EXECUTIVE INTERVIEW - Lonza & Ethris: Advancing mRNA Vaccines: Room-Temperature Stable, Spray-Dried Formulations for Enhanced Mucosal Delivery

mRNA vaccines have rapidly grown in popularity due to their industrial adaptability, responsiveness to new variants, and shorter development timelines. Current market research predicts the mRNA vaccine market to be valued at $18.28 billion by 2030. Despite this growth, challenges associated with developing mRNA vaccines remain, including dependence on ultra-low-temperature storage and complex delivery systems.

To tackle these challenges, Lonza, one of the world’s largest contract development and manufacturing organizations (CDMOs) and Ethris, a clinical-stage biotechnology company pioneering next-generation RNA therapeutics and vaccines, recently announced a collaboration to develop room-temperature stable, spray-dried formulations of mRNA-based vaccine candidates, designed for mucosal delivery that offer a promising approach to combat respiratory diseases.

 Drug Development & Delivery recently interviewed Kim Shepard, Director of Advanced Drug Delivery at Lonza, and Carsten Rudolph, PhD, Co-founder and Chief Executive Officer at Ethris, to discuss the main objectives of the collaboration and the benefits of spray-dried mRNA vaccines.

Q: What is the main goal of the collaboration between Ethris and Lonza?

Dr. Rudolph: Our collaboration with Lonza is part of our broader strategy to develop first-in-class spray-dried mucosal mRNA vaccine candidates that are stable at room temperature and capable of generating a localized immune response, funded by the Coalition for Epidemic Preparedness Innovations (CEPI). The initial focus of the collaboration is to develop a candidate against influenza. By generating a localized immune response at the site where the virus enters the body, we aim to potentially reduce virus transmission and enhance vaccine efficacy, while minimizing systemic exposure. On the other hand, the development of vaccine formulations that remain stable at room temperature addresses significant supply chain issues related to the need for ultra-low-temperature storage for certain mRNA vaccines. Achieving this stability can streamline the production process and lower costs, thereby making vaccine distribution more efficient and scalable.

Ms. Shepard: Our team at Lonza Bend is excited to collaborate with Ethris on their vaccine candidates to target unmet medical needs in the field of non-invasive vaccine delivery. The spray-dried formulations are designed for needle-free administration, which can enhance patient compliance and accessibility. While our collaboration is focused on creating a first-in-class mRNA vaccine candidate against influenza, we look forward to the possibility of expanding to other respiratory diseases in the future.

Q: How does spray-drying technology enhance the stability and delivery of mRNA-based vaccines?

Ms. Shepard: Spray-drying technology significantly improves the stability and delivery of mRNA-based vaccines by transforming liquid formulations into a dry powder. This is essential because the dry powder form is more stable at room temperature, unlike liquid formulations that often need ultra-low temperature storage and rely on a complex supply chain. This stability at higher temperatures helps to address the logistical challenges related to cold chain requirements, making mRNA vaccines more accessible and easier to distribute.

Additionally, the dry powder form of mRNA vaccines provides versatility in delivery methods. Spray drying as a technique enables particle engineering, allowing the material to be designed for delivery to the lung or nose via inhalation. This flexibility allows for targeted delivery to specific areas of the body where mucosal immunity can be induced, enhancing the vaccine’s efficacy by ensuring that the immune response is generated at the site of virus entry.

Q: What are the challenges in producing spray-dried mRNA vaccines?

Ms. Shepard: mRNA vaccines are usually formulated within lipid nanoparticles (LNPs), which can present challenges when creating spray-dried mRNA vaccines. This is primarily related to the stability and integrity of the mRNA and the need for effective encapsulation within LNPs. Consequently, the manufacturing process must be meticulously controlled to ensure the production of consistent and high-quality vaccine particles.

For instance, the size of the LNPs must remain consistent to facilitate effective transfection into cells. Effective delivery to the respiratory tract also requires particles with a median size of at least 20 μm, while minimizing the presence of fine particles that could reach the lungs.

Dr. Rudolph: A primary challenge pertains to the mechanical stress induced during spray drying that can cause aggregation of LNPs in standard formulations. The drying process additionally exposes the formulation to significant heat, damaging most formulations.

As such, it is important to select the excipients carefully to ensure stability. The matrix excipient plays a key role in preventing the aggregation of LNPs during the drying process while maintaining the integrity and activity of the mRNA. Furthermore, 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 added to enhance the aerosol properties of the powder, thereby improving emission from an inhaler device.

Ethris has pioneered a series of proprietary innovations, such as the inclusion of a stabilizing excipient that completely prevents LNP aggregation. Additionally, Ethris’ technology allows formulations to remain stable at temperatures from -20°C up to room temperature and at elevated temperatures. These innovations protect the LNPs from heat damage and aggregation – two common failure points in standard formulations – and ensures particle integrity during nebulization and spray-drying.

By further tailoring our proprietary SNaP LNP^® formulation for spray-drying, Ethris enables Lonza to efficiently apply spray-drying and particle engineering. We provide robust, shear-resistant, and thermostable LNPs to facilitate the spray-drying process, resulting in optimal mRNA encapsulation, particle size, mRNA concentration, excipient composition, and LNP integrity with preserved bioactivity and enhanced physical stability.

Q: What are the benefits of nasal administration of mRNA vaccines over traditional intramuscular injections?

Dr. Rudolph: Nasal administration of mRNA vaccines offers distinct advantages over traditional intramuscular (IM) injections, primarily by inducing robust immunity at the mucosal surface of the respiratory tract – the main entry point for respiratory viruses like SARS-CoV-2 and influenza. Unlike IM vaccines, which mainly generate systemic immunity (IgG antibodies in the bloodstream), studies show that nasal vaccines can rapidly induce both mucosal and systemic immunity, by eliciting strong local production of immunoglobulin A (IgA) and tissue resident memory B and T cells within the nasal and airway mucosa. This dual response forms an effective barrier, intercepting pathogens at the site of entry, and is particularly effective in halting viral shedding and breaking the cycle of person-to-person transmission, something IM vaccines struggle to achieve due to their weaker mucosal response.

Additionally, through targeted delivery of mRNA vaccine, we have shown that we minimize systemic exposure. Our recently finalized Phase 1 study of our nasal formulation demonstrated no systemic bioavailability of the mRNA or expressed protein product.

Another advantage of nasal vaccination is that it is completely needle-free, making it much easier for patients to self-administer. This may improve patient compliance and facilitate mass vaccination campaigns.

Combined with the benefits of room-temperature-stable mRNA formulations, which ensure easy storage and distribution, mucosally delivered mRNA-vaccines are a promising tool for protecting vulnerable patient polulations, controlling respiratory pandemics, and reducing disease spread at the community level.

Q: What are the benefits of enhanced stability of spray-dried formulations and how does Lonza contribute to the development of these formulations for mRNA vaccines?

Ms. Shepard: As a contract development and manufacturing organization (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.

Our sites in Geleen, Netherlands, and Visp, Switzerland, offer integrated mRNA and LNP capabilities. These sites have dedicated process development, analytical services, and cGMP manufacturing for clinical trials. Complementing these capabilities, our team 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.

Q: How does Ethris’ Stabilized Non-Immunogenic mRNA (SNIM RNA) and Stabilized NanoParticle (SNaP) LNP platform facilitate the creation of room-temperature stable vaccine formulations?

Dr. Rudolph: At Ethris, we have created a proprietary lipid formulation with a unique composition and stabilization mix that ensures excellent mRNA stability at temperatures ranging from -20°C to room temperature. This innovation is complemented by our development of lyophilization and rapid rehydration processes, which provide long-term product stability and enable room temperature storage and distribution.

Moreover, we have introduced a stabilizing excipient that can be added to the LNP formulation to completely prevent LNP aggregation caused by mechanical stress, such as shaking during vaccine distribution. Additionally, we are advancing the development of a spray-dried formulation, which not only offers long-term storage but also represents an easily scalable process.