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Caleb Peña

Professor Andaluz

English 100

11 December 2020

mRNA Vaccines ― A New Era In Vaccinology

Vaccines prevent many millions of illnesses and save numerous lives every year. As a result of

widespread vaccine use, the smallpox virus has been completely eradicated and the incidence of

polio, measles, and other childhood diseases has been drastically reduced around the world.

Conventional vaccine approaches, such as live attenuated and inactivated pathogens and subunit

vaccines, provide durable protection against a variety of dangerous diseases. Despite this

success, there remain major hurdles to vaccine development against a variety of infectious

pathogens, especially those better able to evade the adaptive immune response4. Moreover, for

most emerging virus vaccines, the main obstacle is not the effectiveness of conventional

approaches but the need for more rapid development and large-scale deployment. Finally,

conventional vaccine approaches may not be applicable to non-infectious diseases, such as

cancer. The development of more potent and versatile vaccine platforms is therefore urgently

needed.

Nucleic acid therapeutics have emerged as promising alternatives to conventional vaccine

approaches. The first report of the successful use of in vitro transcribed (IVT) mRNA in animals
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was published in 1990 when reporter gene mRNAs were injected into mice and protein

production was detected. A subsequent study in 1992 demonstrated that administration of

vasopressin-encoding mRNA in the hypothalamus could elicit a physiological response in rats6.

However, these early promising results did not lead to substantial investment in developing

mRNA therapeutics, largely owing to concerns associated with mRNA instability, high innate

immunogenicity, and inefficient in vivo delivery. Instead, the field pursued DNA-based and

protein-based therapeutic approaches.

Over the past decade, major technological innovation and research investment have enabled

mRNA to become a promising therapeutic tool in the fields of vaccine development and protein

replacement therapy. The use of mRNA has several beneficial features over subunit, killed, and

live attenuated virus, as well as DNA-based vaccines. First, safety: as mRNA is a non-infectious,

non-integrating platform, there is no potential risk of infection or insertional mutagenesis.

Additionally, mRNA is degraded by normal cellular processes, and its in vivo half-life can be

regulated through the use of various modifications and delivery methods. The inherent

immunogenicity of the mRNA can be down-modulated to further increase the safety profile.

Second, efficacy: various modifications make mRNA more stable and highly translatable.

Efficient in vivo delivery can be achieved by formulating mRNA into carrier molecules, allowing

rapid uptake and expression in the cytoplasm. mRNA is the minimal genetic vector; therefore,

anti-vector immunity is avoided, and mRNA vaccines can be administered repeatedly. Third,
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production: mRNA vaccines have the potential for rapid, inexpensive, and scalable

manufacturing, mainly owing to the high yields of in vitro transcription reactions.

The mRNA vaccine field is developing extremely rapidly; a large body of preclinical data has

accumulated over the past several years, and multiple human clinical trials have been initiated. In

this Review, we discuss current mRNA vaccine approaches, summarize the latest findings,

highlight challenges and recent successes, and offer perspectives on the future of mRNA

vaccines. The data suggest that mRNA vaccines have the potential to solve many of the

challenges in vaccine development for both infectious diseases and cancer.

mRNA is the intermediate step between the translation of protein-encoding DNA and the

production of proteins by ribosomes in the cytoplasm. Two major types of RNA are currently

studied as vaccines: non-replicating mRNA and virally derived, self-amplifying RNA.

Conventional mRNA-based vaccines encode the antigen of interest and contain 5′ and 3′

untranslated regions (UTRs), whereas self-amplifying RNAs encode not only the antigen but

also the viral replication machinery that enables intracellular RNA amplification and abundant

protein expression.

The construction of optimally translated IVT mRNA suitable for therapeutic use has been

reviewed previously. Briefly, IVT mRNA is produced from a linear DNA template using a T7, a
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T3, or an Sp6 phage RNA polymerase. The resulting product should optimally contain an open

reading frame that encodes the protein of interest, flanking UTRs, a 5′ cap, and a poly(A) tail.

The mRNA is thus engineered to resemble fully processed mature mRNA molecules as they

occur naturally in the cytoplasm of eukaryotic cells.

The Complexing of mRNA for in vivo delivery has also been recently detailed. Naked mRNA is

quickly degraded by extracellular RNases17 and is not internalized efficiently. Thus, a great

variety of in vitro and in vivo transfection reagents have been developed that facilitate cellular

uptake of mRNA and protect it from degradation. Once the mRNA transits to the cytosol, the

cellular translation machinery produces protein that undergoes post-translational modifications,

resulting in a properly folded, fully functional protein. This feature of mRNA pharmacology is

particularly advantageous for vaccines and protein replacement therapies that require cytosolic or

transmembrane proteins to be delivered to the correct cellular compartments for proper

presentation or function. IVT mRNA is finally degraded by normal physiological processes, thus

reducing the risk of metabolite toxicity.

A concern that some have had about the mRNA vaccines is that they could change people’s
DNA. But that idea is ‘completely false’ and has ‘no scientific basis’, says Prof. Goldman.

‘The (vaccine) mRNA will not enter the nucleus of the cells, where our DNA is.’

Once the injected mRNA enters a human cell, it degrades quickly and only stays in the body for
a couple of days. This is why people need two injections to develop the best immune response,
he says.
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The vaccine partly works by inducing local inflammatory reactions to trigger the immune
system. This means that it’s normal for many people to experience pain at the site of the injection
and sometimes fever and discomfort for one or two days after the vaccine.

‘This is something that has not been advertised enough,’ says Prof. Goldman.

A November survey in 15 countries found 54% of people were worried about possible side
effects from a Covid-19 vaccine.

One unwanted response to the Pfizer-BioNTech mRNA vaccine came to light during the first day
of mass vaccination in the UK after two people with a history of significant allergies reacted to
the injection. The UK regulatory authority updated its advice to specify that people with a history
of anaphylaxis to medicine or food should not get the shot.
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Works Cited

1. Xu, Shuqin, et al. “MRNA Vaccine Era—Mechanisms, Drug Platform and Clinical

Prospection.” International Journal of Molecular Sciences, vol. 21, no. 18, Sept. 2020, p.

6582. EBSCOhost, doi:10.3390/ijms21186582.

2. How New Technology for a COVID-19 Vaccine Works. AP, 2020. EBSCOhost,

cdnapisec.kaltura.com/p/2503031/sp/250303100/playManifest/entryId/1_3sz9foyr/format

/url/protocol/https.

3. ÇEVİKELLİ YAKUT, Zatiye Ayça, et al. “What We Know about COVID-19 and Its

Treatment.” Journal of Research in Pharmacy, vol. 24, no. 5, Sept. 2020, pp. 602–616.

EBSCOhost, doi:10.35333/jrp.2020.215.

4. “Understanding How COVID-19 Vaccines Work.” Centers for Disease Control and

Prevention, Centers for Disease Control and Prevention, 2 Nov. 2020,

www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/how-they-work.html.

5. “Understanding MRNA COVID-19 Vaccines.” Centers for Disease Control and

Prevention, Centers for Disease Control and Prevention, 23 Nov. 2020,

www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/mrna.html.

6. Whiting, Alex. “Five Things You Need to Know about: mRNA Vaccine Safety.” Horizon,

11 Dec. 2020,

horizon-magazine.eu/article/five-things-you-need-know-about-mrna-vaccine-safety.html.