Messenger RNA vaccines
While the immunostimulatory effects of RNA have been known for nearly 60 years, the possibility of using direct in vivo administration of in vitro transcribed messenger RNA (mRNA) as a means to temporarily introduce genes expressing proteins (including antigens) was demonstrated in 1990 following direct injection of “naked” nucleic acids. Subsequent improvements to stabilize mRNA, to increase the feasibility to manufacture RNA-based products and to decrease RNA-associated inflammatory responses have led to significant advances in the development of mRNA vaccines and therapeutics. There are several reasons that the mRNA platform technology has emerged at the forefront as a vaccine technology. Among these are the rapid speed at which mRNA candidate vaccines can be constructed and manufactured and the necessity to rapidly develop vaccines against newly emergent pathogens, such as emerging influenza virus strains, Zika virus, and most recently SARS-CoV-2, the causative agent of Coronavirus disease (COVID-19).
The global research and development of mRNA vaccines have progressed rapidly in the past few years, with a substantial impetus and major accomplishments occurring following the onset of the COVID-19 pandemic. The authorization/approval of COVID-19 mRNA vaccines and their deployment during the COVID-19 pandemic have provided remarkable proof of concept of the capabilities and feasibilities of mRNA vaccines for human protection. The potential of mRNA vaccine as a technology to rapidly respond to public health emergencies of infectious diseases, in addition to application for prophylactic vaccines for additional infectious diseases, have underscored the need for international regulatory convergence for RNA vaccines.
mRNA Vaccine Standardization
Written standards
During the informal WHO consultations for guidelines for DNA vaccines in 2018 and 2019, it was agreed that a separate document was needed for mRNA vaccines. The rationale was that despite both being nucleic acid vaccines, sufficient differences existed in terms of their manufacturing & control and potential nonclinical & clinical issues, and that there was, at that time, considerably less clinical experience with mRNA technologies. The WHO Expert Committee on Biological Standardization (ECBS) discussed these issues at its meetings in August and December 2020 and supported the development of a document on regulatory considerations for the evaluation of mRNA vaccines, which could be updated as more scientific and clinical data became available. WHO initiated activities in 2020 to review scientific and regulatory issues of mRNA vaccines and set up a drafting group and convened series of experts and public consultations to develop the regulatory considerations for the evaluation of mRNA vaccines. At the 74th meeting of WHO ECBS held during 18–22 October 2021, the Committee adopted the final document- “Evaluation of the quality, safety and efficacy of messenger RNA vaccines for the prevention of infectious diseases: regulatory considerations”. The scope of this document is limited to mRNA and self-amplifying mRNA, packaged in lipid nanoparticles, for in vivo delivery of the coding sequences of a target antigen relevant to active immunization for the prevention of an infectious disease. This document provides information and regulatory considerations regarding key aspects of the manufacture and quality control, and nonclinical and clinical evaluation, of preventive mRNA vaccines against infectious disease for human use.
It should be noted that there remain gaps in the scientific understanding of the types and amount of immunogenicity that any given mRNA vaccine might need to achieve for it to be successful, broadly relevant and durably efficacious against the disease it is intended to prevent. Each vaccine will therefore need to be evaluated in terms of its own benefits and risks.