Advancing mRNA vaccines and therapeutics; the need for improved delivery technologies

By Jaap Rip , Ph.D., Chief Scientific Officer of 20Med Therapeutics

The successful use of mRNA in the pandemic has ushered in a new era of mRNA vaccinations and medicine. In favor of a swift response, not all challenges associated with mRNA vaccines and their delivery were fully addressed. In parallel to improving lipid nanoparticles, it is important to acknowledge that alternative non-LNP technologies merit exploration. 20Med Therapeutics is delivering one alternative platform to LNPs based on polymers.

Vaccinations have proven to be one of the most successful public health interventions, preventing millions of cases of infectious diseases and saving lives. Their use has led to the eradication of smallpox and significant reductions in diseases like polio and measles. This success was recently followed by the use of mRNA vaccines to prevent COVID-19.

COVID vaccines paved the way for more mRNA-based medicine

While the mRNA vaccinations were already under development for a few decades, the COVID pandemic accelerated the development of both the used mRNA and the delivery technology. mRNA vaccines offered a good approach by providing a fast and adaptable method for vaccine development. Their design allowed for rapid modification to match the virus's genetic code, enabling quicker response to emerging variants. Manufacturing efficiency was enhanced with a scalable and cost-effective vaccine production. Additionally, the mRNA platform demonstrated high efficacy in clinical trials, contributing to the swift and successful deployment of the vaccines worldwide. When focusing on the mRNA delivery technology, the used lipid nanoparticles (LNPs) offered advantages for fast response in formulation and scale-up, transfection efficiency, toxicity profile, modularity, combination with different nucleic acid types and sizes, and protection of mRNA from internal degradation. The mRNA vaccine adaptability has advantages for other regularly updated products, such as influenza vaccines. The successful use of mRNA in vaccines has not only led to the awarding of the 2023 Nobel Prize in Medicine to Dr. Katalin Karikó and Dr. Drew Weissman but has also ushered in a new era of mRNA vaccinations and medicine. Nevertheless, not all challenges associated with mRNA vaccines were initially fully addressed, primarily due to the substantial benefits and the need for a swift response to the pandemic. Next generation mRNA vaccines will make use of improved technologies for both the mRNA as the delivery vehicle. This will allow the benefits of mRNA-based vaccines and medicines to reach the entire range of infectious diseases and other indications.

Challenges for next-generation mRNA-based products

New developments aim to improve several aspects of the mRNA vaccine platform. The first challenge is the cold storage requirement and the necessity for cold-chain distribution. Improved thermostability of the vaccines will reduce the costs of distribution and may result in a more equal global distribution. Waning vaccine effectiveness is reported to be faster for the mRNA COVID vaccines compared to other vaccine technologies. The waning vaccine effectiveness may not be limited to SARS-CoV-2 antigens in the mRNA vaccines but needs to be addressed for other mRNA vaccines currently under development. Improvements in the delivery technology may play an important role in the effectiveness, which is illustrated by the adjuvant effect described for the LNP-based vaccines. Alternative delivery technologies may affect the specifics of the immune responses as well as the duration of effectiveness. Depending on the desired immune response, this difference could be advantageous. It is important to note that this immunogenicity in not desired for other applications like repeated injections for therapeutic use. Different applications may benefit from different delivery technologies.

The mRNA vaccines were associated with a higher risk of adverse events compared to other vaccine technologies used during the COVID pandemic. Common side effects include local reactions at the injection site, such as pain and swelling, and systemic reactions, such as fatigue, headache, muscle pain, chills, fever. mRNA vaccine improvements aim to minimize discomfort, thereby increasing acceptance, compliance, and broadening the accessibility of these vaccines for a diverse population. The primary strength of mRNA vaccines lies in their capacity for a rapid response to outbreaks. However, their swift development has brought forth challenges related to the supply of excipients and manufacturing capacities, resulting in competition for distribution and unequal access to vaccines. Future prevention of such issues could be facilitated by alternative technologies that streamline manufacturing processes and utilize readily available or easily manufacturable excipients. Other technologies may reduce the manufacturing costs. Costs are currently driven by the used proprietary technologies for both mRNA as the delivery vehicle. Especially for the LNP delivery technology the ownership of the technologies proved complicated leading to multiple litigations between companies.

20Med’s PNPs as an alternative delivery technology

While efforts are underway to advance next-generation LNPs, it is important to acknowledge that alternative non-LNP technologies merit exploration. These alternatives include polymeric nanoparticles or combined polymer and lipid technologies. At 20Med Therapeutics, we develop polymer-based nanoparticles (PNPs) as an alternative delivery approach for mRNA. Our proprietary technology involves the use of poly(amido)amine-based polymers in combination with mRNA and additional excipients for stabilization. The polymers contain functional groups that help to encapsulate and bind the mRNA resulting in an efficient delivery. The straightforward synthesis of the polymers allows for easy introduction of different functionalities that improve the mRNA delivery and transfection efficiency and can be used to improve and steer the immunogenicity and effectiveness. The stability of mRNA is increased by encapsulation in the PNPs since they protect the payload from nuclease activity. Storage stability can be improved by freeze-drying the final product. The synthetic polymers are biodegradable and in preclinical studies intramuscular administration was well-tolerated. The development of the technology is recently published in Biomaterials Advances. Preclinical studies showed efficiency by successful expression of proteins and vaccination. The formulation process of PNPs is simpler, avoids the use of solvents, and there is no need for additional purification or solvent-removal steps combined with high encapsulation yields of >98%. This improves the scalability and affordability of the production process.

At 20Med Therapeutics, we aim to address the above-mentioned challenges and develop our platform as a solution for effective delivery of mRNA for curative or preventive medicine.

More Reading:

Comparing reactogenicity of COVID-19 vaccines: a systematic review and meta-analysis

Natalina Sutton, Alberto San Francisco Ramos, Emily Beales, David Smith, Sabina Ikram, Eva Galiza, Yingfen Hsia & Paul T. Heath (2022), Expert Review of Vaccines, 21:9, 1301-1318, DOI: 10.1080/14760584.2022.2098719

Waning effectiveness of SARS-CoV-2 mRNA vaccines in older adults: a rapid review

Nanishi E, Levy O, Ozonoff A. Waning effectiveness of SARS-CoV-2 mRNA vaccines in older adults: a rapid review. Hum Vaccin Immunother. 2022 Nov 30;18(5):2045857. doi: 10.1080/21645515.2022.2045857. Epub 2022 Mar 3. PMID: 35240940; PMCID: PMC9196671.

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Evaluation of Waning of SARS-CoV-2 Vaccine–Induced Immunity A Systematic Review and Meta-analysis

?Menegale F, Manica M, Zardini A, et al. Evaluation of Waning of SARS-CoV-2 Vaccine–Induced Immunity: A Systematic Review and Meta-analysis. JAMA Netw Open. 2023;6(5):e2310650. doi:10.1001/jamanetworkopen.2023.10650

A poly(amidoamine)-based polymeric nanoparticle platform for efficient in vivo delivery of mRNA

Adriano P. Pontes, Steffen van der Wal, Karin Roelofs, Anne Grobbink, Laura B. Creemers, Johan F.J. Engbersen, Jaap Rip, Biomaterials Advances, 2023, 213713, ISSN 2772-9508, https://doi.org/10.1016/j.bioadv.2023.213713.