-HA constructs has been achieved. The first constructs were tested in a mouse model and optimization of production, purification and stability of the products is ongoing.
In addition, preparational work on the use of microneedles has been ongoing and dermal administration of influenza vaccines was successfully tested in mice, and results were published.
Within the second project period (18-36 months) the TETRALITE concept, the combination of the seasonal flu vaccine with a novel, potent adjuvant (LVA), was tested in a first-in-human trial. The research on the immunostimulatory role of LVA on human PBMC and dendritic cells has been published. LVA for clinical studies was produced under GMP, tested and released and long-term stability studies are ongoing. Required in vitro as well as in vivo toxicity studies were performed. The latter included acute toxicity studies in rabbits as well as a GLP repeated-dose toxicity study in rabbits. The efficacy of influenza vaccination with the projects’ innovative adjuvants LVA and MDPA, was investigated in the ferret model. The documents for clinical trial application (IB, IMPD) for TETRALITE were written, submitted to and approved by the regulatory authorities and enabled a successful start of the phase I clinical trial in Ghent in October. Preliminary results indicate TETRALITE is safe. Interim immunogenicity analyses of samples was performed in February, full analysis will start in June, when all samples are available. In the meantime preparation of the Phase I study in India as well as the Phase II study in Ghent are ongoing. Exchange of knowledge and know-how as well as harmonization is taking place between all European and Indian partners and collaborators involved, including sponsors, CRO’s, clinical trial sites and laboratories that are involved in humoral and cellular immunogenicity testing.
Also, results in realizing the further improved flu concept PANDEMICPLUS were generated. In silico design and stability were performed for H7, H5 and seasonal strains. Expression (both transient and stable) and purification of all H7-HA constructs has been achieved. The first constructs were tested in a mouse model and optimization of production, purification and stability of the products is ongoing.
In addition, preparational work on the use of microneedles has been ongoing and dermal administration of influenza vaccines was successfully tested in mice, and results were published.
INDIGO will develop next generation influenza vaccines with low antigen dose and low cost. Both vaccine designs aim at single-shot, cost-effective vaccines to elicit optimal, robust and durable antibody responses. With improved vaccines, costs of vaccine and clinical care can be minimized, and individuals would not be taken out of the working environment due to illness. Potential wider applications include the delivery technology where intra-dermal patches are being developed, which makes it feasible to simplify the applications of vaccines in general.
TETRALITE is a novel seasonal flu vaccine candidate offering higher immunity at lower costs than the competitors. The adjuvant LVA is a key factor. It transforms a generic product into an innovative, superior, proprietary vaccine. The product is expected to increase the effectivity from 40% to >90%. Such a 6-fold reduction in the risk of contracting the disease will recapture confidence of end-users and promote vaccine uptake.
TETRALITE is a novel seasonal flu vaccine candidate offering higher immunity at lower costs than the competitors. The adjuvant LVA is a key factor. It transforms a generic product into an innovative, superior, proprietary vaccine. The product is expected to increase the effectivity from 40% to >90%. Such a 6-fold reduction in the risk of contracting the disease will recapture confidence of end-users and promote vaccine uptake.