How mRNA Vaccines Work – Gene Transcription And Translation

Conventional vaccines typically involve growing a virus in various cell lines, injecting a part of the virus into the host, and relying on the host to mount an immunologic response (ie, create antibodies and “memory”) for the next time the virus is encountered. This process can be time-consuming, expensive, and hazardous when scaling up production.

In contrast, the COVID-19 vaccines by Pfizer and Moderna are messenger RNA (mRNA) vaccines. This approach is faster, safer, cheaper, and widely scalable. The genetic sequence of a portion of the virus (in this case, SARS-CoV-2’s spike protein) is determined and the corresponding mRNA sequence is generated in laboratories. This mRNA relies on the cell’s normal machinery (namely ribosomes) to translate it into the protein.

DNA is transcribed into RNA in a cell’s nucleus. RNA is translated into proteins by the cell’s ribosomes. That’s what gene expression boils down to. Remember, this is what your body already does for thousands of proteins.

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TRANSCRIPTION – THE LANGUAGE

The human genome consists of the entire set of nucleic acid sequences spread over 23 paired chromosomes in every single one of our cells. The genome has over 20,000 genes which each code for proteins like receptors, enzymes, ion channels, etc. Much of the genome is not actually involved in coding for protein but provides stability and regulatory functions. Additionally, not all genes are expressed in every cell (ie, kidney cells express different genes than brain cells).

When a gene needs to be translated to a protein, the relevant portion of the double-stranded DNA helix is unwound and an enzyme called RNA polymerase creates a complementary strand of pre-mRNA. This is called transcription. The initial pre-mRNA undergoes processing (sequences called introns are spliced out, a poly(A) tail is added to one end, and a 7-methylguanosine cap is added to the other end). These events signal the mRNA is ready to be exported out of the nucleus into the cell’s cytosol for the next step – translation! There are untranslated regions (UTRs) of mRNA which are very important in regulating the translation process too.

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TRANSLATION TO PROTEINS

mRNA is a language of four “letters” (or what are known as nucleotides): adenine (A), uracil (U), guanine (G), and cytosine (C). DNA shares the same language except for thymine (T) replaces uracil. A and U (or T) pair with two hydrogen bonds. G and C pair with three hydrogen bonds. These letters make a language of three-letter words (called codons). For example AAU-AUG-UAC-GGA-GGG-GAC-UGA-CUU (24 nucleotides, 8 codons). In this language, AUG is the start codon and UAA, UGA, or UAG are all stop codons. In other words, AUG starts the sentence, and UAA, UGA, or UAG are all punctuation options at the end.

Now let’s introduce a group of translators: transfer ribonucleic acids (tRNAs). These molecules contain different anticodon regions which complement the codons on the mRNA. For example, a codon that reads CCA will “link” to a tRNA anticodon which reads GGU. The other part of tRNA carries an amino acid – the building blocks of proteins. The following diagram shows how different codons code for different amino acids.

For example, the start codon (AUG) codes for the amino acid methionine (Met). The codons GUU, GUC, GUA, and GUG all code for the amino acid valine. In other words, there are four different ways to write for valine in the mRNA language. As the ribosome moves from codon-to-codon, tRNAs are adding amino acids to a growing polypeptide chain. Ultimately when the ribosome arrives at a stop codon, the protein is released.

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mRNA Vaccines

mRNA vaccines rely on the aforementioned machinery which our cells normally use to create proteins from genetic material.

mRNA is fairly unstable and easily degraded by the body, so much of the vaccine development involves transporting the mRNA vaccine into the cell for ribosomes and tRNAs to read. This is done by using lipid nanoparticles to “shield” the mRNA and modifying the nitrogenous base/pentose sugar structure of the nucleotides (remember, the letters in the mRNA language). Furthermore, the vaccines are stored and transported at very cold temperatures (-70°C for the Pfizer vaccine, -20°C for the Moderna vaccine) for additional stability.

This mRNA codes for receptor binding domains of SARS-CoV-2’s spike protein. After this mRNA has been translated by ribosomes, the synthesized protein creates a robust CD4⁺ and CD8⁺ T cell response as well as antibodies! Furthermore, the initial mRNA vaccine ultimately is degraded and is not incorporated into the cellular genome.

Many questions remain to be answered regarding the duration of antibody titers and long-term side effects, but hopefully, you found this overview helpful! Drop me a comment below with questions! 🙂