Live Attenuated Virus Stabilization with Poloxamer 407 and Trehalose
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Live, attenuated viral vaccines, such as those for flaviviruses, are prone to degradation and require refrigeration, making them challenging to distribute and store, especially in developing regions, and current stabilizing agents do not provide long-term stability at room temperature or during reconstitution.
Innovation Solution
Compositions combining high molecular weight surfactants, proteins, and carbohydrates, such as trehalose and serum albumin, with EO-PO block copolymers like poloxamer 407, are used to enhance the stability of live attenuated viruses, allowing them to maintain potency for extended periods at various temperatures and withstand freeze-thaw cycles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If live attenuated viruses are stored at room temperature, then distribution and storage become easier, but the viruses degrade rapidly and lose potency
Solution Approach 1:
The patent introduces stabilizing agents including sugars (trehalose, sucrose), polyols (glycerol, mannitol), proteins (albumin, gelatin), and surfactants (poloxamers, polysorbates) as intermediary substances that protect the virus from thermal degradation. These agents form a protective matrix around the virus particles, preventing denaturation and maintaining structural integrity at elevated temperatures, thus enabling room temperature storage while preserving viral potency.
Solution Approach 2:
The invention employs composite stabilizing formulations combining multiple agents (sugars, polyols, proteins, surfactants) in specific concentrations. This composite approach creates synergistic protection where each component addresses different aspects of viral stability - sugars provide cryoprotection and structural support, proteins maintain viral envelope integrity, and surfactants prevent aggregation. The composite formulation achieves superior thermal stability compared to single agents, enabling reliable room temperature storage.
2Reliability
If refrigeration is used to maintain virus stability, then viral potency is preserved, but distribution to developing regions becomes challenging
Solution Approach 1:
The patent fundamentally changes the storage temperature parameter from refrigerated (2-8°C) to room temperature (20-25°C or higher) through the use of stabilizing formulations. The stabilizing agents raise the temperature threshold for viral degradation, effectively shifting the acceptable storage temperature range. This parameter change eliminates the need for refrigeration infrastructure while maintaining viral potency, making distribution to regions without reliable cold chains feasible.
Solution Approach 2:
The invention extracts the refrigeration requirement from the vaccine storage system by incorporating thermal stabilizing agents directly into the vaccine formulation. This removes the dependency on external refrigeration infrastructure, allowing the vaccine to be stored and transported in simple containers without temperature control equipment, thus solving the distribution challenge in developing regions.
3Duration of action of stationary object
If freeze-drying is applied to stabilize the virus, then long-term storage is achieved, but the manufacturing process becomes more complex
Solution Approach 1:
The patent employs inexpensive, readily available stabilizing agents (sugars like trehalose and sucrose, common polyols like glycerol and mannitol, and standard proteins like albumin) that can be easily incorporated into the vaccine formulation without requiring complex manufacturing equipment. These simple, low-cost materials provide effective stabilization that eliminates the need for expensive and complex freeze-drying infrastructure, achieving long shelf life through affordable means.
Solution Approach 2:
The invention changes the physical state parameter of the vaccine from requiring frozen or refrigerated liquid storage to stable liquid or lyophilized powder form through formulation with stabilizing agents. This parameter change allows the vaccine to maintain potency without freeze-drying by using stabilizers that prevent degradation in liquid form at room temperature, thereby simplifying the manufacturing process while achieving long-term stability.
4Reliability
If current stabilizing agents are used, then some protection is provided, but long-term stability at room temperature is not achieved
Solution Approach 1:
The patent uses composite formulations combining multiple stabilizing agents in optimized ratios: sugars (trehalose 5-20%, sucrose 5-20%) provide structural support and water activity control; polyols (glycerol 5-20%, mannitol 5-20%) offer cryoprotection and viscosity control; proteins (albumin 0.1-5%, gelatin 0.1-5%) maintain viral envelope integrity; and surfactants (poloxamer 407 0.01-1%, polysorbate 20 0.01-1%) prevent aggregation. This multi-component composite provides synergistic protection that achieves long-term stability at room temperature, overcoming the limitations of single-agent stabilizers.
Solution Approach 2:
The stabilizing agents are incorporated into the vaccine formulation during manufacturing, providing preliminary protection before storage and distribution. The sugars, polyols, proteins, and surfactants are pre-mixed with the virus in optimal concentrations to create a protective environment that prevents degradation during subsequent storage at room temperature. This preliminary stabilization action ensures long-term potency without requiring refrigeration during distribution.
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
These compositions significantly increase the shelf life of live attenuated viruses, maintaining viral titer for over 24 hours at room temperature and up to 50 days at refrigeration temperatures, and demonstrate improved stability during reconstitution and storage, reducing the need for refrigeration and minimizing vaccine wastage.
Implementation Method 1
compositions combining high molecular weight surfactants, proteins, and carbohydrates, such as trehalose and serum albumin, with EO-PO block copolymers like poloxamer 407
Implementation Method 2
compositions combining high molecular weight surfactants, proteins, and carbohydrates, such as trehalose and serum albumin
Data Source
AI summary
Embodiments herein relate to compositions of and methods for live viruses. In certain embodiments, a live, attenuated virus composition includes, but is not limited to, one or more live, attenuated viruses and compositions to reduce inactivation and/or degradation of the live, attenuated virus. In other embodiments, the live, attenuated virus composition may be a vaccine composition. In yet other compositions, a live, attenuated virus composition may include at least one carbohydrate, at least one protein and at least one high molecular weight surfactants for reducing inactivation and/or degradation of the live, attenuated virus.