The regulatory environment for the development of mRNA vaccines during COVID-19

by Ciaran Greene

Within the last two decades, a growing interest in mRNA-based technologies has seen a surge in the development of mRNA vaccines. Recent technological advancements in RNA biology, stability, and the development of an efficient in-vivo delivery system has accelerated this progression. mRNA-based based vaccines represent a highly potent, scalable and low-cost manufacture platform which may fill the gap between emerging pandemic infectious diseases and a rapid supply of effective vaccines [1]. This has effectively propelled mRNA-based vaccines to the forefront in the race for a SARS-CoV-2 vaccine.

 An increase in the development of mRNA-based vaccines also calls for the development of a robust regulatory-specific framework. Currently there are no RNA-specific vaccine guidelines worldwide. Now more than ever it has become critical to streamline the regulatory pathway for mRNA-based vaccines.

Current landscape of mRNA vaccine development

Currently there are primarily two categories of mRNA constructs in development; conventional, non-replicating mRNA vaccines and self-amplifying mRNA vaccines, which are derived from positive strand RNA viruses.

 The aim in the development of any vaccine is to optimize the benefit (efficacy) while reducing safety risks. In this case, the use of these mRNA constructs has several advantages over subunit, live-attenuated virus as well as DNA-based vaccines. Regarding safety, mRNA is a non-integrating platform and therefore no potential risk of infection is present. Moreover, mRNA is degraded through normal cellular processes. Immunogenicity can also be down-modulated to supplement the safety profile [2]. Regarding efficacy, recent advancements have increased mRNA stability and they have become highly translatable. Modifications in in-vivo delivery systems through the formulation of mRNA synthetic carrier molecules, such as lipid nanoparticles (LNPs), allow rapid uptake and expression in the cytoplasm.

These recent improvements to the mRNA platform have seen a substantial increase in the development of mRNA-based therapeutics and vaccines. This is epitomised in Figure 1, which illustrates the growing number of RNA-based vaccines in development for the SARS-CoV-2 virus shown against the backdrop of other vaccine platforms.

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Regulatory environment for mRNA-based vaccines

mRNA-based medicines are well embedded in the regulatory system, however there is currently no RNA-specific guidance from the Food and Drug Administration (FDA) or the European Medicines Agency (EMA). mRNA falls into the wide-ranging vaccine category of genetic immunogens, therefore many principles defined for plasmid DNA vaccines and gene therapy vectors are applicable to mRNA. However, specific adaptations are required to reflect the uniqueness of mRNA [2]. Currently, the World Health Organisation’s (WHO) “Guidelines for assuring the quality, safety, and efficacy of plasmid DNA vaccines” is regarded as a basic “overarching” guideline applicable for the development of RNA-based vaccines. However, a separate WHO guideline, “points to consider for assuring the quality, safety and efficacy of RNA vaccines” is currently being drafted.

Hinz et al. carried out an extensive review of the European regulatory environment for mRNA-based vaccines, highlighting the different regulatory paths specified for prophylactic infectious disease and therapeutic applications. Despite application disparities, almost all mRNA-based medicines, and explicitly mRNA-based vaccines with the use of recombinant DNA technology processes, must be authorised via centralised procedure. Regulation of clinical development is however the responsibility of the National Regulatory Authority (NRA) [4].

Regulatory considerations for the development of mRNA-based vaccines

The regulatory pathway for the approval of mRNA-based vaccines may not change drastically in the coming years, however specific regulatory issues with respect to manufacture, quality, safety and efficacy will require more stringent guidelines. With this, it becomes important to consider certain regulatory aspects which influence transition through clinical development. These are broadly displayed below in Figure 2.

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With recent progression in mRNA technology, there still however remains certain issues of practicality regarding mRNA vaccine development, specifically in relation to the reactogenicity of RNA, RNA stability, potential toxicity and tissue distribution concerns. To combat these there is currently a strong emphasis on manufacturing and quality controls, and pre-clinical immunogenicity and safety studies. From a clinical perspective, early-phase clinical trials must be designed to capture the immune activation response. Characterization of this immune response in parallel with immune safety monitoring must also be implemented [1]. This will lead the way to gaining reliable early-phase human study data and begin to shift the focus from the monitoring of local and systemic tolerability to long-term safety. Pioneering companies such as BioNTech SE, Moderna Inc. and CureVac N.V. have paved the way during the race for a SARS-CoV-2 vaccine, accelerating through clinical development and in turn establishing a large safety database for novel adjuvants to assure the future safety of mRNA vaccines.

Nucleic acid vaccines, particularly mRNA-based vaccines, have shown great promise and a rapid translation into clinic in comparison with conventional vaccines, as has been demonstrated in current times tackling the COVID-19 pandemic. There is no single “platform” for infectious diseases, however several platforms may become available. In the coming years, regulatory agencies will also hopefully have the capacity to leverage existing pre-clinical data and potentially reduce non-clinical safety testing. For example, mRNA vaccines using the same delivery system may not require in-vivo biodistribution and retention studies once more data is eventually obtained [5].

Because of recent technological and regulatory advances, combined with the highly positive results from several ongoing human clinical trials against the SARS-CoV-2 virus, the outlook for the development of mRNA-based vaccines looks bright as they have cemented themselves as the most promising novel platform against emerging pandemic infectious diseases. Biopharma Excellence has been involved in assisting clients throughout all stages of vaccine development. We provide professional service to our clients by combining sound scientific knowledge on coronavirus and our experience from multiple interactions with agencies focused on the development of SARS-CoV-2 vaccines. Profit from knowledge in establishing and optimizing your development programme in accordance with the expectations of WHO, regulatory agencies, and other stakeholders from a consultancy that is willing to walk extra mile with you and do not hesitate to contact us for more information.

 References

1. Jackson, N.A.C., et al., The promise of mRNA vaccines: a biotech and industrial perspective. NPJ Vaccines, 2020. 5: p. 11.

2. Pardi, N., et al., mRNA vaccines – a new era in vaccinology. Nat Rev Drug Discov, 2018. 17(4): p. 261-279.

3. www.medicalxpress.com, German vials in spotlight as COVID-19 vaccine nears. 2020.

4. Hinz, T., et al., The European Regulatory Environment of RNA-Based Vaccines. Methods Mol Biol, 2017. 1499: p. 203-222.

5. Naik, R. and K. Peden, Regulatory Considerations on the Development of mRNA Vaccines. Curr Top Microbiol Immunol, 2020.