APR January/February 2022 - 71

« FORMULATION AND DEVELOPMENT
Although mRNA technology has been in development for more than
30 years, it was the current pandemic that spurred the translation of
the largely theoretical benefits of mRNA technology into the current
reality of mRNA-based vaccines that have likely saved millions of lives.
In this article, we will provide an overview of this promising technology
platform in the new era of vaccine and therapeutic drug development.
Introduction to Nucleic Acid Vaccines
Conventional vaccines require an antigen to be injected into the
body to induce an immune response in the host. In contrast, mRNA
vaccines use a piece of ribonucleic acid that corresponds to a viral
protein to direct cells to produce copies of that viral protein, which
triggers an immune response. Since recipients are not exposed to
the actual live virus in mRNA vaccines, they cannot become infected
through vaccination.
This innovative platform represents a promising alternative to
conventional approaches in vaccine research and development,
as well as potential revolutionary breakthroughs in therapeutic
medicine. Currently, there are several investigational mRNA-based
vaccine candidates in early-stage clinical development that target
various indications and therapeutic areas, including both preventative
and therapeutic settings.
Advantages and Disadvantages of
mRNA Vaccines
One of the greatest advantages of mRNA over conventional vaccines
is the relatively simple manufacturing process that can rapidly
be scaled to respond to epidemics. The mRNA backbone of these
vaccines remains constant - only the coding region of the vaccine is
changed to address different indications. Once the genetic sequence
of a virus is understood, the coding region of the mRNA backbone
can be rapidly adjusted to encode for the new pathogen. This process
accelerates research and development along with a faster response
to novel threats and efficient, large-scale standardized production.
In addition, production is based on an in vitro cell-free transcription
reaction, which minimizes the risk of cell-derived impurities and viral
contaminants that are often found in other vaccine platforms.1
Another advantage is the ability to mimic various aspects of a natural
viral infection once it enters the cells. Upon cell entry, mRNA produces
viral antigen proteins from within the cells that include natural, posttranslational
modifications that imitate the occurrence of a natural
viral infection. These endogenously produced viral proteins elicit
an enhanced immune response, including stronger B- and T-cell
responses than are seen with traditional protein subunit vaccines.2
Additionally, multiple mRNAs encoding for multiple viral proteins can
be included in a single vaccine, permitting the production of complex
multimeric antigens.
Cost and sustainability of the manufacturing process are the two
leading downsides to the use of this technology. Today, the materials
required for the in vitro transcription enzymatic reaction used to
generate mRNA are expensive and limited. Further, downstream
processing of the vaccine - including mRNA purification steps -
remains difficult to scale and is costly.3 The use of new production
methods such as continuous manufacturing, the reuse of scarce/
high-cost ingredients/compounds and high-throughput purification
methods should mitigate most of these concerns in the future.
The storage of mRNA drug products also remains a concern. There is
little published data on the stability and storage of formulated mRNA
drug product stability (i.e., LNP-mRNA and protein-mRNA complexes).4
For example, the current stability profile of authorized and approved
COVID-19 vaccines requires cold-chain storage, ranging from around
-70 degrees Celsius to -20 degrees Celsius during shipping, and from 2
degrees Celsius to 8 degrees Celsius when diluted for administration.
This is a clear competitive disadvantage in the marketplace and limits
the viability of these vaccines in many regions of the world. Future
generations of mRNA vaccines will need to incorporate changes in
formulation and manufacturing processes to move away from freezing
conditions for long-term storage.
mRNA Vaccine Safety
The safety of vaccine recipients is paramount, and as such remains the
top priority for the development of any vaccine.5 Even after a vaccine is
licensed and recommended for use, health agencies require collection
and monitoring of real-world data (RWD) on safety and effectiveness
across a wide variety of people with diverse characteristics including
age, ethnic background, gender and underlying medical conditions.
Worldwide, cross-pharma and public-private partnerships and
collaborations have been launched to monitor for SARS-CoV-2
variants of concern and to help answer questions relating to longterm,
brand-specific COVID-19 vaccine safety and effectiveness.6
This includes the duration of protection and the benefit of additional
vaccine doses, as well as their interchangeability in real-life settings.
For health authorities to provide guidance and recommendations
about risks and benefits of COVID-19 vaccination, this scientific
information is essential.
In general, mRNA vaccine technology combines the advantages of
live-attenuated vaccines, such as endogenous antigen expression
and T-cell induction, with the outstanding safety profile of inactivated
or protein subunit vaccines. It promotes both humoral and cellular
immune response and induces the innate immune system.
Unlike attenuated or inactivated vaccines, mRNA is precise. It only will
express a specific antigen and induce a directed immune response.
Additionally, expression of the coded antigens is transient since mRNA
is quickly degraded by cellular processes, with no traces found after
two to three days. As a result, the risk of random genome integration is
virtually zero, unlike the theoretical risk of DNA vaccines.
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APR January/February 2022

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