Projects / Programmes
Advanced nano-vaccines based on protein origami combining activators of innate and adaptive immune response
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
vaccine, coiled-coil segments, respiratory syncytial virus antigens, agonists Toll-like receptors
Researchers (18)
Organisations (2)
Abstract
Vaccines are undoubtedly one of the greatest successes of medicine against infectious diseases. Despite remarkable progress in understanding the modus operandi of vaccines, adequate long-term protection against some pathogens still eludes vaccines. An example of such a pathogen is the respiratory syncytial virus (RSV). Infection with the human pneumovirus pathogen RSV causes a wide spectrum of diseases of the lower respiratory tract, responsible for a heavy death toll worldwide. Treatment options against the RSV are limited, and no vaccine is currently available to induce long-term protection against it. Therefore, effective vaccines that neutralize the invading pathogen are required.
The potent immunogenicity of vaccines, based on attenuated or killed pathogens, is based on the action of multiple activators of innate immunity, particularly Toll-like receptors (TLRs), by the molecular components of pathogens, but they may have safety issues due to their heterogeneity. Although vaccines based on isolated antigens are safer, they are often only weakly immunogenic when administered alone. To boost the protective immunity, co-administration of antigens with innate immune response agonists is required, preferentially delivering antigens and adjuvants into the same cellular processing compartments. Additionally, it has been shown that the virus-like, periodic arrangement of antigens triggers a superior vaccination response. Therefore, an optimal vaccine carrier should arrange antigens and agonists of different TLRs in a defined geometric arrangement and preferably combine the cell-specific targeting and internalization signal.
We propose that anchoring of TLR agonists and antigens onto the designed polypeptide scaffold will enable the construction of a new type of nanovaccines to improve the activation of the immune response, antigen presentation, and generation of the protective immunity. The design of advanced nanovaccines will be based on our unique combination of expertise in innate immunity and our recently developed platform for the designed modular polypeptide cage assemblies (aka protein origami) based on orthogonal coiled-coil (CC)-forming peptides. Cross-linking immunologically active domains to self-assembled CC structures will maintain the unity of the nanovaccine as a multifunctional particle, provided that agonists and antigens will be delivered into the same cellular compartments.
We expect to be able to regulate the antigen presentation and balance of the Th1 and Th2 response with our multifunctionally designed vaccine. Subsets of TLR agonists, which can induce antigen cross-presentation from specific dendritic cells and isolated RSV antigens, will be conjugated with the CC-based polypeptide network to form several different, rationally designed RSV nanovaccines. While this proposal focuses on the vaccine against the RSV due to the clear societal need for it, the experience during the project and the derived principles will also be applicable to other vaccines against viral, bacterial, and fungal infections, as well as for the immunotherapy against cancer.
The advantage of the modular CC-based designed scaffolds is its predictable, adjustable, and controllable positioning of the functional molecular domains. This type of designed molecules has significant potential for biotechnological and biomedical applications.
Significance for science
Vaccines have saved millions of lives and have become the most cost-effective medical interventions and are therefore listed among the most important medicine for mankind.
We expect to advance a rational approach to the vaccine design in general and in particular against RSV.
Cutting edge technology. This innovative proposal combines cutting edge technology of synthetic biology and immunology to progress in rationally designed vaccines. The originality of our idea is to use the coiled-coil based platform for direct association of immune response activators for improved antigen presentation.
Impact on the medical sector. We propose to develop an important segment of applications of designed modular coiled-coil-based technology in medicine, which, although a very active area, have not yet been reported. Efficient delivery of therapeutics to selected tissue or target cells in contrast to the systemic application is crucial for minimizing adverse side effects. Viral delivery, although efficient, is limited to the delivery capacity and entails safety concerns. The ability to construct unified scaffolds that enable cell-specific targeting of rationally designed vaccines would represent an important technological breakthrough with important applications in health care. We envisioned self-assembling advanced vaccines combining activation of innate and adaptive immune response through adjuvant and antigenic components.
The relevance of the project is the development of high throughput system for rational design of nanovaccines. The expected results of the project will have a strong impact on vaccine development but also wider, in therapy against cancer, since the developed tools and conceptual advances (e.g. coiled-coil based building elements) could be used in many different fields of life sciences.
Impact beyond medicine. The modular concept of bionanomaterials, designable coiled-coil based polypeptide scaffolds and functionalization will allow technological applications in areas beyond medicine, to produce functional materials as bio-catalysts and enzyme carriers. The biotechnological and chemical industries are expected to be end-users of our innovation.
Measures to maximize the impact. The results of the project on immunology will generate new knowledge; therefore, we expect to publish the results in leading scientific journals. Additionally, the project aims to establish proof of principle in rational design of nanovaccine and to evaluate the potentials of new coiled-coil based technology. The group members have presented results, which are the background of this proposal, at several scientific conferences; therefore, we can expect that results of this project will have a significant scientific impact. Synthetic biology as generator of new materials for health represents one of the emerging technologies within the Horizon 2020. Therefore the project will represent a good foundation for further collaborative projects in synthetic biology.
Significance for the country
The project topic is highly relevant for human health. The project introduces a new conceptual merger between bionanomaterials, coiled-coil based technology and immunology. We also expect new insights on immune response signaling regulation, which will dictate rational design of vaccines. The research topic, nano-vaccine design, is also a strategically very important research area, since there is extensive competition between biotech/pharmaceutical companies with many patents in the field.
From a broader perspective, the developed new technology of the coiled-coil based scaffolds may be used for rationally designed other multi-component drugs with emphasis on development of drugs for therapeutic intervention in cancer immunotherapy.
One goal of our project is the design of an RSV nanovaccine. A number of preclinical and clinical studies have shown that vaccines against RSV are of much interest also for pharmaceutical companies.
Transfer of knowledge into applications and industry. The highest direct impact of the project for the economy and society will be in the development of a specialized new technological platform that will be available for different applications in pharmacy, medicine and biotechnology. These industries are potential partners in developing applications originating from results of the research. The technology may increase the competitiveness and establishment of new companies, which in turn may lead to new jobs for biotechnologists and similar professions. The proposed principles for rationally designed nano-vaccines represent a fundamental technology with potential in other multi drug therapeutic applications.
We already work in collaboration with foreign industries on in vivo assembling coiled-coil based scaffolds. The aim is to evaluate the coiled-coil polypeptide networks to improve the production of industrially attractive metabolites.
The project consortium includes the Centre of excellence ENFIST, which has been funded from the EU funds to provide the critical mass and support the translation of scientific discoveries to industrial partners. An international patent application has been filed for the coiled-coil based materials, which could represent the platform for a biotechnological start-up organized by the members from the Laboratory of Biotechnology of the National institute of chemistry and Centre of excellence ENFIST. Innovations will be protected which enable either licensing or start-up establishments. The technology transfer office of National Institute of Chemistry will support commercialization of the results of innovations generated in the project.
Most important scientific results
Interim report,
final report
Most important socioeconomically and culturally relevant results
Interim report,
final report
