The Long Haul, Part 2: What Is Long COVID?

In the 1890s one of the biggest pandemics in recorded history, known then as the “Russian flu”, swept the world and killed one million people (for perspective, that is out of a world population about ¼ of today’s population). That “flu” is now thought to have been a novel coronavirus. Like the current coronavirus, SARS-CoV-2, the Russian “flu” was a new human pathogen so few people had any natural immunity to it and it was quite lethal. Not only that, but as the pandemic waned, it left in its wake a global wave of long-lasting neurological problems in the survivors. A similar long-lasting post-acute disease wave followed the next big pandemic, the “Spanish” flu of 1918 (which really was due to the influenza virus). The common symptom following the Spanish flu was lethargy so bad that in Tanganyika (modern-day Tanzania), for example, it caused a famine because people were too debilitated to pick the harvest. Other viral outbreaks, including SARS, MERS, and Ebola, also have been associated with long-term sequelae in survivors. However, today’s long COVID complications are far more common and far more variable than the persistent symptoms following these other viral pandemics. The variety of unrelated long COVID symptoms has flummoxed doctors hard pressed to diagnose and, hence, treat the constellation of chronic problems that appear in each patient.

As I wrote in Part 1 of this series, a wave of what has become known as “long COVID” is emerging in many people who have recovered from the acute disease. A recent review chronicling the effects of long COVID reported that “long haulers” commonly experience fatigue, sleep problems, and joint and muscle pain long after their bodies cleared the virus. Other symptoms range from the mundane to the bizarre: brain fog, shortness of breath, fatigue, tremors, tooth loss, racing heart, glaucoma, and diabetes among others. Long haulers are also at a significantly increased risk of dying months after infection. A large study found that after surviving acute COVID-19, patients had a 59% increased risk of dying within six months after their initial diagnosis. This translates into an extra eight deaths per 1000 patients. Thus, the consequences of the acute disease itself are just the tip of the iceberg.

Because the official definition of the chronic problem is fluid, we are still learning what this new malady is. A UK study published last December simply defined the syndrome as a collection of symptoms lasting for more than 28 days after initial diagnosis. However, another British study as well as Britain’s National Institute for Health and Care Excellence vaguely and broadly define long COVID as “signs and symptoms that develop during or after an infection consistent with COVID-19, and that continue for more than 12 weeks and are not explained by an alternative diagnosis”. It does not specify a list of what the symptoms are.

But, there are many. A global survey tallied 205 different symptoms across 10 different organ systems that can persist after COVID infection has cleared, including those affecting the heart, lungs, gastrointestinal system, muscles, and joints. There also are frequent neurological and neuropsychiatric symptoms as highlighted in Part 1 of this series. A sufferer typically has several of these problems at a time (14 different symptoms on average), with the most debilitating usually being one of three: severe breathlessness, fatigue, or “brain fog”. Other common symptoms included compromised function of the lungs, heart, and kidneys sometimes requiring transplantation. There also have been skin rashes, and newly diagnosed diabetes.

What exactly is long COVID? About the only thing we can say with any certitude at this time is that long COVID exists but is not easy to describe, possibly because it really is more than one malady. The only constant between different long COVID patients with different symptoms is that the conditions are a collection of varied symptoms that persist long after the acute disease subsides, which sounds as vague as the British definitions described above. Long COVID clearly represents a new health malady or maladies since it is not generally found in uninfected people, but is common in COVID survivors; yet not all COVID patients experience it. Long COVID can affect any post-COVID patient at any age, but it mostly presents in middle-aged people and seems to slightly prefer women. Even people with asymptomatic CoV-2 infection can have late arising effects that fit the profile of long COVID.  Multiple studies have shown that infected people who do not get acutely ill can still show irregular lung scans, for example. One such study found that nearly 60% of people with asymptomatic infection showed some lung inflammation in CT scans. Other studies have shown that young people with asymptomatic or mild infections can have long lasting cardiac issues, while others show signs of small blood vessel damage.

Some of these symptoms can be similar to other recognized, if not fully understood chronic problems, such as chronic fatigue syndrome (CFS), which is one of the most common complaints that long haulers have. CFS remains a mystery malady with an unknown cause, but it often follows a viral or bacterial infection. It is, therefore, possible that long-COVID CFS-like problems might be no different from classic CFS. It also is possible that CFS-like long COVID symptoms are not at all related to what is recognized as classic CFS, and they are simply different illnesses with similar symptoms. Time and research will tell.

Broadly speaking, there are three types of long COVID patients, according to one NIH scientist. The first are generally characterized by “exercise intolerance”, meaning they feel out of breath and exhausted from even mild physical activity. The second are characterized by cognitive complaints like brain fog and/or memory problems. The third type experiences problems with the autonomic nervous system, which controls things like heartbeat, breathing and digestion. Patients in this group suffer from symptoms such as heart palpitations and dizziness. Impairments of the autonomic nervous system are known as dysautonomia, which is an umbrella term for a variety of syndromes. Physicians treating long-COVID patients say there has been a marked increase in dysautonomia since the pandemic began. A rehabilitation doctor at Mount Sinai Hospital, in New York, says that roughly 80% of people who show up at his long COVID clinic have dysautonomia of one type or another.

Not only do long COVID patients suffer chronic debilitation, they also are at increased risk of dying. One of the largest studies of Covid-19 “long haulers” found that COVID survivors had a 59% increased risk of dying within six months after contracting the SARS-CoV-2 virus. The excess mortality translates into about 8 extra deaths per 1,000 patients. Thus, the pandemic’s hidden toll is that many patients require readmission, and some die, weeks after the viral infection abates.

What causes long COVID? What causes the myriad of symptoms lumped under the long COVID umbrella are being studied, but it seems that not all are actually caused by the CoV-2 virus. Based on what we have gleaned from observations of a few million long COVID patients around the world, the focus is on three possible biological explanations. One is that long COVID is due to a persistent viral infection. A second possible cause could be an autoimmune disorder. The third possibility is that it is a lingering consequence of tissue damage caused by inflammation during the initial, acute infection.

Supporting the first hypothesis that the infection persists even after COVID disease has passed is that some patients very slowly clear the virus completely. The virus or its remnants persist along with the long lasting symptoms. These patients are not infectious so it could be that they harbor some altered form or fragment of the bug which does not replicate, but is nevertheless making some viral product that their bodies are responding to. This is known to occur with other viruses, including measles, dengue and Ebola. RNA viruses are particularly prone to this phenomenon, and CoV-2 is an RNA virus. Direct proof of this hypothesis is lacking, but pertinent clues abound. A study published recently in Nature showed that some people had traces of CoV-2 proteins in their intestines four months after they had recovered from acute COVID-19. Viral products from CoV-2 have also been found in people’s urine several months after their recovery. All this is circumstantial evidence, to be sure, but viral persistence is consistent with long COVID in certain patients.

The second hypothesis, that long COVID is an autoimmune disease, holds that the virus causes something to go awry with the immune system inciting it to attack some of the body’s own tissues. Some evidence backs this idea, too. The immune system is a complex, tightly regulated machine designed to discriminate between your own cells and foreign entities such as viruses. Sometimes this ability to distinguish self from non-self fails and an immune response is generated to one’s own tissues. Some patients suffering from long COVID have badly behaving macrophages, which are immune cells responsible for gobbling up foreign invaders and displaying them to immune cells inciting them to make antibodies or to kill infected cells. Other long COVID patients exhibit abnormal activation of their B-cells, which churn out antibodies against the pathogen that can sometimes cross-react with the body’s own cells causing complications. Since antibodies circulate for several months after an infection, it makes sense that this could cause problems months after recovery from the disease. Again, this evidence is circumstantial, but consistent with the observations in some long haulers.

The third hypothesis about the cause of long COVID holds that the body’s inflammatory response during the acute illness causes long-term damage to cells and tissues leading to chronic inflammation. This sometimes happens with other viral diseases, but it could be particularly likely with COVID-19 since out-of-control inflammation, caused by a cytokine “storm” is a common hallmark of severe cases of acute illness. One guess is that the inflammation damages parts of the autonomic nervous system, or that the virus might damage the cells that line blood vessels, either by infecting them directly and/or via inflammation from the immune response. This could change the way blood flows to the brain and other organs, and may thus explain the brain fog and other organ failure that is sometimes seen. This too remains circumstantial, but consistent with current observations in certain patients.

Bottom line: Long COVID probably embraces several different chronic conditions with different causes. Studies to investigate each of these possibilities are under way.

We will see.


Where did the term “long hauler” come from?

In the early weeks of the pandemic, a school teacher in Portland, Oregon, had a fever and tested positive for COVID-19 at a drive-up site. Because she did not feel well, she did not shower or wash her hair, so she threw on a trucker hat with a picture of a squirrel on it went to get tested, and snapped a selfie to share on social media.

Later that month, she was still experiencing a range of chronic symptoms and had contacted other COVID-positive people who also had persistent problems that their doctors had a hard time diagnosing. So, she decided to set up a support group on Facebook. The trucker hat, which was sitting her coffee table got her thinking of long-haul trucking, which inspired her to name the Facebook group “Long Haul Covid Fighters.” As the group kept growing, members began referring to each other using the bantam handle, “long-haulers.” Eventually the term was picked up by the press and during testimony in September 2020, Tony Fauci used the term to describe patients suffering from the COVID-associated new malady. It stuck.


Don’t Forget The Drugs: An Update

In these pages last March, I reminded readers to be thankful for the vaccines that prevent COVID-19, but to not forget the antiviral drugs that are being developed that might treat the disease. Both vaccines and antivirals are part of the same quiver of weapons we have to fight the pandemic. In that blog post, I mentioned an experimental drug, molnupiravir that was being developed by Merck and Ridgeback Therapeutics. Well, they just posted an encouraging update. It continues to show success at preventing serious disease when given to high-risk people early after infection. Its only side effects were similar to the placebo, meaning it is very safe. In animal studies, the drug also was effective against different CoV-2 variants, including Delta, and against other coronaviruses including SARS and MERS. Molnupiravir is a “prodrug,” which means that it has no activity on its own; rather it is metabolized after ingestion to an active drug that was developed in the early 2000s to treat hepatitis C.

This is a significant step for being able to easily protect high-risk patients at home. The pill that patients take on their own cuts their risk of hospitalization or death by ~50%. The results were so encouraging that the study was halted after consultation with the FDA. Early termination of studies like this is only done when interim data analyses show such good efficacy of a treatment that it would be unethical to continue enrolling subjects, some of whom would receive placebo, thereby being denied an effective therapy.

The drug slows the spread of the virus in infected people by forcing the enzyme that copies the viral genetic material into making so many mistakes the virus cannot reproduce. That, in turn, reduces the patient’s viral load, shortening the infection and damping the type of over-exuberant immune response (cytokine storm) that causes serious problems in many COVID patients. It was not effective when given to already hospitalized, or advanced, patients. It is on track to be approved by the FDA by the end of the year, and would be the first proven and approved oral antiviral drug for treating COVID-19 (neither ivermectin nor hydroxychloroquine have been proven or approved).

The FDA has already cleared another antiviral drug, remdesivir, for treating COVID-19, but it is only used to treat advanced patients who are already hospitalized (interestingly remdesivir was also originally developed to treat hepatitis C and it is also used to treat Ebola). Several lab-produced monoclonal antibody treatments have also been approved by the FDA for treating mild to moderate COVID-19 and they are more successful than molnupiravir at preventing advanced disease. But both remdesivir and the antibody treatments require an intravenous infusion done in a health care setting, making them more complicated and more expensive than just taking a pill at home, which is a decided advantage of molnupiravir. Finally, one of the more effective approved drugs against COVID-19 is the steroid, dexamethasone, but that is only given to very sick patients since its side effects are significant. Therefore, there is much room in the anti-COVID quiver for effective, simple-to-administer drugs such as molnupiravir. Both Pfizer and Roche also have other antiviral drugs that block viral replication in advanced stages of development. Stay tuned.

As of October 5, 2021, the Milken Institute tracker shows that there are 331 “treatments” for COVID-19 in development worldwide. This effort recently got a $3.2 billion boost from the US Antiviral Program for Pandemics, which is a rejuvenated initiative that was started during the MERS outbreak in 2012, but was tabled after MERS fizzled out. Then there is the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program, also sponsored by NIH. These programs focus on developing non-vaccine therapies designed to treat not prevent the disease and they include studies of medicines currently used to treat other diseases (including ivermectin, which has yet to be proven effective) as well as studies of new drugs.

While the news about molnupiravir is encouraging, health experts are concerned that the news also could increase complacency regarding vaccines in the vax-hesitant. It is important to realize that prevention (vaccination) is almost always preferable to treatment (drugs).

Get the vax.

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The Long Haul, Part 1: What Long COVID Is Like

This is the first part of a multi-part blog series on long term morbidity associated with COVID-19 infection (how many parts there will be in the series remains to be determined). When public health scientists assess the impact of a disease on society, they consider both mortality as well as morbidity. In fact, the CDC’s primary assessment of US health is a publication called the Morbidity and Mortality Weekly Report. This blog series was prompted, in part, by repeated assertions by vaccine nay-sayers that since the mortality of COVID is only about 1.5% of those infected (they usually cite a false and much lower mortality rate), the vaccines and mandates are unnecessary. To that naive statement I make three points that the nay-sayers typically ignore:

  1. The Spanish flu had a similarly low mortality rate as COVID-19, but in just 24 weeks during its second wave, it killed more people around the world than were killed in the 10 years of WWI and WWII combined. Hence, just looking at the percent of infected people who die does not tell the whole story if you do not also mention the total number of people infected. One percent of a billion people is a very large number, for example.
  2. By focusing only on the low mortality rate, the vax nay-sayers are engaging in a logical fallacy called “confirmation bias.” That is, they totally ignore the statistics that do not support what they want to believe. What they ignore here is the cost incurred by disease survivors, or the morbidity. Morbidity rates usually swamp mortality rates and, as we shall see in this blog series, long COVID can cause a disproportionate cost to individuals and society in terms of damaged health, lost productivity, increased burden on health systems (which also affects care of critical non-COVID patients) and insurance payors, lost earnings, interrupted careers, and even delayed deaths that are not attributed to COVID, such as suicide, which I discuss below.
  3. Last December, just before the vaccines first rolled out, I reported that COVID-19 deaths had become, by far, the number one killer in the US, which contradicts the “negligible death rate” narrative of the nay-sayers. At that time COVID deaths far outpaced deaths due to cancer and heart disease, the previous top two causes of death in the US. That high COVID death rate dropped because of the vaccines. These facts put the lie to anti-vaxer’s claims that we do not need vaccines or public health mandates because the death rate from COVID is low. The COVID death rate had become very high, but is now much lower precisely because of the vaccines and mandates.

In this post, Part 1 in the series, I relate what long COVID is like to some long haulers. In future posts, I will focus on the costs of long-term COVID, and on the specific devastating health effects long-haul COVID can have on the neurological system, on the kidneys, lungs, and on new-onset Type 1 diabetes. And I will discuss what we have learned about the causes of long COVID and how to treat or manage it.

What is it like for long haulers? I began this blog in April 2020, and one of the first posts I made was about the experience of an emergency room doctor who was on the front lines of the early pandemic working in an ER in NYC, which was very hard hit by the pandemic. She caught the disease and spent a couple of weeks in the ICU recovering from it. But, something was not right with her after she was discharged from medical care, and she was re-admitted to an in-patient psychiatric unit to treat her mind. After a few weeks, she was released to convalesce at her sister’s home. But, she was still not right in her mind and eventually shot herself in the head. Her suicide was not counted as a COVID death. There have been other post-COVID suicides since then.

There are the recent post-COVID suicides of Texas Roadhouse CEO Kent Taylor and "Dawson's Creek" writer Heidi Ferrer and several others, which reveal a heightened risk of suicide as a sequelae of long COVID.

Sometime early in the pandemic, a healthy, young journalist who had recently graduated from journalism school also caught the disease. She eloquently wrote about the ordeal, which began in full four weeks after she had been diagnosed and two weeks after she no longer tested positive for the virus. She wrote how her body shook for five days before checking into a North Carolina hospital not knowing what was wrong. She wrote that two nights before going to the ER, and after being “cured” from COVID-19, she was jolted awake by what felt like a “brain zap.” She staggered into the hallway which she described feeling like it was on a funhouse tilt. She said she felt like she was in a Salvador Dali painting, “distorted and oozing.” When she tried to speak to her husband, the words came out drowsy and slow. I personally found the description of her feelings interesting since a friend of mine who had experimented with drugs in her earlier life once told me about tripping on LSD and feeling like her “face was melting like in a Dali painting.” For the young journalist, long COVID was somewhat similar to the experience of my friend on LSD.

Like 10-30% of the ~200 million, globally (a large number), who have survived COVID-19, the journalist did not get better after she was declared to be COVID-free,  and in fact she said that what came next was much worse than the disease. After a month of non-stop post-COVID malaise, she found herself in the emergency room complaining that she had a “shaky, electric feeling” in her stomach, and that she could not think or sleep. Eight months later the waves of illness had not let up. She was one of the early cases of long COVID, which we now know occurs in 10-30% of COVID survivors (although one study from Italy claimed that >50% of COVID survivors experienced symptoms at least four months after their infection).

The journalist wrote in July 2021, “Since December (2020), I've seen 15 specialists, received eight scans, visited three ERs and--even with insurance--spent $12,000 seeking a return to normal life. Since February, I moved across the country (from North Carolina) to receive treatment from a post-COVID recovery clinic at (the) Keck School of Medicine at the University of Southern California. The clinic refers its patients to specialists depending on their symptoms and provides a social worker. I receive weekly treatment from a physical therapist, occupational therapist and neurologist there.”

“I've had more than 50 symptoms ranging from cognitive impairment, insomnia, vertigo, extreme light and sound sensitivity, and fatigue, to convulsion-like shaking, slurred speech, hair loss, muscle weakness, anxiety.” She said that she was too “foggy” to read or even to watch TV news, which was her occupation. She was unable to write for six months, and had not had a symptom-free day since November 6, 2020, the day she tested positive for Covid-19. Most of these symptoms occurred simultaneously.

She writes on, “Before my illness, I never had any thoughts about suicide. This changed after I got sick. I'm no longer in this dark place, but the months it held me hostage I inched closer to the edge than I ever wished to be. As my brain fog intensified, I developed such a palpable anxiety, it brought with it new compulsive behaviors like "trichotillomania," or hair pulling. The days blended into one dream-state. I had only what I can describe as brain zaps. I'd wash my hair, forget, then wash it again. The further I slipped away from reality, the deeper my depression became.”

“I found myself researching death-with-dignity laws. I learned that Northern European countries have some of the most lenient.” She entertained suicide for the first time in her life. Other post-COVID patients have also described having thoughts of suicide and some have acted on that.

The experience of this journalist and a few million others like her quickly became noticed anecdotally by the medical establishment and the patients were referred to as “long haulers.” Their constellation of symptoms became known as “long COVID,” or more formally Post-Acute Sequelae of COVID-19 (PASC). As long COVID became increasingly recognized, the medical establishment realized that it was something entirely new and that they had little clue on how to deal with it other than try to manage the myriad symptoms, now numbering at more than 200. We now know that long haulers can suffer months of “brain fog,” persistent headaches, chronic fatigue-like symptoms, breathing problems, lung failure (sometimes requiring transplants), new-onset diabetes, depression and/or anxiety, dizziness, muscle and joint pain, and more. These occur in 10-30% of old and young infected people, and even in those who had mild COVID-19.

Medical science is slowly catching up, but progress is slow, not for lack of effort, but simply because medical research takes time. The very recent FAIR Health study of COVID-19 patients, the largest to date, analyzed health records of nearly two million people who have been infected with the virus in the US and found that hundreds of thousands have sought care for new health conditions after their acute illness subsided. New research points to neuropsychiatric changes in Covid-19 survivors potentially due to brain inflammation or to a disruption of blood flow to the brain. Then there are other theories, partly borne out by an Oxford study, that the virus affects serotonin and dopamine neurotransmitters, affecting brain function and physiology. A recent case published in the Journal of Psychiatry Neuroscience and Therapeutics reported that "autoimmune-mediated psychosis" caused a 30-year-old without previous health or psychological conditions to become delusional after recovering from COVID. In response to this increasing concern over long COVID, NIH launched a large nationwide study of long COVID and recently  awarded $470 million to New York University Langone Health. This NIH REsearching COVID to Enhance Recovery (RECOVER) Initiative aims to learn why some people have prolonged symptoms or develop new or returning symptoms after they recover from the acute phase of infection.

In future posts in this blog series, I will cover in more detail what we have learned to date about long COVID. Since the data keep coming in, I cannot predict when this series will end.

So, stay tuned and please ask questions.

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HIV And Coronaviruses: A Bad Combo

Africa is the continent least vaccinated for COVID-19 and it also has been where several CoV-2 variants have arisen: Beta in South Africa, most recently C.1.2 (not yet given a Greek letter designation) also from South Africa, and Eta in Nigeria. A possible reason for the appearance of these variants is because Africa is also home to the most immunocompromised people. HIV is common in Africa and tuberculosis is rampant on the continent.

One HIV-positive woman in South Africa was reported to carry active CoV-2 infection for 216 days, during which time it mutated 30 times according to Tulio de Oliveira, who runs gene-sequencing centers at two South African universities. This is concerning since South Africa has the world’s largest HIV epidemic. It is estimated to have 8.2 million people infected with HIV. While most of these take antiretroviral drugs, which keep the virus at bay, many do not. And neighboring countries, Botswana, Zimbabwe, and Eswatini also have very high HIV infection rates. The burden of HIV, TB and other chronic diseases is higher in these countries than in other countries around the world due to extreme poverty and poor health care for millions of Africans. When these people also become infected with CoV-2, they grow and shed the virus longer than someone with a good immune system and good health care. That means that the virus has longer to mutate in an infected, immunocompromised person.

In wealthier countries in the West, a rich debate is ongoing about whether to add another shot (booster) to already vaccinated people. One of the biggest arguments against this is that those booster vaccines are needed much more in poorer, and woefully under-vaccinated countries, such as those in Africa. The concern is that our boosters come at the expense of basic immunization of these impoverished countries, which facilitates the generation of troublesome viral variants. On the other hand, if CoV-2 is running rampant because the health care infrastructure in these countries is not up to delivering those vaccines, maybe it would be better making sure that richer countries are as protected as possible.

These are the proverbial two horns of a dilemma. Which horn would you choose?


The Differences Between The Moderna And Pfizer mRNA Vaccines

Since the vaccines rolled out, people, including me, have talked about the Pfizer and Moderna vaccines as simply being interchangeable versions of mRNA vaccine technology platforms. They both use part of the CoV-2 viral mRNA sequence to temporarily express parts of the viral spike protein on muscle cells in order to stimulate a protective immune response against the live virus. Since mRNA is very unstable and would quickly degrade if it were injected by itself, both vaccines encapsulate it in lipid nanoparticles, or liposomes, which both protects the mRNA and helps it fuse to cell membranes and insert the genetic material into the cells where it is translated into the protein. So, the Pfizer and Moderna technologies are very similar.  But they are not identical. At first blush, the differences appear subtle, but we are learning that they seem to manifest themselves in different, not-so-subtle biological ways. Let’s take a look at the how the vaccines differ.

The formulation: The lipid nanoparticles that carry the mRNA are a bit different between the Pfizer and Moderna vaccine platforms. While the exact formulations are proprietary intellectual property owned by each company, we do have a little bit of information about how they are similar and how they differ. Both platforms are concoctions of several different lipids designed to spontaneously assemble in aqueous solutions into small, “artificial cells” that encapsulate the mRNA payload. The lipids in both vaccines include polyethylene glycol (PEG), which can have multiple effects on the properties of lipid nanoparticles; they can affect particle size and particle stability. Certain PEG modifications can also prolong the blood circulation time of nanoparticles by reducing clearance of the liposomes by the kidneys and by scavenger immune cells called phagocytes.

The Pfizer vaccine also contains two proprietary lipids known as ALC-0315, and ALC-0159 as well as cholesterol, all in a very precise ratio. The Moderna vaccine platform consists of lipids that are not as well-known publically because the company is in litigation over the intellectual property with Arbutus, which developed the lipids that were licensed by Moderna.

Basically, viruses are naturally occurring liposomes encapsulating genetic material. The nanotechnology community has long been trying to create “artificial” virus-like nanoparticles that do not replicate or spread like a live virus in order to deliver fragile molecules, like mRNA, to cells for therapeutic reasons. Therefore, the goal of therapeutic liposomes is to create a virus-like lipid bilayer membrane (see figure) in order to deliver a drug or vaccine payload to cells. Mixing amphiphilic fatty acids, which are lipids where one end is water soluble (hydrophilic), while the other end is not (hydrophobic), in an aqueous solution allows them to spontaneously assemble into virus-like nanoparticles, or mini-cells. A water soluble payload (mRNA in this case) is captured in the central blue area and is protected by the outer lipid membrane. When these artificial cells bump into a live cell, the lipids on the two membranes fuse dumping the therapeutic payload into the cell’s cytoplasm.

There are endless combinations of amphiphilic lipids which can form such pseudo-cells, the properties of which can be modified depending on which lipids are used. For example, the selection of lipids used in both vaccines give the surface of the liposomes a mild positive charge, which facilitates their ability to stick to the negatively charged membranes of live cells.

What all this means is that the specific lipid formulation used in the Pfizer and Moderna vaccines affects the delivery of mRNA to cells, but we do not have enough detail to be able to suss the effects of the different liposome compositions on the efficacy of the vaccine. Those details mostly remain trade secrets. Liposome_scheme-en

lipid nanoparticle mimics a cell bilayer membrane

mRNA sequence. Both the Moderna and Pfizer vaccines use mRNA that encodes part of the spike protein of SARS-CoV-2, which sits on the surface of the virus and binds with the ACE2 receptor on the cell surfaces of many tissues. mRNA molecules are chains of four nucleosides arranged in a gene-specific sequence code that cells then translate into a specific protein. However, when a foreign mRNA is injected into a body, the mRNA itself can be recognized by the immune system and neutralized before it can enter a cell and express its cognate protein. For this reason, both the Pfizer and Moderna mRNA vaccines have been modified to incorporate a synthetic non-natural nucleoside, 1-methylpseudouridine, which reduces the ability of the immune system to recognize the foreign mRNA and improves its stability and expression of its protein.

The spike molecule consists of two protein subunits, the first of which is responsible for the initial binding with ACE2, while the second promotes the fusion between the virus and the cell membranes. The mRNA sequence incorporated into the Moderna vaccine, mRNA-1273, specifically encodes the pre-fusion form of the second spike protein subunit that is found on the surface of the virus before it binds to the ACE2 cell receptor. The mRNA sequence is modified to produce a spike protein with two amino-acid substitutions at positions 986 and 987 on the protein that help to keep it in the pre-fusion state. In contrast, the mRNA utilized by the Pfizer-BioNTech vaccine (BNT162) only encodes part of the spike protein on the first subunit that specifically binds to the ACE2 receptor. Thus, the two vaccines drive immunity to different parts of the spike protein molecule.

Perhaps more importantly, the dose of mRNA in the two vaccines differs. The Moderna vax delivers a 3-fold higher dose (100 mcg) of mRNA compared to the Pfizer vaccine (30 mcg). This  means that more spike protein antigen to stimulate an immune response is expressed from the Moderna shot.

What does it all mean? Initially, these differences in lipid composition, mRNA sequence, and mRNA dose do not seem to affect vaccine effectiveness. Both are extremely effective at protecting against COVID-19 within a few months after the second shot. But, over time, differences in the effectiveness of the vaccines are showing up.

Last month, the Mayo Clinic released a preprint of a large study of 645,109 patients after vaccination. This assessed the level of protection from infection in people vaccinated with the Moderna or Pfizer vaccines, or who were unvaccinated between January–July, 2021. Both vaccines continued to be very effective at preventing hospitalization, ICU admission, and death relative to unvaccinated people over the period of the study. However, prevention against mild to moderate COVID-19 was somewhat lower for both vaccines in July compared to January. Vaccine immunity faded a bit over that time. Importantly, the efficacy of the Pfizer vaccine faded faster over this time compared to the Moderna vaccine. A more recent CDC analysis of COVID-19 emergency room or urgent care visits for ~33,000 people between June-August 2021, when the Delta variant was predominant in the US, showed that overall the vaccines were 86% effective at protecting against serious COVID-19. But, vaccine efficacy for those who received the Moderna vaccine was 92%, while those receiving the Pfizer vax showed 77% protection.

Similar results were found in another study of 196 vaccinated elder nursing home residents in Canada. Compared to those who received the Moderna vaccine, residents who received the Pfizer shot mounted a 3.89-fold lower antibody response. A Belgium study published August 30, also found that the Moderna vaccine stimulated ~3 times the antibody response as the Pfizer vax. This study looked at 1,647 vaccinated workers at a Belgium hospital. Finally, a Qatar study largely found the same thing; that the Moderna vaccine stimulated a more robust antibody response.

What accounts for the different responses to the different vaccines over time? That is impossible to pinpoint at this time. It could be due to the higher dose of mRNA in the Moderna vaccine. The difference in response over time could also be due to the different mRNA sequences the vaccines contain, or due to the slight differences in the chemical composition of the lipid nanoparticles. Or, any combination of the above could drive quantitatively different immune responses.

Most importantly, though, both vaccines continue to work amazingly well against serious COVID disease, hospitalizations and death. Even while the more infectious Delta variant rages around the world in the face of slowly fading vaccine efficacy, about 95% of COVID-19 hospitalizations and deaths today are in unvaccinated people.

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Long Term Side Effects Of COVID Vaccines

In his nearly 30 years studying vaccines, Paul Goepfert, M.D., director of the Alabama Vaccine Research Clinic at the University of Alabama at Birmingham, has never seen any vaccine as effective as the three COVID vaccines — the mRNA vaccines from Pfizer and Moderna, and the adenovirus-based vaccine from Johnson & Johnson that are currently available in the US. He refers to the 90 percent reduction in infections, and 94 percent protection against hospitalization the vaccines confer. 

Despite this undeniable success, most Americans who have not been vaccinated report long-term safety as a major concern. Nearly a quarter of respondents in Gallup surveys in March and April 2021 said they wanted to confirm the vaccine was safe before getting the shot. And 26 percent of respondents in a survey of parents with children ages 12-15 by the Kaiser Family Foundation in April 2021 said they wanted to “wait a while to see how the vaccine is working” before deciding to get their child vaccinated. 

There are several reasons to not worry about such long term consequences of the vaccines. Vaccines are very temporary medicines, making them different from medicines that people take every day, potentially for years, that can have long term safety issues. Further, decades of vaccine history, plus months of data from more than a billion people around the world who have received the current COVID vaccines starting last December, provide powerful real-life proof that there is little chance that any new dangers will arise more than a couple of weeks following the COVID shot. 

Consider the following:

1. Vaccines are eliminated within hours to a couple of days. Unlike many drugs, which are taken daily and chronically, vaccines are generally one (maybe two)-and-done. Medicines you take every day for months or years can cause side effects that only reveal themselves over time. 

Vaccines are designed to deliver a payload that is quickly eliminated by the body. This is particularly true of the mRNA vaccines as I wrote earlier. mRNA is a very unstable molecule that degrades rapidly (within hours) due to ubiquitous enzymes generally known as RNases. So, after a shot, the vaccine lingers just long enough to stimulate an immune reaction, and then the body’s normal mechanisms eliminate it within hours. The only long term effect after the vaccine is eliminated is the immunological memory it leaves behind.

2. Vaccine side effects, if any, show up within hours to a couple of weeks, never longer: No vaccine has ever shown a side effect that appeared more than two months after injection. This is why the FDA requires only two-months of of followup data after injection for Emergency Use Authorization (or six months as an extra precaution for Full Approval).

That is not to say that there have never been safety issues with vaccines. But in each instance, these issues appeared very soon after vaccination. When the oral polio vaccine was first introduced in the US in 1955, it used a crippled form of the polio virus that in very rare cases, about one in 2.4 million recipients, became activated and caused polio. Cases of vaccine-induced polio occurred between one and four weeks after vaccination, none after one month.

In 1976, it was found that in approximately one in 100,000 patients, a vaccine against swine flu was associated with Guillain-Barré Syndrome, in which the immune system attacks the nerves causing temporary paralysis. These cases occurred in the eight weeks after being vaccinated (in contrast the flu itself causes Guillain-Barré Syndrome 17 times more frequently than the vaccine). Eight-weeks is the longest post-vaccine delay for the appearance of a side effect for any vaccine.

3. Real life experience with COVID vaccines: By the time the COVID vaccines were approved for emergency use in the US in December 2020, we already knew what the short-term side effects were from the clinical trials on tens-of-thousands of people. The side effects seen in these studies, and later confirmed in the real-world experience of vaccinating hundreds of millions of people, were mostly simple tolerability issues, like arm pain, temporary fatigue and headache. These side effects occur a day or two after the vaccine and last 24-36 hrs.

As of June 12, 2021, more than 2.33 billion COVID vaccine doses have been administered worldwide, according to the New York Times vaccinations tracker. And as hundreds of millions of people are vaccinated, we can begin to detect the extremely rare side-effects that would not be seen when only tens of thousands of patients had been vaxed. This has not revealed any side effect occurring after two-four weeks following the shot. Thus, the close scrutiny of these hundreds of millions of vaccine recipients make the COVID vaccines perhaps the most studied vaccine in the history of medicine.

We also now know that a few people receiving the AstraZeneca COVID vaccine experienced a clotting disorder known as thrombotic thrombocytopenia. This occurred in just 79 people among more than 20 million people receiving this vaccine in the UK. A smaller number of cases have occurred with Johnson & Johnson’s vaccine as well. These side effects only happened 1-2 weeks following the shot (and clotting problems occur much more frequently following infection). An even rarer side effect, myocarditis, or inflammation of the heart muscle, has been reported in people receiving Pfizer and Moderna COVID-19 vaccines. This effect was found in about one in a million vaccinated people. None of these cases appeared more than a month after the vaccination.

Finally, on July 12, 2021, the FDA announced that in rare cases (100 reports out of 12.8 million shots given in the US), the J&J vaccine might be associated with Guillan-Barré Syndrome. All of these cases appeared about two weeks after injection.

Bottom line: All of this can be boiled down to this: There are no “long term safety issues” with these or any other vaccine. If you don’t have a side effect 2-8 weeks after the injection, you will not have any further vaccine-related problem down the road.

I challenge anyone to name any vaccine that has had side effects more than a few weeks following the shot.

Therefore, it is mind-boggling that people are avoiding COVID vaccines based on an unwarranted hypothetical concern over long term safety, but they are not at all worried about the reality of COVID mortality and the devastation of “long COVID” symptoms seen in 10% of infected people. That is irrational.

Stay tuned:  A multi-post blog series on the “long COVID” or “long haulers” will soon begin in these pages.

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Evidence That Facemasks Prevent COVID-19

As Delta proliferates while the world tries to get back to normal, requirements to wear facemasks in public are also proliferating. The mask mandates are causing no end of consternation in certain segments of the population, which like to claim that there is no evidence that they prevent disease. Their evidence behind this claim is weak and usually boils down to claiming that the virus is similarly prevalent in states with and without mask requirements. For instance, they like to point out that California, with strict mask mandates, has about the same rate of COVID-19 as Florida, which does not have widespread mask mandates.

But, this is not a strong argument. In research, we carefully design studies to compare experimental vs control groups that are as similar as possible in every way except for the variable we wish to test. In other words, we try to isolate the test variable by making all else as equal as possible. This goal for a well-controlled experiment falls apart when comparing California to Florida—they are very different. Differences include age, population and housing density, reliance on public transportation, climate, humidity, and demographics. All of these variables, if not controlled for, will confound the relationship between mask policies and COVID-19 outcomes because each of these variables also affects the spread of disease.

However, comparing counties within a state helps address at least some of these confounding factors since counties within the same state are generally more similar than two different states at opposite ends of the country. Researchers have done just this in Kansas where 21 counties implemented a mask mandate while the others did not. Counties with a mask mandate saw a significant drop in COVID-19 while counties without a mandate saw a 100% increase in new cases during the period of evaluation.

More recently, the ABC Science Collaboration, a partnership between health scientists, K-12 schools and community leaders, in North Carolina collected infection data from >1 million students and staff members between March-June 2021. More than 7000 students and staff caught COVID-19 during that period and contact tracing showed that >40,000 people had close contact with the infected ones. Very few of these close contacts caught the virus and all of them, the infected cases and their close contacts, wore masks. In other words, in schools with mask mandates, there were no outbreaks despite initial COVID infections. And schools are ripe for creating super-spreader outbreaks.

A systematic review and meta-analysis published in The Lancet, examined the efficacy of face masks in reducing the transmission of different coronaviruses (SARS, MERS, and COVID-19). The authors evaluated 39 studies and found that face masks significantly reduced the risk of coronavirus infection compared to no mask wearing.

An article published in the Proceedings of the National Academy of Sciences in January 2021 also reviewed the evidence supporting the use of face masks and similarly concluded that near-universal adoption of non-medical (i.e., cloth) face masks in public could significantly reduce the R0 value of the virus, which is a measure of how well it spreads. In fact, I earlier discussed in these pages a similar finding by British researchers who concluded that widespread mask-wearing could substitute for herd immunity.

There are several other published studies that reach similar conclusions about facemasks. But, perhaps the most comprehensive study was just reported by researchers at Stanford and Yale. It involved a method called cluster randomization where villages in Bangladesh were randomized to get facemasks or not. It involved some 340,000 people in 600 villages. 100 villages received cloth masks and 200 villages received surgical masks. The remaining 300 villages did not receive any intervention to increase mask wearing. The results showed that increased community masking decreased COVID-19 disease in these real-world settings. Surgical masks performed better than cloth masks at reducing COVID-19 disease, though cloth masks were definitely better than no masks.

On a final note, let me reissue my earlier challenge to anti-maskers: If you really think they do not prevent infection, then next time you have surgery, invite the surgical team to throw the masks out when they open you up.

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