Next-Generation mRNA Vaccines: A Breakthrough in Medical Science
Explore the revolutionary world of next-generation mRNA vaccines in our latest blog post, 'Next-Generation mRNA Vaccines: A Breakthrough in Medical Science.' Delve into the transformative potential of this technology, from its pivotal role in combating COVID-19 to its promising applications in treating a wide array of diseases. Discover how decades of scientific research have culminated in this breakthrough, and how it's reshaping the future of medicine and vaccine development.
1) Introduction
mRNA vaccines are a novel form of
vaccination that employs a molecule known as messenger RNA (mRNA) to stimulate
an immune response. Unlike conventional vaccinations, which deliver weakened or
dead bacteria or viruses to the body, mRNA vaccines provide a fragment of mRNA
corresponding to a viral protein. This mRNA never enters the nucleus and has no
effect on DNA. Once inside the body's cells, the mRNA tells them to create the
viral protein. This protein is recognized as foreign by the immune system, and
antibodies are produced to combat it. These antibodies stay in the body, ready
to react promptly if the individual is exposed to the virus again. Currently,
the only mRNA vaccines that are authorized or recommended are for COVID-19.
a) History and Evolution of mRNA
Vaccines
The history and evolution of mRNA
vaccines span several decades, beginning with the discovery of Messenger RNA
(mRNA) in the early 1960s. In the 1990s, mRNA was utilized to induce mouse
cells to produce a protein, which was the first step toward developing an mRNA
vaccine. In 1992, rats were given mRNA coding for vasopressin, which alleviated
their symptoms of diabetes insipidus. These observations led to the notion that
a live animal's cells may produce a viral or bacterial protein, which the
animal's immune system would subsequently react to.
The intrinsic instability of
mRNA, on the other hand, posed a problem. mRNA is a big molecule that is
fundamentally unstable and susceptible to nuclease breakdown. It also gets the
immune system going. Despite these obstacles, research into delivering mRNA
into cells persisted until the 2010s.
Karikó and colleagues discovered
in 2005 that mRNA generated using modified uridine might resist identification
and breakdown by the immune system, dramatically improving mRNA stability and
immunogenicity in vivo and ushering in a new era in mRNA vaccine development.
Several firms were working on
mRNA vaccines with very steady delivery mechanisms at the time the Coronavirus
Pandemic hit. Moderna and BioNTech, two once-obscure firms, had spent decades
developing RNA-based medications and vaccines until COVID-19 provided them with
the opportunity to put all of their research to use in patients.
The advancement of mRNA
technology enables quick reprogramming of the coding sequence to adjust the
vaccine's immunological response. This adaptability has proven critical in
adapting to novel viral types, such as the Omicron strain. In response to this mutant
variation, both Moderna and Pfizer-BioNTech modified their mRNA vaccines.
The mRNA vaccines introduced the
COVID-19 spike protein blueprints, which are subsequently displayed on cells to
familiarize the immune system with the foreign protein. The interaction of the
mRNA protein product with the immune system helps the body to prepare for
COVID-19 viral infection by producing neutralizing antibodies that prevent the
virus from binding to the human ACE2 receptor and infecting cells.
Years of research and development
have resulted in the effective production of mRNA vaccines. In recent years,
mRNA vaccines for many infectious illnesses such as rabies, influenza, Ebola,
Zika, and dengue virus have entered preclinical research or clinical trials.
The future of mRNA vaccines seems
bright, with continuous research and development targeted at providing
widespread and long-lasting protection against a variety of illnesses. The
ultimate objective is to do away with the necessity for annual immunizations.
The emergence of mRNA vaccines demonstrates the strength of scientific
innovation and the technology's potential to change the area of vaccination.
mRNA vaccines operate by
transferring mRNA into the cells of the body. This mRNA contains the
instructions for producing a protein present on the surface of a particular
virus. Once these proteins are produced by the cells, the immune system detects
them as alien and creates antibodies against them. These antibodies then stay
in the body, ready to respond if the individual is again exposed to the virus.
Because mRNA vaccines do not contain any viruses, they cannot infect people.
They also have no effect on a person's DNA.
c) mRNA Vaccines vs Traditional
Vaccines
mRNA vaccines and regular
vaccinations activate the immune system in distinct ways. Traditional
vaccinations provide weakened or dead germs or viruses into the body, whereas
mRNA vaccines deliver a portion of mRNA that instructs the body's cells to
manufacture a viral protein, eliciting an immune response.
Unlike live-attenuated or viral-vectored
vaccinations, mRNA vaccines are non-infectious and offer no risk of DNA
integration. In addition, unlike protein-based or inactivated vaccines, they do
not require chemicals or cell cultures to be manufactured, reducing the
possibility of contamination with harmful substances. Immune responses to mRNA vaccines have been
found to be extremely effective. Recent advancements in mRNA technology have
enhanced mRNA molecules' stability and distribution efficiency, resulting in a
more effective immune response. Because
mRNA vaccines can be produced and ramped up fast, they are very adaptable to
diverse diseases. The manufacturing method is not dependent on sequencing,
allowing for quick adaption to novel illnesses. The cost of generating mRNA
vaccines is also cheaper than that of other platforms, and it is likely to fall
as technology advances. Because mRNA vaccines can be created and manufactured
more quickly than conventional vaccines, they are an excellent alternative for
reacting to emerging infectious illnesses and novel variations of established
ones. In conclusion, mRNA vaccines have various advantages over conventional
vaccinations, including increased safety, effectiveness, and speed of
manufacture. These advantages make mRNA vaccines a viable platform for treating
a variety of infectious illnesses, and they have already demonstrated
effectiveness in the creation of COVID-19 vaccines.
2) mRNA Vaccine Development
and Delivery Systems
In the pharmaceutical area, mRNA
vaccines are a promising method, particularly in the production of personalized
tumor vaccines. They are third-generation nucleic acid vaccines based on
first-generation attenuated/inactivated vaccines and second-generation subunit
vaccines. The goal of mRNA vaccines is to transfer RNA to cells for translation
and subsequent creation of protein antigens in order to elicit an immunological
response against the antigen and therefore enhance the body's immune
capability.
The SARS-CoV-2 outbreak has
fueled the development of mRNA vaccines, with two mRNA vaccines, mRNA-1273 and
BNT162b2, now on the market. However, hurdles to the development of mRNA
vaccines include their safety, cellular transport, uptake, and reaction to
their manufacture, logistics, and storage.
The main issue that has to be
addressed right now is the low stability and easy breakdown of mRNA molecules.
As a result, the primary difficulty in developing mRNA vaccines is maximizing
stability and delivery mechanisms, which may be handled through rational
molecular design. The efficient entrance of mRNA vaccines into human cells is a
difficult procedure. Naked mRNA, being an exogenous nucleic acid, is quickly
identified by the immune system and swiftly destroyed by nucleases once it
enters the body. As a result, specific delivery mechanisms are needed to
protect injected mRNA from nucleases while yet allowing distribution into
cells.
a) Advantages of mRNA
Vaccines
Because they cannot penetrate the
nucleus, mRNA vaccinations are non-infectious and offer no danger of DNA
integration. As a result, they are less dangerous than live-attenuated or
viral-vectored vaccinations. mRNA vaccines breakdown quickly in the body, and
cells do not readily accept foreign mRNA. Recent science, however, has changed
the mRNA molecule to make it more stable and wrapped the molecules in fats
(known as lipids), enhancing cell transport efficiency. This increases the
effectiveness of the immunological response.
mRNA vaccines may be created and scaled up fast. Because the
manufacturing process is sequence-independent, it is very adaptive to various
infections. The price is also cheaper than on other platforms and will continue
to fall as technology advances. Because mRNA vaccinations do not require
nuclear transcription, there is no risk of integration into the host genome.
This gives DNA vaccinations a major edge.
mRNA vaccines retain the properties of DNA vaccines, such as the ability
to express intracellular antigens, while overcoming the drawbacks of limited
immunogenicity and probable non-specific immunity against the vector.
b) Disadvantages of mRNA Vaccines
Side effects of mRNA vaccinations
include allergies, renal failure, cardiac failure, and infarction. Following
vaccination with either mRNA vaccine, the most common side effects were
headache, tiredness, pyrexia, dizziness, nausea, pain, chills, and pain in
extremities. The vaccine mRNA may be rapidly destroyed after injection,
limiting its usefulness. mRNA vaccines
have the potential to trigger cytokine storms, which are immune system
overreactions. mRNA vaccines require strict storage and transit conditions,
which might limit their global availability.
Despite mRNA vaccines' relatively straightforward manufacturing method,
there are still hurdles and bottlenecks in large-scale production, including a
lack of well-established and cost-effective technologies. To summarize, while
mRNA vaccines have some advantages over regular immunizations, they also have
certain drawbacks. However, continuing research and technical advances are
tackling these problems in order to enhance the safety, effectiveness, and accessibility
of mRNA vaccines.
c) Molecular Design of mRNA
Vaccines
The molecular design of mRNA
vaccines is a complicated process including numerous fundamental components,
each of which is critical to the vaccine's efficacy. mRNA is made up of a 5'
cap, 5' untranslated regions (UTRs), an open reading frame (ORF), 3' UTRs, and
a poly(A) tail.
The 5' cap is a modified
nucleotide found at the 5' end of several primary transcripts, such as
precursor messenger RNA. This process, known as mRNA capping, is highly
controlled and essential for the production of stable and mature messenger RNA
capable of translation during protein synthesis. The 5' cap is made up of a
guanine nucleotide that is linked to mRNA via a unique 5' to 5' triphosphate
connection. A methyltransferase methylates this guanosine on the 7 site right
after capping in vivo. It is known as a 7-methylguanylate cap, abbreviated as
m7G.
The 5' and 3' untranslated
regions (UTRs) are mRNA domains that regulate post-transcriptional gene
regulation. The 5' and 3'UTRs, which are transcribed but seldom translated,
include a plethora of regulatory elements involved in pre-mRNA processing, mRNA
stability, and translation initiation.
The open reading frame (ORF) is a
section of mRNA that is translated into a protein. It is made up of a signal
peptide sequence and a protein-encoding sequence. In the case of COVID-19
vaccines, for example, the ORF encodes the spike protein of the SARS-CoV-2
virus.
The poly(A) tail is a lengthy
adenine nucleotide sequence that is added to a messenger RNA (mRNA) molecule
during RNA processing to boost the molecule's stability.
Despite advances in mRNA vaccine
technology, further work is needed to improve the molecular designs of mRNA
molecules for higher protein expression and structural stability. This includes
the creation of delivery mechanisms to ensure successful vaccination delivery.
Because of their fragility, high
intrinsic immunogenicity, and limited in vivo delivery efficiency, mRNA
vaccines have gotten little funding. However, because to technical advances in
modified nucleotides and delivery vehicles, mRNA vaccines have advanced
swiftly, and several clinical studies have been conducted.
The advantages of mRNA vaccines
are their great safety, efficiency, and yield. Several attempts have been made
to change the structure of IVT mRNA in order to increase its intracellular
stability and translational efficiency.
d) Delivery Systems for mRNA
Vaccines
Because of their easy
manufacturing method, superior safety ratings to DNA vaccines, and the capacity
of mRNA-encoded antigens to be rapidly produced in cells, mRNA vaccines have
emerged as a potential alternative to vaccination. However, delivering mRNA
vaccines into human cells is a difficult task. As an exogenous nucleic acid,
naked mRNA is quickly identified by the immune system and swiftly destroyed by
nucleases after entering the body, significantly reducing the pharmacological
effects of employing naked mRNA as a vaccine. As a result, specific delivery
mechanisms are needed to protect injected mRNA from nucleases while yet
allowing distribution into cells.
Lipid nanoparticles (LNPs) are
one of the most sophisticated delivery technologies for mRNA vaccines. LNPs
carry mRNA into cells, preserve it from destruction, and boost immunological
responses. LNPs were employed in the development of two mRNA-based vaccines,
BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), which have been granted
emergency use authorization (EUA) by the US-FDA to prevent SARS-CoV-2 induced
COVID-19. These vaccines include mRNA encoding the SARS-CoV-2 spike protein,
which is converted into the spike protein once delivered into the cytoplasm,
resulting in an immunological response.
The LNPs utilized in these
vaccines are made up of structural lipids, which are often phospholipids and
cholesterol, as well as a PEG-lipid. These lipids serve to stabilize the
particles, manage their size, and ensure blood compatibility. However, for successful
mRNA distribution, their chemical characteristics and concentrations must be
modified. The PEGylated lipid slows the opsonization process, preventing
phagocyte absorption and lengthening their circulation time in the blood.
Cholesterol and distearoylphosphatidylcholine (DSPC) aid in drug incorporation
into LNPs.
LNPs serve as adjuvants and
contribute to vaccination reactogenicity in addition to delivering mRNA.
Adjuvants are necessary for optimum antigen-specific immune responses, yet they
are frequently a source of reactogenicity, which leads to local and systemic
inflammation. Because the mRNA in these vaccines is not immunogenic, it cannot
work as an adjuvant. Instead, it appears that the LNP administration activates
the innate immune system and acts as an adjuvant. The adjuvanticity of LNP-mRNA
vaccines appears to be more complicated than previously anticipated, and
additional research into immunization techniques and their built-in
adjuvanticity is required to increase the immunogenicity and lower the
reactogenicity of LNP-mRNA vaccine formulations.
3) Types of mRNA Vaccines
a) Non-amplifying/Conventional
mRNA Vaccines
Non-amplifying or standard mRNA
vaccines, such as the Pfizer-BioNTech and Moderna COVID-19 vaccines, are a form
of vaccination that instructs cells in the body to manufacture a viral protein
that stimulates an immune response. This immune reaction, which includes the
development of antibodies, prepares the body to fight the virus if it is
encountered again in the future.
A standard mRNA vaccination is
made out of an open reading frame (ORF) that encodes the antigen of interest.
This ORF is bordered on both sides by untranslated regions (UTRs), and the mRNA
molecule ends with a poly(A) tail. The UTRs and poly(A) tail are critical for
the mRNA molecule's stability and translation.
After being delivered, the mRNA
vaccine penetrates the cells and uses the cell's protein-making machinery to
make the viral protein encoded by the ORF. This viral protein is then presented
on the cell surface, where it is identified as foreign by the immune system.
This initiates an immunological response, including the development of
antibodies against the viral protein. If the individual is later exposed to the
virus, these antibodies will detect and attach to the viral protein,
neutralizing the virus and preventing it from infecting cells.
Conventional mRNA vaccines
include the Pfizer-BioNTech and Moderna COVID-19 vaccines. These vaccinations
have been demonstrated to be very successful in preventing COVID-19, with
studies indicating that they are at least 90% effective in fully immunized individuals.
One of the benefits of mRNA
vaccines is that they can be made rapidly and easily. They also pose no chance
of producing the sickness they are meant to prevent since they only contain a
portion of the virus's genetic material rather than the entire virus.
Furthermore, unlike DNA vaccines, mRNA vaccines do not need entry into the
cell's nucleus and hence do not pose the risk of integrating into the cell's
DNA.
b) Self-amplifying mRNA Vaccines
Self-amplifying mRNA vaccines
(saRNA vaccines) are a form of mRNA vaccination generated from
positive-stranded RNA viruses. Self-amplifying mRNA vaccines contain the viral
replication machinery, as opposed to traditional mRNA vaccines, which have a
single open reading frame (ORF) that encodes the antigen of interest. This
permits the mRNA to proliferate within the cells, resulting in more antigen
synthesis and, as a result, a greater immunological response.
A self-amplifying mRNA vaccine's
structure comprises not only the ORF that encodes the antigen of interest, but
also other ORFs that encode viral replication machinery. The viral
RNA-dependent RNA polymerase, which is capable of duplicating the mRNA molecule
within the cell, is part of this replication machinery. As a result, each cell
that accepts the mRNA vaccination may create several copies of the mRNA,
resulting in increased antigen production and a greater immune response.
Self-amplifying mRNA vaccines
offer the flexibility of plasmid DNA vaccines while improving immunogenicity
and safety. They can be made fast and easily, and they pose no danger of
causing the disease they are meant to prevent. Furthermore, unlike DNA vaccinations,
self-amplifying mRNA vaccines do not need entry into the nucleus and hence do
not pose the risk of integrating into the cell's DNA.
However, effective transport of
the mRNA to the cytoplasm of a cell, where it can multiply and produce the
encoded antigenic protein, is critical to achieving the full potential of these
vaccines. This necessitates the creation of efficient delivery methods, which
is a significant focus of current research.
In preclinical testing,
self-amplifying mRNA vaccines produced significant and robust innate and
adaptive immune responses in small animals and nonhuman primates. If the
promising preclinical evidence with self-amplifying mRNA vaccines is followed
by similarly excellent immunogenicity, potency, and acceptability in human
trials, this platform might establish nucleic acid vaccines as a flexible new
tool for human vaccination.
4) mRNA Vaccine Trials and
Applications
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a) mRNA Vaccine Trials for
Seasonal Influenza
Seasonal influenza is a major
public health hazard, infecting millions of people each year and causing
serious disease. Traditional flu vaccinations have drawbacks, such as the
requirement for yearly updating and varying effectiveness. Because of their flexibility
and speed of manufacture, mRNA vaccines are a possible option. Several mRNA
vaccines for seasonal influenza are now in clinical testing, including
Moderna's mRNA-1010.
In Phase 3 clinical studies,
Moderna's mRNA-1010 vaccine showed excellent results. Across all clinical
studies, including three Phase 3 trials, the vaccine displayed an acceptable
safety and tolerability profile. All co-primary objectives were fulfilled by
the vaccination across all four A and B strains (A/H1N1, A/H3N2, influenza
B/Yamagata, and B/Victoria). When compared to an approved comparator (Fluarix),
all four strains had higher HAI geometric mean titers and seroconversion rates.
Immunogenicity improved across all age categories, but most notably in older
persons.
mRNA-1010 also generated greater
HAI titers against A/H1N1, A/H3N2, B/Victoria, and similar titers to B/Yamagata
in a separate Phase 1/2 head-to-head trial compared to Fluzone HD. The safety
findings in this trial were comparable to earlier ones, which indicated that
the most common symptoms were muscular soreness, headache, weariness, pain, and
edema.
Researchers at the National
Institute of Allergy and Infectious Diseases' (NIAID) Vaccine Research Center
(VRC) are working on another mRNA vaccine for seasonal influenza, known as
H1ssF-3928 mRNA-LNP. This vaccine is now undergoing Phase 1 clinical studies to
determine its safety and capacity to elicit an immunological response. The
vaccine induces a wide immune response against influenza by using a particular
fragment of a viral protein, hemagglutinin (HA). Researchers seek to generate
long-term protection against a wide spectrum of flu viruses by utilizing the HA
stem as the basis for a vaccine.
Traditional flu vaccinations have
significant benefits versus mRNA vaccines. They can be conceived and made
faster than prior technology-based vaccines, which is significant since the flu
virus mutates swiftly. Matching the strains as closely as feasible to the start
of flu season might boost effectiveness. mRNA flu vaccines provide the body
genetic instructions to build parts of the flu virus, which the immune system
subsequently learns to recognize and fight when it encounters the real thing.
b) mRNA Vaccine Trials for Cancer
Because of their potential to
target specific cancer antigens, mRNA vaccines are being investigated in the
field of oncology, making them a possible option for individualized cancer
treatment. Several mRNA cancer vaccines are now in clinical testing, with
preliminary findings indicating that these vaccines can elicit a strong immune
response against cancer cells while remaining safe.
A tailored mRNA vaccination
against pancreatic cancer is one example of an mRNA vaccine being utilized to
treat cancer. A research team lead by Dr. Vinod Balachandran from Memorial
Sloan Kettering Cancer Center (MSKCC) and BioNTech created this vaccine. The
vaccine was developed to assist immune cells in recognizing certain neoantigens
on pancreatic cancer cells from patients. In a limited clinical experiment,
half of the individuals experienced a robust anti-tumor immune response. The
vaccination will soon be evaluated in a bigger clinical study, and the strategy
might potentially be used to treat other forms of fatal cancer.
mRNA vaccines provide various
benefits over traditional vaccination approaches, including high potency, quick
development, low production costs, and safe delivery. More than twenty
mRNA-based immunotherapies have advanced to the clinical trial stage, with
promising results in the treatment of solid malignancies.
BNT122, a tailored cancer vaccine
developed by BioNTech, is now in Phase 2 clinical studies for patients with
various forms of solid tumors. In clinical studies, the vaccine targeted up to
20 neoantigens and had potential anti-tumor effects. RO7198457 is another mRNA
cancer vaccine presently being evaluated in a Phase II clinical study for
patients with ctDNA-positive, resected Stage II (High Risk) and Stage III
Colorectal Cancer.
Despite the encouraging outcomes,
there are still obstacles to face. For example, mRNA cancer vaccines confront
difficulties in terms of stability, immunogenicity, and manufacturing
complexity. More research is required to determine why certain people may not
have a significant immune response to tailored vaccinations.
c) mRNA Vaccine Trials for
Genital Herpes
mRNA vaccines have showed promise
in the treatment of a variety of disorders, including genital herpes, a
sexually transmitted condition caused by the herpes simplex virus. There is
currently no cure for genital herpes, and current therapies merely assist
manage symptoms. mRNA vaccines, on the other hand, represent a novel way to
preventing and treating this illness.
mRNA vaccines have showed promise
in the treatment of a variety of disorders, including genital herpes, a
sexually transmitted condition caused by the herpes simplex virus. There is
currently no cure for genital herpes, and current therapies merely assist
manage symptoms. mRNA vaccines, on the other hand, represent a novel way to
preventing and treating this illness.
Several mRNA vaccines for genital
herpes are now being developed in preclinical trials. These vaccines are
designed to elicit a strong immune response against the herpes simplex virus.
BNT163, an mRNA vaccine developed
by BioNTech, is being tested to prevent genital herpes lesions. The Phase I
trial, which includes 108 people, assesses the vaccine's safety and
immunogenicity. The vaccine contains three HSV-2 glycoproteins designed to help
inhibit HSV cellular invasion and dissemination while also counteracting HSV
immunosuppressive effects. This study's preliminary findings are expected in
the second half of 2023. Moderna is also working on a herpes mRNA vaccine,
extending its mRNA pipeline with a vaccination against herpes simplex virus 2
(HSV-2).
Antiviral medicines, which are
now used to treat initial clinical and recurring bouts of genital herpes or as
daily suppressive therapy, can partially manage the signs and symptoms of
genital herpes. These medications, however, do not remove latent virus or
impact the risk, frequency, or severity of recurrences once the therapy is
stopped.
d) Future Prospects of mRNA
Vaccines
The success of mRNA vaccines for
COVID-19 has opened up new avenues for their application in other disorders.
mRNA vaccines are being researched for a range of infectious illnesses,
including HIV, Zika, and rabies, in addition to seasonal influenza, cancer, and
genital herpes.
Moreover, mRNA vaccines have the
potential to transform customized treatment. In oncology, for example, mRNA
vaccines may be tailored to target specific cancer antigens, allowing for a
more individualized approach to cancer treatment.
5) Challenges and
Solutions in mRNA Vaccine Development
While promising, the development
of mRNA vaccines is not without hurdles. These include mRNA stability and
degradation difficulties, manufacturing hurdles, and cold storage needs.
However, answers to these issues are being found, opening the path for the
widespread use of mRNA vaccines.
a) Stability and Degradation of mRNA
The stability of mRNA is an
important consideration in the creation of mRNA vaccines. Because
ribonucleases, enzymes found in all cells that may degrade mRNA, are present,
mRNA is intrinsically unstable and can decay fast. This instability may
restrict the vaccine's efficacy.
mRNA vaccine stability is
intimately related to mRNA structure, excipients, lipid nanoparticle (LNP)
delivery methods, and production procedures. Because of the intrinsic features
of mRNA vaccines and their interaction with lipid nanoparticles, they are significantly
unstable throughout their life cycles, affecting their efficacy and global
accessibility.
In vivo stability is mostly
connected with mRNA's intrinsic qualities, such as the optimization of the
regulatory region, coding sequence, 5′-cap, poly-A tail, and untranslated
region. Critical quality attributes (CQAs) such as mRNA integrity, fragment length,
lipid nanoparticle (LNP) particle size, and lipid composition are predominantly
linked with in vitro stability.
The mRNA molecules are modified
to boost their stability. The addition of modified nucleosides, such as
pseudouridine, for example, can aid to preserve mRNA against destruction.
Pseudouridine () has been demonstrated to stabilize mRNA. In mammalian cells,
-containing mRNAs are more stable than unmodified mRNAs with similar nucleotide
sequences generated in vitro.
Other RNA modifications have been
demonstrated to impact mRNA stability, including N6-methyladenosine (m6A),
N6,2′-O-dimethyladenosine (m6Am), 8-oxo-7,8-dihydroguanosine (8-oxoG),
5-methylcytidine (m5C), and N4-acetylcytidine (ac4C).
The use of lipid nanoparticles to
encapsulate mRNA can preserve it from degradation and boost its distribution
into cells. Lipid nanoparticles have successfully reached the clinic for the
delivery of mRNA; in particular, lipid nanoparticle-mRNA vaccines against
coronavirus illness 2019 (COVID-19) are presently in clinical use.
Lipid nanoparticles have been
widely explored and are already being used in the clinic to transport small
compounds, siRNA medicines, and mRNA. Notably, two approved coronavirus disease
2019 (COVID-19) vaccines, mRNA-1273 and BNT162b, deliver antigen mRNA via lipid
nanoparticles.
b) Manufacturing Challenges and
Solutions
Manufacturing mRNA vaccines on a
wide scale offers a number of problems, including the necessity for efficient,
repeatable, and scalable manufacturing techniques. The finished product must be
clean and devoid of impurities, which complicates the process even further.
mRNA vaccines are more cost
effective than most biologicals since they do not involve the utilization of
cell cultures. However, the manufacturing process remains complicated,
requiring many phases that must be carefully monitored and controlled. Because
the manufacturing method is not dependent on the antigen encoded in the
template, it may be standardized. As a result, the mRNA vaccine platform is
more adaptable for production. However, a well-established manufacturing
platform remains absent, and a variety of step combinations are available.
One of the most difficult issues
in the production of mRNA vaccines is the potential of contamination, notably
from ribonuclease (RNase) enzymes. RNase enzymes are ubiquitous, and RNase
contamination is the most common cause of mRNA breakdown. The presence of the
enzyme RNase can degrade product quality by destroying mRNA. While RNAses
perform a variety of important roles in the body, they can destroy the active
mRNA component in a medicinal product, compromising performance.
Automated and closed system
production procedures are being developed to solve these problems. These
technologies have the potential to improve the efficiency and repeatability of
mRNA vaccine manufacturing while simultaneously lowering the danger of contamination.
Automated systems can help to streamline processes. Manual operations with
several phases or that need many operators can be merged into a single machine
with a single operator, lowering product turnover time and the number of staff
needed in the operating space. As a result, the facility's manufacturing
capacity will rise.
Closed systems are intended to
keep the product out of the room environment. This is often accomplished by
using sterile barriers and connections, or by using single-use technologies
(SUTs) such as bioreactors and tubing. Closed systems provide several advantages
over open systems, including lower contamination risk, increased batch-to-batch
uniformity, and the flexibility to operate in a grade C manufacturing facility
rather than a more expensive grade A or grade B facility.
In addition to automated and
closed system manufacturing procedures, the use of in-process controls and
analytical methods can assist to assure product quality. At each stage of the
production process, rigorous analytics to assess mRNA quality are required.
Unrecognized quality flaws can result in decreased mRNA efficacy, poor clinical
trial outcomes, and costly delays, as well as a danger to regulatory approval.
However, mRNA vaccine analysis is still in its early stages, and a variety of
methodologies are now required to test mRNA quality, including sequence
identity, concentration, integrity, purity, and safety.
Manufacturers can limit the
danger of RNase contamination by using certified RNase-free consumables and
well-defined raw materials, minimizing manufacturing time and reducing the need
for manual processing, and maintaining high facility hygiene standards.
c) Cold Storage Requirements and
Solutions
Cold storage requirements for
mRNA vaccines, such as those produced by Pfizer-BioNTech and Moderna for
COVID-19, are mostly owing to the mRNA molecule's intrinsic instability.
Because mRNA is particularly vulnerable to RNase enzyme breakdown, it must be stored
and administered under strict sterile conditions and at low temperatures.
The Pfizer-BioNTech COVID-19
vaccine needed to be stored at -80°C at first, with a shelf life of up to 6
months. However, according to latest CDC guidelines, the Pfizer-BioNTech
vaccine can now be kept at refrigerated temperatures ranging from 2°C to 8°C
(36°F to 46°F) for up to 10 weeks.
The Moderna COVID-19 vaccine, on
the other hand, requires storage at -20°C, which is within the temperature
range of a common freezer, and may be stored in the refrigerator for up to 30
days.
These ultra-cold storage needs
provide substantial logistical issues, especially in areas with insufficient
cold chain infrastructure. This has prompted research to create mRNA vaccines
that can withstand greater temperatures. One such technique is to encapsulate
the mRNA with lipid nanoparticles (LNP), which can increase vaccine stability
to some extent.
Another option being investigated
is lyophilization, a procedure that eliminates water from vaccines, perhaps
allowing for room temperature storage. A rabies vaccine produced with a
protamine-mRNA combination, for example, demonstrated exceptional thermostability.
When kept at -80, 5, or 25 °C for 12 months, the lyophilized vaccine retained
its effectiveness in mice.
CureVac has also produced CVnCoV,
an LNP-based mRNA vaccine that can be kept at substantially warmer temperatures
(5 °C) for at least three months, demonstrating superior thermostability than
vaccines from Moderna or Pfizer.-BioNTech
6) The Future of mRNA Vaccines
The efficacy of mRNA vaccines in
combating COVID-19 has shown that they have the potential to treat various
illnesses and improve world health. As research and development continue, the
future of mRNA vaccines will most likely include their application to a broader
spectrum of illnesses, optimization for better efficacy and stability, and a
continued involvement in pandemic preparedness.
a) mRNA Vaccines for Other
Diseases
The versatility and quick
creation capabilities of mRNA vaccines make them an appealing alternative for
treating disorders other than COVID-19. Researchers are looking at the
possibility of mRNA vaccines for both infectious diseases like HIV, Zika, and rabies,
as well as non-infectious diseases including cancer and autoimmune disorders.
mRNA vaccines, for example, are
being studied as a possible tool for individualized cancer treatment due to
their ability to target specific disease antigens. Furthermore, mRNA vaccines
are being researched for their potential in preventing and treating seasonal
influenza, providing a more flexible and quickly producible alternative to
standard flu vaccinations.
b) Optimizing mRNA Vaccines for
Future Use
As mRNA vaccine technology
advances, attempts are being made to optimize these vaccines for greater
efficacy, stability, and use. This involves study on mRNA stability and
degradation, manufacturing process refinement, and cold storage needs.
Researchers, for example, are
investigating the use of modified nucleosides and lipid nanoparticles to boost
mRNA stability and transport into cells. Furthermore, the development of
automated and closed-loop manufacturing procedures can aid in increasing the
efficiency and repeatability of mRNA vaccine production while lowering the
danger of contamination.
c) The Role of mRNA Vaccines in
the COVID-19 Pandemic
The COVID-19 pandemic has
underlined the significance of developing and deploying vaccines quickly in
response to new infectious illnesses. mRNA vaccines, like as those developed by
Pfizer-BioNTech and Moderna, have played an important part in the worldwide
response to the pandemic, proving their potential as a formidable weapon in
pandemic preparedness.
The effectiveness of mRNA
vaccines in the COVID-19 pandemic has increased research and investment in this
technology, clearing the possibility for future pandemics to employ them. As
new infectious illnesses arise, the capacity to rapidly design and manufacture
mRNA vaccines might be an important component of worldwide efforts to prevent
and manage epidemics.
To summarize, the future of mRNA
vaccines seems bright, with the potential for usage in a wide range of
illnesses and a continuing role in pandemic preparedness. As research and
development continue, mRNA vaccines are anticipated to become a more essential
weapon in the battle against infectious illnesses and other health concerns.
7) New Companies coming out with Next-Generation
mRNA Vaccines
CureVac is a worldwide
biopharmaceutical firm that has been at the forefront of developing mRNA
technology for medicinal applications for over 20 years. Dr. Ingmar Hoerr,
Steve Pascolo, Florian von der Muelbe, Günther Jung, and Hans-Georg Rammensee
formed the firm in 2000, and it is located in Tübingen, Germany. Dr. Ingmar
Hoerr, the company's creator, made the ground-breaking discovery that the
hitherto unstable biomolecule mRNA might be employed as a therapeutic vaccine
or agent when given directly into tissue.
CureVac's unique RNA technology
platform has been utilized to develop revolutionary therapies that allow the
body to make its own anti-inflammatory and therapeutic medications. The
company's principal emphasis is on producing mRNA-based vaccines to prevent
infectious illnesses, and it has a robust clinical pipeline in areas such as
preventive vaccines, cancer medicines, antibody therapeutics, and rare disease
therapy.
CureVac has been working on mRNA
vaccines for infectious illnesses such as rabies, influenza, and COVID-19.
CV7202, for example, is a rabies vaccine candidate being tested in a phase 1
clinical study at CureVac. In addition, the business is collaborating with GSK
on a multivalent, modified mRNA seasonal influenza vaccine candidate, which has
just proceeded into Phase II clinical trials.
CureVac has been developing
modified mRNA COVID-19 vaccine candidates in partnership with GSK in the
context of the COVID-19 pandemic. The Phase 2 trial of these vaccine candidates
has just commenced, with the first participant scheduled to be dosed in August
2023. The study's goal is to assess the safety, reactogenicity, and
immunological responses to single booster doses of two COVID-19 vaccine
candidates with changed mRNA.
CureVac's work is backed by a
number of stakeholders, including the Bill and Melinda Gates Foundation and
Dietmar Hopp, who first invested in the firm in 2005 and has remained a staunch
backer of the company and its mRNA technology. In addition, the business is
working with CRISPR Therapeutics to create new Cas9 mRNA structures for gene
editing applications.
CureVac's work on mRNA technology
has the potential to transform the area of vaccines and medicines, providing a
more rapid and flexible approach to combating infectious illnesses. The use of
mRNA technology in vaccinations, for example, might improve vaccine efficacy
and allow vaccines to be produced closer to the start of the flu season,
offering a better match to the season's circulating influenza strains.
Translate Bio, a clinical-stage
messenger RNA (mRNA) therapies firm, has been developing mRNA vaccines for
numerous illnesses, including COVID-19, seasonal flu, and cystic fibrosis, in
collaboration with Sanofi, a multinational biopharmaceutical company.
MRT5500 or VAW00001 is a COVID-19
vaccine candidate developed by Sanofi and Translate Bio. The development of
this vaccine, however, was terminated in September 2021. Sanofi emphasized the
difficulties of doing placebo-controlled experiments with other mRNA vaccines
currently on the market, such as Pfizer's and Moderna's. Despite this, the
business announced "promising results" from its preliminary studies.
In addition, Sanofi and Translate
Bio have begun a phase 1 clinical study of an mRNA vaccine for seasonal
influenza. The start of the research puts the partners ahead of Moderna and
Pfizer in the quest to demonstrate that mRNA vaccines are as good as or better
than existing technologies in preventing flu. The researchers will test the
safety and immunogenicity of two mRNA vaccine formulations targeted to protect
against A/H3N2, a type of influenza linked with more severe flu seasons.
MRT5005 is an investigational
messenger RNA-based therapy for cystic fibrosis developed by Translate Bio.
This therapy intends to spray synthetic mRNA into cystic fibrosis patients'
lungs, causing them to create a crucial protein called as cystic fibrosisTR.
However, in an early-stage experiment, the therapy failed to enhance patients'
lung function. Despite this setback, Translate Bio remains optimistic, viewing
the findings as a "data-driven foundation" for a next-generation
medicine.
Sanofi announced plans to buy
Translate Bio in August 2021, expanding its capabilities to explore the promise
of mRNA technology to produce best-in-class vaccines and medicines. The deal
was estimated to be worth $3.2 billion. Following the completion of the tender
offer, a Sanofi fully owned subsidiary will combine with Translate Bio.
The collaboration between Sanofi
and Translate Bio is an important step forward in the development of mRNA
vaccines and treatments. Despite significant disappointments, the cooperation
is still investigating the possibilities of mRNA technology in the treatment of
many infectious illnesses.
Arcturus Therapeutics is a
biotechnology startup working on mRNA vaccines for a variety of infectious
disorders, including COVID-19, influenza, and cystic fibrosis. The company's
approach to these disorders is to employ its unique LUNAR® technology, which is
designed to deliver RNA therapeutics to target cells.
ARCT-154, a self-amplifying mRNA
(sa-mRNA) vaccine for COVID-19, is being developed by Arcturus. Early studies
of this vaccine have yielded encouraging results, with evidence showing that it
successfully boosts the immune system. Three variants of the vaccine produced
an immunological response against the virus's D614G form in a modest phase 1/2
experiment. The B.1-variant targeted booster (ARCT-154) worked the best,
eliciting a wide, cross-neutralizing immune response that lasted up to a year
after the booster without the need for a booster dose.
ARCT-154 exhibited 56.6%
effectiveness against symptomatic COVID-19 and 95.3% efficacy against severe
COVID-19 in a phase 3 study. When tested against the ancestral strain, the
vaccine also passed a non-inferiority test against Pfizer's Comirnaty.
Arcturus has also collaborated
with CSL Seqirus on the development and commercialization of self-amplifying
mRNA vaccines. Arcturus will license their self-amplifying mRNA technology to
CSL Seqirus to support the research, development, manufacture, and commercialization
of vaccines for COVID-19, influenza, pandemic preparedness, and three other
globally prevalent respiratory infectious diseases. Arcturus is also developing
mRNA vaccines for influenza. The vaccines LUNAR®-FLU (Seasonal) and LUNAR®-FLU
(Pandemic) are now under preclinical testing. The business has teamed up with
CSL Seqirus to create and market self-amplifying mRNA vaccines for influenza.
Arcturus is working with the
Cystic Fibrosis Foundation to produce LUNAR®-CF, an mRNA medication, to treat
cystic fibrosis. This mRNA replacement treatment is intended to introduce a
fresh copy of the CFTR mRNA into CF patients' airways. The CFTR mRNA is
aerosolized into the airways after being encased in the LUNAR® delivery
platform, allowing the mRNA to create a fully functional CFTR protein in
CFTR-deficient cells. Arcturus has extended its existing cooperation with the
Cystic Fibrosis Foundation to pursue ARCT-032, a cystic fibrosis experimental
mRNA treatment. The foundation has boosted its investment in this mRNA therapy
candidate to $25 million.
In addition to the foregoing,
Arcturus is working on an mRNA therapy to treat ornithine transcarbamylase
deficiency, a fatal hereditary condition. LUNAR®-OTC from the firm is intended
to help patients create healthy functional OTC enzyme in their liver cells.
eTheRNA is a renowned Belgian
biotechnology business specializing in the development of mRNA vaccines for the
treatment of cancer and infectious disorders. The work of the firm is focused
on the utilization of mRNA technology and lipid nanoparticle (LNP) delivery
systems.
In recent years, mRNA vaccines
have showed significant promise, notably with the successful creation and
deployment of COVID-19 vaccines. These vaccines function by delivering mRNA
molecules into the body, which are subsequently taken up and converted into
protein antigens by antigen-presenting cells. This mechanism initiates an
immunological response, which can be beneficial in the fight against illness.
The work of eTheRNA in this
sector is primarily focused on the creation of mRNA-LNP vaccines. These
vaccines transfer mRNA into cells using lipid-based nanoparticles (LNPs). LNPs
have been critical to the development of mRNA vaccines because they allow for
effective mRNA production while also providing the vaccine with adjuvant
qualities that stimulate robust immune responses.
eTheRNA has made tremendous
progress in the creation of mRNA-LNP cancer vaccines. The business has
customized mRNA-LNP formulations to generate large tumor-specific CD8 T cell
responses, which are required for successful cancer vaccines. This research improved
mRNA absorption by numerous immune cell types and gave new insights into the
underlying processes of efficient mRNA-LNP-based anticancer immunotherapy.
In addition to its work on cancer
vaccines, eTheRNA is developing mRNA vaccines for infectious illnesses. For
example, the business has been assisting in the development of Africa's first
mRNA COVID-19 vaccine.
Various investors have
acknowledged and supported eTheRNA's initiatives. In August 2022, Novalis
LifeSciences conducted a €39 million Series B2 funding round, which included
participation from many current investors. This capital will be utilized to
further investment in eTheRNA's integrated mRNA technology platform and to
pursue the company's partnership-driven business strategy.
8) Conclusion
Finally, next-generation mRNA
vaccines have demonstrated significant promise in offering outstanding
preventive and therapeutic benefits against a variety of illnesses. The
COVID-19 pandemic has advanced the development of mRNA vaccines, and their
effectiveness has opened up new avenues for future use in the battle against
infectious illnesses, cancer, and other health risks. Compared to conventional
vaccinations, mRNA vaccines have various benefits, including speedier
manufacture, reduced production costs, and the capacity to swiftly adapt to new
pathogens or strains.
mRNA vaccines are predicted to
play an increasingly vital role in treating numerous health concerns and
improving global health outcomes as research and development proceed.
FAQ’s
mRNA vaccines are a type of
vaccine that use a copy of a molecule called messenger RNA (mRNA) to produce an
immune response. The mRNA provides instructions for our cells to make a protein
that triggers this response
mRNA vaccines work by teaching
our cells how to make a protein that triggers an immune response. This immune
response, which produces antibodies, is what protects us from getting infected
if the real virus enters our bodies
3) Do mRNA vaccines affect a
person's DNA?
No, mRNA vaccines do not alter or
interact with our DNA in any way. The mRNA from the vaccine never enters the
nucleus of the cell, where our DNA is kept
4) Can mRNA vaccines give me
COVID-19?
No, mRNA vaccines cannot make you
sick with COVID-19. The vaccines do not contain the live virus that causes
COVID-19
5) What are the side effects of
mRNA vaccines?
Common side effects include
discomfort at the injection site, fatigue, headache, muscle pain, joint pain,
and chills. These side effects are usually mild and don't last long
Yes, mRNA vaccines are safe. They
have undergone rigorous testing in clinical trials to ensure their safety and
efficacy. The FDA will only authorize or approve a vaccine if it is effective
and does not cause serious side effects
7) Why should I get an mRNA
vaccine for COVID-19?
Getting vaccinated helps protect
you from getting COVID-19 and may also prevent you from getting seriously ill
even if you do get infected. Additionally, your vaccination also protects
others around you, particularly people at increased risk for severe illness
from COVID-19
8) Can I get the mRNA vaccine if
I'm pregnant?
Yes, mRNA vaccines are not
contraindicated during pregnancy. However, pregnant women should consider the
risks of COVID-19, which may be more severe in pregnant women, and the
uncertain risk of vaccination
9) Do mRNA vaccines contain
microchips or make you magnetic?
No, mRNA vaccines do not contain microchips,
and they cannot make you magnetic. They are free from metals such as iron,
nickel, cobalt, lithium, and rare earth alloys
10) Do mRNA vaccines cause new
variants of the virus?
No, mRNA vaccines do not create
or cause variants of the virus that causes COVID-19
11) Can I receive different mRNA
vaccines for my first and second dose?
In exceptional situations where
the first-dose vaccine product cannot be determined or is no longer available,
any available mRNA COVID-19 vaccine may be administered to complete the mRNA
COVID-19 vaccination series
12) Do mRNA vaccines prevent
infection or just the disease?
While most vaccines, including
mRNA vaccines, do not completely prevent infection, they do prevent the disease
from spreading within the body and causing severe illness
13) How many doses of the mRNA
vaccine do I need?
For the Pfizer-BioNTech and
Moderna mRNA vaccines, two doses are recommended for most people. The second
dose acts as a booster, better preparing the immune system to fight infection
14) What happens if I have an
allergic reaction to the first dose of the mRNA vaccine?
People who have an immediate
allergic reaction to the first vaccine dose should not receive additional doses
of either mRNA COVID-19 vaccine
15) Can I still transmit the
virus after getting vaccinated?
Yes, it is still possible to
transmit the virus after getting vaccinated. However, vaccination greatly
reduces the risk of severe disease and transmission
16) Do mRNA vaccines contain
preservatives or other harmful ingredients?
No, mRNA vaccines do not contain
preservatives, tissues, antibiotics, food proteins, medicines, latex, or metals
17) Will mRNA vaccines affect
fertility?
No, mRNA vaccines will not affect
fertility. They are recommended for people who are pregnant, trying to get
pregnant now, or might become pregnant in the future, as well as their partners
18) Are mRNA vaccines recommended
for immunocompromised individuals?
Yes, people who are moderately or
severely immunocompromised have the option to receive additional doses of an
age-appropriate bivalent mRNA vaccine
19) Can children receive mRNA
vaccines?
Yes, children aged 6 months and
older are recommended to receive bivalent mRNA COVID-19 vaccines
20) Are mRNA vaccines effective
against COVID-19 variants?
Yes, mRNA vaccines have shown to
be effective against several variants of the virus. However, research is
ongoing as new variants emerge
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