An explanation of the science behind mRNA vaccines, and why Moderna and Pfizer are interchangeable

By Charlotte Volk

The basic “instruction manual” or “source code” of life is deoxyribonucleic acid, or DNA. DNA is made up of nucleotides, each consisting of a sugar, a phosphate group, and one of four different molecules called bases: adenine (A), thymine (T), cytosine (C), and guanine (G). These molecules match up with each other – A with T, and C with G. Ribonucleic acid, or RNA, is also made up of nucleotides, but substitutes a different base called uracil (U) for T. There are several types of RNA, but the important type here is messenger RNA, or mRNA. DNA is found in the nucleus of the cell and is too fragile to leave. Therefore, a messenger (hence the name) or intermediary is required to carry the instructions from DNA out of the cell: mRNA is this intermediary. Once the mRNA leaves the cell, a protein complex called the ribosome reads the mRNA sequence in groups of three nucleotides, called codons. For each codon read by the ribosome, it creates an amino acid. These amino acid sequences are then folded and shaped in various different ways to form proteins. However, there is one important thing to keep in mind. Since there are four different bases (A, U, C, and G), there are 4^3=64 different ways to arrange them in groups of three, and thus 64 different codons. However, there are only 20 amino acids. This creates redundancy, where several different codons code for the same amino acids. For example, the mRNA sequences AUC GAU and AUU GAC both code for isoleucine-asparagine [1, 2].

 

In order to develop a vaccine for SARS-CoV-2, scientists needed to get the immune system to recognize and develop a defense against the spike protein on the surface of the viral cells. The spike proteins themselves cannot replicate, and thus cannot give us COVID-19, but merely train the immune system to recognize and attack the SARS-CoV-2 virus. The mRNA itself degrades quickly, and cannot self-replicate, or affect your DNA [3, 4]. However, if the mRNA sequence of the spike protein was directly included in a vaccine, the immune system would recognize this mRNA as foreign to the body and attack it before it could be translated into the spike protein. Fortunately, researchers discovered that replacing every U nucleotide in mRNA with a modified base called 1-methyl-3’-pseudouridylyl would confuse the immune system enough to prevent its destruction [5, 6]. Instead, the modified mRNA sequence would be safely translated by the cell into the spike protein.

 

However, there is still a problem with this approach. On the coronavirus itself, the spike proteins retain their shape because they are attached to the body of the virus. However, when the spike proteins assemble independently from the rest of the virus, as in the vaccine, they cannot properly maintain their structure and soon collapse. This is an issue because the immune system must presented with the spike protein in the same form as it will be on the SARS-CoV-2 virus itself, so it can create antibodies against the correct viral spike protein and not the collapsed version. Several years ago, while studying MERS and SARS, which are both coronaviruses, researchers at the McLellan lab at the University of Texas at Austin discovered a way to slightly modify the mRNA sequence of the spike protein so that it will assemble into the proper structure on its own. They did this by modifying two codons in the viral mRNA sequence, changing two of the amino acids at the base of the spike protein to proline. Proline is a large, rigid amino acid, which serves as a prop or splint to force the spike protein into the correct structure, even when detached from the virus. This allows the immune system to make antibodies against the correct spike protein, rather than the collapsed version, ensuring the vaccine’s efficacy [7].

 

Researchers at Stanford have reverse-engineered the sequences of both the Moderna and Pfizer vaccine [8]. Dr. Jeff Gilchrist, an adjunct research professor in Systems and Computer Engineering at Carleton University, whose research interests include biomedical informatics and medical information systems, was able to isolate the spike encoding region of both vaccine mRNA sequences. In collaboration with Ryan Imgrund, a biostatistician, and Dr. Wesley Hung, a neuroscientist, he confirmed that the spike protein amino acid sequence of the Pfizer vaccine and the Moderna vaccine were identical, even though the mRNA sequences differed slightly. This is because of the redundancy in codons explained above. For example, as Dr. Gilchrist explains, Pfizer has the codons AGA ACA CCT, which are encoded as arginine-threonine-proline. Moderna has the codons CGG ACC CCA, which are also encoded as arginine-threonine-proline. If you had enough time and patience, you could replicate these results yourself using the codon table shown on the following page! This confirms that Moderna and Pfizer are using the exact same spike protein from the McLellan lab, and that the only differences between the two vaccines are the specific dosage, buffers used in the vaccine, and time between shots. The reason that these vaccines do not just merely duplicate the viral spike protein mRNA sequence is that mRNA with a higher GC content, which means a higher amount of G and C bases, is more efficiently translated into a protein. So, in the vaccines, U bases have generally been changed to C or G bases wherever possible to improve efficiency [9].

 

Recently, there has been some confusion over the interchangeability of mRNA vaccines. While public health officials and the scientific community agree that Moderna and Pfizer vaccines are interchangeable [10], it sometimes helps to understand the science behind it. Hopefully, this explanation is useful to people seeking to understand more about these vaccines. I’ll end this with a personal plea – please get vaccinated, as soon as you can, with whichever vaccine is available to you. I personally got Pfizer for my first dose, and Moderna for my second dose (both doses were administered by one of the biggest hospitals in Canada). People are still dying, and the prevalence of the Delta variant in Canada means that getting your second dose is more necessary than ever to protect yourselves and others.

 

 

[1]       Nature Education, “Unit 2: How do cells decode genetic information into functional proteins?,” Essentials of Cell Biology Nature Education, 2010. [Online]. Available: https://www.nature.com/scitable/ebooks/essentials-of-cell-biology-14749010/122996756/

[2]       Wikipedia. “DNA and RNA codon tables.” https://en.wikipedia.org/wiki/DNA_and_RNA_codon_tables(accessed July 25, 2021).

[3]      Reuters Fact Check, “Fact Check-COVID-19 vaccines are not infectious; you can’t transmit the vaccine to an unvaccinated individual,” Reuters, May 4, 2021. [Online]. Available: https://www.reuters.com/article/factcheck-vaccines-transmission-idUSL1N2MR1VU

[4]       Reuters Fact Check, “Fact Check-mRNA cannot be ‘spread’ from COVID-19 vaccines; mRNA is not contagious and it is destroyed by cells shortly after injection ” Reuters. [Online]. Available: https://www.reuters.com/article/factcheck-covid-mrna-idUSL1N2LS337

[5]       K. Kariko, M. Buckstein, H. Ni, and D. Weissman, “Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA,” Immunity, vol. 23, no. 2, pp. 165-75, Aug 2005, doi: 10.1016/j.immuni.2005.06.008.

[6]       World Health Organization. “Messenger RNA encoding the full-length SARS-CoV-2 spike glycoprotein.” https://web.archive.org/web/20210105162941/https://mednet-communities.net/inn/db/media/docs/11889.doc (accessed July 25, 2021).

[7]       C. L. Hsieh et al., “Structure-based design of prefusion-stabilized SARS-CoV-2 spikes,” Science, vol. 369, no. 6510, pp. 1501-1505, Sep 18 2020, doi: 10.1126/science.abd0826.

[8]      D. E. Jeong et al. Assemblies of putative SARS-CoV2-spike-encoding mRNA sequences for vaccines BNT-162b2 and mRNA-1273 [Online] Available: https://github.com/NAalytics/Assemblies-of-putative-SARS-CoV2-spike-encoding-mRNA-sequences-for-vaccines-BNT-162b2-and-mRNA-1273/blob/main/Assemblies%20of%20putative%20SARS-CoV2-spike-encoding%20mRNA%20sequences%20for%20vaccines%20BNT-162b2%20and%20mRNA-1273.docx.pdf

[9]       Gilchrist, J. [@jeffgilchrist], “COVID-19: Pfizer and Moderna vaccines reverse engineered,” Twitter, Jun. 17, 2021. [Online] Available: https://mobile.twitter.com/jeffgilchrist/status/1405482204810076163

[10]     National Advisory Committe on Immunization. “Summary of NACI rapid response of June 1, 2021.” Government of Canada. https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/recommendations-use-covid-19-vaccines/rapid-response-interchangeability/summary.html (accessed July 25, 2021, 2021).

Authors

*

Top