Development of an mRNA vaccine against COVID-19

Introduction

mRNA encapsulated in lipid nanoparticles (LNP-mRNA) has become a new type of vaccine platform based on evidence of de facto clinical efficacy and safety and manufacturing capability, as demonstrated by two leading products against COVID-19 under emergency use authorization. Compared to conventional vaccine modalities such as inactivated and protein-based vaccines, the lead time for LNP-mRNA vaccine development is generally shorter once the optimization of antigen and the formulation has been streamlined [1]. Since mRNA is a fragile molecule and LNP-mRNA is structurally complex, further approaches are currently focused on acquiring a more effective and stable formulation. The aim of this AMED project is to obtain marketing authorization for a new type of LNP-mRNA vaccine against COVID-19.

Antigen Sequence of LNP-mRNA Vaccine for COVID-19

The spike protein (S protein) expressed on the surface of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to play a critical role in infection. It is composed of two subunits, S1 and S2, with a receptor binding domain (RBD) in the S1 subunit directly interacting with one of the host receptors, angiotensin-converting enzyme 2 [2]. Among several different antigen sequences that we originally designed DS-5670. As for LNP-mRNA production, original technology developed by Daiichi Sankyo Co, Ltd was adopted.

DS-5670 has four competitive characteristics as shown below.

• Efficient encapsulation of mRNA in LNP

• High transfection efficiency of mRNA into cells

• Low toxicity due to a novel cationic lipid

• Druggable and eligible for in-house production

Taking advantage of these characteristics, we were encouraged to develop an LNP-mRNA vaccine with a superior product profile.

Phase 1/2 Study

The Phase 1/2 study was a randomized, placebo-controlled, double-blind, dose-escalation study to assess the safety, immunogenicity and recommended dose in healthy Japanese adult (20 years or older and under 65 years) and healthy Japanese elderly (65 years or older and under 75 years) subjects.

Manufacturing of Lipid Nano Particle-mRNA

To quickly manufacture the investigational drug, subsidiary companies of Daiichi Sankyo Co., Ltd. specialized in each function were used to establish the manufacturing system. Regarding the preparation of template DNA for mRNA synthesis, a group company in Germany was utilized in order to speed up the handling of recombinant microorganisms. As for mRNA synthesis and the formulation of LNP-mRNA, functions of each subsidiary company with the technological capabilities of API manufacturing, drug product manufacturing, or filling were utilized. By closely linking process development and manufacturing, the investigational drug product DS-5670 for the Phase 1/2 study was able to be produced in a timely manner.

Efforts toward Practical Application

Currently, the Phase 1/2 trial is ongoing, and the design of Phase 2 and Phase 3 clinical trials as well as a study plan for novel SARS-CoV-2 variants are being discussed with the PMDA.

With the support of AMED and the Ministry of Health, Labour and Welfare, production equipment is rapidly being introduced and launched at our vaccine plant in DSBT. We are planning to establish production at a rapid pace for the swift and stable supply of COVID-19 vaccine in the near future.

Acknowledgment

This work is supported by the AMED and MHLW for the development and production of a COVID-19 vaccine.

References

• 1.   Pardi,  N.,  Hogan,  M. J.,  Porter,  F. W. and  Weissman,  D. 2018. mRNA vaccines-a new era in vaccinology. Nat. Rev. Drug Discov. 17: 261–279.
• 2.   Shang,  J.,  Wan,  Y.,  Luo,  C.,  Ye,  G.,  Geng,  Q.,  Auerbach,  A. and  Li,  F. 2020. Cell entry mechanisms of SARS-CoV-2. Proc. Natl. Acad. Sci. USA 117: 11727–11734.