Periodic Reporting for period 3 - INDIGO (Effective and Affordable Flu Vaccines for the World)
Periodo di rendicontazione: 2023-04-01 al 2024-09-30
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.
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.
For the TETRA-LITE concept, an affordable seasonal flu vaccine with high efficacy at low cost, two clinical studies were performed in the EU. In preparation thereof, the adjuvant was produced under GMP, tested and released and long-term stability studies were started. Required in vitro as well as in vivo toxicity studies were performed. The research on the immunostimulatory role of LVA on human PBMC and dendritic cells had been published and after approval of the clinical trial application for TETRA-LITE, the vaccine was succesfully tested in a first-in-human trial in Ghent. Results of this first clinical trial were published: TETRA-LITE was found safe and in addition, 1/5 of an antigen dose combined with LVA was as immunogenic as a full dose of a commercially available vaccine without adjuvant.
In a Phase 1b study that followed, again safety and immunogenicity of the vaccine were tested, both in younger and older adults and with a full antigen dose. The safety of TETRA-LITE was confirmed and immunogenicity is currently being determined, with extra attention for the immunological mechanisms underlying the action of the adjuvant.
Also, a proof-of-concept study was performed in India, to prepare for the phase I clinical trial in India. Exchange of knowledge and know-how as well as harmonization has been 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. The Clinical Trial application for the Phase 1 clinical trial in India is ready to be submitted. Meanwhile, stability testing of the GMP grade LVA for clinical trials reached the 3rd year timepoint successfully and stability studies are ongoing throughout the duration of the project.
For the further improved flu concept PANDEMICPLUS, in silico design and stability were performed for H7, H5 and seasonal strains. Expression (both transient and stable) and purification of several constructs has been achieved. The constructs are being tested in a mouse model as well as human PBMCs to identify a lead candidate.
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. A new collaboration partner in India was approved by the funder and studies with the patches are ongoing.
In a Phase 1b study that followed, again safety and immunogenicity of the vaccine were tested, both in younger and older adults and with a full antigen dose. The safety of TETRA-LITE was confirmed and immunogenicity is currently being determined, with extra attention for the immunological mechanisms underlying the action of the adjuvant.
Also, a proof-of-concept study was performed in India, to prepare for the phase I clinical trial in India. Exchange of knowledge and know-how as well as harmonization has been 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. The Clinical Trial application for the Phase 1 clinical trial in India is ready to be submitted. Meanwhile, stability testing of the GMP grade LVA for clinical trials reached the 3rd year timepoint successfully and stability studies are ongoing throughout the duration of the project.
For the further improved flu concept PANDEMICPLUS, in silico design and stability were performed for H7, H5 and seasonal strains. Expression (both transient and stable) and purification of several constructs has been achieved. The constructs are being tested in a mouse model as well as human PBMCs to identify a lead candidate.
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. A new collaboration partner in India was approved by the funder and studies with the patches are ongoing.
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 transforms a generic product into an innovative, superior, proprietary vaccine. If effectivity can be achieved at lower cost, the vaccine could become more broadly available, also in countries that currently cannot afford it. Current studies test whether the combination of the adjuvant combined with a full dose commercially available vaccine could increase the efficacy in older adults, a decreased 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 transforms a generic product into an innovative, superior, proprietary vaccine. If effectivity can be achieved at lower cost, the vaccine could become more broadly available, also in countries that currently cannot afford it. Current studies test whether the combination of the adjuvant combined with a full dose commercially available vaccine could increase the efficacy in older adults, a decreased risk of contracting the disease will recapture confidence of end-users and promote vaccine uptake.