Since the beginning of the coronavirus pandemic, there have been many thousands of articles and commentaries published on almost every imaginable aspect of the SARS-Cov-2 virus and the COVID-19 pandemic it has caused. They have appeared online, in journals, on preprint servers, in newspapers, and on blogs. As much as we might try to keep up, there will always be important facts or developments we might have missed, so below are a few that should help us understand some of the nuances of the pandemic.
#1 THERE APPEARS TO BE AN IMPORTANT DIFFERENCE IN EFFICACY BETWEEN THE Pfizer-BioNTech AND Moderna COVID-19 VACCINES.
The difference pertains to the efficacy across different demographic groups—specifically, people of different ages. According to the FDA’s analysis of the Pfizer-BioNTech vaccine, in the clinical trials on almost 44,000 subjects, it was 95.0% effective in persons aged 16-55, and 93.8% effective in those over age 55—that is, essentially the same. By contrast, regulators’ review of the clinical studies with the Moderna vaccine found a pronounced age-dependent difference: “The [Vaccine Efficacy] in participants ≥65 years of age appears to be lower than in younger adults 18 to <65 years (86.4% compared to 95.6%)” (emphasis added).
That is shown in the indicated portion of this table, from an article in the New England Journal of Medicine that reported the results of Moderna’s clinical trials:
![Moderna vaccine clinical trial results.]()
Source: New England Journal of Medicine.
Thus, of every hundred people under age 65 vaccinated with the Moderna vaccine, we can expect that about five will fail to develop an immune response after the two shots; among those 65 or over, about 14 will not be successfully immunized. (The failure rate for the Pfizer-BioNTech vaccine was approximately five in a hundred for all age groups.) The numbers are small, but the bottom line is, if you’re 65 or older and you have a choice, I’d recommend that you get the Pfizer-BioNTech vaccine.
#2 VACCINES’ ABILITY TO PREVENT SYMPTOMATIC COVID-19 IS NOT THE SAME THING AS COMPLETELY PREVENTING THE ESTABLISHMENT OF INFECTION (WHICH IS CALLED “STERILIZING IMMUNITY”).
Because of how the trials were designed, “efficacy” was defined as a positive test for the SARS-CoV-2 virus genetic material (RNA) and at least one symptom, such as fever, cough, fatigue, or loss of taste or smell. But that doesn’t rule out the possibility that people who are “successfully” vaccinated (no positive test for the virus and no symptoms) could become infected and spread the virus to other people. Given that possibility, and also (as discussed above) the reality that fewer than 100% of people given the shots will be protected, it is essential that we continue to practice the non-pharmaceutical preventive measures: masking, social distancing, frequent handwashing, and avoiding crowds in enclosed spaces.
Going forward, we will need to know about the impact of vaccines on virus transmission, but for that, we will need new clinical studies with contact tracing to monitor the spread from vaccinated and unvaccinated participants. (One suggestion, by biostatistician Natalie Dean, is to design such a study using college students, because “they aren’t prioritized for [receiving vaccine under the Emergency Use Authorizations], and transmission is higher in congregate settings.”)
#3 CORONAVIRUS VACCINES ARE NOT NEW.
Coronavirus infections are common in companion animals and economically important livestock and vaccines to prevent these infections have been widely employed in veterinary medicine for many years. They have been administered to dogs, cattle, pigs, and poultry. (The animal coronaviruses are sufficiently different from SARS-CoV-2 that the veterinary vaccines would not prevent COVID-19 in humans.) The more than a dozen veterinary vaccines licensed in North America have been developed with an array of technologies and platforms, including genetic engineering—but none, as yet, with the messenger RNA technology (mRNA) used for the Pfizer-BioNTech and Moderna vaccines.
#4 THE “NOVEL” TECHNOLOGY TO MAKE THE APPROVED COVID-19 VACCINES ISN’T FUNDAMENTALLY NEW.
Many reporters and commentators have dutifully noted that vaccines have traditionally been composed of killed or attenuated (weakened) viruses so that they can elicit an immune response without causing disease. The Pfizer-BioNTech and Moderna COVID-19 vaccines, however, are made with a genetic engineering technology called messenger RNA (mRNA), which acts in a novel way. When injected into a person’s muscle, the mRNA is read by the cells’ protein-synthesizing machinery and gives rise to numerous copies of a version of the SARS-CoV-2 virus “spike protein,” which is on the surface of the virus and plays a key role in attaching to the host’s cells.
Those proteins elicit an immune response, so that if the person who has been injected subsequently comes into contact with the infectious SARS-CoV-2 virus, the body’s antibodies and immune cells are prepared to neutralize it.
However, there’s a link missing in that narrative about the continuum from traditional vaccine development techniques to mRNA—namely, “subunit vaccines,” which are conceptually similar to using mRNA for vaccines. A good example is Merck’s hepatitis B vaccine Recombivax, which has been around for more than 30 years. What is injected and stimulates the immune response in that case is a non-infectious viral protein that is synthesized in genetically engineered baker’s yeast grown in huge fermentation vats. The protein, which is analogous to the coronavirus’ spike protein, is purified and used as the active substance in the vaccine.
A similar example is GlaxoSmithKline’s shingles vaccine Shingrix, which contains a glycoprotein (a protein linked to a carbohydrate) that is a component of the varicella zoster virus, and which is synthesized in genetically engineered Chinese hamster ovary cells.
There is also a COVID-19 vaccine using this technology being developed by Maryland-based Novavax. It contains proteins produced in genetically engineered insect cells that resemble the “spike” proteins found on the surface of the coronavirus, and which elicit an immune response after being injected.
The Merck, GlaxoSmithKline, and Novavax subunit vaccines are something of an intermediate approach between the killed or attenuated vaccines and the mRNA ones because the antigen injected is a protein, whereas the mRNA vaccines cause a protein to be synthesized in the vaccine recipient after injection. An understanding of this continuum of approaches to vaccination should help to demystify COVID-19 vaccines for the considerable number of people who may be hesitant about taking a novel vaccine developed and approved in record time.
#5 THE MONOCLONAL ANTIBODY DRUGS TO TREAT COVID-19 ARE GOING BEGGING.
In November, the FDA issued two Emergency Use Authorizations for monoclonal antibody drugs produced by Eli Lilly and Regeneron Pharmaceuticals, respectively, that treat mild to moderate cases of COVID-19 in adults and older pediatric patients at high risk for progressing to severe illness. They are expensive, and in short supply, but paradoxically, U.S. health officials are seeing a lack of demand for these drugs that can help to keep infected people out of the hospital.
Testing delays (they need to be infused intravenously within 10 days of the onset of symptoms), red tape, and shortages of staff for intravenous administration are preventing many patients from getting these drugs, which consist of laboratory-produced antibodies that mimic those produced in response to infection. This Wall Street Journal headline says it all: “Highly Touted Monoclonal Antibody Therapies Sit Unused in Hospitals.”
There is an important “news you can use” message here: If you are diagnosed with COVID-19, have symptoms, and qualify for these drugs, insist on getting them immediately.
#6 THE NEW, MORE INFECTIOUS “U.K. SARS-CoV-2” VARIANT (B.1.1.7) IS MORE DANGEROUS, EVEN IF NOT MORE VIRULENT.
Much of the reporting about this new variant of the SARS-CoV-2 virus, B.1.1.7, which has quickly become the predominant strain in parts of the U.K. and has now been detected in about three dozen other countries worldwide, including in various parts of the United States, has characterized it as more transmissible, but not more deadly. Preliminary analyses suggest it is in the range of 56%-70% more transmissible than other circulating SARS-CoV-2 strains. However, that characterization is misleading in two respects.
First, the more transmissible the virus is, greater numbers of people will be infected and will be hospitalized, and more—in the sense of absolute numbers—will die. Thus, although perhaps not more likely to kill a particular individual who becomes infected, overall, the death toll from the viral variant will be higher because of its ability to infect more people.
Second, as World Health Organization epidemiologist Maria Van Kerkhove has pointed out, “The more of this virus circulates [because of greater transmissibility], the more opportunity it will have to change” to something worse. She concluded, “We’re playing a very dangerous game here.”
#7 WHEN SOMEBODY TELLS YOU THAT IT’S SILLY TO IMPOSE LOCKDOWNS OR TAKE VACCINES BECAUSE OF AN ILLNESS “WITH A SURVIVAL RATE OF 99.9%,” YOU’RE ABOUT TO BE SOLD A BILL OF GOODS.
First of all, a conservative estimate of the death rate is not 0.1% (which would correspond to a survival rate of 99.9%), but probably well above 0.2%. That might not sound like a lot, but when applied to a huge number of cases, it can be catastrophic—as it has been: COVID-19 has killed 375,000 Americans, been diagnosed in over 22 million, and certainly infected several times that number.
Second, “herd immunity,” the point at which a sufficiently large fraction of the population is immune to infection because of natural infection or vaccination and causes the pandemic to wane, is thought to be upwards of 80% in the case of COVID-19. In the absence of vaccines, achieving herd immunity would require the infection of approximately 264 million Americans, which would result in an unimaginable death toll.
Moreover, deaths and death rates are far from the whole story. The persistence of symptoms for months after “recovery” from the acute illness of COVID-19 is common, even in people who have suffered only mild cases of illnesses. According to the Mayo Clinic, the most common persistent signs and symptoms are fatigue, shortness of breath, cough, joint pain, and chest pain; and “the virus can damage the lungs, heart, and brain, which increases the risk of long-term health problems.”
We have come a long way in understanding COVID-19, but much remains unknown. As British Prime Minister Winston Churchill said about World War II, at the end of 1942, “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.” As to the COVID-19 pandemic, the scientific and medical communities in the public and private sector will continue to produce important new products and knowledge so we can get to the end as quickly as possible. In the meantime, it is more important than ever to heed their advice about taking precautions to flatten the curve.
Critical but Little-Known Facts About the COVID-19 Pandemic.
Henry Miller, M.S., M.D.
Since the beginning of the coronavirus pandemic, there have been many thousands of articles and commentaries published on almost every imaginable aspect of the SARS-Cov-2 virus and the COVID-19 pandemic it has caused. They have appeared online, in journals, on preprint servers, in newspapers, and on blogs. As much as we might try to keep up, there will always be important facts or developments we might have missed, so below are a few that should help us understand some of the nuances of the pandemic.
#1 THERE APPEARS TO BE AN IMPORTANT DIFFERENCE IN EFFICACY BETWEEN THE Pfizer-BioNTech AND Moderna COVID-19 VACCINES.
The difference pertains to the efficacy across different demographic groups—specifically, people of different ages. According to the FDA’s analysis of the Pfizer-BioNTech vaccine, in the clinical trials on almost 44,000 subjects, it was 95.0% effective in persons aged 16-55, and 93.8% effective in those over age 55—that is, essentially the same. By contrast, regulators’ review of the clinical studies with the Moderna vaccine found a pronounced age-dependent difference: “The [Vaccine Efficacy] in participants ≥65 years of age appears to be lower than in younger adults 18 to <65 years (86.4% compared to 95.6%)” (emphasis added).
That is shown in the indicated portion of this table, from an article in the New England Journal of Medicine that reported the results of Moderna’s clinical trials:
Source: New England Journal of Medicine.
Thus, of every hundred people under age 65 vaccinated with the Moderna vaccine, we can expect that about five will fail to develop an immune response after the two shots; among those 65 or over, about 14 will not be successfully immunized. (The failure rate for the Pfizer-BioNTech vaccine was approximately five in a hundred for all age groups.) The numbers are small, but the bottom line is, if you’re 65 or older and you have a choice, I’d recommend that you get the Pfizer-BioNTech vaccine.
#2 VACCINES’ ABILITY TO PREVENT SYMPTOMATIC COVID-19 IS NOT THE SAME THING AS COMPLETELY PREVENTING THE ESTABLISHMENT OF INFECTION (WHICH IS CALLED “STERILIZING IMMUNITY”).
Because of how the trials were designed, “efficacy” was defined as a positive test for the SARS-CoV-2 virus genetic material (RNA) and at least one symptom, such as fever, cough, fatigue, or loss of taste or smell. But that doesn’t rule out the possibility that people who are “successfully” vaccinated (no positive test for the virus and no symptoms) could become infected and spread the virus to other people. Given that possibility, and also (as discussed above) the reality that fewer than 100% of people given the shots will be protected, it is essential that we continue to practice the non-pharmaceutical preventive measures: masking, social distancing, frequent handwashing, and avoiding crowds in enclosed spaces.
Going forward, we will need to know about the impact of vaccines on virus transmission, but for that, we will need new clinical studies with contact tracing to monitor the spread from vaccinated and unvaccinated participants. (One suggestion, by biostatistician Natalie Dean, is to design such a study using college students, because “they aren’t prioritized for [receiving vaccine under the Emergency Use Authorizations], and transmission is higher in congregate settings.”)
#3 CORONAVIRUS VACCINES ARE NOT NEW.
Coronavirus infections are common in companion animals and economically important livestock and vaccines to prevent these infections have been widely employed in veterinary medicine for many years. They have been administered to dogs, cattle, pigs, and poultry. (The animal coronaviruses are sufficiently different from SARS-CoV-2 that the veterinary vaccines would not prevent COVID-19 in humans.) The more than a dozen veterinary vaccines licensed in North America have been developed with an array of technologies and platforms, including genetic engineering—but none, as yet, with the messenger RNA technology (mRNA) used for the Pfizer-BioNTech and Moderna vaccines.
#4 THE “NOVEL” TECHNOLOGY TO MAKE THE APPROVED COVID-19 VACCINES ISN’T FUNDAMENTALLY NEW.
Many reporters and commentators have dutifully noted that vaccines have traditionally been composed of killed or attenuated (weakened) viruses so that they can elicit an immune response without causing disease. The Pfizer-BioNTech and Moderna COVID-19 vaccines, however, are made with a genetic engineering technology called messenger RNA (mRNA), which acts in a novel way. When injected into a person’s muscle, the mRNA is read by the cells’ protein-synthesizing machinery and gives rise to numerous copies of a version of the SARS-CoV-2 virus “spike protein,” which is on the surface of the virus and plays a key role in attaching to the host’s cells.
Those proteins elicit an immune response, so that if the person who has been injected subsequently comes into contact with the infectious SARS-CoV-2 virus, the body’s antibodies and immune cells are prepared to neutralize it.
However, there’s a link missing in that narrative about the continuum from traditional vaccine development techniques to mRNA—namely, “subunit vaccines,” which are conceptually similar to using mRNA for vaccines. A good example is Merck’s hepatitis B vaccine Recombivax, which has been around for more than 30 years. What is injected and stimulates the immune response in that case is a non-infectious viral protein that is synthesized in genetically engineered baker’s yeast grown in huge fermentation vats. The protein, which is analogous to the coronavirus’ spike protein, is purified and used as the active substance in the vaccine.
A similar example is GlaxoSmithKline’s shingles vaccine Shingrix, which contains a glycoprotein (a protein linked to a carbohydrate) that is a component of the varicella zoster virus, and which is synthesized in genetically engineered Chinese hamster ovary cells.
There is also a COVID-19 vaccine using this technology being developed by Maryland-based Novavax. It contains proteins produced in genetically engineered insect cells that resemble the “spike” proteins found on the surface of the coronavirus, and which elicit an immune response after being injected.
The Merck, GlaxoSmithKline, and Novavax subunit vaccines are something of an intermediate approach between the killed or attenuated vaccines and the mRNA ones because the antigen injected is a protein, whereas the mRNA vaccines cause a protein to be synthesized in the vaccine recipient after injection. An understanding of this continuum of approaches to vaccination should help to demystify COVID-19 vaccines for the considerable number of people who may be hesitant about taking a novel vaccine developed and approved in record time.
#5 THE MONOCLONAL ANTIBODY DRUGS TO TREAT COVID-19 ARE GOING BEGGING.
In November, the FDA issued two Emergency Use Authorizations for monoclonal antibody drugs produced by Eli Lilly and Regeneron Pharmaceuticals, respectively, that treat mild to moderate cases of COVID-19 in adults and older pediatric patients at high risk for progressing to severe illness. They are expensive, and in short supply, but paradoxically, U.S. health officials are seeing a lack of demand for these drugs that can help to keep infected people out of the hospital.
Testing delays (they need to be infused intravenously within 10 days of the onset of symptoms), red tape, and shortages of staff for intravenous administration are preventing many patients from getting these drugs, which consist of laboratory-produced antibodies that mimic those produced in response to infection. This Wall Street Journal headline says it all: “Highly Touted Monoclonal Antibody Therapies Sit Unused in Hospitals.”
There is an important “news you can use” message here: If you are diagnosed with COVID-19, have symptoms, and qualify for these drugs, insist on getting them immediately.
#6 THE NEW, MORE INFECTIOUS “U.K. SARS-CoV-2” VARIANT (B.1.1.7) IS MORE DANGEROUS, EVEN IF NOT MORE VIRULENT.
Much of the reporting about this new variant of the SARS-CoV-2 virus, B.1.1.7, which has quickly become the predominant strain in parts of the U.K. and has now been detected in about three dozen other countries worldwide, including in various parts of the United States, has characterized it as more transmissible, but not more deadly. Preliminary analyses suggest it is in the range of 56%-70% more transmissible than other circulating SARS-CoV-2 strains. However, that characterization is misleading in two respects.
First, the more transmissible the virus is, greater numbers of people will be infected and will be hospitalized, and more—in the sense of absolute numbers—will die. Thus, although perhaps not more likely to kill a particular individual who becomes infected, overall, the death toll from the viral variant will be higher because of its ability to infect more people.
Second, as World Health Organization epidemiologist Maria Van Kerkhove has pointed out, “The more of this virus circulates [because of greater transmissibility], the more opportunity it will have to change” to something worse. She concluded, “We’re playing a very dangerous game here.”
#7 WHEN SOMEBODY TELLS YOU THAT IT’S SILLY TO IMPOSE LOCKDOWNS OR TAKE VACCINES BECAUSE OF AN ILLNESS “WITH A SURVIVAL RATE OF 99.9%,” YOU’RE ABOUT TO BE SOLD A BILL OF GOODS.
First of all, a conservative estimate of the death rate is not 0.1% (which would correspond to a survival rate of 99.9%), but probably well above 0.2%. That might not sound like a lot, but when applied to a huge number of cases, it can be catastrophic—as it has been: COVID-19 has killed 375,000 Americans, been diagnosed in over 22 million, and certainly infected several times that number.
Second, “herd immunity,” the point at which a sufficiently large fraction of the population is immune to infection because of natural infection or vaccination and causes the pandemic to wane, is thought to be upwards of 80% in the case of COVID-19. In the absence of vaccines, achieving herd immunity would require the infection of approximately 264 million Americans, which would result in an unimaginable death toll.
Moreover, deaths and death rates are far from the whole story. The persistence of symptoms for months after “recovery” from the acute illness of COVID-19 is common, even in people who have suffered only mild cases of illnesses. According to the Mayo Clinic, the most common persistent signs and symptoms are fatigue, shortness of breath, cough, joint pain, and chest pain; and “the virus can damage the lungs, heart, and brain, which increases the risk of long-term health problems.”
We have come a long way in understanding COVID-19, but much remains unknown. As British Prime Minister Winston Churchill said about World War II, at the end of 1942, “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.” As to the COVID-19 pandemic, the scientific and medical communities in the public and private sector will continue to produce important new products and knowledge so we can get to the end as quickly as possible. In the meantime, it is more important than ever to heed their advice about taking precautions to flatten the curve.
Henry I. Miller, a physician and molecular biologist, was a Research Associate at the National Institutes of Health and the founding director of the FDA’s Office of Biotechnology. You can find him online or on Twitter at @henryimiller.
Nothing contained in this blog is to be construed as necessarily reflecting the views of the Pacific Research Institute or as an attempt to thwart or aid the passage of any legislation.