SARS-CoV-2 is a positive-sense single-stranded RNA virus. Being a single-stranded RNA virus, it is unstable and vulnerable to frequent mutations. There have been over 1.8 MILLION SARS-CoV-2 mutated strains identified and entered into the GISAID database. Fortunately, not every mutation causes a significant enough change for us to lose sleep over. However, several variants of concern (VOC’s) have been identified, and more will inevitably be identified that deserve discussion to understand their interplay with current vaccines available.
But first, let’s pretend we are all budding virologists and set the stage by looking at the SARS-CoV-2 viral genome. The following graphic is a basic representation of the viral structure with the RNA sequence hidden inside that encodes at least 29 proteins.
SARS-CoV-2 structural proteins (SP) are encoded by 4 genes including the E (envelop), M (membrane), S (spike) and N (nucleocapsid) genes. The remainder non-structural proteins (NSP) are mostly enzymes or functional proteins that play a role in viral replication and induce a person’s responses to infection.
The mRNA vaccines contain synthetic mRNA, which serves as a blueprint that codes for just ONE of these proteins, the spike protein (the red box part of the genome in the diagram above). The mRNA itself is quite fragile and the body rapidly breaks down this synthetic mRNA and it is eliminated from the body within a few days. It does NOT enter the nucleus of the cell, it does NOT alter your DNA and does NOT multiply in your body forever, despite false claims that this can happen. In fact, the spike protein is only kept around for about 2-3 weeks to train the immune system. After this, it too is degraded and excreted.
T-cells and B-cells work together during a viral infection (and following vaccination) to induce both a cell-mediated and antibody-mediated immunity, respectively. In cell-mediated immunity, T-cells kill the virus-infected cells. In antibody-mediated immunity, antibodies neutralize the virus itself. The mRNA vaccines mimic a natural infection on a significantly blunted scale. This is with the intention that if your body meets the real virus in the future, it is ready and armed to fight the invader and (hopefully) prevent symptomatic or severe infection. If the vaccine is effective enough, this could potentially even suppress the viral replication enough to decrease the risk of transmitting the virus to another person. As this whole process is short-lived (< 3 weeks), the likelihood of delayed adverse effects (months or years) from this vaccine technology is highly improbable. Especially when compared to natural infection, which does this same process with 28 ADDITIONAL proteins.
I was told the PCR test is counting the flu as COVID-19?
On July 21st, the CDC announced that it will be retiring it’s 2019-nCoV PCR panel. Somehow people interpreted this to mean there was an issue with the accuracy of the test. It is not being retired because it can’t tell the difference between influenza and SARS-CoV-2. That is false. It is being retired because there are more efficient tests now. We used to have to obtain multiple different swabs to test for different infections (i.e., one for influenza, one for SARS-CoV-2 and one for RSV). The new swab will be able to check for all of these with one swab. That’s only one swab that needs to be shoved into the nose of a patient instead of three. Plus, there are over 250 different PCR tests currently approved for emergency use to detect COVID-19.
How do we know these tests don’t accidentally measure the flu as COVID-19?
Because the test was developed to look for the presence of a nucleic acid found only in the covid virus. It has been studied before it was ever approved to make sure it didn’t react with other viruses.
So, what’s the deal with these variants?
Viruses mutate, as should be very apparent to everyone at this point. However, not all mutations have significant consequences while others do. A common point of misinformation currently circulating is that viruses can only mutate to become less lethal. This is not accurate. While it certainly would be in the best interest of a virus for it to be less lethal and more transmissible, it is not always possible to be both.
Viruses are constantly changing in multiple ways. Antigenic drift occurs when the genes of a virus go through a series of small changes until the host organism’s immune system no longer recognize the virus. This is often caused by point mutations in a gene and can result in epidemics (large infections in a single community). More dramatically, antigenic shift occurs when the virus undergoes a more abrupt change so drastic that a large portion of the population does not have adequate immunity.
This has been the cause of four major influenza pandemics since the 19th century. The Ebola outbreak in 2016 is another example of evolutionary changes that resulted in a more transmissible and more lethal illness. Other examples include Zika virus and Hepatitis B to name a few. Not to mention that it has already been documented in several SARS-CoV-2 variants (Peer reviewed sources here, and here, and here, and here, and here.)
Plus, you can’t overlook the fact that even if the virus is less lethal, it can certainly still cause an excess of death when the healthcare system is over-run with everyone getting ill at one time. This has been demonstrated repeatedly through this pandemic on a global scale and likely a major factor in the wide range of case fatality rates between regions over time.
LOWER mortality does not always mean LESS mortality...
For example, let’s say we have two viral strains. One is 50% more lethal but less transmissible. The other is less lethal but 50% more transmissible. Initially, the more lethal strain will cause more deaths. However, over time, the more transmissible strain will cause an exponential growth in the number of infections, ultimately causing significantly more death. While it certainly is possible that the SARS-CoV-2 virus will eventually mutate into less lethal strains over time, it does not negate the fact that there is still a significant amount of chronic illness and mortality associated with the current strains circulating at this time.
Variants of Concern (VOC)
VOC’s are variants that demonstrate one or more of the following:
- Increase in transmissibility
- Increase in virulence of change in clinical disease presentation
- Decrease in effectiveness of public health and social measures or available diagnostics, vaccines, therapeutics
Alpha Variant
United Kingdom, September 2020
Key Spike Protein Mutations: N501Y, A570D, D614G, P681
- 50% increased transmission than earlier strains (R0 4-5)
- Potential increased severity based on hospitalizations and case fatality rates
- Monoclonal antibody treatments still effective (BAM fact sheet, Regen-CoV fact sheet)
- Vaccines very effective against symptomatic infection, hospitalization, death, and possibly transmission
- 7 x more likely to require hospitalization
- 2.3 x more likely to require admission to the Intensive Care unit
Beta Variant
South Africa, May 2020
Key Spike Protein Mutations: K417N, E484K, N501Y, D614G
- 50% more transmissible than the original strain (R0 of 4-5)
- Monoclonal antibodies Bamlanivimab and Etesevimab are not effective
- Monoclonal antibody Regeneron is sill effective
- 9.4 x more resistent to antibodies to prior infection
- 10.3 to 12.4 x more resistant to vaccination (Wang et al., Wu et al., Madhi et al. Cele et al.)
- Possibly more severe infection (Pearson, et al., Funk, et al.)
- 6 x more likely to require hospitalization
- 3 x more likely to require admission to the Intensive Care Unit
- 1 x more likely to result in death
Gamma Variant
Japan/Brazil, November 2020
Key Spike Protein Mutations: K417N/T, E484K, N501Y, D614G
- 2.4-fold more transmissible
- Previous infection provides only 54-79% protection against reinfection
- Significantly reduced susceptibility to the monoclonal antibodies Bamlanivimab and Etesevimab
- Monoclonal antibody Regeneron (Regen-CoV) still appears to be efficacious
- 3.4 x more resistant to antibodies from prior infection
- 3.8-4.8 x more resistant to vaccination
- 6 x more likely to require hospitalization
- 2 x more likely to require admission to the Intensive Care Unit
- 60% less likely to result in death
Delta Variant
India, October 2020
Key Spike Protein Mutations: L452R, T478K, D614G, P681R
- Currently the cause of 98% of all cases in the United States
- 64% more transmissible than alpha variant
- 200% more transmissible as the original Wuhan strain (R0 5-8)
- Potential reduction in neutralization by some monoclonal monoclonal antibody treatments
- 9 x more resistant to antibodies from prior infection and vaccination
- 86% increased risk of hospitalization if unvaccinated
- 62% less likely to require hospitalization if vaccinated in Scotland
- Fully vaccinated people with breakthrough infections from this variant appear to be infectious for a shorter period to time
- Produces 1,000 X more viral particles than other variants
- Remain infectious longer (18 days vs 13 days)
- P681R mutation. The mutation lies at the junction between two subunits of SARS-CoV-2’s spike protein, at a site that allows the human cellular enzyme furin to cleave the spike into two parts. This cleavage, some experiments suggest, primes spike proteins in a way that allows them to fuse more readily with a host cell’s membrane, according to a detailed description in Nature.
Lambda Variant
Peru, December 2020
Key Spike Protein Mutations: L452Q, F490S, D614G
- Not currently a VOC, but likely will be in the future
- Highly infectious and T76I and L452Q are responsible for this property
- RSYLTPGD246-253N, L452Q and F490S confer resistance to antiviral immunity
- mRNA vaccines still highly effective
- 3.05 x reduction in neutralization of Lambda variant from inactivated virus vaccine CoronaVac
- Regen-CoV monoclonal Ab still effective
So, does the Delta variant cause more lethal disease?
The answer is a bit complicated. We know that the delta virus produces a much higher amount of virus (viral load) in patients than was seen with earlier strains of the SARS-CoV-2 virus. We are talking 1,000x more virus being present when infection occurs. As we know from several studies, the more virus that is present, the more severe the infection tends to be. This is the whole premise behind treatments with monoclonal antibodies like Bamlanivimab and Regen-CoV, which work by decreasing viral load.
One Canadian study suggested the Delta variant is associated with a 120% increased risk of hospitalization, 287% increased risk of ICU admission, and 137% increased risk of death compared to the original Wuhan strain.
Scottish researchers published a paper in the Lancet in June showing a 2-fold increase in the rate of hospitalization in patients infected with the Delta variant, suggesting it causes more severe infection. Further, based on data from December 2020 through March 2021 looking at the Alpha, Beta, and Gamma variants, we know that all of these variants were also associated with an increased rate of severe disease, hospitalization, and ICU admission. Still, fortunately, this was not associated with an overall increase in the rate of death.
Bottom Line: The verdict is still out regarding whether the Delta variant is more lethal. But there is more to the story…
The Delta variant is significantly more contagious...
We know that the Delta variant is significantly more contagious than other strains. It has a current estimated reproductive number (R0) of 5-8. Meaning each person infected will infect another 5-8 people, on average.
However, despite a significant increase in cases, we aren’t really seeing a corresponding increase in death like we did with other community outbreaks over the last year and a half. So, what gives?
Is this the effect of the vaccine, or is Delta less deadly?
This decrease in death only appears to hold true in areas where vaccination is over 50%. Ukraine is one of the least vaccinated countries, with only 6% of their population fully vaccinated. Deaths in Ukraine from the current outbreak follow a trajectory that more closely mirrors what we have seen before vaccines were available.
Source: Reuters
Hopefully, the overall trend seen in highly vaccinated continues, and the mortality of this virus stays low. That would be the ideal situation, and it is certainly possible. Based on data from the U.K., the Delta variant currently has a low case fatality rate of just 0.2% for the general population. This is likely because a large portion of the people most at risk of dying from COVID-19 has been vaccinated in the United Kingdom. Most Delta variant hospitalizations occur in those under the age of 50 and in those who are unvaccinated. So, we cannot simply use the data we have today and compare it to early 2020, when we knew significantly less about this virus today, to determine if it is more lethal in comparison. Regardless of severity, this is not the only marker for public health concerns.
The Delta variant causes similar amount of virus in vaccinated and unvaccinated...
In a pre-print study of 218 patients with Delta variant infections, those vaccinated had viral loads that were essentially the same as those who were unvaccinated. This contradicts data from breakthrough cases seen in earlier variants suggesting the vaccine may no longer protect against transmission. While this is a huge bummer, there is some positive data from this study.
We already know that a high viral load is associated with more severe illness. In this study, despite equal viral loads at the time of diagnosis, those who were vaccinated had a significantly more rapid decrease in the amount of virus they produces as well as much less severe illness (see table).
Similar reports of viral load have been seen in other cluster outbreaks, suggesting it is highly probable that vaccinated patients can spread infection from the Delta variant. This makes herd immunity significantly more challenging to obtain through vaccinations alone. Again, this is a bummer. Although we do have more evidence that vaccines offer significant individual protection and likely lowers your chance of dying if you get infected.
But the news says vaccinated people are testing positive. Does that mean the vaccines aren't working?
Compared to the original virus, all the variants thus far are better at evading the immune system’s antibody response, some better than others. That’s because so-called neutralizing antibodies recognize and bind to the spike proteins on the virus’s surface, preventing the virus from infecting cells. But if the virus mutates its spike protein, then the antibodies may not bind as well, and the virus gains an advantage.
Having a certain portion of vaccinated patients become infected is completely expected. The vaccine isn’t an impenetrable forcefield (it would be a lot cooler if it were). It is a layer of armor to offer protection comparable to wearing a seatbelt while riding in a car. It won’t completely prevent death and debility, but it should still make those situations much less likely if used correctly. The CDC stopped collecting data on all symptomatic breakthrough cases in April (they still collect data on hospitalization and death). Fortunately for us, most states continue to collect this data and can be accessed here and in the picture below.
As you can see, even as the Delta variant makes up most cases in the United States, the vast majority of symptomatic cases are occurring in those who are unvaccinated.
Remember, the initial goal of vaccine effectiveness was only 50%. While that may seem like a low bar, this would still be more effective than the flu shot. When the CDC removed the mask mandate for vaccinated individuals in May of 2021, the dominant circulating variant was Alpha. The breakthrough rate of infection was very low, and those breakthrough cases had very low viral loads, suggesting a low rate of transmission if you were vaccinated.
So, what is the available data from around the world telling us about the vaccines’ effectiveness? Let’s look at the significant studies.
Qatar - July 9th, 2021
- Assessed vaccine efficacy for Moderna against Alpha and Beta variants for hospitalization and death
- Qatar has a population that comprises mainly working-aged adults
- Used a matched test-negative, case-control study design
United Kingdom - June 14th, 2021
- This is a pre-print study that has not been peer-reviewed
- Estimated vaccine efficacy against symptomatic disease and hospitalization
Scotland - June 14th, 2021
- 19,543 confirmed SARS-CoV-2 infections included in analysis between April 1 and June 6, 2021
- At the start of the study period, only 7.6% of the population was fully vaccinated
- Increased to 39.4% by the end of the study period
- Vaccinated patients were 62% less likely to require hospitalization
UK REACT-1 Study - pre-print
Elliott, et al., 2021
- 989,233 volunteers screening for prevalence of COVID-19 in the UK
- Used self-reported vaccination status and patients swabbed themselves at home
- 527 tested positive (100% of these were the Delta variant)
- 44% of infections occurred in fully vaccinated individuals
- Highest prevalence of infection was among people 12 to 24 years old
Results:
- 1 in 26 chances of being infected with Delta variant if you were exposed and vaccinated
1 in 13 chances of being infected with Delta variant if you were exposed and unvaccinated
United Kingdom - August 12th, 2021
- A total of 19,109 people included in this study
- Compared vaccination (Pfizer and AstaZeneca) status in persons with symptomatic Covid-19 with vaccination status in persons who reported symptoms but had a negative test
- Then did a secondary analysis for Alpha or Delta variant
Israel - July 23rd, 2021
Recent data from Israel is a bit more concerning about the ability of the current vaccines to prevent symptomatic infections with the Delta variant. Before you panic, let’s look at the actual data in more detail. The purple bar represents all vaccinations to date, and the colored bars represent the month of vaccination. Regardless of when the person was vaccinated, there is a high effectiveness rate against hospitalization and severe COVID-19.
However, the vaccine’s effectiveness against all infections was 39% in this study regardless of when people were vaccinated. More concerning is that those who received their vaccines in January 2021, were only 16% protected against developing an infection. Fortunately, the protection against hospitalization and severe COVID-19 is still very high (82% and 86%, respectively).
Qatar - August 11th, 2021
- Pre-print study (not yet peer reviewed)
- To determine the effectiveness of Pfizer and Moderna against Delta variant from March to July against all infections (symptomatic or asymptomatic)
Why does the Israel data look so different from the United Kingdom?
I don’t think we have a definite answer yet. A few notable differences are important to note:
First, vaccine strategies were not the same: Israel was aggressive with providing as many people a 2-dose regimen and stuck to the 3-week interval between first and second doses. On the other hand, the UK delayed many of their second doses by 12 weeks to offer a larger initial spread across their population. This may have provided the UK a significant advantage. Studies such as this one and this one have shown that increasing the time between dosing intervals offers a more robust immune response.
Secondly, there could be waning immunity: Clinical data shows antibody levels persist for at least 6 months following vaccination and that neutralizing antibody levels are highly predictive protection against symptomatic infection. However, as we just observed, the Pfizer vaccine may lose its effectiveness to protect against symptomatic infection over time. More data needs to emerge to determine if this is the reason for the differences between the UK and Israel vaccine effectiveness.
The more critical take-home message here is that Israel and the UK have > 60% of their populations vaccinated; both had surged in cases with the Delta variant WITHOUT any significant surges in severe cases or death. It is too early to entirely blame waning immunity as the cause of differences in the data between the UK and Israel. However, based on this data, I would not be surprised if we see new recommendations for booster vaccines in the coming days to weeks.
A follow-up study published out of Oxford University on August 12th showed the effectiveness of the Pfizer vaccine against symptomatic infections begins to drop after 3 months. In light of this data, Israel began administering booster vaccines to those 50 years of age and older. So far a total of 1.1 million booster shots has been administered (roughly 12% of their population). A Maccabi Healthcare Services study then surveyed 150,000 of these patients and compared them to a sample of patients who received their second dose of the vaccine in January and February. They found, that with a booster, the efficacy of the Pfizer vaccine against all infections (not just hospitalizations and death) increased to 86%.
How does this compare to what we are seeing in the United States?
The Mayo Clinic published data of the mRNA vaccines over a 7-month period covering both the time when the Alpha variant was the predominant strain and when the Delta variant became the predominant strain. The three groups analyzed included unvaccinated individuals, those who were fully vaccinated with Moderna, and those who had been fully vaccinated with Pfizer. This was conducted with patients across multiple Mayo Clinic Health System sites in multiple states (Minnesota, Wisconsin, Arizona, Florida, and Iowa). Results of vaccine effectiveness is outlined in the table.
While the data clearly seems to favor Moderna, it should again be stressed that both vaccines retained significant protection against hospitalization during July, at 75-81%, a decline from May of just 12-14 points. Likewise, in the earlier UK analysis Pfizer and AstraZeneca showed continuing efficacy against hospitalization due to the Delta variant, even though you aren’t as protected from developing a symptomatic infection.
A study that was just published on August 18th from the CDC, looked at the rate of hospitalizations in New York between vaccinated and unvaccinated from May through July as the Delta variant became the dominant strain making up over 98% of infections. As expected, they found the rate of effectiveness of the vaccine declined from 91.7% to 79.8% over the summer months. However, vaccine effectiveness against hospitalization remained stable at 91.9% to 95.3% as hospitalizations in unvaccinated patients continued to increase with the Delta variant.
But, the news is telling me that outbreaks have more vaccinated cases than unvaccinated. Does that mean these large international studies all got it wrong?
On August 6th, the CDC released a report of an outbreak of COVID-19 cases following multiple large public gatherings in Barnstable County, Massachusetts in July. Headlines of this outbreak peppered media headlines and the country lost their minds…so let’s unpack what really is going on here.
There were 469 cases during events over July 4th that attracted over 60,000 people to the area. The baseline vaccination rate in Massachusetts at the time of this study was 69%. Of the 469 cases, 90% were thought to be the Delta variant based on random genetic testing of 133 samples. While 74% of the positive patients were fully vaccinated, 21% were asymptomatic, 1.2% were hospitalized, and no deaths were reported. Again, viral load was similar in vaccinated and unvaccinated patients.
The biggest shock behind this data is that some are misinterpreting the results as a failure for the vaccine. At first glance, the 74% number was suggested by some to mean you are more likely to get infected if you were vaccinated. In cognitive psychology, judging an outcome without understanding the base rate of vaccinations is known as the base rate fallacy.
For example, did you know that the vast majority of surgical-related deaths involve right-handed surgeons? Is that because right-handed surgeons aren’t as good as left-handed surgeons? No, it’s because 90% of surgeons are right-handed.
For example, if 83% of the population is vaccinated and there is an outbreak with 50% of cases occurring in the vaccinated group and 50% of them occurring in the unvaccinated group. This is what it could look like…
Headlines would read (as they did with Israel), “50% of COVID-19 cases occur in vaccinated). You don’t have to be an epidemiologist to understand that the group on the left looks very different than the group on the right. While each group has the same number of infected individuals, the rate of infection amongst vaccinated individuals is 2%, while the infection rate in unvaccinated individuals is 6.5 times more likely.
How about a real-world example specific to COVID-19. Iceland is currently experiencing a surge in cases, with 67% occurring in vaccinated people. Iceland is a bit easier to use as a reference of understanding as we don’t know the vaccination status of all the visitors to Barnstable County, Massachusetts. So, is Iceland showing the world that vaccines don’t work?
Let's break it down...
There were 2,239 total positive cases in Iceland from July 9th to August 10th. Of these, 1,503 were vaccinated, and 684 were unvaccinated. 86% of the population is fully vaccinated, with a total population of about 357,000 (90% of men and 96% of women have received at least one dose of a vaccine, and children are currently not eligible).
When we correct for the baseline vaccination rate in each group….
We see that the baseline rate of breakthrough cases in vaccinated people is 6 per 1,000, while the infection rate for unvaccinated patients is 18 per 1,000. Therefore, the actual rate of infection is 3x higher than that for vaccinated people. On top of that, Iceland is one of the most vaccinated countries globally, and despite this outbreak, there have been ZERO Covid-related deaths since late May.
My point with this exercise is that headlines do not negate the fundamentals of scientific data. Yes, it concerns that current vaccines do not appear to offer protection against the transmission of the disease. Yes, it worries that newer strains are less effective against the present variants. However, the vaccine continues to provide strong evidence of protection against severe disease. In a July 25th report from the National Center for Immunization and Respiratory Disease, the vaccine offers
- 3-fold reduction in risk of infection
- 8-fold reduction in risk of symptomatic disease
- 25-fold reduction in risk of hospital admission or death
At the time of this report, a total of 6,239 hospital admissions and 1,263 deaths have occurred in vaccinated patients. 98% of cases in Michigan and 97% of all cases nationwide are in unvaccinated or incompletely vaccinated people. This is an incredible thing, considering COVID-19 was the LEADING cause of death in the United States just eight months ago.
Will variants eventually evolve to evade vaccines completely?
So, we know that mutations are occurring, and there is concern those mutations could eventually evade the current protective response to the vaccines. In the UK, the expert advisory board SAGE predicted that new variants would eventually overcome existing vaccines. Just as antibiotics breed resistance in bacteria, vaccines can incite changes that enable diseases to escape their control.
Fortunately, we have data that shows the vaccines can lower the rate at which mutations are generated. In a pre-print longitudinal analysis of over 1.8 million SARS-CoV-2 genomes from 183 countries or territories, vaccine breakthrough patients harbored viruses with significantly lower diversity than unvaccinated patients. Meaning, this could be evidence that COVID-19 vaccines are fundamentally restricting the evolution of new variants.
Of course, this will only matter if we become more aggressive with vaccination on a global scale. One of the best hopes of winning this contest is to get as many people immunized now as possible to reduce the likelihood of even more variants appearing that might evade protection for the current vaccines.
How does natural infection compare to the protection of the vaccine?
Evidence of natural immunity from SARS-CoV-2 infection versus vaccination is a bit mixed and something that should be more aggressively studied, particularly in the face of vaccine resistance.
In a November 2020 study from the University of Missouri School of Medicine, researchers showed that < 1% of patients who recovered from a severe COVID-19 infection were re-infected. Of those that were, the average time of reinfection was 3.5 months, and 3.2% of those patients died.
A large multicenter study published in The Lancet in April, showed that those with a previous COVID-19 infection had an 84% lower risk of becoming re-infected and a 93% lower risk of symptomatic disease over the 7-month observation period. Further, data published this month show antibody levels to SARS-CoV-2 remain high up to 13 months post-infection, even with mild infections.
In a peer-reviewed study published in June, researchers showed that the antibodies from the vaccine more targeted to the receptor-binding domain of the SARS-CoV-2 spike protein than antibodies elicited by natural infection and had greater binding breadth. This suggests that vaccine-induced immunity was more equipped to handle mutations in this region than those from natural disease.
In another peer-reviewed study from June published in Nature, researchers showed that the Pfizer vaccine produced more neutralizing antibodies than unvaccinated individuals who recovered from COVID-19 but did not require hospitalization.
One month later, a pre-print study of patients who recovered from severe SARS-CoV-2 infection, showed infection produces B-cell responses that continue to evolve for at least one year. During that time, memory B-cells express increasingly broad and potent antibodies that were resistant to mutations found in the current variants of concern. When compared to SARS-CoV-2 naïve patients vaccinated with either mRNA vaccine, natural infection produced antibodies with greater potency and breadth when compared to antibodies obtained from vaccination alone, suggesting those vaccinated following illness will have heightened immune protection.
A study from the Cleveland Clinic tracked cases in healthcare workers who were either vaccinated or previously had COVID-19. They found that the rate of reinfection is essentially the same between the two groups. Another study out of Qatar similarly found that the chance of reinfection is low among those who previously had COVID-19 and those who were vaccinated.
Then, on August 13th, the CDC released a study comparing the effectiveness of COVID-19 vaccines versus natural immunity from prior SARS-CoV-2 infection. In this study, being unvaccinated was associated with 2.34 times the odds of reinfection compared with being fully vaccinated. A concurrent study showed the Pfizer and Moderna vaccines prevented 96% of hospitalizations, and the Johnson & Johnson vaccine prevented 84% of hospitalizations in adults aged 65-74 years old. It is important to note that these studies took place before the Delta variant showed up in the United States. Newer data shows antibody response from natural infection is likely similarly suppressed as is seen with the vaccines.
It is essential to point out that none of these studies included the Delta variant in the analysis. If you have had prior infection, you likely have some level of protection. Getting vaccinated after an infection has been shown to give people a substantial boost in neutralizing antibodies.
In a peer-reviewed publication from June, research showed that antibody levels obtained after a mild natural infection were similar to getting a single dose of either mRNA vaccine. This suggests that a natural infection essentially serves as the “first dose” of a two-dose vaccine.
While there isn’t as much robust data on protection from natural infection as there is for vaccines, it is reasonable based on current data to infer that your risk of reinfection would be similar to those who are partially vaccinated. This aligns with data from the CDC study showing 2.34 times increased odds of reinfection. In this study, patients requiring hospitalization had antibody levels that were much higher, effectively identical to those who have received both doses of an mRNA vaccine, but this started to wane after 6-8 months.
Another study in JAMA showed that, compared with unvaccinated participants, those who had received at least ONE dose had higher antibodies and a nearly 50-fold increase in neutralizing activity.
Bottom line: Reinfection is rare due to the complex nature of our immune systems. While you likely have a good deal of protection from natural immunity, you would most certainly benefit from vaccination, especially if your course was mild on your initial infection. Based on timing on reinfection and waning antibodies, the time at which this should be done hypothetically appears to be ideal, around 1-2 months following a mild infection and 3-6 months following a severe infection. Some evidence suggests those with prior infection (even if mild) may have an equal or higher benefit to a single dose of the vaccine compared to those who were uninfected but received two doses.
Is herd immunity still even possible?
The herd immunity threshold is generally agreed to be the proportion of the population that needs to be immune to tip a disease into decline. It occurs when the “typical” person goes on to infect fewer than one other person due to naturally acquired or vaccine-induced immunity. The idea underlying herd immunity is that the proximity of immune individuals shields others who are still susceptible to infection, Fine explains. And, with enough immune people in the population, the herd becomes a defensive wall that denies the virus pathways to keep spreading. Pre-variant models predicted that 67% of the people would need to get vaccinated to reach herd immunity.
With data showing variants have the potential to decrease the effectiveness of vaccines against asymptomatic infection and with newer data showing vaccines may not reduce the rate of transmission as they initially did, this certainly seems like a less obtainable goal long term.
Our best tool in the fight to herd immunity would be to get everyone vaccinated before we meet a variant that renders our vaccines ineffective. This is seemingly becoming unobtainable given the apparent war against vaccination. In some sense, vaccination is now more relevant to personal protection instead of protecting the herd, which was not the case 8 months ago.
Some people say the vaccines can make COVID-19 worse if you get infected...is that true?
When people say this, they are referring to a process called antibody-dependent enhanced (ADE). ADE is when a disease is made worse or more severe in a person already exposed to the virus through previous infection or vaccination compared to people who were never exposed or vaccinated. ADE has occurred with vaccines in the past in the 1960s to Respiratory Syncytial Virus and Measles and in 2016 to Dengue. However, it isn’t unique to just vaccines but seen from the natural illness itself.
A quick primer…
There are four different strains of the Dengue virus. If you get infected and recover from one strain and get infected to another strain, ADE occurs, and your illness is significantly more severe than it was the first time.
People are worried that ADE could happen with the SARS-CoV-2 virus. This is because there was suspicion from some of the animal models with vaccines studied with the initial SARS-CoV-1 virus in 2002. In these studies, hypersensitivity reactions similar to ADE were seen. However, there are several reasons why it’s improbable to happen with the current vaccines.
- Since the early stages of vaccine development, scientists targeted a protein on the virus that was least likely to cause ADE.
- Most people have been infected with other coronaviruses in their lifetime, and ADE has not been identified as a result of these infections.
- Experimental animals vaccinated against SARS-CoV-2 did not develop enhanced disease when challenged, or infected, with the virus.
- In human studies, people previously infected with coronavirus were infected with different types of coronavirus, and they did not experience enhanced disease.
- When people with COVID-19 received plasma containing SARS-CoV-2 antibodies, they did not experience enhanced disease.
- If ADE was occurring, you wouldn’t just see cases with vaccinated patients. You would see significantly worse disease for those who are re-infected or infected after vaccination. We aren’t seeing that. In fact, we are seeing the opposite. ADE is an acute problem, if it was going to be an issue, we would have seen it by now. At least for the current known strains.
Bottom Line: The concerns that were raised by what happened with SARS-1 are understandable, but we now have six separate pieces of evidence that suggest that ADE is not currently an observed problem with this virus or with this vaccine associated with this virus.
But, I heard these vaccines are toxic to my cells...
A video is currently circulating saying the mRNA vaccines are toxic to the body. Specifically, they claim in the video that the mRNA vaccines produce a spike protein that is toxic to cells based on a paper saying the spike protein impairs blood vessel function. The only problem with this is the article was written based on the spike protein from natural SARS-CoV-2 infection and NOT from the vaccine.
The spike protein produced from the mRNA vaccines is similar but not identical to that of a natural infection. Research shows that only 1% of the spike protein injected by the vaccine even enters circulation, if at all. The liver rapidly destroys the part that does. The mRNA does not stay in the body and is gone within two weeks. There is no actual evidence that the spike protein from the vaccine can hurt normal, healthy cells.
So, what is the current known risk of getting COVID-19?
The age-adjusted death rate increased by 15.9% in 2020, compared to 2019. 345K deaths had COVID-19 as a contributing cause in 377.883 deaths (91.5 per 100,000 people or 11% of deaths). Throughout most of 2020, COVID-19 was the 3rd leading cause of death in the United States, rising to the #1 spot in January before abruptly falling to 7th place after initiation of vaccines.
For most of the pandemic, assessing the actual number of patients who have been infected or died from COVID-19 has been difficult. Johns Hopkins has a well-organized tracker of case fatalities (the number of deaths vs. the number of known positive cases) for those interested in this data. Meaning, for all patients who tested positive in the U.S. by swab, 1.7% of them have died.
As discussed in previous posts on this topic, the case-fatality rate is not the most accurate measure of mortality from a virus. Not all cases obtain a diagnostic swab, and tracking all cases is a nearly impossible feat. The CDC estimates that only 24% of all infections and 26% of symptomatic infections are reported. Further estimates suggest that only 55% of hospitalizations and 77% of COVID-19 related deaths were reported. Therefore, in July of 2021, the CDC released estimated adjustments of symptomatic illnesses, hospitalizations, and deaths in the United States. Following this, social media exploded with misleading claims minimizing the overall risks of the SARS-CoV-2 virus.
For example, based on the CDC adjusted estimates, if someone between 18 and 49 years old develops a symptomatic COVID-19 infection, they would have just a 0.07% chance of dying. That means there is a 99.97% that person will ultimately survive. But is this the only measurable outcome that matters to the population as a whole? Absolutely not.
LOWER mortality does not always mean LESS mortality...
Using this same data set, that same age bracket has a 2.5% chance of being hospitalized if they develop symptoms of COVID-19. That means, for every 50 people infected, one will require hospitalization. In a community where 2,000 people get infected simultaneously, 40 of them will need to be hospitalized in just this seemingly low-risk age group alone. With hospital and ICU shortages at critical levels across the country, this is an enormous issue from a public health perspective. This is one way that negating the risk of SARS-CoV-2 on an individual level has the very real potential to increase the risk to the entire community.
When scientific researchers define the quality of evidence, expert opinions and case reports have the least evidence, while randomized controlled clinical trials are near the highest quality of evidence. The large studies for the COVID-19 vaccines gave us a rather good insight into the overall safety expectations of these vaccines.
The results of these studies are covered in detail in an earlier post. We know that the overall incidence of serious adverse events is relatively low. These studies included a large number of people compared to other vaccines.
The average size of phase 3 vaccine trials to assess early adverse events ranges from 2,358 to 80,427 participants. The mRNA trials for the COVID-19 vaccine included 70,000 participants.
I believe a big misconception about safety monitoring from this point out is that people are waiting for some larger trial showing more information years down the road. This is unlikely to happen because it would be very abnormal for this to occur with vaccine studies. Once a vaccine is approved by the FDA in phase 3 trials, it is rolled out to the general population. At that point, it would not be ethical to keep a control group for the vaccine.
Vaccine history tells us that while a delayed adverse effect of a vaccine can occur, it will most likely happen in the first 6-8 weeks. Vaccines are not like a medication you take for years and years and then develop some rare cancer. With the mRNA vaccines particularly, the effective risk of an adverse event is substantially lower than the risk of natural infection (more on this later). Your body uses the mRNA, and it is degraded within two weeks and excreted from the body. It doesn’t hang around. Even if the spike protein made by the mRNA were toxic to your body, it wouldn’t be more harmful than the spike protein produced by the SARS-CoV-2 virus itself. It just isn’t probable.
So, instead of long-term trials, vaccine adverse events are monitored with self-reporting systems such as the Vaccine Adverse Event System (VAERS) in the United States and Yellow Card in the United Kingdom. At this point, most governmental bodies have some sort of reporting system for this purpose.
It is critical to understand that these systems are not designed to catch every person with a vaccine adverse event. That baseline data is obtained from the original safety trials. Instead, they are intended to pick up trends in conditions that are so rare that they could have been missed in the initial studies (i.e., something that occurs in more than 1 in 70,000 cases for the mRNA vaccines).
It is also essential to know that these reporting systems are like the app “Yelp.” Anyone can report something into the database, and just because it is there doesn’t mean it is accurate or that there aren’t multiple reports for the same incident. I can go on there and say I got a vaccine and my head fell off, and it would add to the count of reported deaths. So, when you see 9,000 death reports listed on this system, it does NOT mean there were 9,000 deaths from the vaccine by any means.
The CDC reviews every report that is made in VAERS. Medical charts are reviewed, and those cases are followed up for accuracy. There have been 4.78 billion doses of COVID-19 vaccines delivered. It is a statistical probability that a portion of those people would have developed a disease or died regardless of whether they got the vaccine. If a medication or a vaccine causes disease, it isn’t going to do it 1,000 different ways. Again, the purpose of these reporting systems is to find TRENDS in disease that occurs at a higher than expected rate in the general population. Knowing the background rate for a particular condition is extremely important when determining disease trends.
So, what adverse events have been identified?
Thrombosis-Thrombocytopenia Syndrome (TTS)
- General background rate: 2-5 cases per million people per year (CVST)
- Rate from COVID-19 INFECTION: 39 cases per 1 million infections
- Rate from COVID-19 VACCINES:
- CDC: 7 cases per 1 million vaccines
- Australia: 7.5 cases per 1 million vaccines (14 cases per 1 million AstraZeneca vaccines) – 6 deaths
- Canada: 1.4 cases per 1 million vaccines
TTS is a syndrome characterized by a blood clot in the brain’s veins (central venous sinus thrombosis) in conjunction with thrombocytopenia (low blood platelet counts). As of August 11th, this phenomenon has been seen in 42 patients who received the Johnson & Johnson vaccine and a few reports in Europe in people who received the AstraZeneca vaccine. Two cases were reported in VAERS from the Moderna vaccine. No cases have been reported from the Pfizer vaccine.
This adverse event is rare, with an overall occurrence rate of about 7 per 1 million vaccinated women between 18 and 49 years old. For women 50 years and older and men of all ages, this adverse event is even rarer. Australian monitoring systems have reported a rate of 14 per 1 million vaccines (104 cases, 6 died) from AstraZeneca.
However, it is crucial to understand that this disease is not unique to the vaccine. The American Heart Association/American Stroke Association Stroke Council Leadership published a report in the journal Stroke, showing that the risk of developing CVST blood clots is 8 to 10 times higher following a COVID-19 infection compared to the risk associated with receipt of a COVID-19 vaccine.
Anaphylaxis
- Rate from NON-COVID-19 VACCINES: 1.3 cases per 1 million vaccines
- Rate from COVID-19 VACCINES:
- CDC: 2-5 cases per 1 million vaccines
- Canada: 3 cases per 1 million vaccines
Severe allergic reactions, including anaphylaxis, can occur after any vaccination. Prior to COVID-19, the general rate of anaphylaxis following any vaccine was about 1.3 cases per 1 million vaccines. The current estimated rate of anaphylaxis from the COVID-19 vaccines is 2 to 5 cases per 1 million vaccines.
Guillain-Barré Syndrome
- General background rate: 10-20 cases per million people per year
- Rate from COVID-19 INFECTION: 150 cases per 1 million infections
- Rate from COVID-19 VACCINES:
- CDC: 1.2 cases per 1 million vaccines (mRNA) and 8 cases per 1 million J&J vaccines
- Australia: 10 cases per 1 million AstraZeneca vaccines (suspected, not confirmed)
- Canada: 1.1 cases per 1 million vaccines
GBS is a rare disorder where the body’s immune system damages nerve cells, causing muscle weakness and sometimes paralysis. While most people fully recover from GBS, some can have permanent nerve damage. As of August 11th, there have been 161 cases of GBS entered into the VAERS reporting system. These are still being investigated to see if there is a causal link to the vaccine. The only vaccine in which this was reported is the Johnson & Johnson vaccine. These cases are primarily in men over the age of 50.
The estimated incidence of GBS cases following an mRNA vaccine was 1.2 per 1 million vaccines, and following the Johnson & Johnson vaccine was 8 per 1 million vaccines.
The incidence of GBS in the general population is 10-20 cases per million people per year. With 161 cases reported following the 13,784,136 J&J vaccines delivered, would put an estimated incidence of 11 cases per 1 million vaccines. For reference, the influenza vaccine causes an extra 1-2 cases per 1 million vaccines given. Again, an actual causal link to COVID-19 vaccines causing GBS is still being investigated. As with other adverse events, GBS also occurs at a higher rate from infection with SARS-CoV-2 than it does from vaccination, with an incidence of 150 cases per 1 million infections.
Myocarditis/Pericarditis
- General background rate: 100-200 cases per million people per year in all age groups. 8 cases per 1 million children per year. 18 cases per 1 million adolescents between the ages of 15-18.
- Rate from COVID-19 INFECTION: 450 cases per 1 million infections
- Rate from COVID-19 VACCINES:
- CDC: 4.8 cases per 1 million vaccines
- Canada: 8 cases per 1 million vaccines
- Europe: 1.4 cases per 1 million vaccines
As of August 11, 2021, VAERS has received 1,306 reports of myocarditis or pericarditis. The CDC and FDA have confirmed 762 of these cases after more than 300 million doses. Most cases have been reported after mRNA COVID-19 vaccination (Pfizer-BioNTech or Moderna), particularly in male adolescents and young adults. The highest incidence was in males between the ages of 16 and 19 years—the average onset of symptoms around 3.5 days following administration of the vaccine.
The CDC estimates the incidence of myocarditis/pericarditis following vaccines to 4.8 cases per 1 million vaccines. In an independent review of 2 million patients vaccinated across 40 hospital systems in the US, the incidence of myocarditis was found to be higher than the CDC estimate. Researchers determined the true incidence to be closer to 10 cases per 1 million vaccines for myocarditis and 18 cases per 1 million vaccines for pericarditis. This suggests the actual incidence is likely under-reported. Again, myocarditis and pericarditis occur at a much higher rate from COVID-19 infection than from the vaccine, occurring in 450 people per 1 million infections.
The overall incidence of myocarditis/pericarditis is higher than would be expected in the general population, suggesting it is likely a true adverse event occurring from vaccination. A risk-benefit analysis for COVID-19 vaccination and risk of myocarditis/pericarditis was done by the CDC and the benefits of vaccination (prevention of COVID-19 disease and associated hospitalizations, ICU admissions, and deaths) outweighed the risks in all populations for which vaccination has been recommended.
The balance of benefits and risks varied by age and sex because cases of myocarditis were primarily identified among males aged <30 years, and the risks of poor outcomes related to COVID-19 increase with age. Per million second doses of mRNA, COVID-19 vaccine administered to males aged 12–29 years, 11,000 COVID-19 cases, 560 hospitalizations, 138 ICU admissions, and six deaths due to COVID-19 could be prevented, compared with 39–47 expected myocarditis cases after COVID-19 vaccination.
Among males aged ≥30 years, 15,300 COVID-19 cases, 4,598 hospitalizations, 1,242 ICU admissions, and 700 deaths could be prevented, compared with three to four expected myocarditis cases after COVID-19 vaccination. This analysis did not include the potential benefit of preventing post-COVID-19 conditions, such as prolonged symptoms and MIS-C.
In a June analysis of 323 patients with myocarditis following COVID-19 vaccination, 309 (96%) were hospitalized. Acute clinical courses were generally mild; among 304 hospitalized patients with known clinical outcomes, 95% had been discharged at the time of review, and none had died. Most patients experienced resolution of symptoms with conservative treatment, such as receipt of nonsteroidal anti-inflammatory drugs.
Death
There have been no definitive numbers as to the number of people who have died due to the vaccine. As of August 16th, VAERS has a total of 6,789 reports of deaths following vaccination for a rate of 0.0019%. Remember, this comes with the massive caveat that these cases have not been reviewed to establish a causal link to COVID-19 vaccines. Remember, anyone can make a report in this system. So, it is highly improbable that all of these reported deaths will ultimately be linked to the vaccine.
For the sake of argument, let’s say that you don’t trust the CDC and you think they are hiding vaccine-related deaths. We do have data from other countries that can offer some insight. Let’s look at Canada. As of August 6th, a total of 50,254,577 COVID-19 vaccine doses had been administered. There was a total of 169 deaths reported following vaccines. Of these, only six deaths following a diagnosis of TTS were confirmed to be related to the vaccine. Sixty-nine reported deaths were felt unlikely linked to the vaccine, and 94 are either still under investigation or has insufficient information to determine a causal link.
International Vaccine Safety Reporting Systems
How do these risks compare to the risks from COVID-19 infection?
We certainly can’t get any straight data from the CDC at this time about most definitive risks. However, Canada is a reasonable population to poll as they offer a breakdown of specific reports suspected to be from vaccine administration. A total of 50,254,577 vaccine doses have been administered in Canada. The following chart uses risks compiled from the ECDC, the Government of Canada, and the Australian Department of Health compared to peer-reviewed publications of disease incidence associated with acute COVID-19 infections. While it is highly probable that the incidence of these diseases may be underestimated in vaccine reporting systems, this gives a summary of data that is CURRENTLY available. The following table is a summary of the current risk per 100,000 people between the vaccines and COVID-19.
COVID-19 infection has other risks
The age-adjusted death rate in the United States increased by 22.9% in 2020, compared to 2019. Based on population growth, the yearly expected excess death rate increase is typically no greater than 2.5% per year. COVID-19 was a contributing cause in 377,883 deaths in 2020 (91.5 per 100,000 people or 11% of deaths). Throughout most of 2020, COVID-19 was the 3rd leading cause of death in the United States, rising to the #1 spot in January before falling to 7th place in June. In the united states, 188 per 100,000 people have already died from COVID-19 (0.18% of the population).
Source: CDC
"Not Dead" doesn't mean "Recovered"
The chances of dying if you catch Covid-19 vary significantly according to your age and overall health, with older people and those with underlying conditions facing a much higher risk. Different countries are likely to have different death rates, depending partly on the age and health of their populations, the quality of their healthcare, and other factors that we may not yet understand. Even if your age group is at low risk of dying from COVID-19, this doesn’t mean this is the number of people who will recover without complication or long-term issues.
Multisystem Inflammatory Syndrome in Children (MIS-C)
Severe hyperinflammatory syndrome occurring 2–6 weeks after acute SARS-CoV-2 infection among persons < 21 years old. The majority of cases occur between the ages of 12 and 20 years. It results in a wide range of manifestations, including myocarditis. Estimates of myocarditis in patients with MIS-C have ranged from 23% to 60%, though a more significant proportion (80% in one study) do have some form of cardiac involvement. Even without myocarditis, MIS-C is a severe illness. 60-70% of cases require hospitalization, and 1-2% will die. It has an estimated occurrence is 1 in every 3,200 children infected with SARS-CoV-2.
Long COVID Syndrome
COVID-19 can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery. A systematic review and meta-analysis (remember, these are the highest quality evidence) of 18,251 publications were published on August 9th, assessing the long-term effects of COVID-19. In this study, they found a total of 55 long-term effects associated with a SARS-CoV-2 infection. The prevalence of residual symptoms is about 35% in patients treated for COVID-19 outpatient, but around 87% among cohorts of hospitalized patients.
In the first study of long covid in children suggests that more than 50% of children aged between 6 and 16 years old who contract the virus have at least one symptom lasting more than 120 days, with 42.6% impaired by these symptoms during daily activities.
Source: Lopez-Leon, et al.
Conclusion
Overall, the decision to vaccinate (especially in younger age groups) should consider the individual benefit-risk ratio and take into account the public health benefits of vaccination. As for adults, the children who will benefit most from vaccination will be those with underlying conditions, such as cancer, cardiac disorder, diabetes, hypertension, or kidney disease, which have been shown to confer a risk of hospitalization that is similar to the risk in some adult age groups without underlying conditions.
Vaccinating children and adolescents will also prevent long-term sequelae associated with SARS-CoV-2 infection, for which the burden in children is uncertain, and multisystem inflammatory syndrome, which has been shown to affect some children who have experienced only mild acute infections.
- 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