How Does an mRNA Vaccine Work?

Conventional Vaccines

How does the Oxford/AstraZeneca vaccine work?^[1]

It is based on a harmless adenovirus from a chimpanzee, which has been engineered in the lab to include genes from the coronavirus that causes Covid-19. When the genetically modified adenovirus is injected into human cells, they make coronavirus proteins that prime the immune system to respond to future infections with coronavirus.

Several other Covid-19 vaccines in development, including the Russian Sputnik-V and candidates from Johnson & Johnson of the US and CanSino of China, use adenoviruses.

In contrast, the Moderna and Pfizer/BioNTech vaccines use mRNA technology.

What's mRNA?

mRNA is a molecule used by living cells to turn the gene sequences in DNA into the proteins that are the building blocks of all their fundamental structures. A segment of DNA gets copied (or transcribed) into a piece of mRNA, which in turn gets read by the cell’s tools (i.e., ribosomes) for synthesizing proteins. 

Figure 1.  Assessing Pfizer's mRNA vaccine that targets the SARS-CoV-2 coronavirus (details)

mRNA Vaccine^[2]

The Moderna and Pfizer/BioNTech vaccines use mRNA technology, which carries coronavirus genes into cells in microscopic droplets of oily lipid rather than in another virus (or virus vector).

Moderna’s mRNA-1273 consists of a strand of mRNA that tells the body to produce the spike protein the coronavirus uses to latch onto human cells. If the vaccine works as intended, the body will start producing the proteins soon after injection, prompting the immune system to react and build up protective antibodies that neutralized the virus.

Unlike DNA, a stable molecule, mRNA is notoriously fragile. Numerous enzymes present throughout the body break it down. Making matters worse for vaccine researchers, the immune system is hypervigilant about foreign RNA, identifying and destroying it before it can spur the protein-manufacturing process. In the 1990s, “we couldn’t envision it being feasible,” says Barney Graham.^[3]

In 2005, University of Pennsylvania researchers Katalin Kariko and Drew Weissman found that a slight modification to the mRNA molecule could reduce the immune reaction, making it much more amenable for use in drugs or vaccines. (Since then, scientists have found ways to reduce mRNA’s other vulnerability inside the body, protecting it from enzymes by encapsulating it in lipid nanoparticles.)

At beginning, no one knew whether mRNA technology would work against coronavirus – but it does. It’s an extraordinary moment for science.  It’s so beautifully simple it almost seems like science fiction.  See [9] for a good explanation of how Pfizer's mRNA vaccines work.  Based the author's opinion, he claimed that:

We should all be very grateful, and I am sure the Nobel prizes will arrive in due course.

Pro's and Con's of mRNA Vaccines

Pros

• The great advantages of mRNA vaccines are speed and flexibility. 
• mRNA can be synthesized more rapidly than the viral proteins or whole viruses used in conventional vaccines.
• No finicky live cells or hard-to-handle viruses are needed, and the basic chemistry is straightforward.

Cons

• mRNA's are fragile and need extra cold temperature to preserve and transport (cold chain)
• The Oxford/AstraZeneca vaccine can be kept long term at 2C to 8C, the temperature of a conventional fridge. For comparison, the mRNA vaccines developed by Pfizer/BioNTech and Moderna require much lower temperatures of -70C and -20C respectively.
• mRNA vaccines will be priced at higher prices than Oxford/AstraZeneca vaccine's

Not the First Time

This is not the first time that an mRNA vaccine has been used in humans:^[8]

1. The first human trial is for prostate cancer in 2009
• Overall, that mRNA vaccine was well tolerated and had a good safety profile. 
2. The second first human trial is for rabies in 2013
• The study ran from 2013-2016, and continues to collect long-term safety data. But overall, this vaccine was deemed generally safe and tolerable. 
3. mRNA vaccines are now in use in clinical trials for HIV, the Zika virus, and influenza.

Unknowns of Covid-19 mRNA Vaccines

• Disease prevention and transmission prevention
• How long will protection last, especially in those who are at greatest risk? 
• Are these vaccines efficient enough not only to stop the recipients falling ill when exposed, but also to stop them getting infected altogether – or to reduce the transmission of the virus to others?
• Safety
• Unlike drugs, which are given to treat people who are sick, vaccines are offered to everyone:
• Side-effects are only tolerable if they are pretty mild and short-lived
• Severe illness caused by vaccines should preferably be nonexistent, or at least vanishingly rare.
• Any risk of genetic side-effects?  
• Making DNA from RNA – so called reverse transcription – is something that only a certain kind of virus, like HIV, can do.
• Ultimately, confidence in the safety of vaccines is something that comes from experience.

References

1. How the Oxford-AstraZeneca vaccine works and why it matters
2. Do mRNA vaccines for Covid signal a new era in disease prevention?
3. Moderna Wants to Transform the Body Into a Vaccine-Making Machine
4. RNA vaccines: an introduction
5. Developing mRNA-vaccine technologies
6. All eyes on a hurdle race for a SARS-CoV-2 vaccine
7. The tiny tweak behind COVID-19 vaccines
• Prepandemic coronavirus research by Jason McLellan and Barney Graham led to a trick for stabilizing the prefusion form of spike proteins.
8. What Are The Long-Term Safety Risks Of The Pfizer and Moderna Covid-19 Vaccines?
9. Reverse Engineering the source code of the BioNTech/Pfizer SARS-CoV-2 Vaccine
10. Antibody response induced by mRNA vaccination differs from natural SARS-CoV-2 infection