mRNA Technology Development And Three Major Applications In Future

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mRNA Technology: Development And
Three Major Applications In Future

The mRNA technology might be new to the public, however, this is an innovation that
researchers have been wagering on for a long time. It not only shows the potential to be
very safe and effective for SARS-CoV-2, but also shows hope for other infectious
diseases.

From mRNA discovery to mRNA vaccine

The idea of mRNA was first conceived by Sydney Brenner and Francis Crick on 15 April
1960 at King's College, Cambridge. During the summer of 1960, Brenner, Jacob, and
Meselson conducted an experiment in Meselson's laboratory at Caltech which established
the existence of mRNA. From the first successful extraction of mRNA in 1960, to today's
epoch-making COVID-19 mRNA vaccine by modifying mRNA, this technology is taking on
great significance at an unexpected speed.

The story of mRNA vaccines traces back to the early 1990s when Katalin Karikó, a
researcher from the University of Pennsylvania, began testing mRNA technology as a
form of gene therapy. In 1990, researchers at the University of Wisconsin in the United
States discovered that injecting mRNA into the muscle tissue of mice can have a
therapeutic effect. These findings laid the foundation for the emergence of RNA vaccines.
There are many essential discoveries that led to the establishment of the RNA therapy
field. Since then, countless studies and experiments that have flourished over the years
led to the flourishing potential of mRNA technology now.

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Figure 1. Timeline of Key Discoveries in RNA Therapy

The first mRNA-based COVID-19 vaccine

By the end of 2019, 15 candidate mRNA vaccines for infectious diseases had entered
clinical trials. At that time, it was believed that it would take at least 5-6 years for mRNA
vaccines to obtain regulatory approval. But those expectations were upended when the
COVID-19 pandemic overtook the world in early 2020. In the next few months, the
development, manufacturing and deployment of mRNA vaccines have entered a stage of
rapid leapfrogging.

As of June 18, 2021, 185 COVID-19 vaccine candidates were in the preclinical
development stage, and another 102 had entered clinical trials. Of those in clinical trials,
19 were mRNA vaccines. On December 11, 2020, Pfizer–BioNTech vaccine
BNT162b2 received emergency authorization from the FDA and became the first mRNA
drug approved for use in humans. The vaccine was the first COVID-19 mRNA vaccine to
be authorized by a stringent regulatory authority for emergency use and the first cleared
for regular use. A week later, Moderna vaccine mRNA-1273 was also authorized for use

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in the United States. Ultimately, they were the first SARS-CoV-2 vaccines authorized in
the United States, the United Kingdom, Canada, and several other countries.

clinical trials of mRNA vaccines against infectious disease beyond COVID-19

In addition to COVID-19 vaccines, which
vaccines are also used the mRNA technology?

According to an article published by the Boston Consulting Group in a magazine on
September 2, as of July 31, 2021, global mRNA companies have 180 products under
development, of which 76 are prophylactic vaccines, 32 are therapeutic vaccines and 72
are therapeutic drugs. Among the 76 prophylactic vaccines, 22 are COVID-19 vaccines,

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and 40 are vaccines for other infectious diseases. 21 of the 32 therapeutic vaccines are
tumor vaccines, including 16 single cancer vaccines and 5 personalized tumor vaccines.
Of the 72 therapeutic drugs, 13 are for cancer treatment, 20 are for rare diseases, and 17
are for respiratory diseases. This means that mRNA technology is probably used in
three major areas—prophylactic vaccines, therapeutic vaccines and therapeutic
drugs.

Current profile of the mRNA technology pipeline (Source: Nature Reviews Drug
Discovery)

Three major applications of mRNA technology

Vaccines and drugs based on mRNA technology currently being developed can be
divided into three major application directions according to their potential mechanisms of
action: prophylactic vaccines, therapeutic vaccines and therapeutic drugs. The main field
of diseases involved are oncology, autoimmunity and respiratory system.

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1. Prophylactic vaccines

Prophylactic vaccines will continue to dominate the mRNA field in the next 15 years,
because prophylactic vaccines currently have a large number of research and
development pipelines, higher probability of success (POS), and the advantages of mRNA
over other vaccine technologies.

The current mRNA industry R&D activities are also mainly focused on prophylactic
vaccines. 77% of mRNA companies have at least one preventive vaccine in R&D stage. In
the short term, most of the preventive vaccine revenue will still come from COVID-19
products, while in the medium and long term, other vaccines against diseases such as
respiratory syncytial virus and influenza may cover a wider range of people.

Although the competition for vaccines may be very fierce, mRNA has obvious advantages
over other technologies in terms of speed of development, at least in terms of the
protection against COVID-19. Therefore, it is expected that preventive mRNA vaccines
will win a larger market share than other technical types of vaccines.

2. Therapeutic vaccines

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Therapeutic vaccines are likely to be a niche space for mRNA products, but due to the
size of the patient population and the possible dominant position in therapies for multiple
tumor-associated antigens, they have huge market potential. However, the clinical,
regulatory and manufacturing risks in this area are still high.

The development of mRNA therapeutic vaccines is currently mainly focused on
immuno-oncology (IO), and candidate vaccines can be classified according to whether
they target a single or multiple antigens.

Single-antigen vaccines offer a new way to target difficult-to-treat drug targets. If
successful, they may gain high value in a relatively small patient population. Practitioners
in the development of single-antigen vaccines include mRNA-5671 for KRAS mutant
cancers developed by Moderna/Mersk and BNT113 for HPV-16+ cancers developed by
BioNTech, both in Phase I. However, although peptide vaccines are in the early stages of
development, they may bring competitive pressure to mRNA vaccines.

Currently, most mRNA therapeutic vaccines (19 out of 26 known targets) are multi-antigen
vaccines, such as personalized cancer vaccines (PCV), where mRNA vaccines is superior
to peptide vaccines. Personalized cancer vaccines provide preliminary safety and efficacy
data, such as Moderna's mRNA-4157 as a monotherapy and in combination with
pembrolizumab.

3. Therapeutic drugs

Therapeutic drugs will be the opportunistic field of mRNA products, involving multiple
indications, but compared with other therapies, whether it has clinical advantages is still
unclear, and there are also higher clinical risks. Long-term opportunities will depend on
technological advances in areas such as delivery systems and gene editing.

For protein replacement therapies, mRNA platforms may have delivery advantages over
standard recombinant protein strategies in some cases, but there is no clear solution to

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the technical challenges faced in the near future, including the lack of organ selectivity
and the potential demand for frequent delivery and high immunogenicity. Initially, as
therapeutic drugs utilize the immune system, for example, mRNA encoding bispecific
antibodies binds to CD3 on T cells and target antigens on tumor cells, which may limit
mRNA therapy to address a subset of oncology indications. For genetic diseases and rare
diseases, mRNA therapy may need to compete with gene therapy. The latter is already in
a more advanced stage of clinical trials for genetic diseases and can provide patients with
a more continuous supply of therapeutic protein.

In the short term, the mRNA market is only supported by COVID-19 vaccines, and is
estimated to exceed US$50 billion in 2021 in the market. Between 2023 and 2025, a
decline is expected due to reduced demand for COVID-19 vaccines in major markets and
lack of new product launches, while enhanced injections and wider global use may
support sales of approximately US$20 billion in this segment of mRNA technology. As
other prophylactic mRNA vaccines and therapeutic mRNA vaccines enter the market, the
market sales is expected to rebound from 2028 and reach US$23 billion by 2035. It is
expected that prophylactic vaccines will remain the cornerstone of the mRNA field, with a
market share of more than 50% by 2035. Therapeutic vaccines for cancer are about 30%,
while the proportion of therapeutic drugs is less than 20%.

It is expected that with the advancement of science and the development of technology,
mRNA technology will be used more widely. As a leading PEG supplier, Biopharma
PEG supplies a variety of high purity PEG derivatives, PEG linkers and ADC linkers to
empower drug research & development. We supply some PEG products as ingredients
used in COVID-19 vaccines. For more information, please visit website at PEGs for
COVID-19 Vaccines.

References:
[1] Diverse Applications of mRNA Technology
[2] mRNA vaccines for infectious diseases: principles, delivery and clinical translation

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[3] Evolution of the market for mRNA technology

Related article:
[1] mRNA Technology: Current Trends and Prospects
[2] Lipid Nanoparticles: mRNA Therapies' Golden Partner