After Lonza announced the collaboration with Ethris to develop spray-dried mRNA vaccines for Respiratory Disease Prevention, European Pharmaceutical Manufacturer spoke to Carsten Rudolph, PhD, co-founder and chief executive officer, Ethris and Kim Shepard, director of advanced drug delivery at Lonza to learn more.
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Collaboration concept.
What are the primary objectives of the collaboration between Ethris and Lonza in developing spray-dried mRNA vaccines?
Shepard: The collaboration between Lonza and Ethris aims to develop spray-dried mRNA vaccines with several key objectives. One of the primary goals is to create vaccine formulations that are stable at room temperature, addressing significant supply chain challenges associated with the need for ultra-low-temperature storage for some mRNA vaccines. This stability can simplify the production process and reduce costs, making vaccine distribution more efficient and scalable.
Another focus of the collaboration is on mucosal delivery, such as through nasal administration. This method aims to generate localised immune responses at the site of virus entry, potentially reducing virus transmission. The spray-dried formulations are designed to enable needle-free administration, which can improve patient compliance and accessibility. Initially, the collaboration is targeting the development of a first-in-class mRNA vaccine candidate against influenza, with the potential to expand to other respiratory diseases.
How does spray-drying technology enhance the stability and delivery of mRNA-based vaccines?
Shepard: Spray-drying technology significantly enhances the stability and delivery of mRNA-based vaccines by converting liquid formulations into a dry powder. This transformation is crucial because the dry powder form is more stable at room temperature compared to liquid formulations, which often require ultra-low temperature storage. This stability at higher temperatures helps overcome the logistical challenges associated with cold chain requirements, making mRNA vaccines more accessible and easier to distribute.
Moreover, the dry powder form of mRNA vaccines offers versatility in delivery methods. It can be administered through various routes, such as nasal sprays, inhalers. This flexibility allows for targeted delivery to specific areas of the body, enhancing the efficacy of the vaccine by ensuring that the immune response is generated at the site of virus entry.
mRNA vaccines are typically formulated within lipid nanoparticles (LNPs), and the careful selection of additional excipients for spray-dried mRNA in LNPs is critical. The matrix excipient plays a vital role in preventing the aggregation of LNPs during the drying process, while also maintaining the integrity and activity of the mRNA. Additionally, it must ensure consistent physical stability and preserve the particle's morphology during storage. Common matrix excipients include sugar alcohols, polysaccharides, and certain polymers. For respiratory delivery, additional excipients may be included to enhance the aerosol properties of the powder, thereby improving emission from an inhaler device.
What advantages does nasal administration of mRNA vaccines offer over traditional intramuscular injections, particularly in achieving mucosal immunity?
Shepard: Nasal administration of mRNA vaccines offers several advantages over traditional intramuscular injections, particularly in achieving mucosal immunity. One of the primary benefits is the ability to generate a localized immune response at the site of virus entry, such as the nasal passages and respiratory tract. This localized immunity can be more effective in preventing the initial establishment and spread of respiratory viruses. Studies have found that mucosal immunity is also conveyed to all mucosal tissues in the body via the lymphatic system, enabling additional indications beyond the respiratory tract.
Nasal vaccines can induce the production of mucosal antibodies, specifically Immunoglobulin A (IgA), which are present in the mucous membranes of the nose and throat. These antibodies play a crucial role in neutralising pathogens at the entry points, potentially providing a first line of defence against infection. In contrast, intramuscular injections primarily induce systemic immunity, which may not be as effective in preventing infections at mucosal surfaces.
Additionally, nasal administration is non-invasive and needle-free, which can improve patient compliance and reduce the discomfort associated with injections. This method also has the potential to provide broader protection by stimulating both mucosal and systemic immune responses, enhancing overall vaccine efficacy.
What specific expertise does Lonza contribute to the development of spray-dried formulations for mRNA vaccines?
Shepard: As a leading contract development and manufacturing organisation (CDMO), Lonza brings a wide array of expertise to the development of spray-dried mRNA vaccine formulations. One of the strongest areas of expertise we have is related to advanced particle engineering, particularly mastering the spray drying process to create powder particles with precisely controlled properties essential for stability and delivery. This is complemented by our extensive experience handling sensitive biologics, which is especially helpful in selecting the appropriate excipients to protect the delicate mRNA molecules and their lipid nanoparticle (LNP) carriers from degradation during the drying process and throughout the product's shelf life.
Additionally, our team at Lonza provides end-to-end support in bringing these complex formulations from the laboratory to large-scale production. This involves robust process development and meticulous scale-up under stringent Good Manufacturing Practice (GMP) conditions, ensuring consistency and quality.
How does Ethris' Stabilised Non-Immunogenic mRNA (SNIM RNA) and Stabilised NanoParticle (SNaP) LNP platform facilitate the creation of room-temperature stable vaccine formulations?
Rudolph: Ethris has developed a proprietary lipid formulation with a unique composition and stabilization mix that allows excellent mRNA stability at temperatures ranging from -20°C to room temperature. The company has developed lyophilization and rapid rehydration processes, providing product stability for long term storage and distribution at room temperature. Additionally, Ethris has developed a stabilizing excipient that can be added to the LNP formulation which completely prevents LNP aggregation caused by mechanical stress such a shaking during e.g. distribution of vaccines. Ethris is further working on the development of a spray-dried formulation which offers long-term storage and is an easily scalable process.
What are the anticipated challenges in producing spray-dried mRNA vaccines, and how do Ethris and Lonza plan to address them?
Shepard: Producing spray-dried mRNA vaccines presents several challenges, primarily related to the stability mRNA and the need for effective encapsulation in lipid nanoparticles (LNPs). As a result, the manufacturing process must be precisely controlled to produce consistent and high-quality vaccine particles, addressing solubility and other challenges.
For an mRNA-LNP dry powder for intranasal delivery, a unique set of quality attributes needs to be achieved for a successful product. The integrity and activity of the mRNA itself must be preserved, as well as its encapsulation efficiency within the LNPs. The size of the LNPs must also remain the same to enable effective transfection into cells. To achieve effective delivery to the respiratory tract, particle engineering is also crucial. For intranasal delivery, particles with a median size of ~20µm are targeted, while simultaneously reducing fine particles which could travel into the lung. A fine balance of formulation and process approaches must be considered to preserve the mRNA and LNPs while enabling sufficient drying and particle engineering to achieve a high-quality powder.
How might the development of room-temperature stable, spray-dried mRNA vaccines impact global vaccine distribution and accessibility, especially in low-resource settings?
Shepard: The development of room-temperature stable spray-dried mRNA vaccines have the potential to address key challenges in accessibility, particularly in low-resource settings. As of today, all FDA-approved vaccines require some form of cold chain distribution. However, the “final mile” of vaccine distribution can present some of the biggest challenges in developing nations. Particularly in warm climates, the last few days before patient administration carry the highest risks. Recent data shows that up to a quarter of vaccines see temperature excursions and must be discarded. Spray-dried vaccines eliminate the need for cold-chain logistics, which can result in distribution to regions that lack the necessary infrastructure. Reducing cold-chain needs can also substantially reduce the cost of distribution and enable better stockpiling of supplies for epidemic/pandemic readiness. Furthermore, automated manufacturing processes used to create these vaccines will shorten production timelines, enabling faster responses to outbreaks and reducing costs to ensure affordability.
What is the projected timeline for the development and potential clinical trials of the spray-dried mRNA vaccine candidates resulting from this collaboration?
Shepard: This collaboration will first address feasibility and pre-clinical bodies of work to demonstrate a robust proof-of-concept in appropriate non-clinical studies. We look forward to learning more and progressing forward with clinical trials in mind.
Are there plans to apply the spray-drying formulation technology to mRNA vaccines targeting diseases other than influenza?
Shepard: We’re not able to share any specific plans at this time. Though the principles of an influenza mRNA-based vaccine are certainly of interest to other respiratory diseases, such as RSV and COVID.
How does the funding from CEPI support the objectives of the Ethris and Lonza collaboration in advancing spray-dried mRNA vaccine technology?
Rudolph: CEPI’s funding supports proof-of concept research for the development of Ethris’ spray-dried mucosal vaccine platform, which is stable at room temperature and capable of generating a localised immune response. It also supports the establishment of an automated manufacturing process that simplifies production, reduces costs, and supports rapid, scalable vaccine development. The spray-dried mRNA vaccine formulations will be manufactured by Lonza, first focusing on a candidate against influenza. In addition to that, Ethris aims to develop a spray-dried formulation for its other programs in asthma and primary ciliary dyskinesia. CEPI’s funding is part of its goal of improving access to RNA-based vaccines by enhancing their thermostability through spray-drying technology. Spray-drying is a cost effective and easily scalable process and the gold standard for achieving particles that can be applied via nasal or inhaled administration. It offers room-temperature stability and simplifies distribution.