RNA vaccine

From Wikipedia, the free encyclopedia

Jump to navigationJump to search
See also: DNA vaccine
This article is missing information about storage temperature. Please
expand the article to include this information. Further details may exist
on the talk page. (November 2020)

An RNA vaccine or mRNA (messenger RNA) vaccine is a new type of vaccine for
providing acquired immunity through an RNA containing vector, such as lipid
nanoparticles.[1]
Just like normal vaccines, RNA vaccines are intended to induce the production
of antibodies which will bind to potential pathogens and activate T-cells that recognize
specific peptides presented on MHC molecules. The RNA sequence codes
for antigens, proteins that are identical or resembling those of the pathogen. Upon the
delivery of the vaccine into the body, this sequence is translated by the host cells to
produce the encoded antigens, which then stimulate the body's adaptive immune
system to produce antibodies against the pathogen.
Another form of the mRNA vaccination is one in which the mRNA encodes for a fully
human IgG antibody. In this form, the mRNA codes for antibodies that are identical or
resembling those of the antibodies found in a patient with a prior history of
potent immunity.[2]
Although mRNA vaccines have entered clinical studies, there are currently no RNA
vaccines approved for human use. In spite of the inability of these vaccines to reach the
market, RNA vaccines have been understood to offer multiple advantages over DNA
vaccines in terms of production, administration, and safety. [3][4] They have also shown to
be promising in clinical trials involving humans.[4] RNA vaccines are also thought to have
the potential to be used for cancer in addition to infectious diseases.[5] In response to
the COVID-19 pandemic, RNA vaccines are currently under development[6] to assist in
curbing or even potentially eliminating the pandemic.

Contents

• 1Advantages over DNA vaccines

• 2Adverse effects and risks
• 3Delivery
o 3.1Ex vivo
o 3.2In vivo
▪ 3.2.1Naked mRNA injection
▪ 3.2.2Lipid nanoparticles
• 4Viral vectors
• 5History
• 6See also
 • 7References

Advantages over DNA vaccines[edit]

In addition to sharing the advantages of DNA vaccines over protein vaccines, RNA
vaccination offers further benefits that make it a more viable alternative to DNA
vaccines. Some of these are outlined below.

• The mRNA is translated in the cytosol. Therefore, there is no need for the
RNA to enter the cell nucleus, and the risk of being integrated to the
host genome is averted.[1]
• Modified nucleosides (e.g. pseudouridines, 2'-O-methylated nucleosides) can
be incorporated to mRNA in order to suppress immune response stimulation
to avoid immediate degradation and produce a more persistent effect through
enhanced translation capacity.[7][8][9]
• The open reading frame (ORF) and untranslated regions (UTR) of mRNA can
be optimized for different purposes (which is a process called sequence
engineering of mRNA), for example through enriching the guanine-cytosine
content or choosing specific UTRs known to increase translation. [10]
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.[11][12]

Adverse effects and risks[edit]

• The mRNA strand in the vaccine may elicit an unintended immune reaction.
To minimise this, the mRNA vaccine sequences are designed to mimic those
produced by mammalian cells (for example monkey cells). [13]
• A possible concern could be that some mRNA-based vaccine platforms
induce potent type I interferon responses, which have been associated not
only with inflammation but also potentially with autoimmunity. Thus,
identification of individuals at an increased risk of autoimmune reactions
before mRNA vaccination may allow reasonable precautions to be taken. [14]

Delivery[edit]
The methods of delivery can be broadly classified by whether the RNA transfer to cells
happens within (in vivo) or outside (ex vivo) the organism.
Ex vivo[edit]
Dendritic cells (DCs) are a type of immune cells that display antigens on their surfaces,
leading to interactions with T cells to initiate an immune response. DCs can be collected
from patients and be programmed with mRNA. Then, they can be re-administered back
into patients to create an immune response. [15]
In vivo[edit]
Since the discovery of in vitro transcribed mRNA expression in vivo following direct
administration, in vivo approaches have become more and more attractive. [16] They offer
some advantages over ex vivo methods, most significantly by avoiding the cost of
harvesting and adapting DCs from patients and by imitating a regular infection.
However, there are multiple obstacles for these methods that are yet to be overcome for
RNA vaccination to be a potent procedure. Evolutionary mechanisms that prevent the
infiltration of unknown nucleic material and promote degradation by RNases should be
avoided in order to initiate translation. In addition, the mobility of RNA on its own is
completely dependent on regular cell processes because it is too heavy to diffuse,
consequently it is bound to be eliminated, halting translation.
Naked mRNA injection[edit]
The mode of mRNA uptake has been known for over a decade, [17][18] and the use of RNA
as a vaccine tool was discovered in the 1990s in the form of self-amplifying mRNA.[19] 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. Kreiter et al. demonstrated, in
comparing different routes, that lymph node injection leads to the largest T cell
response.[20] The mechanisms and consequently the evaluation of self-amplifying mRNA
could be different, as they are fundamentally different by being a much bigger molecule
in size.[1]
Lipid nanoparticles[edit]
The idea of encapsulating mRNA in lipid nanoparticles has been attractive for a number
of reasons.[21] Principally, the lipid provides a layer of protection against degradation,
allowing more robust translational output. In addition, the customization of the lipid 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.[22] The nanoparticles can be administered to the
body and transported via multiple routes, such as intravenously or through the lymphatic
system.

Viral vectors[edit]
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, alphaviruses and rhabdoviruses, each of which can
differ in structure and function.[23] Many clinical studies have utilized such viruses to
attempt combating a range of diseases in model animals such
as mice, chicken and primates.[24][25][26]

History[edit]
Previous attempts included clinical trials in the late 1990s using dendritic cells against
metastatic prostate tumors[27] and in the early 2000s considering the direct injection of
mRNA as a prophylactic against melanoma.[28] In response to the COVID-19 pandemic,
RNA vaccines are currently under development[29] to assist in curbing or even potentially
eliminating the pandemic.

See also[edit]
• DNA vaccination
• Vaccine
• Immune system

References[edit]
1. ^ Jump up to:a b c Verbeke, Rein; Lentacker, Ine; De Smedt, Stefaan C.; Dewitte, Heleen
(October 2019). "Three decades of messenger RNA vaccine development". Nano Today. 28:
100766. doi:10.1016/j.nantod.2019.100766.
2. ^ "Moderna Announces Dosing of the First Monoclonal Antibody Encoded by mRNA in a
Clinical Trial". businesswire.com. Retrieved 25 July 2020.
3. ^ Pascolo, Steve (2006). "Vaccination with Messenger RNA". DNA Vaccines. Methods in
Molecular Medicine. 127. pp. 23–40. doi:10.1385/1-59745-168-1:23. ISBN 1-59745-168-
1. PMID 16988444.
4. ^ Jump up to:a b Armbruster; Jasny; Petsch (2019-09-27). "Advances in RNA Vaccines for
Preventive Indications: A Case Study of A Vaccine Against Rabies". Vaccines. 7 (4):
132. doi:10.3390/vaccines7040132. PMC 6963972. PMID 31569785.
5. ^ McNamara, Megan A.; Nair, Smita K.; Holl, Eda K. (2015). "RNA-Based Vaccines in Cancer
Immunotherapy". Journal of Immunology Research. 2015:
794528. doi:10.1155/2015/794528. PMC 4668311. PMID 26665011.
6. ^ "An updated guide to the coronavirus drugs and vaccines in development". STAT. 2020-03-
19. Retrieved 2020-03-21.
7. ^ Karikó, Katalin; Buckstein, Michael; Ni, Houping; Weissman, Drew (August 2005).
"Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside
Modification and the Evolutionary Origin of RNA". Immunity. 23 (2): 165–
175. doi:10.1016/j.immuni.2005.06.008. ISSN 1074-7613. PMID 16111635.
8. ^ Karikó, Katalin; Muramatsu, Hiromi; Ludwig, János; Weissman, Drew (2011-09-
02). "Generating the optimal mRNA for therapy: HPLC purification eliminates immune
activation and improves translation of nucleoside-modified, protein-encoding mRNA". Nucleic
Acids Research. 39 (21): e142. doi:10.1093/nar/gkr695. ISSN 1362-
4962. PMC 3241667. PMID 21890902.
9. ^ Pardi, Norbert; Weissman, Drew (2016-12-17), "Nucleoside Modified mRNA Vaccines for
Infectious Diseases", RNA Vaccines, Springer New York, 1499, pp. 109–
121, doi:10.1007/978-1-4939-6481-9_6, ISBN 978-1-4939-6479-6, PMID 27987145
10. ^ Schlake, Thomas; Thess, Andreas; Fotin-Mleczek, Mariola; Kallen, Karl-Josef (November
2012). "Developing mRNA-vaccine technologies". RNA Biology. 9 (11): 1319–
1330. doi:10.4161/rna.22269. ISSN 1547-6286. PMC 3597572. PMID 23064118.
11. ^ Berglund, Peter (June 1998). "Enhancing immune responses using suicidal DNA
vaccines". Nature Biotechnology. 16 (6): 562–5. doi:10.1038/nbt0698-562. PMID 9624688.
12. ^ Vogel, Annette B.; Lambert, Laura; Kinnear, Ekaterina; Busse, David; Erbar, Stephanie;
Reuter, Kerstin C.; Wicke, Lena; Perkovic, Mario; Beissert, Tim; Haas, Heinrich; Reece,
Stephen T. (February 2018). "Self-Amplifying RNA Vaccines Give Equivalent Protection
against Influenza to mRNA Vaccines but at Much Lower Doses". Molecular Therapy. 26 (2):
446–455. doi:10.1016/j.ymthe.2017.11.017. ISSN 1525-
0016. PMC 5835025. PMID 29275847.
13. ^ "RNA vaccines: an introduction". PHG Foundation. Retrieved 13 April 2020.
14. ^ Pardi, Norbert; Hogan, Michael J.; Porter, Frederick W.; Weissman, Drew (April
2018). "mRNA vaccines — a new era in vaccinology". Nature Reviews Drug
Discovery. 17 (4): 261–279. doi:10.1038/nrd.2017.243. PMC 5906799. PMID 29326426.
15. ^ Benteyn, Daphné; Heirman, Carlo; Bonehill, Aude; Thielemans, Kris; Breckpot, Karine
(2014-09-08). "mRNA-based dendritic cell vaccines". Expert Review of Vaccines. 14 (2):
161–176. doi:10.1586/14760584.2014.957684. ISSN 1476-0584. PMID 25196947.
16. ^ Wolff, J.; Malone, R.; Williams, P; Chong, W; Acsadi, G; Jani, A; Felgner, P. (1990-03-23).
"Direct gene transfer into mouse muscle in vivo". Science. 247 (4949): 1465–
1468. Bibcode:1990Sci...247.1465W. doi:10.1126/science.1690918. ISSN 0036-
8075. PMID 1690918.
17. ^ Probst, J.; Weide, B.; Scheel, B.; Pichler, B. J.; Hoerr, I.; Rammensee, H.-G.; Pascolo, S.
(August 2007). "Spontaneous cellular uptake of exogenous messenger RNA in vivo is nucleic
acid-specific, saturable and ion dependent". Gene Therapy. 14 (15): 1175–
1180. doi:10.1038/sj.gt.3302964. PMID 17476302.
18. ^ Lorenz, Christina; Fotin-Mleczek, Mariola; Roth, Günter; Becker, Christina; Dam, Thanh
Chau; Verdurmen, Wouter P. R.; Brock, Roland; Probst, Jochen; Schlake, Thomas (July
2011). "Protein expression from exogenous mRNA: Uptake by receptor-mediated endocytosis
and trafficking via the lysosomal pathway". RNA Biology. 8 (4): 627–
636. doi:10.4161/rna.8.4.15394. ISSN 1547-6286. PMID 21654214.
19. ^ Zhou & Berglund (1994). "Self-replicating Semliki Forest virus RNA as recombinant
vaccine". Vaccine. 12 (16): 1510–1514. doi:10.1016/0264-410x(94)90074-4. PMID 7879415.
20. ^ Kreiter, S.; Selmi, A.; Diken, M.; Koslowski, M.; Britten, C. M.; Huber, C.; Tureci, O.; Sahin,
U. (2010-11-02). "Intranodal Vaccination with Naked Antigen-Encoding RNA Elicits Potent
Prophylactic and Therapeutic Antitumoral Immunity". Cancer Research. 70 (22): 9031–
9040. doi:10.1158/0008-5472.can-10-0699. ISSN 0008-5472. PMID 21045153.
21. ^ Reichmuth, Andreas M; Oberli, Matthias A; Jaklenec, Ana; Langer, Robert; Blankschtein,
Daniel (May 2016). "mRNA vaccine delivery using lipid nanoparticles". Therapeutic
Delivery. 7 (5): 319–334. doi:10.4155/tde-2016-0006. ISSN 2041-
5990. PMC 5439223. PMID 27075952.
22. ^ Paunovska, Kalina; Sago, Cory D.; Monaco, Christopher M.; Hudson, William H.; Castro,
Marielena Gamboa; Rudoltz, Tobi G.; Kalathoor, Sujay; Vanover, Daryll A.; Santangelo, Philip
J.; Ahmed, Rafi; Bryksin, Anton V. (2018-03-14). "A Direct Comparison of in Vitro and in Vivo
Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak
Correlation". Nano Letters. 18 (3): 2148–
2157. Bibcode:2018NanoL..18.2148P. doi:10.1021/acs.nanolett.8b00432. ISSN 1530-
6984. PMC 6054134. PMID 29489381.
23. ^ Lundstrom, Kenneth (2019-03-01). "RNA Viruses as Tools in Gene Therapy and Vaccine
Development". Genes. 10 (3): 189. doi:10.3390/genes10030189. ISSN 2073-
4425. PMC 6471356. PMID 30832256.
24. ^ Huang, Tiffany T.; Parab, Shraddha; Burnett, Ryan; Diago, Oscar; Ostertag, Derek; Hofman,
Florence M.; Espinoza, Fernando Lopez; Martin, Bryan; Ibañez, Carlos E.; Kasahara,
Noriyuki; Gruber, Harry E. (February 2015). "Intravenous Administration of Retroviral
Replicating Vector, Toca 511, Demonstrates Therapeutic Efficacy in Orthotopic Immune-
Competent Mouse Glioma Model". Human Gene Therapy. 26 (2): 82–
93. doi:10.1089/hum.2014.100. ISSN 1043-0342. PMC 4326030. PMID 25419577.
25. ^ Schultz-Cherry, Stacey; Dybing, Jody K.; Davis, Nancy L.; Williamson, Chad; Suarez, David
L.; Johnston, Robert; Perdue, Michael L. (December 2000). "Influenza Virus (A/HK/156/97)
Hemagglutinin Expressed by an Alphavirus Replicon System Protects Chickens against
Lethal Infection with Hong Kong-Origin H5N1 Viruses". Virology. 278 (1): 55–
59. doi:10.1006/viro.2000.0635. ISSN 0042-6822. PMID 11112481.
26. ^ Geisbert, Thomas W.; Feldmann, Heinz (November 2011). "Recombinant Vesicular
Stomatitis Virus–Based Vaccines Against Ebola and Marburg Virus Infections". The Journal
of Infectious Diseases. 204 (suppl_3): S1075–S1081. doi:10.1093/infdis/jir349. ISSN 0022-
1899. PMC 3218670. PMID 21987744.
27. ^ Heiser, Axel; Coleman, Doris; Dannull, Jens; Yancey, Donna; Maurice, Margaret A.; Lallas,
Costas D.; Dahm, Philipp; Niedzwiecki, Donna; Gilboa, Eli; Vieweg, Johannes (February
2002). "Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate
 CTL responses against metastatic prostate tumors". The Journal of Clinical
Investigation. 109 (3): 409–417. doi:10.1172/JCI14364. ISSN 0021-9738. PMID 11828001.
28. ^ Weide, Benjamin; Carralot, Jean-Philippe; Reese, Anne; Scheel, Birgit; Eigentler, Thomas
Kurt; Hoerr, Ingmar; Rammensee, Hans-Georg; Garbe, Claus; Pascolo, Steve (February
2008). "Results of the first phase I/II clinical vaccination trial with direct injection of
mRNA". Journal of Immunotherapy (Hagerstown, Md.: 1997). 31 (2): 180–
188. doi:10.1097/CJI.0b013e31815ce501. ISSN 1524-9557. PMID 18481387.
29. ^ "An updated guide to the coronavirus drugs and vaccines in development". STAT. 2020-03-
19. Retrieved 2020-03-21.