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RNA vaccine
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Main page A ribonucleic acid (RNA) vaccine or messenger RNA (mRNA) vaccine is a type of vaccine that
uses a copy of a natural molecule called messenger RNA (mRNA) to produce an immune response. [1] The
Contents
Current events vaccine transfects molecules of synthetic RNA into immunity cells. Once inside the immune cells, the
Random article vaccine's RNA functions as mRNA, causing the cells to build the foreign protein that would normally be
About Wikipedia produced by a pathogen (such as a virus) or by a cancer cell. These protein molecules stimulate an adaptive
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immune response which teaches the body how to identify and destroy the corresponding pathogen or cancer
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cells.[1] The delivery of mRNA is achieved by a co-formulation of the molecule into lipid nanoparticles
Contribute which protect the RNA strands and helps their absorption into the cells.[2][3]
Help Reactogenicity , the property of a vaccine of being able to produce common, expected adverse reactions, is
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similar to that of conventional non-RNA vaccines.[4] People susceptible to an autoimmune response may
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have an adverse reaction to RNA vaccines.[4] The advantages of RNA vaccines over traditional protein
Recent changes
Upload file vaccines are superior design and production speed, lower cost of production,[5][4] and the induction of both
cellular as well as humoral immunity .[6] The Pfizer–BioNTech COVID-19 vaccine requires ultracold storage
Tools before distribution,[1] but other mRNA vaccines do not, such as the COVID-19 vaccines by Moderna ,
What links here CureVac and Walvax .
Related changes
In RNA therapeutics , mRNA vaccines have attracted considerable interest as COVID-19 vaccines . By
Special pages
Permanent link December 2020, there were two novel mRNA vaccines for COVID-19 that had completed the required eight-
Page information week period post-final human trials and were awaiting emergency use authorization (EUA): the Moderna
Cite this page COVID-19 vaccine (mRNA-1273) and the Pfizer–BioNTech COVID-19 vaccine (BNT162b2). [1] On 2
Wikidata item December 2020, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) became the first
medicines regulator to approve an mRNA vaccine, authorizing the Pfizer–BioNTech COVID-19 vaccine
Print/export
(Comirnaty) for widespread use.[7][8][9] On 11 December 2020, the US Food and Drug Administration (FDA)
Download as PDF
issued an EUA for the Pfizer-BioNTech COVID-19 vaccine and the US Centers for Disease Control and
Printable version
Prevention (CDC) recommended its use in those aged 16 and older on 12 December 2020.[10][11] On 19
In other projects December 2020, the CDC recommended the use of the Moderna COVID-19 vaccine in adults after the FDA
Wikimedia Commons granted an EUA.[12][13]

Languages The use of RNA in a vaccine has been the basis of substantial misinformation circulated via social media,
wrongly claiming that the use of RNA alters a person's DNA (a biologically impossible occurrence).[14]
‫العربية‬
Deutsch
Contents []
Español
Français 1 History
Bahasa Indonesia 2 Mechanism
Bahasa Melayu 3 Delivery
Português 3.1 Ex vivo
Русский 3.2 In vivo
中文 3.2.1 Naked mRNA injection

19 more 3.2.2 Polyplex vector

3.2.3 Lipid nanoparticle vector

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RNA vaccine - Wikipedia

Edit links 3.2.4 Viral vector

4 Side effects and risks
4.1 General
4.2 Storage
5 Advantages
5.1 Traditional vaccines
5.2 DNA vaccines
6 Vaccine hesitancy
7 Efficacy of mRNA vaccines for COVID-19
8 Self-amplifying RNA
9 See also
10 References
11 External links

History
In 1989, researchers at the Salk Institute , the University of California, San Diego, and Vical published work
demonstrating that mRNA, using a liposomal nanoparticle for drug delivery, could transfect mRNA into a
variety of eukaryotic cells .[15] In 1990, the University of Wisconsin reported positive results where "naked"
(or unprotected) mRNA was injected into the muscle of mice.[3] These studies were the first evidence that in
vitro transcribed (IVT) mRNA could deliver the genetic information to produce proteins within living cell
tissue.[3]

The use of RNA vaccines goes back to the 1990s. The in vitro demonstration of mRNA in animals was first
reported in 1990,[16] and the use of mRNA for immunization was proposed shortly thereafter.[17][18] In 1993,
Martinon demonstrated that liposome-encapsulated RNA could stimulate T-cells in vivo, and in 1994, Zhou
& Berglund published the first evidence that RNA could be used as a vaccine to elicit both humoral and
cellular immune response against a pathogen.[3][19][20]

Hungarian biochemist Katalin Karikó attempted to solve some of the main technical barriers to introducing
mRNA into cells in the 1990s. Karikó partnered with American immunologist Drew Weissman, and by 2005
they published a joint paper that solved one of the key technical barriers by using modified nucleosides to get
mRNA inside cells without setting off the body's defense system.[3][21] Karikó arrived at her key insight after
she focused on why transfer RNA used as a control in an experiment did not provoke the same immune
reaction as messenger RNA.[22] Harvard stem cell biologist Derrick Rossi (then at Stanford) read Karikó
and Weissman's paper and recognized that their work was "groundbreaking",[21] and in 2010 founded the
mRNA-focused biotech Moderna along with Robert Langer , who also saw its potential in vaccine
development.[21][3] In 2013, DARPA, the US government organization responsible for emerging
technologies for use by the military, saw the potential of the technology for defense against pandemics and
invested $25 million in the company.[23] Like Moderna, BioNTech also licensed Karikó and Weissman's
work.[21]

Up until 2020, these mRNA biotech companies had poor results testing mRNA drugs for cardiovascular,
metabolic and renal diseases; selected targets for cancer; and rare diseases like Crigler–Najjar syndrome ,
with most finding that the side-effects of the mRNA delivery methods were too serious.[24][25] mRNA
vaccines for human use have been developed and tested for the diseases rabies , Zika, cytomegalovirus , and
influenza , although these mRNA vaccines have not been licensed.[26] Many large pharmaceutical companies
abandoned the technology,[24] while some biotechs re-focused on the less profitable area of vaccines, where
the doses would be at lower levels and side-effects reduced.[24][27]

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At the onset of the COVID-19 pandemic , no mRNA drug or vaccine had been licensed for use in humans. In
December 2020, both Moderna and Pfizer–BioNTech obtained emergency use authorization for their
mRNA-based COVID-19 vaccines, which had been funded by Operation Warp Speed (directly in the case of
Moderna and indirectly for Pfizer–BioNTech).[21] On 2 December 2020, seven days after its final eight-week
trial, the UK's Medicines and Healthcare products Regulatory Agency (MHRA), became the first global
medicines regulator in history to approve an mRNA vaccine, granting emergency authorization for Pfizer–
BioNTech's BNT162b2 COVID-19 vaccine for widespread use.[7][8][28] MHRA CEO June Raine said "no
corners have been cut in approving it",[29] and that, "the benefits outweigh any risk". [30][31] On 11 December
2020 the FDA gave emergency use authorization for the Pfizer–BioNTech COVID-19 vaccine.[32]

Mechanism
Further information: Immune system

The goal of a vaccine is to stimulate the

adaptive immune system to create
antibodies that precisely target that
particular pathogen . The markers on the
pathogen that the antibodies target are
called antigens .[33]

mRNA vaccines operate in a very

different manner from a traditional
vaccine .[1] Traditional vaccines
stimulate an antibody response by
injecting antigens , an attenuated virus
(weakened or harmless virus), or a
recombinant antigen-encoding viral
vector (carrier virus engineered to have
antigens[citation needed]) into muscles. An illustration of the mechanism of action of the RNA vaccine
These antigen-containing ingredients are
prepared and grown outside the body.

In contrast, mRNA vaccines introduce a short-lived [34] synthetically created fragment of the RNA sequence
of a virus into the vaccinated individual. These mRNA fragments are taken up by dendritic cells – a type of
immune system cell – by phagocytosis .[35] The dendritic cells use their own internal machinery
(ribosomes ) to read the mRNA and produce the viral antigens that the mRNA encodes before destroying the
mRNA.[4] Although non-immune cells can potentially absorb vaccine mRNA, manufacture spikes, and
display spikes on their surfaces, dendritic cells absorb the mRNA globules much more readily.[36]

Once the viral antigens are produced by the host cell, the normal adaptive immune system processes are
followed. Antigens are broken down by proteasomes , then class I and class II MHC molecules attach to the
antigen and transport it to the cellular membrane, "activating" the dendritic cell.[37][failed verification] Once the
dendritic cells are activated, they migrate to lymph nodes , where the antigen is presented to T cells and B
cells.[38] This eventually leads to the production of antibodies that are specifically targeted to the antigen,
resulting in immunity.[33]

The benefit of using mRNA to have host cells produce the antigen is that mRNA is far easier for vaccine
creators to produce than antigen proteins or attenuated virus.[37][1][4] Another benefit is speed of design and
[39]

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RNA vaccine - Wikipedia

production. Moderna designed their mRNA-1273 vaccine for COVID-19 in 2 days. Another advantage of
RNA vaccines is that since the antigens are produced inside the cell, they stimulate cellular immunity , as
well as humoral immunity.[6][40]

mRNA vaccines do not affect or reprogram DNA inside the cell. The synthetic mRNA fragment is a copy of
the specific part of the viral RNA that carries the instructions to build the antigen of the virus (a protein
spike, in the case of the main coronavirus mRNA vaccines), and is not related to human DNA. This
misconception was circulated as the COVID-19 mRNA vaccines came to public prominence, and is a
debunked conspiracy theory .[41][42]

The mRNA should degrade in the cells after producing the foreign protein. However, because the specific
formulation (including the exact composition of the lipid nanoparticle drug delivery coating) is kept
confidential by the manufacturers of the mRNA vaccines, details and timings have not been researched yet
by third parties.[43]

Delivery
The method of vaccine delivery can be broadly classified by whether the RNA transfer to cells happens
within (in vivo) or outside (ex vivo) the organism. [3]

Ex vivo
Dendritic cells are a type of immune cells that display antigens on their surfaces , leading to interactions
with T cells to initiate an immune response. Dendritic cells can be collected from patients and programmed
with the desired mRNA. Then, they can be re-administered back into patients to create an immune
response.[44]

In vivo
Since the discovery that introducing in vitro transcribed mRNA leads to the expression in vivo following
direct administration, in vivo approaches have become more and more attractive. [45] They offer some
advantages over ex vivo methods, particularly by avoiding the cost of harvesting and adapting dendritic cells
from patients, and by imitating a regular infection. There are still obstacles for these methods to overcome
for RNA vaccination to be a potent procedure. Evolutionary mechanisms that prevent the infiltration of
unknown nucleic material and promote degradation by RNases need to be circumvented to initiate
translation. In addition, RNA is too heavy to move around on its own inside the cell via diffusion , making it
vulnerable to being discovered and eliminated by the host cell.

Naked mRNA injection

A naked injection means that the delivery of the vaccine is simply held in a buffer .[46] This mode of mRNA
uptake has been known for since the 2000s. The first worldwide clinical studies (Tübingen, Germany) used
intradermal injections of naked mRNA for vaccination.[47][48]

The use of RNA as a vaccine tool was discovered in the 1990s in the form of self-amplifying mRNA.[49][50]
The two main categories of mRNA vaccines are non-amplifying (conventional, viral delivery), and molecular
self-amplifiying mRNA (non-viral delivery). When mRNA is delivered non-virally it enters the cell's
cytoplasm and can amplify and express the antigenic protein.[51][52]

It has also emerged that the different routes of injection , such as into the skin , blood or to muscles , resulted
in varying levels of mRNA uptake, making the choice of administration route a critical aspect of delivery.
One study showed, in comparing different routes, that lymph node injection leads to the largest T cell

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response.[53]

The mechanisms and consequently the evaluation of self-amplifying mRNA may be different, as self-
amplifying mRNA is fundamentally different by being a much bigger molecule in size.[3]

Polyplex vector

Cationic polymers can be mixed with mRNA to generate protective coatings called polyplexes . These
protect the recombinant mRNA from ribonucleases and assist its penetration in cells. Protamine is a
natural cationic peptide and has been used to encapsulate mRNA for
vaccination.[non-primary source needed][54]

Lipid nanoparticle vector

The first time the FDA approved the use of lipid nanoparticles as a drug delivery system was in 2018, when
the agency approved the first siRNA drug, Onpattro .[55] Encapsulating the mRNA molecule in lipid
nanoparticles was a critical breakthrough for producing viable mRNA vaccines, solving a number of key
technical barriers in delivering the mRNA molecule into the host cell.[55][56] Research into using lipids to
deliver siRNA to cells became a foundation for similar research into using lipids to deliver mRNA.[57]
However, new lipids had to be invented to encapsulate mRNA strands, which are much longer than siRNA
strands.[57]

Principally, the lipid provides a layer of protection against degradation, allowing more robust translational
output. In addition, the customization of the lipid's outer layer allows the targeting of desired cell types
through ligand interactions. However, many studies have also highlighted the difficulty of studying this type
of delivery, demonstrating that there is an inconsistency between in vivo and in vitro applications of
nanoparticles in terms of cellular intake.[58] The nanoparticles can be administered to the body and
transported via multiple routes, such as intravenously or through the lymphatic system .[55]

One issue with lipid nanoparticles is that several of the breakthroughs leading to the practical use of that
technology involved the use of microfluidics . Microfluidic reaction chambers are difficult to scale up since
the entire point of microfluidics is to exploit the microscale behaviors of liquids. The only way around this
obstacle, as of 2021, is to conduct the process in a massively parallel fashion by building a great many
microfluidic reaction chambers to run in parallel, a novel task requiring custom-built equipment. As of
February 2021, this was thought to be the primary bottleneck in the manufacturing of mRNA vaccines.[59][60]
Pfizer later revealed that it had utilized the massively parallel approach to solve this problem. After verifying
that impingement jet mixers could not be directly scaled up,[61] Pfizer made about 100 of the little mixers
(each about the size of a U.S. half-dollar coin ), connected them together with pumps and filters with a "maze
of piping,"[62][63] and set up a computer system to regulate flow and pressure through the mixers.[61]

Another issue is the availability of the novel lipids used to create lipid nanoparticles, especially ionizable
cationic lipids. Before 2020, such lipids were manufactured in small quantities measured in grams or
kilograms, and they were used for medical research and a handful of drugs for rare conditions. As the safety
and efficacy of RNA vaccines became clear by late 2020, the few companies able to manufacture the
requisite lipids were confronted with the challenge of scaling up production to respond to orders for several
tons of lipids.[60][64]

Viral vector
Further information: Viral vector vaccine

In addition to non-viral delivery methods, RNA viruses have been engineered to achieve similar
immunological responses. Typical RNA viruses used as vectors include retroviruses , lentiviruses ,

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alphaviruses and rhabdoviruses , each of which can differ in structure and function.[65] Clinical studies
have utilized such viruses on a range of diseases in model animals such as mice , chicken and
primates .[66][67][68]

Side effects and risks

Reactogenicity is similar to that of conventional, non-RNA vaccines. However, those susceptible to an
autoimmune response may have an adverse reaction to RNA vaccines.[4] The mRNA strands in the vaccine
may elicit an unintended immune reaction. To minimize this, mRNA sequences in mRNA vaccines are
designed to mimic those produced by host cells.[5]

Strong but transient reactogenic effects were reported in trials of novel COVID-19 RNA vaccines; most
people will not experience severe side effects which include fever and fatigue. Severe side effects are defined
as those that prevent daily activity.[69]

General
Before 2020, no mRNA technology platform (drug or vaccine) had been authorized for use in humans, so
there was a risk of unknown effects.[40] The 2020 coronavirus pandemic required faster production capability
of mRNA vaccines, made them attractive to national health organisations, and led to debate about the type of
initial authorization mRNA vaccines should get (including emergency use authorization or expanded access
authorization) after the eight-week period of post-final human trials.[70][71]

Storage
Because mRNA is fragile, some vaccines must be kept at very low temperatures to avoid degrading and thus
giving little effective immunity to the recipient. Pfizer–BioNTech's BNT162b2 mRNA vaccine has to be
kept between −80 and −60 °C (−112 and −76 °F).[72][73] Moderna says their mRNA-1273 vaccine can be
stored between −25 and −15 °C (−13 and 5 °F),[74] which is comparable to a home freezer,[73] and that it
remains stable between 2 and 8 °C (36 and 46 °F) for up to 30 days.[74][75] In November 2020, Nature
reported, "While it's possible that differences in LNP formulations or mRNA secondary structures could
account for the thermostability differences [between Moderna and BioNtech], many experts suspect both
vaccine products will ultimately prove to have similar storage requirements and shelf lives under various
temperature conditions."[40] Several platforms are being studied that may allow storage at higher
temperatures.[4]

Advantages
Traditional vaccines
RNA vaccines offer specific advantages over traditional protein vaccines.[5][4] Because RNA vaccines are
not constructed from an active pathogen (or even an inactivated pathogen), they are non-infectious. In
contrast, traditional vaccines require the production of pathogens, which, if done at high volumes, could
increase the risks of localized outbreaks of the virus at the production facility.[5] RNA vaccines can be
produced faster, cheaper, and in a more standardized fashion (with fewer error rates in production), which
can improve responsiveness to serious outbreaks.[4][5] For example, the Pfizer-BioNTech vaccine originally
required 110 days to produce (before Pfizer began to optimize the manufacturing process to only 60 days),
but this was still far faster than traditional flu and polio vaccines.[62] Within that larger timeframe, the actual
production time is only about 22 days: two weeks for molecular cloning of DNA plasmids and purification of

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DNA, four days for DNA-to-RNA transcription and purification of mRNA, and four days to encapsulate
mRNA in lipid nanoparticles followed by fill and finish.[76] The majority of the days needed for each
production run are allocated to rigorous quality control at each stage.[62]

DNA vaccines
In addition to sharing the advantages of theoretical DNA vaccines over established traditional protein
vaccines, RNA vaccines also have additional advantages over DNA vaccines. The mRNA is translated in
the cytosol , so there is no need for the RNA to enter the cell nucleus , and the risk of being integrated into the
host genome is averted. [3] Modified nucleosides (for example, pseudouridines , 2'-O-methylated
nucleosides) can be incorporated to mRNA to suppress immune response stimulation to avoid immediate
degradation and produce a more persistent effect through enhanced translation capacity.[77][78][79] The open
reading frame (ORF) and untranslated regions (UTR) of mRNA can be optimized for different purposes (a
process called sequence engineering of mRNA), for example through enriching the guanine-cytosine content
or choosing specific UTRs known to increase translation.[80]

An additional ORF coding for a replication mechanism can be added to amplify antigen translation and
therefore immune response, decreasing the amount of starting material needed.[50][81]

Vaccine hesitancy
Further information: Misinformation related to the COVID-19 pandemic and vaccine hesitancy

There is misinformation implying that mRNA vaccines could alter DNA in the nucleus.[14] mRNA in the
cytosol is very rapidly degraded before it would have time to gain entry into the cell nucleus. (mRNA
vaccines must be stored at very low temperature to prevent mRNA degradation.) Retrovirus can be single-
stranded RNA (just as SARS-CoV-2 vaccine is single-stranded RNA) which enters the cell nucleus and uses
reverse transcriptase to make DNA from the RNA in the cell nucleus. A retrovirus has mechanisms to be
imported into the nucleus, but other mRNA lack these mechanisms. Once inside the nucleus, creation of
DNA from RNA cannot occur without a primer , which accompanies a retrovirus, but which would not exist
for other mRNA if placed in the nucleus.[82][83] Thus, mRNA vaccines cannot alter DNA because they
cannot enter the nucleus, and because they have no primer to activate reverse transcriptase.

In November 2020, The Washington Post reported on novel mRNA vaccine hesitancy amongst healthcare
professionals in the United States, citing surveys that "some did not want to be in the first round, so they
could wait and see if there are potential side effects".[84]

Efficacy of mRNA vaccines for COVID-19

It is unclear why the novel mRNA COVID-19 vaccines from Moderna and Pfizer–BioNTech have shown
potential efficacy rates of 90 to 95 percent when the prior mRNA drug trials on pathogens other than
COVID-19 were not so promising and had to be abandoned in the early phases of trials.[85] Physician-
scientist Margaret Liu stated that it could be due to the "sheer volume of resources" that went into
development, or that the vaccines might be "triggering a nonspecific inflammatory response to the mRNA
that could be heightening its specific immune response, given that the modified nucleoside technique reduced
inflammation but hasn't eliminated it completely", and that "this may also explain the intense reactions such
as aches and fevers reported in some recipients of the mRNA SARS-CoV-2 vaccines". These reactions
though severe were transient and another view is that they were believed to be a reaction to the lipid drug
delivery molecules.[85]

Unlike DNA molecules, the mRNA molecule is a very fragile molecule that degrades within minutes in an

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exposed environment, and thus mRNA vaccines need to be transported and stored at very low
temperatures.[86] Outside the cell, or its drug delivery system, the mRNA molecule is also quickly broken
down by the host.[5] This fragility of the mRNA molecule is a hurdle to the efficacy of any mRNA vaccine
due to bulk disintegration before it enters the cells, which could lead people to believe, and act as if they are
immune when they are not.[86][5]

Self-amplifying RNA
Self-amplifying RNA (saRNA) is a technology similar to mRNA, except the saRNA produces multiple
copies of itself in the cell before producing proteins like mRNA does. This allows smaller quantities to be
used and has other potential advantages.[87][88] saRNA vaccines are being researched, including development
of a malaria vaccine .[89]

See also
ARCT-021
CureVac COVID-19 vaccine
Walvax COVID-19 vaccine
DNA vaccine
Nucleoside-modified messenger RNA
RNA therapeutics
Timeline of human vaccines

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External links
Roberts J (April 2020). "Five things you need to know
Scholia has a profile for RNA
about: mRNA vaccines" . Horizon. vaccine (Q85795487).
Blackburn L (October 2020). "RNA vaccines: an
introduction" . PHG Foundation. University of Cambridge.
"Understanding mRNA COVID-19 Vaccines" . Centers for Disease Control and Prevention.
"Understanding and Explaining mRNA COVID-19 Vaccines" . Centers for Disease Control and
Prevention.

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