Flagellin Nanoparticles for Targeted Vaccine Delivery
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Solution Overview
Problem
Current adjuvants, such as flagellin, can induce inflammatory immune responses and have significant side effects, limiting their use in vaccination due to their systemic application and potential for severe reactions.
Innovation Solution
Development of self-assembling protein nanoparticles incorporating flagellin or its derivatives, which are engineered to lack the C-terminal portion of the D0 domain responsible for inflammasome activation, allowing for co-localization with antigens and reduced inflammatory responses by forming nanoparticles with specific oligomerization domains and linkers that optimize adjuvant and antigen presentation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If flagellin is used as a conventional adjuvant injected together with the antigen, then the adjuvant effect is enhanced, but the inflammatory immune responses and side effects increase
Solution Approach 1:
The flagellin molecule is segmented into functional domains: the D1 domain is retained for TLR5 binding adjuvant activity, while the C-terminal portion of D0 that triggers inflammasome activation is removed. This segmentation allows separation of beneficial adjuvant effects from harmful inflammatory responses.
Solution Approach 2:
The harmful C-terminal portion of the D0 domain is extracted and removed from the flagellin molecule. This extraction eliminates the inflammasome activation capability while preserving the TLR5 binding functionality in the D1 domain, thereby reducing side effects while maintaining adjuvant effect.
2Object-generated harmful factors
If flagellin is formulated as a particulate system, then the side effects are reduced and adjuvant effect is concentrated, but the device complexity increases
Solution Approach 1:
The modified flagellin adjuvant and the antigen are merged into a single nanoparticle structure through co-localization. The flagellin D1 domain is displayed on the nanoparticle surface alongside the antigen, creating an integrated formulation that delivers both components to the same lymph node, concentrating the adjuvant effect while simplifying administration compared to separate injections.
Solution Approach 2:
The nanoparticle acts as an intermediary carrier that delivers both the modified flagellin adjuvant and the antigen to the target lymph node. This intermediary structure enables co-localization of adjuvant and antigen, ensuring they reach the same immune cells simultaneously while reducing systemic side effects through targeted delivery.
3Object-generated harmful factors
If the C-terminal portion of D0 is removed to reduce inflammatory responses, then the inflammasome activation is reduced, but the adjuvant potency may be affected
Solution Approach 1:
Different regions of the flagellin molecule are assigned different functional qualities: the D1 domain is optimized for TLR5 binding and adjuvant activity, while the D0 domain is modified to eliminate inflammasome activation. This local quality differentiation ensures that each domain performs its specific function without interfering side effects, maintaining adjuvant potency while reducing inflammation.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The nanoparticles effectively co-localize the adjuvant with the antigen, reducing side effects and enhancing the adjuvant effect while minimizing inflammatory responses, thereby improving vaccine efficacy and safety.
Implementation Method 1
self-assembling protein nanoparticle consisting of aggregates of a multitude of building blocks
Implementation Method 2
ND1 is a protein that forms oligomers (ND1)m of m subunits ND1, ND2 is a protein that forms oligomers (ND2)n of n subunits ND2
Data Source
AI summary
The present invention relates to self-assembling protein nanoparticles constructed from suitable oligomerization domains and further incorporating the TLR5 binding protein flagellin as an adjuvant molecule. Furthermore, the invention relates to the use of such nanoparticles for vaccination.