The COVID-19 Vaccine: What You Need to Know
On Thursday December 10th, the FDA approved an Emergency Use Authorization (EUA) for Pfizer's new mRNA COVID-19 vaccine for people aged 16 years and older, and on Friday December 18th, Moderna's mRNA COVID-19 vaccine received an EUA for people aged 18 years and older. Both vaccines have begun arriving here in Oregon for phase 1a of the national vaccination campaign, and at the time of this writing, thousands of healthcare professionals have already received their first dose.
While these vaccines are a momentous achievement for public health, and mark a turning point in this pandemic, they are also the first vaccines ever made that had an anti-vax movement organized against them before they even existed. Millions of Americans are unsure whether they want to take the vaccine that has the power to end the worst pandemic in human history. The good news, though, is that these vaccines, like all vaccines, are among the safest medicines we have. Vaccines have to meet higher safety standards than the drugs used to treat the conditions they prevent; because we give vaccines to healthy people. Here I will describe how these two vaccines work, and what you should know about them.
What is the COVID-19 Vaccine?
Pfizer's and Moderna's mRNA vaccines are the first to reach the market for use in the US. These two vaccines will likely be used to vaccinate the majority of US citizens over the next year. They are also the first and only licensed vaccines to use synthetic mRNA to elicit an immune response to a disease.
What is mRNA?
To best understand how mRNA vaccines work, we must first understand how mRNA works in the body. First, our DNA, which contains all of the genes that determine everything about who we are, is transcribed into strands of messenger RNA (mRNA) in the cell nucleus. It is then transported outside of the nucleus of the cell into the cytosol (aka the rest of the cell outside the nucleus), where a cellular machine called a ribosome reads the mRNA strand and translates it into a protein, one amino acid at a time. This process of DNA being transcribed to mRNA and then translated into protein is summarized in the picture to the right, and is often referred to as the central dogma of cellular biology.
Viruses can also use mRNA to create proteins, and are unique in their "life cycle" in that they will use the cellular machinery of the host cells they infect to carry out that process. There are different ways that they can do this, but the simplest occurs in what are known as positive sense RNA viruses. These viruses have genomes coded into single strands of RNA that look just like the mRNA that our cells create themselves, and therefore can be directly translated by our ribosomes into proteins. These RNA genomes code for all of the other proteins the virus needs to reproduce, including the proteins to replicate the RNA strand itself. Coronaviruses, including SARS-COV-2, the strain of coronavirus that causes COVID-19, are positive sense RNA viruses.
It is important to know that there are many strands of mRNA in our cellular cytosol at a given time, and that they are all rapidly degraded after being translated into proteins.
How did mRNA vaccines come about?
In the 1990s, a Hungarian-born scientist named Katalin Kariko had the idea that we could harness the last step of the gene expression process, translating mRNA into proteins, by creating mRNA that coded for whatever proteins we wanted, and using our cells' own mRNA translation system to create proteins in our bodies that could help us combat various diseases. Through years of research and repeated failures, she and her colleagues eventually learned how to create and deliver to the body synthetic mRNA strands that coded for different proteins. Since that time, mRNA technology has been used in clinical trials for vaccines for influenza, Zika, Rabies, and Cytomegalovirus (CMV), and various cancer treatment medications.
Unlike other methods for creating vaccines, mRNA vaccines don't require samples of any actual virus or other pathogen; they only require a knowledge of the genetic sequence coding for the proteins we want to create. This means vaccines can potentially be made much more quickly and easily using mRNA. So, when the genetic sequence of SARS-COV-2, was posted online on January 10th, 2020, biotech companies had all that they needed to start creating a vaccine. Just 42 days later, Moderna (a company named by combining the words Modified and RNA) had synthesized an experimental mRNA vaccine.
How do the COVID19 vaccines work?
Pfizer and Moderna's mRNA vaccine both work by coding for a protein called the spike protein, which is found on the surface of SARS-COV-2. The mRNA is delivered to our cells inside of a protective lipid envelope. This envelope is taken up immediately by the cells at the site of the vaccine injection. Once inside the cytosol, the cell breaks down the envelope to release the mRNA inside, which then binds to a ribosome to be translated into the spike protein. This entire process happens just as it would if you were infected with COVID19, except that instead of translating the complete viral mRNA, with instructions to make copies of the entire virus, which then go on to infect other cells, our cells are translating the synthetic mRNA that only provides instructions to express a single protein.
After being translated into protein, the mRNA is disassembled by the cell as it normally would be, and the spike proteins are taken to the cell membrane, where our body's immune system recognizes them as foreign, and creates an immune response to isolate and destroy them, as it normally would when exposed to the spike proteins of the virus itself. During this process, our immune system creates memory cells that code for the antibodies that recognize and bind to the spike protein, so that the next time our body is exposed to the spike protein, those antibodies will be ready to isolate and destroy the protein quickly, before the virus it is attached to has a chance to replicate and cause infection.
This method of vaccination allows us to use our body's own cells to create the proteins we need to learn how to be immune to the disease, rather than requiring researchers to isolate, handle, and replicate virus in a lab. It also allows us to create a simpler vaccine that requires no adjuvants, preservatives or other additional ingredients; just the synthesized mRNA and its lipid envelope, and our body does the rest.
In the near future, we could see vaccines that code for proteins of multiple different viruses and bacteria on a single synthetic strand of mRNA, allowing our body to create and develop immunity to dozens of proteins at once. It is theoretically possible that we could combine many or even all of our current vaccinations into a single shot, as well as create vaccines to multiple other dangerous diseases at the same time. Realistically, though, the barriers to this kind of medical innovation may prove to be insurmountable, as vaccines are historically not very profitable for pharmaceutical companies, and their value is consistently underappreciated and unfairly scrutinized by the public.
How were these vaccines created so quickly?
The bottom line is money. When there's enough money and public pressure, we can make incredible strides in improving and protecting public health. The graphic below, courtesy of an article from the journal Nature, shows how the development process differed for COVID19 compared to traditional vaccine development.
First, researchers were able to skip several years of design and preclinical studies because we already had existing information from research into vaccines for SARS-Cov and MERS-Cov.
Then, researchers were able to streamline and expedite clinical trials and production of vaccine; because they didn't have to worry about cost-benefit and risk analyses to determine whether it would be financially prudent for them to continue with vaccine development. The guaranteed market for the vaccine and large amounts of funding and public pressure also allowed Pfizer and Moderna to begin mass production of their vaccines "at risk", before the phase 3 trials had even concluded.
Conducting the trials themselves was also significantly easier than normal for two reasons. First, unlike with most clinical trials, it was incredibly easy to find people willing to sign up for the trials. Second, because the pandemic has been so poorly controlled, it did not take very long at all for enough people in the study to get sick for the researchers to have enough data to draw conclusions about the effectiveness of the vaccine. If our politicians and the general public were as passionate about other areas of scientific research and discovery as they have been about controlling COVID-19, there's no telling how many other breakthrough vaccines and medicines we could develop at a record pace.
As the above graphic makes clear, no steps were skipped in the making of these vaccines. We simply had the means to do everything faster. The phase 3 trials for Pfizer included 43,000 participants, while those for Moderna had 30,000 participants, and both have now had over two months of safety data. These are the same numbers that we would expect with any other vaccine. Two months is the standard length of time required to establish safety data; because that is generally considered the maximum time period in which a vaccine side effect might first show up, although almost all side effects will happen within the first 2 weeks.
What is an Emergency Use Authorization, and why are the Vaccines not being Licensed normally?
The Emergency Use Authorization granted by the FDA allows us to begin administering the vaccine before we have adequate efficacy data to license it like we normally would. As of now, we know that the Pfizer and Moderna vaccines are about 95% effective at reducing illness from COVID-19, and that they are safe for use in the general adult population. What we don't know is how long the immunity they generate lasts, and we need to know that before the vaccine can be licensed. Only time will be able to tell us definitively whether we can expect long term immunity, or if booster shots or another, more effective vaccine, may one day be necessary. Pfizer and Moderna's phase 3 trials will continue for another 2 years, during which time we will be able to learn how long the immunity from the COVID vaccines lasts.
How will the vaccine be distributed?
The COVID vaccines are currently licensed for adults only (16 and up for Pfizer, 18 and up for Moderna), and are scheduled to be administered first to healthcare workers and residents and staff of Long Term Care Facilities (LTCFs), who are at the highest risk of acquiring and transmitting the virus. Once additional supply of vaccine is available, public health officials will begin providing vaccine to essential workers and those at highest risk for serious disease: people with chronic illnesses and those over the age of 65. Next, we will be able to provide vaccinations to the general public. With this approach, we hope to be able to slow and eventually stop the spread of the pandemic as quickly as possible. Recent estimates are that we should be able to vaccinate 100 million Americans by Fall of 2021.
What are the side effects of the vaccine?
80-89% of people vaccinated will have at least one local symptom (pain, redness, or swelling around the injection site), and 55-83% will have at least one systemic symptom, such as headaches, muscle or joint aches, fatigue, chills, or fevers. A small percentage of people will have more severe pain and fever that requires them to miss work for a few days. Most symptoms begin within 3 days after vaccination and resolve in 1 to 3 days.
0.5-1.0% of people have had allergic reactions to the vaccine. There have only been a handful of severe allergic reactions, so far all from the Pfizer vaccine, and the NIH is now beginning a study to determine the possible causes of those reactions.
So far, there are no other significant side effects known to be associated with either vaccine.
How is vaccine safety being monitored?
The COVID vaccine will be monitored for safety indefinitely, just as all other vaccines are, using the Vaccine Adverse Events Reporting System, which collects enormous amounts of data to help inform further studies, and is among the most robust safety reporting mechanisms in medicine.
In addition, the CDC is rolling out a new V-Safe program, which allows patients who have received the vaccine to opt-in for two week follow up via text messages on their smart phones. Serious adverse events that are reported will be followed up by a call directly from the CDC.
Is the vaccine safe for children?
We currently know that the vaccine is safe and effective in adults. As the CDC puts it, "while vaccine safety and efficacy data in [children and adolescents] are limited, there are no biologically plausible reasons for safety and efficacy profiles to be different than those observed in persons 18 years of age and older." However, we will need to wait for phase 3 trials to be done in children before we can know for certain. Pfizer has included children aged 12 to 18 in their initial trials, but does not have enough data yet to prove that their vaccine is safe and effective in that age group. Both companies have begun testing the vaccine in adolescents. Once they can establish safety and effectiveness in this younger age group, it is likely they will begin trials for children under 12.
Is the vaccine safe for pregnant or lactating mothers?
The data here is again limited, but there is no reason to think the vaccine will be any less safe for mothers or their breastfed infants. We will learn more as further trials are completed in these groups, but women eligible for the vaccine can receive it while pregnant or breastfeeding if they like, and should speak with their doctors about the uncertainties and benefits. Remember that pregnant women are at potentially higher risk from COVID-19 infection, so minimizing their risk for the disease is more important in this population.
What are the contraindications to getting the vaccine?
The only contraindication to getting the vaccine is a history of severe allergic reaction to any of the components of the vaccines. The CDC considers a history of anaphylactic reaction to any other allergen a precaution, but not a contraindication to getting the vaccine. This means it is very likely safe, but it is a good idea to speak with your doctor about whether you're comfortable getting it, and what type of monitoring might be good to do afterwards. I personally have a history of anaphylactic allergy to yellow jacket venom, and plan to get vaccinated as soon as I can.
Should I wait until more people have gotten the vaccine before getting it myself?
No. This idea is based on two faulty premises. First, it assumes the CDC, the FDA, and the hundreds of scientists, public health professionals, and doctors who have studied and reviewed the safety of the vaccines have authorized their use with the intention of using the vaccine recipients as guinea pigs. This is abominable and wrong, and contradicts the very purpose of the licensure process. We already know that the vaccines are safe for use in the general population, and that will not change no matter how much more data we get. We may learn about new risks associated with the vaccine, but we have enough data to show that receiving the vaccine is far safer than remaining unvaccinated in the wake of the pandemic. Second, this idea assumes that the people getting vaccinated first are more expendable than those who have the financial and social security to wait until later to get vaccinated, which is also wrong.
What about long term side effects from the COVID vaccine?
There is no reason to believe that there will be any long term side effects of the COVID vaccine. Any problems caused by the mRNA, the spike protein made by our cells, or the antibodies and immune response that our body generates to the vaccine, should have shown up already. It is possible that there are some very rare side effects that we will not be able to detect until after millions of people are immunized, but by definition these side effects will pose a lower risk to the public than the risk for catching and suffering severe illness or death from COVID-19, which is infecting and killing people at very high rates.
Furthermore, any long term side effects that could theoretically be generated by the COVID vaccine would almost certainly also be generated by infection with COVID-19 itself. Any autoimmune reaction that could be caused by our antibodies attacking the spike protein generated from the vaccine should also be caused by those same antibodies attacking spike protein generated from the virus, which would cause a significantly greater immune response, as it is also generating antibodies to over a dozen other viral proteins, and trying to ward off millions of viruses disseminated throughout the body, rather than a small number of a single type of protein made by a few cells in your arm.
What about Antibody Dependent Enhancement (ADE)?
Some people have raised concern about a phenomenon known as Antibody Dependent Enhancement (ADE), in which certain respiratory illnesses have been known to be more severe in those who already generate antibodies to the disease; because the additional antibodies created during the infection lead to further inflammation in the body. While this is a real phenomenon, there is no evidence that it happens with COVID, or with the COVID vaccine. We can say this with high confidence because thousands of people who have received the COVID vaccine have been subsequently exposed to the virus, and either had a mild illness, or no illness at all. In other words, the vaccine works as it's intended. Also, if ADE were a significant possibility from COVID, we should have already seen people having more severe illnesses due to COVID after recovering from an initial infection. This has not happened.
Could the mRNA persist in my cells or alter my DNA?
No. Some online bloggers with a cursory knowledge of biochemistry have suggested that the mRNA in the vaccine might somehow persist in our cells or be integrated into our genome to alter our DNA. You may find articles talking about the mRNA being "stabilized" or "altered" to be able to persist in cells, and about enzymes called Reverse Transcriptase and DNA Integrase that incorporate foreign genes into our genome. These claims are bunk.
The synthetic mRNA in the vaccine has not been "stabilized" in anyway. It gets disassembled within hours of entering the cytosol, just as any other mRNA strand would be. As I described earlier, our cells see countless strands of mRNA moving through the cytosol all of the time. These strands may be transcribed from our DNA, or introduced to our cells from foreign viruses or bacteria. If our bodies didn't know how to disassemble and eliminate mRNA from our cells, we would not be able to survive. If our bodies integrated random strands of mRNA into our genomes, we would already have not only the genes for SARS-COV-2 integrated into our genomes, but those of millions of other naturally occurring viruses as well. Obviously, this hasn't happened.
Furthermore, if all that we had to do in order to alter our genome was inject mRNA into our arms, we would be able to cure every genetic disease known to man. Gene therapy, the field of creating treatments designed to cure genetic diseases by modifying the faulty genes that code for those diseases, is a very complicated and difficult science, and has far more failures than successes. The idea that incorporating foreign genes into our DNA is as simple as giving us a shot of mRNA is preposterous.
Are you 100% sure that the vaccine will not cause serious problems for me?
No. This is perhaps the most important point to understand about not just the COVID vaccine, but about the scientific process in general. There is uncertainty in everything. Scientists learn how to measure that uncertainty, and make informed decisions based on the best available evidence, and then speak plainly about that evidence and uncertainty.
Charlatans and snake-oil salesmen learn to capitalize on that uncertainty and turn it into fear, which they then sell to the public in order to turn a profit. The irony here is that there is almost always more uncertainty about the product being sold by these merchants of fear than there is about the product they are demonizing. Jude Law, in the 2011 thriller Contagion, played the role of one such charlatan, and the lies and fear that he spread and profited from in that film have been copied almost exactly by a number of similarly morally bankrupt people in the last year.
Over a quarter of a million people have died already in the US alone because of this illness, and many of them would not have, if not for misinformation claiming that the pandemic is either not real, or not serious, or that masks don't work. This pandemic is far from over. We can expect to watch tens of thousands of our loved ones die of COVID-19 in 2021, and many of them will die directly because of widespread misinformation about the COVID vaccine, and the inevitable lag in immunization rates that will follow.
Based on the evidence we currently have available, the COVID-19 vaccine is the safest and most effective way to reduce the risk of getting and transmitting the COVID-19 virus, is significantly safer than infection with COVID-19, and, together with ongoing social distancing, masks, and hand washing, is the only way that we will be able to contain and move on from this pandemic, which has irreversibly changed all of our lives, and the lives of our children.
It is entirely reasonable and appropriate to have questions or concerns about the COVID vaccine. I tell all of my patients that they should feel comfortable with the medical decisions they make for themselves and their children. If you are still unsure whether you are ready to take the COVID vaccine, speak with an informed medical professional. Our providers at Oregon Pediatrics are happy to answer your questions about the vaccine, and in the coming months we will be able to tell you first hand what it's like to receive the vaccine, as our entire staff will be getting vaccinated in order to continue to protect our patients to the best of our ability.
References and Further Reading: