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mRNA Vaccines: A Mini Review

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Gnanavel Venkatesan, SF Virol Res J, 2017, 2:1

SciFed Virology Research Journal

Mini Review Open Access

mRNA Vaccines: A Mini Review

1
Sasi Kumar, 2Amit Kumar, 3Monu Karki, *4Gnanavel Venkatesan
*4
Division of Virology, ICAR-IVRI, Mukteswar 263 138, Nainital, Uttarakhand, India

Abstract
Nucleic acid-based vaccines are vaccines that containing DNA or RNA encoded with the
target antigen. These type of vaccines are novel, safe, effective, mimicking of live infection, and low
risk of reversion to virulence. RNA-based vaccines offer a safety in their delivery to the cytoplasm.The
characteristics feature of mRNA presents challenges as a nucleic acid-based vaccine approach. mRNA
platform offers strong safety profile and minimal genetic construction for expression of antigen. Here,
the review summarizes the concept of the recent mRNA vaccine development, mechanism of action and
their applications in immunotherapy and vaccine research.

Keywords and therefore it avoids oncogenesis and mutagenesis [6].

mRNA Vaccines Types; Self-Amplifying;
Mechanism; Immune Response; Applications
Introduction
Nucleic acid-based vaccines (NAVs) like DNA or
RNA- based vaccines consist of antigen-encoding genes.
Nucleic acid-based vaccines are more tolerable and safe
like other vaccines [1, 2]. DNA vaccines have been found
to elicit a less immune response than other vaccines. RNA
vaccines induce both cellular and humoral immunity.
Unlike DNA, mRNA has more advantages than DNA
vaccines [3]. The mRNA was first discovered in 1961. The
messenger RNA based applications and therapeutics were
first implemented in 1989. In vitro-transcribed mRNA
vaccines encode only required proteins for expression. In
this review, we provide the mRNA based vaccines, types,
mechanism and delivery of mRNA based vaccines and
their applications.
mRNA Vaccines
mRNA vaccines are safe, simple, inexpensive and
possess maximum flexibility. Particularly compared with
peptide vaccines, they have self-adjuvanting property, lack
of MHC haplotype restriction and do not need to enter the
nucleus [4, 5]. mRNA does not integrate into the genome
These vaccines are momentary information carrier due to
early metabolic degradation within few days. Any protein
can be encoded for development of therapeutic and
prophylactic vaccines, without affecting the properties of
the mRNA.
Types of mRNA Vaccines
There are two forms of mRNA vaccines: self-
amplifying mRNA vaccines and conventional non-
amplifying mRNA-based vaccines [7]. Both of these
vaccines are well tolerated, safe, and capable of inducing
immune responses [8, 9].
*Corresponding author: Gnanavel Venkatesan, Division of Virology,
ICAR-IVRI, Mukteswar 263 138, Nainital, Uttarakhand, India. E-mail:
gnanamvirol@gmail.com; Tel: +91 5942-286346
Received December 14, 2017; Accepted January 09, 2018; Published
January 24, 2018
Citation: Gnanavel Venkatesan (2017) mRNA Vaccines: A Mini Review. SF
Virol Res J 2:1.
Copyright: © 2017 Gnanavel Venkatesan. This is an open-access article
distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium,
provided the original author and source are credited.

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 Citation: Gnanavel Venkatesan (2017) mRNA Vaccines: A Mini Review. SF Virol Res J 2:1.

1. Self-Amplifying mRNA Vaccines (SAM)
The self-amplifying vaccines are larger molecules
that encode self-amplifying alphavirus genomes and
antigen of interest [10]. The structural proteins in the
genome are replaced by a gene of interest. Compared with
non-amplifying vaccines, self-amplifying vaccines have a
high level of expression of encoded antigen in the host.
The duration of expression by self-amplifying vaccines
with non-immunogenic luciferase reporter proteins lasts
Table 1: Pre-Clinical Self-Amplifying mRNA Vaccines for Different Infectious/Non-Infectious Diseases
for 2 months [11]. The vector systems like alpha virus,
picornavirus, flavivirus provide inherent adjuvant effects
and high transient transgene expression. The delivery
system consists of viral and non-viral delivery system.
The viral delivery system is facilitated by the alpha virus
genome. The non-viral delivery system is achieved by
emulsions, lipids, and polymers, or other compounds.
Table 1 enlists the pre-clinical self-amplifying vaccines.

Disease Target Antigen References

Influenza Nucleoprotein (NP) Lazzaro et al., 2015 [12]
Influenza Hemagglutinin and nucleocapsid De´ Moulins et al., 2015 [13]
Influenza Hemagglutinin and nucleocapsid McCullough et al., 2014 [14]
Influenza Hemagglutinin Brazzoli et al., 2015 [15]
Influenza Hemagglutinin Oreshkova et al., 2014 [16]
Influenza Hemagglutinin Hu et al., 2017 [17]
Influenza Hemagglutinin Bahl et al., 2017 [18]
Rabies Glycoprotein Brito et al., 2015 [19]
Dengue virus Ectodomain of E85 Khalil et al., 2014 [20]
HPV E6 and E7 van de Wall et al., 2015 [21]
RSV Fusion glycoprotein Pepini et al., 2017 [22]
HIV HIV gp140 Bogers et al., 2015 [23]
HCV HCV glycoprotein (E1 and E2) Brito et al., 2015 [19]
HCV HCV Non-structural proteins Ip et al., 2014 [24]
RSV RSV fusion glycoprotein Brito et al., 2014 [25]
Cytomegalovirus gH/gL glycoprotein complex Brito et al., 2015 [19]
Enterovirus-71 Epitope SP70 Huang et al., 2015 [26]
Ebola virus Glycoprotein Pyankov et al., 2015 [27]
Cytomegalovirus Pentamer Wen et al., 2014 [28]
Cytomegalovirus hCMVgB and pp65-IE1 fusion Brito et al., 2014 [25]
Zika virus glycoproteins Pardi et al., 2017 [29]
HIV-1 glycoproteins Pardi et al., 2017 [30]
HIV-1 glycoproteins Pardi et al., 2017 [30]
Hemophilia B hFIX DeRosa et al., 2016;
Cancer/Tumour Tumour specific antigens (TSAs) Ramaswamy et al., 2017 [31, 32]
Cancer/Tumour Tumour specific antigens (TSAs) Oberli et al., 2017; Kranz et al., 2016;
Defrancesco, 2017
[33, 34, 35]
RSV: Respiratory Syncytial Virus; HIV: Human Immunodeficiency Virus; HCV: Hepatitis C Virus; HPV: Human Papilloma
Virus.

2. Conventional Non-Amplifying mRNA-Based
Vaccines
mRNA synthesis is obtained from ex-vivo
transcription of a cDNA from purified and invariant
plasmid DNA by a Bacteriophages T3, T7 or SP6 RNA
polymerase enzyme [36]. A regular cap analog (‘m7G(5′)-
ppp-(5′)G’) is included [37] or a poly(A) tail and the cap
may be added by post-transcription. The contaminants like
nucleotides, abortive transcripts, and oligonucleotides [38]
are removed from samples by extraction and precipitation

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 Citation: Gnanavel Venkatesan (2017) mRNA Vaccines: A Mini Review. SF Virol Res J 2:1.
steps. Pure mRNA products are separated by a single
chromatographic step or HPLC [39] for increased protein
expression [40]. After transcription, plasmid DNA is
digested by DNAse. The non-amplifying vaccines are
Table 2: Pre-Clinical Non-Amplifying mRNA Vaccines for Different Infectious/Non-Infectious Diseases
Disease Target Antigen
HIV HIV-1 gag
Allergy Grass pollen allergen
Cancer Fβ2
Cancer Ovalbumin
Cervical cancer HPV-16 E7 Peptide
HIV: Human Immunodeficiency Virus; HPV: Human Papilloma Virus.
mRNA Optimization
For translation, cytoplasmic availability and
stability, mRNA requires optimization. Cap and poly
(A) tail are essential for cytoplasmic stability. mRNA is
capped by using regular cap analog or by using vaccinia
virus capping complex [47]. The correct orientation of the
cap is obtained by the use of anti-reverse’’ cap analogs
(ARCAs) [48]. Phosphorothioate modified ARCA is used
for increasing the half-life and translation efficiency [49].
The length of the poly (A) tail should be between 120-
150 nucleotides [50, 51]. The efficiency of polysome
formation is increased by increasing the length of poly (A)
tail. In mRNA, poly (A) tail is added by recombinant poly
(A) polymerase and by encoding poly (A) on the pDNA
template [52]. α globin 3’-UTR is used for stabilization
of mRNA and β globin 5’-UTR is used for improving
translation efficiency [53]. Examples of 5’-UTRs include
tobacco etch virus 5’-UTR [54], human heat shock protein
70 5’-UTR [55]. Pseudouridine, chemically modified
nucleoside is also used to enhance the translation and
stability [56]
Delivery System for mRNA Vaccines
The non-viral delivery system has more potential
and advantageous than the viral delivery system [19, 57].
Non-viral methods are preferred over the viral delivery
system for their safety and cost-effectiveness [58, 59]. The
non-viral methods for delivery of vaccines include naked
mRNA vaccines, gene gun, protamine condensation;
adjuvant based vaccines, and encapsulated mRNA vaccines.
The positive-sense RNA viruses, alpha viruses are used for
the viral delivery system. The glycoproteins (E1 and E2)
of alpha virus used for endosomal escape and cell targeting
in the host. In addition to direct delivery by viral or non-
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delivered by non-viral methods. Table 2 enlists the pre-
clinical conventional non-amplifying vaccines reported
worldwide.
References
Zhao et al., 2014; Phua et al., 2014 [41, 42]
Hattinger et al., 2015 [43]
Van der Jeught et al., 2014 [44]
Fotin-Mleczek et al., 2014 [45]
Heidenreich et al., 2015 [46]
viral mediated methods, Ex vivo transfected mRNA is an
alternative to the naked mRNA vaccination. In this method,
mRNAs are transfected with monocytes, macrophages, T
cells, dendritic cells (DCs) and mesenchymal stem cells
(MSC) [60] before administration. A strong immune
response may be induced by ex vivo transfected mRNA
vaccination when compared to naked mRNA vaccination
which offers only optimal expression.
Mechanism of Action
mRNA vaccines stimulate host machinery system
through their self-adjuvanting property. mRNA induces
cytolyticCD8+ T cell response and type-I-IFN-mediated
innate immune response [34]. The innate immune response
results in cytokine and chemokine production at the
site of injection [22, 61]. Both non-amplifying and self-
amplifying vaccines can promote CD4+ T cells, CD8+
T- cells and antibody-producing B-cells [7, 25, 62]. The
activation of B cells through MYD88/TLR7-dependent
signalling pathway by RNA may produce a stimulus
to regulate adaptive immunity. A schematic diagram
indicating the mechanism of action of mRNA vaccines in
host immune system is shown as Figure 1.
mRNA Vaccines Adjuvants
As discussed earlier, mRNA vaccines are found
to possess self-adjuvanting property. mRNA vaccines
supplemented with the adjuvant molecules are used to
stimulate CTL activity and pAPCs. Some of the adjuvant
molecules supplemented with mRNA vaccines are
protamine, CPG motifs, poly I:C RNA, invariant chain/
LAMP-1, GM-CSF and Co-stimulatory molecules like
CD40. Among these Adjuvants, GM-CSF mRNA and
CD40 mRNA improved the induction of CTL activity and
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 Citation: Gnanavel Venkatesan (2017) mRNA Vaccines: A Mini Review. SF Virol Res J 2:1.

Figure 1: Schematic Diagram Showing the Preparation of mRNA Vaccines and its Mechanism of Action on Host Immune System after Delivery

pAPCs respectively [63-65]. include prophylactic and therapeutic vaccines, cancer

immunotherapy, allergy tolerization, protein replacement,
Clinical Applications of mRNA Vaccines genome engineering, gene editing, genetic reprogramming
The clinical applications of the mRNA of cells and tissue engineering. Potenatial broad area of
application of mRNA vaccines is depicted as Figure 2.

Figure 2: Potentials of mRNA Vaccines in Biomedical Sciences

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 Citation: Gnanavel Venkatesan (2017) mRNA Vaccines: A Mini Review. SF Virol Res J 2:1.

Briefly, the applications of mRNA vaccines in different mRNA vaccination using three different influenza antigens,
biomedical field is mentioned as below. namely HA, NA, and NP is found to protect against the
clinical disease. This new vaccine method induced strong
Infectious Diseases antigen-specific B and T cell responses demonstrating
For vaccination against the infectious diseases, that mRNA vaccine is superior for vaccination against
mRNA encoded with the virus associated antigens is infectious pathogens and potentially other vaccine targets.
injected and the first mRNA vaccine protective efficacy mRNA vaccines for some of the infectious diseases like
was demonstrated against influenza as a paradigm [66]. The dengue virus, human papilloma virus, cytomegalovirus,
Table 3: Applications for mRNA Vaccines, Targeted Antigens and their Methods of Delivery

Purpose Antigen Method

Infectious disease -virus-associated antigens mRNA injection
vaccines -Ex vivo DCs transfected mRNA
injection
Cancer Immunotherapy -Standardized preselected -mRNA injection
-Individualized -Ex vivo DCs transfected mRNA
shared antigens/neo antigens injection
-Ex vivo T cells transfected mRNA
injection
Allergy tolerization -Allergens -mRNA injection
Protein replacement -Associated proteins -Ex vivo transfection
(vasopressin, P-selectin, -Ex vivo DCs transfected mRNA
VEGF-A, Erythropoietin) injection
-Ex vivo monocytes, macrophages and
MSCs transfected mRNA injection
Gene editing and genome engineering -Nucleases and transposases -Ex vivo transfection
-Ex vivo gene defects -gene editing
-Ex vivo autologous/allogenic T cells-
gene editing
Genetic reprogramming -Transcription factors -Ex vivo transfection
of cells and tissue -progerin
engineering

DC: Dendritic Cell; VEGFA: Vascular Endothelial Growth Factor A; MSC: Mesenchymal Stem Cell.

influenza, ebola virus, entero virus, rabies and HIV are
under pre-clinical trials as listed in Table 3.
Cancer Immunotherapy
mRNA encoded with a tumour associated antigens
(TAA) or total tumor RNA [6] can be then delivered to
the host in order to elicit an immune response against the
antigen of interest. Similarly, mRNA encoded with chimeric
antigen receptor (CAR) or TAA-specific T cell receptor
(TCR) has been transfected into natural killer cells or T
cells by electro oration [67]. Transfected cells carrying such
mRNA-encoded receptors are able to recognize and kill
tumor cells that express the target antigen. By this mRNA
encoded with various antigen-specific receptors and their
antitumor activity was evaluated in animal models [68, 69].
The mRNA based vaccines for cancer immunotherapy in
clinical trialsinclude prostate cancer, colorectal carcinoma,
melanoma, glioblastoma, hepatocellular carcinoma and
acute lymphoblastic leukaemia [57].
Allergy Tolerization
The immunoglobulin E (IgE) mediated type
I allergic diseases are treated with antigen-specific
immunotherapy. As the mRNA has the strong TH1
immuno stimulatory capacity [70], encoded mRNA can
induce IgG antibodies and T cell response that compete
with the binding sites in IgE antibodies.
Genome Editing
Genome editing is the best alternative for the gene

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 Citation: Gnanavel Venkatesan (2017) mRNA Vaccines: A Mini Review. SF Virol Res J 2:1.
therapy. Transcription activator-like effectors nucleases
(TALENs), zinc finger nucleases (ZFNs) and clustered
regularly spaced short palindromic repeat-CRISPR-
associated protein 9 (CRISPR-Cas9) are the powerful
tools for site-specific modification of genomes [71-73].
But these methods have disadvantages like nonspecific
editing which can be minimized by mRNAs encoded
with ZFNs, TALENs and Cas9 that can edit genomes by
disrupting or integrating sequences [57, 74-77]. Similarly,
transposase-encoded mRNA can be used for transposon-
mediated stable gene transfer [56].
Protein Replacement Therapy
The proteins which are not expressed, non-
functional foreign protein can be supplemented by protein
replacement therapy through encoded mRNAs. As an
example, mRNA encoded with surfactant protein B (SPB)
was used against the congenital lethal lung disease caused
by the lack of the SPB protein [78], Regulatory T cell
transcription factor fork head box protein P3 (FOXP3)
used against the airway hyperresponsiveness and allergen-
induced tissue inflammation [79], vascular endothelial
growth factor A (VEGF-A) against myocardial infarction in
mice [80]. For mRNA based protein replacement delivery,
post-translational modifications have to be considered
like proteolytic processing and protein convertases or
endoprotease for protein cleavage.
Reprogramming of Cells
mRNA is used to modulate the cell phenotype
and cell function. mRNA encoded with Yamanaka stem
cell factors are inducing pluripotency and also used for
differentiation of induced pluripotent stem cells (iPSCs)
[81, 82]. For an example, mRNA encoded with myoblast
determination protein into iPSCs results in the direct
differentiation of myocyte-like cells.
Conclusion
In the initial pre-clinical studies, it was clear that
mRNA vaccines are safe, cost-effective and do not require
the cold chain. The activity observed by mRNA vaccines in
prophylactic and therapeutic vaccines and immunotherapy
in the models have high impressive effects. mRNA
based vaccines will become a groundbreaking platform
for vaccination against infectious diseases and cancer
immunotherapy in future area of immunoprophylaxis.
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