How does the vaccine work?
SARS-CoV-2 is an RNA virus. The RNA that’s in the live virus codes for 29 different proteins. When the virus enters a cell during a natural infection, the RNA in the cell is chopped up into smaller pieces of mRNA, which serves as a template to code for 29 proteins to make more virus and the cycle continues.
Unlike most current vaccines, the Pfizer and Moderna vaccines do not contain material from the virus. Instead, it contains synthesized messenger RNA (mRNA), which serves as a blueprint that codes for just ONE of these proteins, the spike protein. This provides just enough training to the immune system to build antibodies. The mRNA itself is quite fragile, so it is encased in a shell made of lipids, or fats to keep the body’s immune system from destroying it before it gets into the cell.
Once inside the cell, the mRNA stays in the cytosol and does NOT enter the nucleus. Here, ribosomes transcribe the mRNA and make the spike protein. Our immune system then recognizes this spike protein and mounts an immune response against this protein. This is what causes the majority of mild symptoms from vaccines that may be similar to the real infection, but typically significantly more mild. After the mRNA is encoded, it is destroyed by the cell.
Why is the premise of mRNA vaccines so incredible?
Vaccines have given us great successes in the control of many diseases, including smallpox, polio, measles, mumps, rubella, and more. Can you imagine if we still had all these diseases, plus COVID-19?
Traditional vaccines use an inactivated virus or parts of a live but attenuated virus to stimulate an innate immune response and induce a T- and B-cell immune response. DNA vaccines do the same, but research has shown the potential for integration into human genome. However, an RNA vaccine CANNOT do this, as it never enters the nucleus of a cell. It couldn’t even if it wanted to as humans do not have the enzymes needed to do this. There is no way it can integrate into human DNA…it’s just not possible. Social media claims that this can happen are just not true.
Traditional vaccines take a long time because vaccine developers need to grow large amounts of virus, attenuate or inactivate the virus and this is quite difficult to do in a short period of time. That is why the influenza virus is a “best guess” of the strain that will be most prevalent the next year. It takes all year to produce it. With mRNA vaccines, you just need to know the genetic code and large amounts of vaccines can be produced within days to weeks. This could change the vaccine game forever.
Further, it is incredible that the effectiveness appears to be as high as it is for the Pfizer/BioNTech and Moderna vaccines (roughly 95% after the second dose). For comparison, the seasonal flu vaccine is only 40% effective at preventing the yearly flu (ranging 10-60% based on how good the guess is).
Without a vaccine, herd immunity is unlikely anytime soon.
Herd immunity is when the majority of the population becomes immune to a particular disease allowing transmission to be halted. This provides protection to individuals who aren’t immune. The number of people who will need to have immunity to reach herd status depends on the disease. In a previous post, we discussed the basic reproduction number, R0 (pronounced R-naught).
Simply put, when the R0 is > 1, the infection will spread in a population and if it is < 1, it will fizzle out.
We can calculate the number of people who will need to be infected naturally, or obtain immunity through vaccine to reach herd immunity with the equation 1-1/R0. There are a lot of variables to accurately determine an R0. Most current estimates put the R0 somewhere between 2.5 and 4. So, if we err on the side of caution and go with an R0 of 4, then 75% of the population will need to be infected naturally or achieve immunity to achieve herd immunity.
A recent study published in JAMA suggesting that < 10% of the U.S. has antibodies to COVID-19 at this time. As of November, the current rate of infection is roughly 1.3% of the population per month. If nobody gets the vaccine, it would take 4.5 years to reach herd immunity. More concerning would be the amount of time we would be allowing mutated strains to emerge.
If 60% of people get the vaccine, we theoretically reach herd immunity in just 2 months.
So, how many people are currently willing to get the vaccine?
- September poll – 50% of Americans willing to get vaccine
- November poll – 58% of Americans willing to get vaccine
- December poll – 60% of Americans willing to get vaccine
Reasons people gave for not wanting the vaccine.
- 37% felt it was too rushed
- 26% want to wait for confirmation that vaccine is safe
- 12% don’t trust any vaccines
- 15% think the vaccine is too political
- Despite the majority saying they would get a vaccine, only 37% said they were comfortable being in the first wave
What are the current known risks of the mRNA vaccines?
Nothing we do in healthcare is without risk. 10% of the population claims they have an allergy to Penicillin. However, we don’t avoid it’s use altogether because of this. We understand that the risk of allergies outweigh the risk of untreated infections. Adverse reactions to vaccines are to be expected. We can never have zero risk. The more important question should be, is the degree of risk worth the possible benefit?
The most common adverse effects from the Pfizer-BioNTech and Moderna vaccines are quite mild and resolve in a day or two. Preliminary data from the Moderna vaccine suggests up to 10% of people can experience mild symptoms for 7 days, but so did nearly 9% of the people in the placebo group.
The majority of people won’t have more than a sore arm for a day or two, some body aches, or a mild headache. This doesn’t mean you are infected with COVID. Its not possible to get COVID directly from an mRNA vaccine. It does produce a stronger immune response than some other vaccines, and that is the beauty of the design. Just understand that you will likely feel something, but it is unlikely dangerous and should resolve in a day or two with Tylenol, Motrin, and rest. An overview of published data from the Pfizer/BioNTech and Moderna vaccine trials are summarized below.
Pfizer – 36,621 participants
- Ages > 16 years old
- 95% effective (52% after first dose)
- 2 doses (day 0, 21)
Ingredients
- mRNA
- Lipids
- Potassium chloride
- Monobasic potassium phosphate
- Sodium chloride
- Dibasic sodium phosphate dehydrate
- Sucrose
Adverse Events
- 73% had NO symptoms after vaccine
- Symptoms milder in those > 55 years old
Of the 27% who had side effects:
- Injection site pain – 84%
- Fatigue – 63%
- Headache – 55%
- Muscle pain – 38%
- Chills – 14%
- Joint pain – 11%
- Fever – 16%
- Bells Palsy – 4 patients
Serious adverse events – 0.6% (0.5% in placebo)
Anaphylaxis – 0%
Moderna – 30,350 participants
- Ages > 18 years old
- 94.5% effective (80% after first dose)
- 2 doses (day 0, 28)
Ingredients
- mRNA
- Lipids
- Tromethamine
- Tromethamine hydrochloride
- Acetic acid
- Sodium acetate
- Sucrose
Adverse Events
- 16% had NO symptoms after vaccine
- Symptoms milder for those > 65 years old
Of the 84% who had side effects:
- Injection site pain – 92%
- Fatigue – 70%
- Headache – 63%
- Muscle pain – 60%
- Chills – 45%
- Joint pain – 45%
- Fever – 15%
- Bells Palsy – 4 patients (1 in placebo)
Serious adverse events – 1% (1% in placebo)
Anaphylaxis – 0%
There were a total of 6 people who died during the Pfizer/BioNTech study (2 in vaccine group and 4 in placebo group. Of those who died in the vaccine group, one was from cardiac arrest 62 days after the vaccine and 1 was from arteriosclerosis 3 days after the vaccine. There were a total of 13 people who died in the Moderna study (6 in the vaccine group and 7 in the placebo group). Of those who died in the vaccine group, 2 were > 74 years of age with pre-existing cardiac disease, 1 died of cardiopulmonary arrest 21 days after the first dose, 1 died of a myocardial infarction 45 days after the second dose, 1 died of trauma and 1 (a 70-year-old with a history of cardiac disease) was found deceased at home 57 days after the second dose. These deaths are unlikely due to the vaccine, as they occurred with higher prevalence in the placebo groups and occurred at rates similar to those of the general population.
What we don’t know
- How long immunity will last after vaccination
- If those who receive the vaccine can still transmit infection to others
- Long-term safety data
- Data in pregnant women, children, and those who are immunocompromised
But aren't mRNA vaccines new, how do we know they aren't dangerous?
It is important to realize that side effects to vaccines are common. I mean, we are literally trying to activate an immune response. Severe adverse reaction from all vaccines occur at a rate of 1.3 for every 1,000,000 vaccines given. There have been over 2,000,000 vaccines given in the first week with only 8 anaphylactoid type reactions reported, all treated without issue. We can expect common side effects to perhaps be slightly more prominent than the influenza vaccine based on what we know so far, and it may be worth scheduling your vaccine when you have a day off of work the next day. Available data suggests the vaccines appear relatively safe, which is why they were approved for Emergency Use Authorization through the FDA. It certainly seems more safe then COVID-19 at the moment.
While this is the first mRNA vaccine to be widely distributed and approved for emergency use by the FDA, they aren’t exactly new by any means.
Research of mRNA vaccines really started 30 years ago when scientists began to explore ways to make vaccine development easier. The first trial of mRNA transfer occurred in 1990 and showed that injecting RNA directly into the muscle of mice lead to measurable protein production that lasted for at least 2 months (Wolff, 1990). This was really the first proof of concept that mRNA could be used for vaccine development. In 1992, injection of vasopressin mRNA in rats led to a reversal of diabetes insipidus in rats (Jirikowski, 1992). However, the interest in developing mRNA technology didn’t gain much steam at this point. The largest problem being that the body’s natural defenses would likely destroy the mRNA before it would reach the target cell and the low antibody responses seen (Zhang, 2019). Further, there was concern that by injecting naked mRNA into humans could activate the immune system and cause a dangerous overactive immune responses as seen in some early animal models (Zhang, 2019).
For these reasons, RNA vaccine development was put on the backburner and DNA vaccines were more actively pursued throughout much of the 1990’s. However, some believe that an early focus on DNA rather than RNA sent the field down the wrong path (DeFrancesco, 2017). mRNA vaccines may be more appealing as they cannot cause an infection like whole virus vaccines can and they cannot integrate into host DNA as they do not enter the nucleus of the cell, but are transcribed in the cytosol and rapidly degraded (Nanomedicine, 2020). Current advances in mRNA vaccine technology no longer use naked mRNA for injection, rather they protect the mRNA in a lipid nanoparticle (small balls of fats) that protect the mRNA to prevent both rapid degradation by the body as well as an overactive immune response. This technology is currently being used in the BioNTech/Pfizer and Moderna COVID-19 vaccines, and is also not new technology as using lipids to translate mRNA into cells has been studied since the 1970’s (Dimitriadis, 1978).
Prior to COVID-19, several companies had already been funding mRNA vaccine research (BioNTech, CureVac, Infectious Disease Research Institute, Moderna, and Synthetic Genomics). Let’s take a look at the available published data.
Rabies mRNA Vaccine (CureVac)
The first human trail for an mRNA vaccine actually began in 2013 against rabies virus (Alberer, 2017). This was a proof of concept trial with participants getting an initial series off 3 injections, followed by a booster 1 year later in non-pregnant adults age 18-40. The first bit of data from this trial, which is still ongoing, was published in 2017. Out of the 101 patients in the initial trial, 1 patient had what was considered a severe allergic reaction occurring on day 7, that resolved without issue. Other adverse events reported were rather mild (myalgias, pain at injection site). Ongoing monitoring for long-term adverse events are ongoing, with the last update published in 2018 (NCT02241135). While the vaccine has so far proven to be fairly safe, the major issue with this study is that the delivery methods trialed did not keep antibody titers for very long. Regardless, it showed proof of concept for mRNA vaccines in humans.
Influenza mRNA Vaccine (Moderna)
In 2019, Moderna published data from 2 placebo randomized controlled trials from 2015-2017 using mRNA vaccines against 2 avian influenza strains (Feldman, 2019). A total of 357 adults, ages 18-64, were included in the 2 trials. Not a single serious adverse event was reported from the vaccines. More importantly, no immune-mediated medical conditions or chronic illnesses have been reported. Further, antibody titers were better sustained than in the Rabies study.
Zika mRNA Vaccine (Moderna)
Data from the Moderna Phase 1 human trial of 120 patients that begain in July of 2019 (NCT04064905) was last updated in October of 2020. Common adverse effects were the same as most all vaccine trials (pain, redness, and swelling at the injections site, fever, headache, chills, body aches). Again, no severe adverse events have been reported and no immune-mediated medical conditions. Specific interim data from this ongoing study can be found here.
Cytomegalovirus mRNA Vaccine (Moderna)
Currently, this trial includes 252 patients and is in Phase 2, with the last data updated in September of 2020. Phase 1 showed adequate titers out to 12 months since the trial started in September of 2019. More importantly, adverse events were similar to those seen in other mRNA studies, such as local pain and swelling, fever, headache, myalgias, etc. No serious adverse events have been identified in the first 12 months of this study.
Other prophylactic mRNA vaccines currently being studied in various preclinical and clinical phase 1 development include vaccines against human metapneumovirus and parainfluenza virus 3 (hMPV/PIV3), pediatric respiratory syncytial virus (RSV), Epstein-Barr virus (EBV), and Influenza H7N9.
Further, therapeutic mRNA-based treatments are being studies for Chikungunya virus, autoimmune hepatitis, and IL-2 specific autoimmune disorders, propionic acidemia, methylmalonic acidemia, phenylketonuria, and glycogen storage disorder type 1a. Moderna is also studying mRNA vaccines in the prevention of multiple cancers (i.e., melanoma, non-small cell lung cancer, colorectal cancer, and pancreatic cancer).
What if I just take my chances with COVID-19
Influenza kills an average of 389,000 people yearly worldwide. Over the last 10 months, COVID-19 has killed 1,697,679 people and counting. This doesn’t include the unknown number of secondary consequences from an over-run healthcare system to include patients who will have a delayed diagnosis of other diseases such as cancers, diabetes, heart disease, mental health, and substance abuse as well as the economic impact of restrictions.
The case fatality rate is the number of deaths divided by confirmed cases. According to Johns Hopkins, case fatality rates are 1.8% in the United States, 3.3% in the United Kingdom, and 2.2% globally. Case fatality isn’t the exact number of people who die from the illness, because we can assume a number of people will get the disease and never get tested. Further, we can assume more people who have been diagnosed will eventually die. This number varies widely during the outbreak and can be affected by capabilities of treatment facilities and the ability to manage a surging population of patients.
You may hear of another statistic, known as the Crude Fatality Rate. This is the number of people who die of a disease in a given population. Currently, this value for the United States is 0.1% and often incorrectly used minimizes the deadliness of this disease. This means that roughly 100 people have died per 100,000 people in the population. This is incredibly misleading as 100% of the population has not been infected.
A recent study published in JAMA, revealed that less than 10% of the U.S. population currently has detectable antibodies, suggesting only 1 in 10 people have been infected after 10 months. So, the true number of people who are at risk of dying from COVID is certainly higher than frequently quoted 0.1%. I would suggest that based on this knowledge, if 100% of the U.S. population would get infected, somewhere around 1% can be expected to die as a result of infection as an educated estimate with control measures currently in place. The current estimates from the CDC, suggest this number is 0.5-1.5%. This value would no doubt be higher if everyone got infected at the same time as many hospital systems are already overwhelmed.
Just because you are young and healthy, doesn't mean you can't get incredibly sick.
A recent study of 513 young adults (age 18-49) with NO medical conditions hospitalized with COVID-19 in the United States showed that 22% (1 in 5) were admitted to the ICU, 10% were on a ventilator, and 0.6% died (Owusu, 2020). Data from early in the pandemic suggested that overall, 81% of patients will have mild disease, 14% will need to be hospitalized, and 5% will need the intensive care unit (Wu et al., 2020). In a study published in JAMA last week of 64,781 patients hospitalized with COVID-19 in the U.S. during the first wave, 20.3% of patients hospitalized for COVID-19, died.
Let's say you don't die...there may still be long-term effects of COVID.
While the exact long-term effects of COVID-19 are not entirely known, we do have 10 months of data and the long-term effects on different organ systems is quite concerning. Only 12% of patients who were hospitalized are free of symptoms after 60 days. Symptoms of fatigue, shortness of breath, cough, joint pain, chest pain, rash, or hair loss and loss of taste and smell has been reported to linger for months in some patients.
Cardiovascular Effects
- Imaging tests taken months after recovery from COVID-19 have shown lasting damage to the heart muscle, even in people who experienced only mild COVID-19 symptoms. This may increase the risk of heart failure or other heart complications in the future.
- In a German study of 100 patients recovered from COVID-19, 78% had cardiac involvement on cardiac MRI 2.5 months after infection and 60% of people have cardiac inflammation. More concerning, chronic comorbidities and severity of COVID-19 infection did not correlate with these findings.
- In a study of 26 college athletes who did not require hospitalization, 46% of them had evidence of myocarditis or myocardial injury by cardiac MRI (mean test 12-53 days after infection).
Neurologic Effects
- Even in young people, COVID-19 can cause strokes, seizures, and Guillain-Barre syndrome and may increase the risk of developing Parkinson’s disease and Alzheimer’s disease.
- 1 in 7 hospitalized patients develop neurological disorders (stroke, meningitis/encephalitis, seizures (Frontera, et al.).
- 50% of those with brain dysfunction were under the age of 63
- Inflammatory CNS syndromes
- Encephalopathies (Helms, et al.)
- Stroke (5.7% in severe disease, 0.8% in non-severe disease) (Mao, et al.)
- Guillain-Barré Syndrome (Toscano, et al.)
- “Brain fog” and mood swings have been reported up to 2-3 months after illness.
- 1 in 5 patients may develop a mental health disorder within 3 months of getting the virus (Taquet, et al.).
Chronic cognitive decline, aging the brain by 10 years, even in mild cases not requiring hospitalization (Hampshire, et al., Zhou, et al.).
Lung Effects
- The type of pneumonia often associated with COVID-19 can cause long-standing damage to the lungs. The resulting scar tissue can lead to long-term breathing problems.
- 16% of patients hospitalized with COVID-19 will have a pulmonary embolism (Desai, et al.).
- In a study of 55 patients, 65% had persistent symptoms and 71% had imaging abnormalities such as interstitial thickening and fibrosis 3-months after hospital discharge.
- In a study of 57 patients, significant lung dysfunction was seen in 50% of patients 1 month after discharge.
We also have some useful data from case series following the 2003 SARS outbreak.
In a 2-year prospective study of 123 patients who recovered from SARS, 53% had significant lung damage at 2 years. 30% of healthcare workers and 7% of non-healthcare workers were unable to work at 2 years. Further, if patients still had symptoms at 6 months, they still had them at 2 years.
In a 4-year follow-up study of 233 SARS survivors, 40% had active psychiatric illness and 30% were formally diagnosed with chronic fatigue syndrome.
In a 15-year follow up study of 78 SARS survivors, 38% still had abnormal lung imaging. 22% of patients had restrictive lung disease at the 4-year follow up in this study, and fortunately all had returned to normal function by pulmonary testing criteria at 15 years.
I already had COVID-19, should I get the vaccine?
The short answer is…eventually. We don’t know exactly how long people will keep antibodies against SARS-CoV-2 after natural infection. One thing we do know is, the Pfizer and Moderna vaccines produce antibody levels roughly 4-times higher than those seen in natural infections. So what does the data show?
In a study published in July of 2020, patients still had high levels of antibodies at 4 months post infection, while those with asymptomatic or mild cases may show a more rapid decay. Newer research suggests neutralizing antibodies are still present for at least 5-7 months in symptomatic patients, and perhaps longer. While the duration of antibody presence is still unknown, we do know that re-infection is unlikely within 90 days of initial infection.
Roughly 2% of participants in the Moderna vaccine trial had detectable antibodies before receiving the vaccine with no poorly associated outcomes. Currently, the CDC recommends patients who have been infected or have received monoclonal antibody treatment (i.e. Bamlanivimab) wait to get vaccinated until they have recovered from their illness. The terminal half life of Bamlanivimab is 17.6 days and was identified for at least 29 days after treatment. Until an abundance of vaccine is available, those who have been infected or received monoclonal antibody treatment should consider waiting 90 days to allow others, who have not been infected, to get the vaccine.
Pregnant and lactating women as well as those immunocompromised were excluded from the mRNA trials. What do their respective societies think?
Patients with Allergies
Allergic reactions to vaccines, in general, are rare with the incidence of anaphylaxis estimated at 1.31 in 1 million doses given. According to the American College of Allergy and Immunology, individuals with common allergies to medications, foods, inhalants, insects, and latex are no more likely than the general public to have an allergic reaction to the mRNA COVID-19 vaccines. Those with a history of severe allergic reaction to polyethylene glycol (in Miralax, Toothpaste, baby wipes, cosmetics), should not get the vaccine. Data related to risk in individuals with a history of allergic reactions to previous vaccinations and/or mast cell activation syndrome/idiopathic anaphylaxis is very limited and evolving. A decision to receive a vaccine should be undertaken by you with your physician. The CDC recommends that people who have had a severe allergic reaction to any vaccine or injectable therapy not receive the mRNA vaccine at this time. Those with a history of allergic reactions should be monitored for 30 minutes following injection, if they do receive the vaccine.
Immunocompromised Persons
People with HIV or other immunocompromising conditions or those who take immunosuppressive medications or therapies might be at an increased risk of severe COVID-19. The vaccine safety profile is not entirely known in this population.
The American College of Allergy and Immunology endorses the fact that mRNA vaccines are not living vaccines, and can be used in immunocompromised patients. They do mention that there is a possibility of a diminished immune response to the vaccine in patients on immunosuppressive medications and it is uncertain if patients with a weakened immune system will respond to the COVID-19 vaccine. The CDC recommends immunocompromised persons still receive the COVID-19 vaccine unless otherwise contraindicated.
Pregnant and Lactating Women
Pregnant and lactating women were excluded from the mRNA COVID-19 trials, as they are from almost all vaccine trials. However, there were women who became pregnant during the studies. Adverse outcomes of these patients have not been reported. The risks of any vaccine should be weighed against the risks of not getting the vaccine. Available data tells us that pregnant patients are at an increased risk for more severe disease, 5.4 times more likely to need hospitalization, 2.6 times more likely to require intensive care and mechanical ventilation.
The American College of Obstetricians and Gynecologists (ACOG) states that the vaccine should not be withheld from pregnant women. Further, the Society of Meternal Fetal Medicine (SMFM) states that the safety risk of mRNA vaccination for pregnant or lactating women appears low, and recommends that pregnant and lactating women should be offered vaccination as these vaccines are not live vaccines and are not thought to be a risk in vertical transmission or to a breastfeeding infant.
A study of the Moderna COVID-19 vaccine looking at animal developmental and reproductive toxicity in rats was submitted to the FDA on December 4, 2020. FDA review of this study concluded that a dose of 100 μg given prior to mating and during gestation periods did not have any adverse effects on female reproduction, fetal/embryonal development, or postnatal developmental except for skeletal variations which are common and typically resolve postnatally without intervention.
The CDC recommends the mRNA COVID vaccine be offered to pregnant and lactating women, particularly if part of a high-risk group (i.e. healthcare personnel) and this decision should be based on discussion with their obstetrician.
SMFM will continue to monitor data as it becomes available on COVID-19 vaccine efficacy and safety to evaluate appropriateness in pregnancy, and we will update recommendations on the SMFM COVID-19 website.
Pediatric Use
The Pfizer/BioNTech mRNA vaccine included people down to age 16, while the Moderna vaccine used the inclusion of 18 years or older. These are the age cutoffs for each vaccine under the FDA Emergency Use Authorization. Moderna does have an ongoing study using mRNA vaccine against RSV in children, but this is still in Phase 1 of development. Further, Moderna has started clinical trials on mRNA vaccines for those aged 12-17 years. So stay tuned.
Conclusion
There has been a polarization of opinions and a distrust in the medical sciences over the last year, which hurts my heart. I have no financial interests and I have no personal gain (other than the fact that I preferred life without COVID). I have never diagnosed anyone with COVID-19 who did not test positive for it, and I don’t know anyone who has. The people I do know spend countless hours at the hospital treating patients with this disease and spend countless hours at home dissecting the emerging literature to learn how to beat this thing.
I read the studies and I trust the peer reviewed nature of medical literature. More importantly, I have faith in the good nature of the people in my field. I see the ugliness that this disease causes on a daily basis. People in their 20’s with blood clots in their lungs. Pregnant women with heart failure. People in their 30’s who go to bed with a cough and never wake up. I see people in their 60’s with acute confusion that mimics that of advanced Alzheimer’s disease. In March, I was admitting people with COVID-19 to the hospital. In December, I am admitting families with COVID-19. The reports are not hype and this is not meant to be a scare tactic…it is our reality.
While I cannot say with 100% certainty that the vaccine will harm nobody, I have confidence in the evidence at present to know it is better than the alternative. That is why I got my vaccine on Friday, December 18, 2020. I hope you do the same when it’s your turn to choose.
FYI: My only side effect was a moderately sore arm for about a day. I will update after I get my second dose.
- Monoclonal Antibodies for COVID-19 – An evidence based update - January 18, 2022
- COVID-19 Vaccines in Pregnancy - January 6, 2022
- COVID-19 Boosters….are they necessary? - October 8, 2021