Biotechnology Breakthroughs: Messenger RNA Vaccines for Covid-19

The two first Covid-19 vaccines to release successful Phase III data are both mRNA vaccines. This is a relatively new but promising medical biotechnology. In this second post we’ll explore the biology behind mRNA vaccines and break down the initial Pfizer and Moderna clinical data. For an overview of mRNA molecules and mRNA medicines read our first post.


Vaccines work by training the body to recognize proteins produced by a disease-causing organism such as a virus or bacteria. Some vaccines are made of weakened or inactivated pathogens. Other vaccines are made of a subunit of the pathogen such as just the pathogen’s outer shell (capsid) or a protein that only the pathogen produces. mRNA vaccines are yet another type of vaccine that are made of a “pre-form” of a pathogen’s protein, i.e. the mRNA instructions that enable cells to manufacture an antigen.

In the case of the mRNA vaccines developed for Covid-19 the synthesized mRNA molecules code for the SARS-CoV-2 spike protein. This protein is embedded on the surface of the virus and helps it enter our cells. It’s also one of the first viral proteins that a person’s immune system would encounter following infection with SARS-CoV-2. This makes the spike protein an ideal antigen for the body to learn how to recognize and respond to. In both vaccines, the mRNA strands that code for SARS-CoV-2 spike protein are packaged in round lipid nanoparticles.

3D print of a spike protein of SARS-CoV-2. On the virus model, the virus surface (blue) is covered with spike proteins (red). Credit: NIH

When an mRNA vaccine is administered this is what happens:

  1. A patient is given a vaccine shot usually in the left or right upper arm.
  2. The lipids in the nanoparticle packing merge with the lipid bilayer of muscle cells and the mRNA is released into these cells.
  3. These mRNA molecules find and connect to ribosomes in the cell.
  4. The ribosomes use the mRNA’s codon code as a template to build the spike proteins. While some of these proteins stay in the cell, many are released into the body.
  5. Immune system cells called APC (Antigen Presenting Cells) detect the spike protein, identify them as antigens, and display them on their cell surface. These cells then travel to areas like the lymph nodes where other immune system cells are clustered.
  6. These APCs activate helper T cells which, in turn, alert other immune cells including naïve B cell and killer T cells.
  7. Naïve B cells divide rapidly to produce both plasma B cells and memory B cells specific to the spike antigen. The former produces millions of antibodies. (If this was an active infection with a live virus these antibodies would help the body neutralize the multiplying virus.) While the latter store information about the antigen and can stimulate a rapid immune response if a future infection occurs.
  8. The killer T cells search the body for any infected cells and destroy them.
  9. Eventually, most T and B cells die. But many memory cells can stay in the body for decades.
  10. If a vaccinated person is exposed to the virus SARS-CoV-2, memory cells in the body quickly recognize it and begin rapidly producing antibodies. These antibodies trigger a cascade of additional immune defenses. In particular, they bind to the spike proteins of the invading viruses and stops the virus from entering cells.
Sciencia58 an the makers of the single images Domdomegg, [1], Fæ, Petr94, Manu5, CC BY-SA 4.0 https://creativecommons.org/licenses/by-sa/4.0, via Wikimedia Commons

In many ways, the mRNA vaccines are very similar to past vaccines. In fact, steps 5-10 are universal across all types of vaccines. The major difference is when, where, and how the antigen is produced. Another slight difference is that scientists have observed that mRNA vaccines have a more diverse effect across the immune system. For example, both mRNA Covid-19 vaccines trigger a strong killer T cell response. These cells, while not as long-lasting as antibodies, persist in the body for months and play a key part in cellular immunity. This may be one reason for the high efficiency observed in current mRNA vaccine tests.

The Covid-19 mRNA Vaccine Trials

Both mRNA Covid-19 vaccines are currently in Phase III testing and have released preliminary results. In these Phase III tests one group of people received two doses of the vaccine on days 1 and 22/29 (depending on which mRNA vaccine) while another group received placebo shots. All participants were then surveyed about Covid-19 symptoms and side effects in the following weeks. Anyone who reported symptoms was tested for the virus. All this was done under double-blind conditions which meant that neither the participants nor the researchers knew who got the treatment and who got the placebo.

Credit: CDC Vaccine Safety Process. Modified.

Both developers (Pfizer and Moderna) decided to take an initial peek at their vaccine’s performance when ~100 participants had tested positive for Covid-19. The treatment (placebo or vaccine) of just these individuals was then unmasked. While one hundred may seem like a small number it’s a reflection of the national infection rate for Covid-19 which is estimated to be around 1%. At this rate, a study involving 40,000 participants would likely only observe 400 total Covid-19 cases.

The Pfizer study involved 43,000 participants and to date has observed 170 symptomatic Covid-19 cases. Of these 162 occurred in the placebo group and 8 occurred in the vaccine group. The Moderna study involved 30,000 participants and to date has observed 95 symptomatic Covid-19 cases. Of these 90 were in the placebo group and 5 were in the vaccine group. These ratios are what were used to generate the 90% and 94.5% efficiency ratings that you may have heard in the news. Both are very promising.

It’s important to note that these are initial findings. Both studies are continuing and set to release a larger data set as additional cases emerge. For example, Moderna has said it will take another look at the vaccine to placebo ratio when 164 participants test positive for Covid-19. These later findings will not only be larger datasets but will also provide information about how long the vaccine protects individuals and whether there are any long term side effects. It’s also important to note that both tests relied on participants reporting Covid-19 symptoms. This means that the tests are measuring the ability of the vaccine to prevent the negative health effects of Covid-19 but not their ability to prevent infection. The latter will likely be more directly measured in later studies.

heavily infected with SARS-COV-2 virus particles (orange), isolated from a patient sample. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland.NIAID

“When I heard the over 90% efficacy, I felt I was living a dream.” Albert Bourla, CEO of Pfizer CEO.

“I take one step at a time. I’ll take the 94.5% effective for now and we’ll worry about the durability of the effect next.” Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases.

 

RESOURCES

Ready to bring current events into your classroom, provide science-based information about this important but charged topic, and review key concepts like molecular biology’s central dogma? Here are some key resources. Start by checking out our previous blog post about the molecule mRNA and the field of mRNA therapeutics.