Fact Vs. Fiction: COVID-19 Vaccines

A collection of PNWU scientists team up to demystify the COVID-19 mRNA vaccine by explaining how the vaccines work and offering expert insight into whether or not they will be safe and effective.

Fact vs. Fiction: COVID-19 Vaccines

A collection of PNWU scientists team up to demystify the COVID-19 mRNA vaccine by explaining how the vaccines work and offering expert insight into whether or not they will be safe and effective.

Two new vaccines have received Emergency Use Authorization (EUA) from the Food and Drug Administration (FDA) to prevent COVID-19.

Although developed by different companies, both vaccines use the same approach.

With standard vaccines, a protein produced by a microorganism is injected. With each of these new vaccines, a molecule that codes for that protein is injected instead, allowing the person to make the “foreign” protein, which avoids injecting infectious particles or even the viruses themselves.

Once human cells take up the molecular message (known as “messenger ribonucleic acid” or “mRNA”) that codes for the protein, an immune response to the “foreign” protein can be initiated.

Unprecedented technology? Not exactly…

This mRNA vaccine technology dates back 30 years to the year 1990.1

Moderna -- the second company to receive an EUA for a mRNA COVID-19 vaccine, and part of Operation Warp Speed -- was founded in 2010 and has specialized in mRNA technology development. In fact, the letters “rna” at the end of the company’s name (Moderna) represent this very technology.

Are these vaccines safe and effective?

Each currently approved mRNA vaccine to prevent COVID-19 has been deemed “safe and effective” by multiple expert panels, both within and outside the US FDA. The vaccines have good, albeit imperfect, safety and efficacy in large trials.

Nearly 74,000 people participated in the pivotal clinical trials of the first two approved mRNA vaccines. As of this writing (December 23, 2020) more than one-million people have received the first of two doses in the public phase 1 rollout of the vaccine.2 Common post-vaccination effects include those that indicate that the vaccine is working, as the immune system appropriately responds to the fleeting presence of a “foreign” protein which it will react to if and when an actual infection was to occur.

How Do the Vaccines Work?

These mRNA-based vaccines deliver the molecular code for a “foreign” protein to the human host cell.

The protein of the SARS CoV-2 virus that was chosen to stimulate an immune response is that virus’ unique spike (“S”) protein. These are the typically red “spikes” seen sticking out from the diameter of the virus, as seen in major media images. “Coronaviruses” are named for these protrusions since they form a “crown” (or “corona”) of protein molecules on the surface of the virus. These proteins are strongly immunogenic, and the immune system mounts an impressive response to fight them.

Before injection, the fragile mRNA is encased in a fat globule, which protects it from degradation after injection into a muscle and allows it to pass across human cell membranes. Development of this technology was a game-changer for vaccines, because free mRNA is normally destroyed quickly by ubiquitous endonucleases in most biological fluids.

Once inside the host cell, the vaccine’s mRNA molecule goes, as is normal, to a ribosome, the “workbench of protein synthesis.” The ribosome doesn’t know or care that the mRNA didn’t originate from the cell’s nucleus (as usual), so the mRNA molecule from the vaccine is translated, as usual, into a protein with its corresponding amino acid sequence. In the case of these vaccines, that is the “spike” protein. After the mRNA is translated into its corresponding protein, it is degraded within the cell (as usual).

Production and release of the “spike” protein peaks about 48 hours after vaccination and lasts about a day. When the newly manufactured “foreign” spike protein (from the coronavirus) is released from human cells, it is recognized as “foreign” by the human immune system, triggering a response that lasts far longer than the protein does (as it is degraded by natural proteases in biological fluids).

The immune system cells that first see the “foreign” “S” protein begin their training to recognize, remember, and begin to fight any invader that makes or is marked by the “S” protein. This is the premise upon which the immune system’s memory will rely if and when it does encounter a coronavirus. It also explains many of the adverse effects of the vaccine.

When the immune system responds to a foreign protein, common mild-to-moderate vaccine side effects are to be expected; in fact, they are a sign that the vaccine is working – which is good! In vaccinology this is referred to as “reactogenicity.”

The mRNA vaccines used to prevent COVID-19 have similar reactogenicity profiles as other vaccines (often derived from injected foreign proteins, or even attenuated viruses) already licensed for use.3 An additional benefit of mRNA vaccines is that their manufacturing process is not only cell-free, but contains no human or animal products, preservatives, or adjuvants (substances that enhance the immune system reaction).

The Science

The terms “nucleic acid” and “RNA” (above) might sound familiar, as the RNA molecule is a somewhat lesser known relative of its more famous DNA cousin, which encodes the entire human genome and resides in the cell’s nucleus.

In contrast to its famous cousin, mRNA’s function is associated with the cytoplasm of the cell and does not interact with the host cell’s DNA or genome. mRNA is made naturally in human cells, as needed, and usually is the intermediary between the human genomic DNA and ribosomal synthesis of all the proteins the human body needs.

Pfizer’s Vaccine

The Pfizer-BioNTech mRNA vaccine to prevent COVID-19 in people 16 years of age and older was the first vaccine to be granted an Emergency Use Authorization by the FDA. The technical name for this vaccine is mRNA “BNT162b2.”

The vaccine is given intramuscularly in two 30 microgram doses at least 21 days apart. This vaccine needs ultracold storage at around -70oC (approximately -94oF) but can be stored for 5 days at refrigerated temperatures.

During its pivotal trial,4 an independent data monitoring committee consisting of four infectious disease experts and one statistician (all with expertise in assessing vaccine safety, immune response, and efficacy) met weekly to monitor the results in all 43,548 participants. No safety concerns were identified.

Fatigue, headache, muscle pain, joint pain, and injection site soreness were the most commonly reported symptoms in both the vaccine group and the placebo (saline) group.

The overall effectiveness of the vaccine in all age, sex, race, ethnicity, and country of origin participants taken together was a highly significant 95%, beginning 7 days after the second dose; efficacy estimates were similar in all subgroups, regardless of age, gender, race/ethnicity, or geography. Importantly, 9 of the 10 severe COVID-19 cases among subjects were in the placebo group.

After independent review by an FDA Advisory Council consisting of US national experts in epidemiology, virology, infectious disease, vaccinology and other applicable areas of science and medicine, the FDA accepted their recommendation to grant the EUA for BNT162b2 on December 11, 2020.5 The data were subsequently reviewed independently by many other authoritative bodies, including the Western States Scientific Safety Review Workgroup.

Moderna’s Vaccine

The Moderna mRNA vaccine to prevent COVID-19 in people 18 years of age and older was the second vaccine to be granted an Emergency Use Authorization by the FDA. The technical name for this vaccine is “mRNA-1273.”

In contrast to the Pfizer-BioNTech mRNA vaccine, the Moderna vaccine was produced in conjunction with the National Institutes of Health as part of the U.S. Operation Warp Speed initiative.

This vaccine is given intramuscularly in two 100 microgram doses at least 28 days apart. Unlike the Pfizer-BioNTech mRNA vaccine, the Moderna vaccine does not need ultracold storage, but can be shipped and stored at normal freezer temperatures. It can be kept at normal refrigerator temperatures for up to 30 days and at room temperature for up to 12 hours.6

Analogous to the Pfizer-BioNTech vaccine, an independent data monitoring committee (in this case chartered by the National Institutes of Health) assessed the safety of 30,420 subjects in its pivotal clinical trial (which has not yet been published in full form). No safety concerns were identified.

Fatigue, headache, muscle pain, joint pain, and injection site soreness were the most commonly reported symptoms.

The overall effectiveness of the vaccine in all age, sex, race, ethnicity, and country of origin participants taken together was 94.1% after beginning 7 days after the second dose. Importantly, all 30 cases of severe COVID-19 infection occurred in the placebo group.

These data were made public and reviewed by another independent FDA Advisory Council consisting of national experts in epidemiology, virology, infectious disease, vaccinology and other applicable areas of science and medicine, which voted unanimously for its approval.7 The FDA accepted this recommendation and granted a EUA for mRNA-1273 on December 18, 2020.6

Going Forward

Both pivotal trials will continue follow-up for 2 years. Additional planned analyses in the trials include: an analysis of vaccine efficacy against asymptomatic infection, how long the vaccine confers protection (mRNA vaccines have the added benefit of making it easier to produce booster shots or administer seasonal shots as are now done with annual flu shots), and extending data collection in the 12-15 year old group (in the case of the Pfizer-BioNTech vaccine).

The CDC also has planned effectiveness studies that will allow for additional data collection in the broader population.

 

Written by Kimberly Taylor, Ph.D., William Elliott, M.D., Ph.D., Albert Brady, M.D., and Julie Randolph-Habecker, Ph.D.

  1. Pardi, N., Hogan, M., Porter, F. et al. mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov 17, 261–279 (2018). https://doi.org/10.1038/nrd.2017.243
  2. CDC COVID Data Tracker – COVID Vaccines in the United States. https://covid.cdc.gov/covid-data-tracker/#vaccinations
  3. Vaccines and Related Biological Products Advisory Committee December 10, 2020 Meeting Presentation - BNT162b2 Vaccine Candidate Against COVID-19. https://www.fda.gov/media/144325/download
  4. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020; epub 10 DEC 20; doi: 0.1056/NEJMoa2034577.
  5. FDA EUA Issuance Letter to Pfizer, Inc. (December 11, 2020). https://www.fda.gov/media/144412/download.
  6. FDA EUA Issuance Letter to ModernaTX, Inc. (December 18, 2020). https://www.fda.gov/media/144636/download.
  7. Vaccines and Related Biological Products Advisory Committee December 17, 2020 Meeting Presentation - Emergency Use Authorization (EUA) Application for mRNA-1273. https://www.fda.gov/media/144583/download.
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