virus and immunology science

Naturally Immune? You Still Better Get A Vaccine

Over 43 million Americans have reported cases of COVID-19. Many of them likely have some level of immunity that can be quite protective, even without vaccination. Even before vaccines were available, individuals who recovered from COVID-19 had detectable T-cell responses, and reinfections were rare, at least prior to the emergence of the more contagious Delta variant. This is what people refer to colloquially as “natural immunity,” to distinguish it from immunity conferred by vaccination. Some people claim that natural immunity is better and preferable to vaccine immunity and that a history of infection should count as much as being vaccinated when considering vaccine mandates. Is all this true? Well, like what we have seen and heard during the pandemic, a lot of truths have been spread, same with lies and disinformation. The story around natural immunity follows this pattern. Let me try to sort all this out here with a focus on whether previously infected people should consider getting vaccinated.

Natural infection can confer immunity to COVID. Like most viruses, previous infection with SARS-CoV-2 does confer immune protection against future re-exposure to the virus. Several peer-reviewed studies conducted in the early months of the pandemic, before vaccines were available, found that people previously infected were around 80% less likely to test positive for the virus during the next viral surge. These included studies of healthcare workers in the UK, the Danish population, and patients at the Cleveland Clinic, a large health system in Ohio and Florida.

Other data from the UK Office for National Statistics showed that between May and August 2021, a prior infection offered around the same level of protection against the Delta variant as vaccination. (Note that very recent and preliminary observations in South Africa suggest that infection with the new Omicron variant is high in people previously infected with other CoV-2 variants. However, since Omicron is so new and data on it are very sketchy at this time, this review will not further comment on this variant.)

A recent large Israeli study found that people who had been fully vaccinated with two Pfizer shots were 13 times more likely to later get infected with CoV-2 than those who had a prior infection. It also suggested that immunity from infection was longer lasting than that from vaccination. The study also showed that natural immunity plus the vaccine offered protection that was even stronger than either natural or vaccine immunity alone. This is one of the very few studies suggesting that natural immunity is better than vaccine immunity and has not been peer-reviewed. Furthermore, the subsequent rise of Delta since the end of this study confounds the issue a bit since Delta has been shown to be more infectious than the viruses the study subjects were exposed to. 

In the most recent review of the current scientific evidence by the CDC, they concluded that both fully vaccinated and those previously infected with the virus have a low risk of re-infection for at least six months, but that the two forms of immunity appear to have different strengths. Vaccination with mRNA vaccines produced higher concentrations of neutralizing antibodies—the type that prevent the virus from entering cells—than natural infection, although, over time, the antibody levels waned in both groups. However, long lasting immune memory conferred by natural infection appeared to be stronger than that conferred by vaccination.

Over time, immune B cells typically evolve to produce antibodies that better recognize an antigen, and an earlier study published in Nature found that antibodies produced by naturally immune memory B cells continued to evolve at least a year after infection. In contrast, antibodies produced by memory B cells in vaccinated people did not change much over time. This would suggest that over time, antibodies produced by natural immunity gain greater ability to respond to re-infection with the virus than antibodies produced by vaccination. One possible reason for this difference in the evolution of the anti-viral antibodies was that pieces of virus remain in the body for weeks after infection and continue to engage the immune cells, whereas vaccine lipid nanoparticles quickly fade away providing less immune stimulation. 

On the other hand, vaccine immunity might be better. So, as we have seen, a few reports suggest that natural immunity is superior to vaccine immunity. However, more studies suggest the opposite and even show that not everyone who catches COVID-19 will have effective immunity to re-infection. A CDC study reported that 36% of previously infected people did not form any antibodies against the virus. This is in stark contrast to antibody formation reported in 100% of people who received just one dose of an mRNA vaccine. Furthermore, the CDC reported in August that COVID survivors who went unvaxed were more than twice as likely as vaccinated people to get infected again contrasting with the Israeli study I mentioned earlier. Yet another CDC study looking at data from ~190 hospitals in nine states confirmed that unvaccinated people who survived an infection several months earlier were more than five times more likely to get COVID again than vaccinated people.

The reason that natural immunity might not always be effective is because the natural exposure to the virus is highly variable. People naturally infected are exposed to widely different doses of virus via different routes and possibly to different viral strains, all of which conspire to confer different degrees of protection. In contrast, vaccinated people receive standardized doses of the same viral antigen via the same route of exposure, making them more likely to develop a uniform degree of immunity. Researchers found that some people who had been infected had high antibody levels to the virus, while others had low levels, reflecting this variability in natural infection. This was substantiated by a new study from the University of Pittsburgh that also found that in many cases antibody levels from a prior infection are not high enough to protect people from getting sick again. Then, an Oxford study found that both long term T and B cell immune responses were highly variable in naturally immune people. The investigators took monthly samples of blood from infected subjects and measured their T and B cell responses over time. Interestingly, the variability in their responses was clearly identified as early as one-month post infection. Those with the weakest immunity at one month (25% of the subjects) had no detectable antibodies after six months. This contrasts to vaccine immunity, which does fade a bit over six months, but still remains consistently strong months after full vaccination. 

Finally, new evidence from an NIH-supported study from the Fred Hutchinson Cancer Research Center, Seattle showed that antibodies from vaccinated people better recognized the mutated spike proteins from viral variants than antibodies from naturally immune people who had not been vaccinated. In other words, vaccinated people seem better able to respond to mutated spike proteins present in new viral variants.

The bottom line. In sum, while natural immunity can be effective, most evidence shows that vaccines typically give rise to consistently better antibody and long term T and B cell responses.

Having made this point, it is important to further note that a combination of both types of immunity, or so-called hybrid immunity, appears to be stronger than either alone. Researchers found that vaccination of naturally infected people boosted antibody and memory B cells to levels higher than seen in those with just either type of immunity. People with prior COVID-19 who received even one vaccine dose had half the risk of a breakthrough infection than unvaccinated people with prior COVID-19. Another study from researchers at the Icahn School of Medicine in New York found that a single dose of either the Pfizer or Moderna vaccines produced more antibodies in people who had previously had COVID-19 than two vax doses did in those who had never encountered the virus. It also found that people with prior infection report more unpleasant, but not serious side effects from vaccination. Vaccinating previously infected people also elicits important cross-variant neutralizing antibodies that better protect them against the known viral variants. Hybrid immunity also appears to work in the other direction: A study of vaccinated people who were then infected during a July 4 holiday weekend outbreak on Cape Cod found that they produced higher levels of antibodies and T-cells directed against the virus. In sum, vaccination helps those with natural immunity (and everyone they interact with) and vice versa

For these reasons, the CDC now recommends that people who have had COVID-19 be vaccinated because the shots plus natural immunity have been shown to offer better protection than natural immunity alone.


The Long Haul, Part 3: Long Neurological COVID

As I have noted before in this series, acute COVID-19 often appears with neurological symptoms ranging from loss of smell to severe depression to stuttering to brain fog, mania and psychosis. It sometimes has been linked to suicidal ideation. In addition, long haulers often have cognitive symptoms and structural brain changes similar to those seen in aging brains and in those with Alzheimer’s disease. An early survey of 153 COVID-19 patients in the UK and a more recent study of people hospitalized with the acute disease in Italy both found that about a third had neurological symptoms of some kind ranging from sensory problems, motor impairment, and cognitive issues that persist after clearing the acute infection. Other estimates of neuro involvement in long COVID have trended even higher. Many people who survived earlier coronavirus infections such as SARS and MERS also experienced neurological impairments up to 3.5 years after acute infection. Obviously many of these symptoms of long COVID are very serious while others are more annoyances. So, what is going on? Researchers have pretty well cataloged the unusual range of long COVID’s neurological symptoms and now are at the very early stages of understanding their causes and how to treat the problems. Here, I label long COVID that primarily manifests itself with neurological symptoms as “long neuro COVID” in order to distinguish it from other long COVID problems that primarily involve the lungs, heart, or other organs.

What is long neuro COVID like? In the early days of the pandemic, a newly minted English MD worked on the front lines in a COVID ward and soon became a patient herself. Being 35 and healthy she expected to quickly recover but underwent the long haul, which she has written about. The acute phase of the disease lasted about two weeks, but by 4-5 weeks, she was experiencing new persistent problems including tachycardia with a resting heart rate of 140 bpm (normal is 60-100) that would increase to 170 after minimal exertion such as getting a glass of water. She also was breathless with a resting respiratory rate of 20-24 (12-16 is normal), saying it felt like her “body forgot to breath.” She described cyclic bouts of pins and needles in all four extremities, and whole-body shaking as violent as if she were having a seizure. There were feelings of impending doom, and, despite extreme mental and physical exhaustion, she was unable to sleep, which eventually led to hallucinations. Those symptoms slowly subsided over a few months only to be replaced by intense pain very deep in one ear. This ultimately led to tinnitus and some hearing loss and a diagnosis of encephalitis. Ten months later, she wrote that  she was recovering but was far from normal. She suspected that these symptoms were driven by a dysfunctional autonomic nervous system, a condition called dysautonomia. The autonomic nervous system is what regulates your organs and allows you to breath, your heart to beat, your gut to move food through it, and controls your blood pressure without you having to think about it all. Since her experience in early 2020, it has been confirmed that long neuro COVID can wreak havoc with both the peripheral and central nervous systems.

 

After two years of long COVID, we now know that long neuro COVID symptoms are wide ranging; some are devastating, like stroke, encephalitis, and even psychosis or mania, or even suicide. Other neuro symptoms are more subtle such as cognitive decline, loss of smell, hearing loss, balance problems, fatigue, memory problems, and difficulty concentrating or brain fog. Others are bizarre, such as stuttering. This seemingly unrelated range of symptoms suggests that there might be several different subtypes of long neuro COVID, possibly arising from distinct pathologies.

Back in July 2020, one of the first studies was published describing neurological symptoms that appeared long after the initial COVID disease. This since has been followed by several other reports of neurological or neuropsychiatric problems long after recovering from acute COVID disease. One study by Oxford scientists published last February, found that about 33% of post-COVID patients are left with long term mental health or neurological symptoms including brain fog, headaches, dizziness, and cognitive problems such as difficulty doing simple math. Some studies have shown an elevated incidence of PTSD, and seizures or movement disorders  long after COVID recovery. Other post-COVID patients have new-onset depression, psychosis, and suicidal behavior as reported in JAMA Psychiatry by a Columbia University research team this past spring. In this large study investigators examined electronic health records of more than 236,000 COVID-19 patients, mostly in the US. The researchers compared their records with records from those who experienced non-COVID respiratory tract infections during the same time frame and found an increased incidence in anxiety and mood disorders in post-COVID patients. More than three months after diagnosis, these common psychiatric diagnoses were found in about 34% of COVID survivors. Other studies confirmed that having the disease led to doubled risk for anxiety, depression and sleep disorders.

Importantly, researchers did not see an increased incidence of other neurological problems such as Parkinson’s disease or Guillain-Barré syndrome in long COVID patients, both of which sometimes follow viral infection. This suggests that long neuro COVID involves a select subset of neurological problems rather than an indiscriminate neurological malady.

Similarities between long COVID and Alzheimer’s disease. The cognitive issues seen in many long neuro COVID patients share intriguing similarities with Alzheimer’s disease (AD) and normal aging. Thus, an international group of researchers found that more than half of patients 60 or older who had been infected with the CoV-2 virus showed acceleration of Alzheimer’s-like symptoms such as cognitive decline. Other researchers at the University of Texas Health Science Center, San Antonio studied more than 200 older adults from Argentina who had COVID-19. Those who had a persistent loss of smell were more likely to experience AD-like cognitive issues. Importantly, the area of the brain affected in AD overlaps with the area that processes smell. It also might be relevant that the sense of smell, which is often lost in COVID patients, is also often reduced in AD patients.

Three to six months after they were infected, more than half of these patients still struggled with AD-like cognitive challenges including persistent forgetfulness, difficulty sequencing tasks, and forgetting words and phrases. How sick a patient was with acute COVID-19 was not an indicator of whether they would experience this cognitive decline. In other words, AD-like symptoms also occurred in people who only had mild COVID.

COVID-19, of course begins as a respiratory disease and investigators have long been tuned in to the potential links between respiratory diseases and the brain. For example, AD-like changes in cognition and behavior were also observed in people with Severe Acute Respiratory Syndrome (SARS) and with Middle East Respiratory Syndrome (MERS). Infection with other respiratory viruses can also increase the risk of Alzheimer’s.

Together, these findings suggest that some patients with long neuro COVID might have an acceleration of Alzheimer’s-related symptoms and pathology, but it is too soon to conclude that long neuro COVID causes AD, or even that AD and COVID-related cognitive dysfunction are even related. A major distinction between classical AD and AD-like long COVID is that the latter do not show the amyloid brain plaques which are pathognomonic of AD, which suggests that these could be distinct cognitive maladies with overlapping symptoms. Furthermore, other studies showed that worse cognitive scores in long COVID patients correlated with patients who had lower oxygen saturation during a 6-minute walk test. This makes it possible that persistent oxygen deprivation in the brain due to lung compromise during COVID could cause cognitive difficulties in these patients.

At this point, these observations simply raise many unanswered questions on whether there is a real overlap with COVID and Alzheimer's disease. But, it is too soon to say that COVID-19 increases a person's risk for Alzheimer's vs causes a different neurological problem symptomatically related to AD.

What causes long neuro COVID? Long COVID represents a broad category of over 200, often unrelated symptoms encompassing 10 organ systems. It likely consists of multiple different maladies with manifold causes, of which long neuro COVID is at least one broad category. Based on its biology and range of symptoms, long neuro COVID also likely entails more than one specific problem. It makes sense then that the many different manifestations of long neuro COVID would arise from different causes. Such seems to be the case. Researchers have cataloged several genetic, structural, inflammatory, and infectious correlates to the various symptoms, painting a complicated picture. Then things get really confusing since viral infection of neurological tissues and/or the attendant inflammatory responses could cause the observed structural changes and all this could be predisposed or mitigated by genetics. In other words, things are as clear as mud right now about what causes long neuro COVID. Investigators are just now making basic observational correlates between the neurological changes and long neuro COVID symptoms, and these correlations will be followed by the harder studies to learn just how these changes might cause the plethora of symptoms that have been documented.

On the genetic front, a Stanford U team found that long neuro patients manifest widespread changes in gene expression in the region of the brain involved in complex processing of human thought. These genetic changes affected genetic pathways that play a role in mental illnesses such as schizophrenia and depression. Although these results were made in the brains of patients who died of acute COVID disease, such fundamental changes in gene expression in the brains of patients with acute COVID would plausibly lead to long-lasting post-COVID effects. Similar changes in gene expression were not found in the brains of people who died from flu or from nonviral causes, which strengthens a possible cause and effect relationship of gene expression changes to some long neuro COVID symptoms.

But, what causes changes in brain gene expression? Is it directly due to viral infection in the brain or secondarily due to the immune inflammatory response to the virus? Maybe both? Or is something else involved? Evidence exists for all these possibilities.

One report on 111 unvaccinated patients from the Chicago area showed that 56 who had long neuro COVID cognitive problems showed a particular immunological signature that was not found in people who cleared the acute infection without long term problems. The severity of cognitive deficits correlated with reduced memory T cell responses to certain parts of the virus, and with enhanced antibody (or B cell) responses to one of the viral proteins. Furthermore, it has been observed that females are more prone to devleop long neuro COVID. Since women also are more likely to get autoimmune disease, some have put these observations together to suggest that there might be an autoimmune component to some long neuro COVID symptoms.

The above study assessed the anti-CoV-2 immune responses of T and B cells from the peripheral blood but not from the brains of the patients. In other words, it did not address whether the immune response in the body affects brain function or whether an antiviral immune response directly occurs in the brain affecting cognitive function. Other researchers have shown that the virus can indeed enter the brain via the nose and spread from the olfactory lobe to the frontal and temporal lobes of the brain. Other confirmatory studies have found viral protein expression in cortical neurons of autopsied brain tissues, and have directly shown that the virus can infect neurons in tissue culture. While these findings are consistent with direct infection of the brain and the possibility of immunological damage to the organ, they do not settle the question of whether viral infection itself might directly damage the central nervous system, or whether it is the immune reaction to the virus that causes the problems.

Perhaps confounding all of this are the results of a large study on gross brain structure conducted by researchers at the University of Oxford and at the NIH. In this study, researchers used the UK Biobank, an existing database, which contains brain imaging data from >45,000 people in the UK going back to 2014. This means that there was pre-COVID baseline imaging data the researchers could compare to post-COVID brain images. New images were collected from 394 of these patients who caught COVID and compared to their pre-COVID images and to 388 controls who did not catch COVID-19. The groups were otherwise matched based on age, sex, common disease risk factors, etc. The results showed that those who caught COVID suffered significant loss of gray matter in the frontal and temporal lobes on the left side of the brain. This brain loss was found regardless of COVID disease severity. Those who were COVID-free had no brain tissue loss. Interestingly, these regions of the brain are responsible for smell, taste, memory, and emotion, all of which can be affected in long neuro COVID patients. We also often talk about the left temporal lobe in the context of aging and Alzheimer’s disease because that is where the hippocampus is located, which plays a key role in memory and other cognitive processes associated with aging and AD. While it is normal to see reduction in gray matter with age, the COVID-linked changes were greater than that typically seen during normal aging. All of this raises questions about how COVID might affect the natural aging process in the brain.

In addition to these genetic, immunological, and structural changes in the central nervous system of COVID patients, autopsies also have revealed clotting in multiple organs including the brains of many patients. About one in 50 COVID brains showed evidence for an ischemic stroke, which is when a blood clot interrupts blood flow to a region of the brain downstream from the clot. Ischemic strokes in COVID patients tended to be more severe and more likely to result in severe disability or death than stroke in non-COVID individuals. Again, while these findings were made on autopsies of patients suffering from acute COVID, these ischemic strokes would have caused long term manifestations presenting as long neuro COVID.

There are other, very specific and very peculiar neurological symptoms that might arise from more specific neurological abnormalities. For example, some long COVID patients display hearing loss and or balance problems which suggest vestibular involvement that could be due to CoV-2 infection of the inner ear. Scientists at MIT and Stanford found that the ACE2 protein, which is the cell receptor for the CoV-2 virus, is expressed on certain inner ear cells obtained from surgery patients. Since inner ear tissue is difficult to obtain, the researchers directed stem cells to develop into inner ear cell precursors or that could assemble into primitive inner ear  organoids in tissue culture and showed that the CoV-2 virus could infect them. Together, these observations support, but do not prove, that infection of the inner ear is a cause of hearing and balance issues in some long neuro COVID patients. It is relevant to note that it is not unusual for hearing loss and balance disorders to be caused by other viral infections of the inner ear.

Then there also are the rare long COVID patients who develop an odd stuttering problem. Typically, stuttering originates in the complex circuity of the brain that controls speech and this speech disruption usually appears when children are learning to talk. However, “neurogenic stuttering” can arise in adults after brain trauma. Since only a few researchers are investigating long COVID-associated stutter, the cause is not well understood, but, the link between neurogenic stuttering and brain injury raises the possibility that inflammation and/or micro-clotting caused by the virus or by the immune response to the virus in the brain microvasculature could lead to the neurological damage that causes stuttering.

Bottom line. These many new findings, while provocative, do not yet fully tell us how long neuro COVID arises, or how to treat it. But, they raise many new questions: What do these COVID-related brain changes mean for the process and pace of brain aging in long COVID patients? Over time does the brain recover? How do we medically deal with these patients? Can we prevent long neuro COVID? Etc.

Stay tuned, we will see.

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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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A Critical Federal Vaccine Mandate

In response to the viral pandemic, the military ordered all service personnel to receive a controversial vaccine against the virus. The edict also prohibits military families and other civilians who live in high virus transmission areas from entering military bases. Furthermore, military personnel suspected of having contact with infected people are ordered to quarantine. All this was met with stiff opposition from many troops, from certain States, and even from Congress.

COVID-19 in 2021? 

No. Smallpox in 1777.

In 1777 facing an outbreak of smallpox that threatened his troops’ combat readiness, General George Washington ordered that all troops in the Continental Army be inoculated against smallpox. At the time, vaccination against smallpox was quite rare and not widely known. It involved a procedure known as variolation, where a small amount of pus from an active smallpox blister was scratched into the arm of a recipient. The low dose of the smallpox “pathogen” (the world did not know about viruses at that time) would, hopefully, just make the person sick and not kill him while conferring resistance to future smallpox exposure. Variolation was quite controversial and was even prohibited in Washington’s home state, Virginia. Variolation, in fact, did kill a relative of the King George of England. The relative was given too high a dose of pus and developed a full blown case of lethal smallpox. Many others also died from the procedure, hence the controversy.

When the revolution began, the Continentals faced not only the British military, but also the highly contagious smallpox virus carried by European troops coming from England and Germany. Europeans were well exposed to the disease where many survived and had protective immunity. Smallpox was relatively unknown in the Colonies so the colonists did not have that level of protection, and part of Washington’s genius was to realize that. As European troops arrived in Boston and New York, the virus spread through those cities and as the troops deployed, the disease threatened to run rampant through the colonies, potentially decimating the country and the Continental Army.

Washington, who survived smallpox as a child, was somewhat familiar with the rare practice of variolation, which was brought to England from Constantinople in 1721 by Lady Mary Wortley Montagu. By ordering it for his troops, despite stiff opposition from the Continental Congress, he acted as perhaps the country’s first public health advocate and averted a potentially disastrous epidemic among his troops.

After the battles of Lexington and Concord, the Continental Army encamped across the Charles River from Boston, which was stricken with smallpox from the arriving British soldiers. Washington prohibited anyone from Boston from entering his camps. He also swiftly quarantined anyone suspected of being infected, which was perhaps the first example of contact tracing. Washington’s actions were very heady stuff for the pre-epidemiology, pre-infectious disease era.

Washington did not immediately order variolation since he knew that the significant side effects of the procedure would temporarily incapacitate the troops who would take a few weeks to recover. Instead, he waited until the fighting subsided and both sides took a breather. Then he ordered the vaccinations against the wishes of the Continental Congress which initially forbade army surgeons from performing variolation.  Washington first ordered that all new recruits undergo the procedure believing that they would be healthy by the time they were battle ready and when the war was battle was ready for them.

Washington’s prescience was soon proven. Several thousand Continental troops marched on Quebec under Major General John Thomas who refused to follow Washington’s vaccination orders. He, and one-third of his 10,000 soldiers died from the pox and the force was soundly defeated.

Washington then moved to inoculate his main army and by 1777, 40,000 soldiers had been vaccinated in defiance of Congress. Infection rates in the Continental Army dropped from 20% to 1% and, after seeing these results, lawmakers soon repealed bans on variolation across the Colonies. One historian claims that Washington’s decision to inoculate his troops “…was the most important strategic decision of his military career.”

That radical decision could be a big reason why we do not today have the Union Jack flying over these 50 colonies. I find all of this to be an amazing, but little known fact about the American Revolution. Variolation might have been as important to the Colonists’ victory as was the French Navy finally showing up at Yorktown.

Immunology rocks as much as French naval cannons!

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COVID-19 mRNA Vaccines Safe For Pregnant Women

I have received a few questions about the safety of the coronavirus vaccines for pregnant and lactating women. I discussed toward the end of one blog post about how maternal immunity can benefit the baby by passing the mother’s antibodies across the placenta and given in mother’s milk, thereby protecting neonates whose immune systems are still developing.

Now, an analysis of the CDC’s Vaccine Adverse Event Reporting System, and the “v-safe after vaccination health checker," and its associated v-safe pregnancy registry, shows that the Pfizer and Moderna mRNA vaccines appear to be safe for mothers and babies. The analysis examined almost 36,000 pregnant women who received one of the mRNA vaccines, and was reported in the New England Journal of Medicine.

Compared to non-pregnant women, pregnant women who were vaccinated reported more injection-site pain, but fewer incidents of headaches, myalgia (muscle pain), chills, and fever. About 14% of vaccinated pregnant women suffered pregnancy loss while about 9% of neonates born to vaccinated women suffered adverse events, and 3% of them were undersized. No neonatal deaths were reported. The important thing is that the incidence of these outcomes was similar to the incidence observed in pregnant women before the pandemic arose. Most of the pregnant women who were evaluated were vaccinated in the third trimester.

The study concluded that the data revealed no obvious warning signals for pregnant women who receive the mRNA vaccines. But, it also advised that followup with women vaccinated earlier in pregnancy is warranted.

Stay tuned.


Vying With Viral Variants

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The back story: There are four known CoV-2 variants in the US that are more transmissible than the parent strain. They are the UK variant, which is 70% more infectious and 60% more deadly than the original strain. There also are Californian and Brazilian variants that are more transmissible, but it is not yet known if they are more deadly. However, in Brazil, their variant is associated with a significant increase in infections and ICU stays for young, healthy, unvaccinated people. Fortunately, the current vaccines seem to be effective at preventing infection with these strains.

More worrisome is the South African variant that is 50% more transmissible. It is worrisome because the AstraZeneca vaccine is not very effective against this variant, and a very recent, but a small study out of Israel suggests that the Pfizer vax might have reduced efficacy against the S. African variant. It is not yet known if this strain causes more serious disease. These findings provide evidence that mutation can produce new viral strains that can evade the immune response to the viral spike protein.

Two other variants, the so-called New York variant, and a second Brazilian variant have early signs of being more infectious or even being able to reinfect people who previously had COVID-19. Data are still being collected in order to better understand the risk that these variants pose. Stay tuned.

You can follow the variants in the US here.

The bottom line is that the world is in a race to roll out vaccines faster than troubling virus variants can arise. The UK is expected to reach herd immunity​ early next week. Infections there dropped by 60% during March, with deaths dropping more rapidly, indicating that the vaccines are helping prevent severe illness and viral spread. Meanwhile, the US leads the world in total vaccines administered (175 million), with 43% of the adult population having received at least one shot. More than 700 million doses have been administered world-wide.

The major concern is that a too-slow vaccine distribution, such as what has happened in Brazil, will encourage more virulent variants to arise. If we don’t quickly achieve herd immunity across the world, it probably will just be a matter of time before a variant arose that renders the current vaccines useless, and we would have to start over.

What is a world to do? Besides increasing surveillance of viral variants, a couple more prevention initiatives are in the works. One is economic and the other scientific.

Economics of viral mitigation: The economic approach is detailed in an article by the Associated Press Economics Writer, Martin Crutsinger. Basically, the International Monetary Fund (IMF) proposes giving $650 million to support vulnerable countries struggling to deal with a global pandemic. Along with that, the Group of 20 major industrial countries issued a joint statement that announced a six-month moratorium on debt payments by 73 of the world’s poorest countries.

The rationale behind these actions is to ensure that poor countries, where vaccinations are lagging due to lack of resources and infrastructure, can pick up the pace of vaccination. Their lag in rolling out shots is a threat to the whole world, even while wealthy countries are approaching herd immunity. In order to beat the variants, vaccines are needed to quickly create herd immunity and stop viral spread before a variant that can avoid vaccine immunity appears. When countries lag in vaccinations, the virus continues to spread increasing the chance for an immune-avoiding variant to pop up. Such a variant can then spread to countries that are highly vaccinated, starting the pandemic over again because the current vaccines would be ineffective. We would be back at square one.

Science to the rescue: So far, all the vaccines, except one from China, which uses the whole virus, direct the immune response to the viral spike protein that is used to attach to receptors on the surface of cells in your body. The viral variants we are concerned about show mutations in the spike protein that allow them to become more infectious, and in one case, to be less affected by some of the vaccines. In addition to trying to  nip the virus in the bud by quickly building world-wide herd immunity, new vaccine strategies are being developed to quickly respond to newly arising CoV-2 variants, and even to respond to entirely new strains of viruses that will arise in the future.

  • One way to do this is to begin developing booster shots as soon as a coronavirus variant becomes a significant concern. With the new mRNA, and adenovirus vaccine delivery technology, this is eminently possible. It just requires scientists around the world being vigilant for new variants. Pfizer, Moderna, AstraZeneca, and Johnson & Johnson have all said they’re starting work on developing booster shots to the known variants.
  • Last week, the US government announced a pact with CureVac to tackle variants, pairing artificial intelligence to predict future mutations that can be quickly addressed with modern vaccine technology. London-based GlaxoSmithKline is also working with CureVac on mutant-quelling vaccines.
  • Another strategy is to identify viral molecules other than the spike protein that the immune system can recognize. Efforts are underway to test the immunogenicity of what is called the CoV-2 nucleocapsid, or N protein, which wraps itself around the viral RNA. If successful, future vaccines could incorporate both the N and S (or spike) proteins, which would require the virus to mutate both of those genes in order to avoid vaccine-induced immunity, a greatly tougher task for the virus.
  • Researchers at Moderna, Novavax, and the University of Oxford are designing multivalent vaccine strategies to protect against multiple CoV-2 variants with a single shot, and even against new viruses that might emerge in the future. A similar strategy is used with the annual flu vaccine, which usually incorporates four different influenza strains in one shot. It is also used with measles, mumps, and rubella vaccines. Some vaccines against pneumonia target as many as 23 variants of that pathogen.
  • Finally, a wholly new vaccine technology has shown recent success in animal studies. It works by chemically attaching many short viral protein sequences from different CoV-2 variants, and even from completely different coronaviruses, to engineered nanoparticles that are then injected. In mice, this single vaccine induced an antibody response capable of neutralizing many different coronavirus strains. If successful, this could represent a universal vaccine capable of neutralizing CoV-2 and its variants, as well as other coronaviruses such as SARS and MERS with a single vaccine. And it can be easily modified to quickly respond to future viral epidemics caused by novel coronaviruses or other viruses that will certainly arise. The technology is being developed at Cal Tech using technology developed by collaborators at Oxford University. The nanoparticle platform is a “cage” made from 60 identical proteins. Each of those proteins has a small protein tag that functions like a piece of Velcro to which the viral protein sequences stick resulting in a vaccine nanoparticle with short protein sequences from four to eight distinct coronavirus strains on its surface. If successful, this could prevent infection and disease for several different viruses with a single shot.

 We are in a revolutionary era of vaccinology. BioX marches on.


Vaccine Disinformation

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There is a lot of misinformation and downright disinformation out there regarding face masks, hydroxychloroquine, ivermectin, the seriousness of COVID-19, etc. Many of these I already addressed in prior posts (see here and here). In this post, I focus solely on vaccine misinformation and disinformation in hopes my unvarnished explanation of the science might help vaccine skeptics make decisions based on facts rather than on disinformation spread by people with an anti-vaccine agenda, or who want to sell you something.

Several anti-vaccine disinformation themes have been circulating over the past weeks and a friend recently sent me a video by an MD that was full of disinformation and dishonesty. The video was thinly disguised marketing propaganda by Houston-based Dr. Steve Hotze. He is an MD, who does not seem to practice much medicine anymore, but has built an alternative medicine empire that pushes many vitamin and mineral supplement nostrums that he claims is all you need to fight the virus and other diseases. In other words, he advises people to avoid the vaccines and, instead, buy his concoctions. In December 2020, the FDA and FTC sent him a cease-and-desist letter to stop claiming that his supplements can treat diseases, especially COVID-19. The FDA found the products and marketing to be misleading. The FTC found him in violation of interstate transportation laws. I address his several points below, many of which have been echoed by other anti-vaxers.

  • The vaccines do not confer immunity to the virus and COVID-19. There is very much evidence that the vaccines do provide immunity against CoV-2 and strongly protect against COVID-19. That evidence is found in the many reports of antibody production, of T cell anti-viral responses, of cytokine responses to the vaccines, and in recently published reports out of Israel that the vaccines retard virus transmission. Then there are the several studies showing that the vaccines strongly prevent COVID-19 disease. Hotze and others provide zero evidence to back their allegations and ignore data that contradict their points.
  • These are not vaccines, but experimental gene therapies. The mRNA shots from Pfizer and Moderna, and the modified adenovirus vaccines from Johnson & Johnson and AstraZeneca are indeed vaccines. Researchers whittled down the virus genome to the essential viral spike genetic sequence needed to confer immunity. This means that the minimally effective part of the virus genome, rather than the whole viral genome, is used to provide protection from future infection. Old fashioned vaccines grew batches of viruses and then crippled them so that upon injection, they would infect cells, use their genetic information to express all their viral molecules on the cells, but not spread. The current vaccines simply use the genetic sequence for the spike protein, eliminating all other viral genetic sequences. That single genetic sequence is translated into the spike protein that is expressed on your cell surfaces much like what would have happened with an inactivated, whole virus vaccine. Therefore, the current vaccines are no more “gene therapy” than the whole virus vaccine. Both require expression of viral genes in order to alert the immune system.

Also, the term “gene therapy” conjures images of "Frankenscience." This is wrong. First, vaccines are not “therapy,” which is something that treats a disease after you catch it. Rather vaccines are prophylaxis, which prevents you from catching the disease in the first place. Gene therapy is a still developing field that works to replace, correct, or “knock-out” aberrant genes that cause non-viral health problems.

Furthermore, as I posted earlier, these vaccines are not experimental or hastily developed. They are based on vaccine platforms that have been over a decade in development, and, in some cases, have been used to develop human vaccines to rabies and Ebola. The only novel thing about them is using the CoV-2 spike protein to drive a protective immune response to subsequent infection with the virus. These spike-protein vaccines have been tested in tens of thousands of volunteers in phase 3 trials, and now have been injected into tens of millions vaccine recipients around the world. The vaccines have been wildly successful at preventing COVID-19, and have been proven to be very safe (see below). These are not experimental vaccines, but well developed, and well tested vaccines.

  • The vaccines alter your DNA. They absolutely do not. It is biologically impossible for them to do that. I discussed this fallacy in a prior post.
  • There is no off switch for the viral gene expression caused by the vaccines. This too is not at all true. No vaccine in history has had its viral genes expressed long term. In fact, your cells continually produce their own mRNA to direct production of cellular proteins that drive cell function. Cells are also full of enzymes called RNases that digest mRNA once it has done its job. Thus, your own mRNA is very short lived in your cells. The same is true for the viral mRNA inserted into cells from an inactivated viral vaccine, from an adenovirus-based vaccine, or from an mRNA vaccine. The mRNA will only last a day or two in your cells before it is digested and permanently disappears. This is the off switch.
  • We do not know about the long-term or delayed responses to the vaccines. Yes we do. First, I challenge people who purport to be worried about long-term effects to name one vaccine that has ever had a long-term adverse effect. As I described above, vaccines are short-lived; their only long-lasting legacy are memory T and B cells that protect you from future exposure to the pathogen.

On the other hand, delayed adverse effects were a potential concern when the vaccine was being developed as I described earlier, but that has proven to be of no concern. There is a rare adverse response to prior exposure to a pathogen, whether naturally or via vaccine. This is called Antibody Dependent Enhancement (ADE) of the infection. This was seen with the vaccine against the Dengue virus where the antibody response actually enhanced viral infection in new cells. Because of this, all new vaccines to novel viruses are carefully tested for potential ADE effects.

During the early stages of anti-CoV-2 vaccine development, caution prevailed, and the vaccines were assessed for potential ADE, as reported earlier in these pages. The clinical trials showed absolutely no evidence for ADE. Since then, millions of people around the world have been vaccinated and not a single case of ADE has been found.

Therefore, concern over ADE was theoretical and never became a practical matter. Anti-vaxers who keep bringing this up as a concern, such as Dr. Hotze, and America’s Frontline Doctors choose to ignore demonstrable facts in favor of continued fear mongering and appealing to emotions. A few countries around the world have begun arresting people for spreading such disinformation that disuades people from being vaccinated, which can lead to deaths caused by the disease.

  • Many people have died from the vaccines. That is flat wrong, and in fact, the opposite is true. In the US, ~550,000 people have died from recognizable COVID-19 while only nine (out of several million vaccinated people) might have died due to vaccine complications (discussed below). The CDC has a Vaccine Adverse Event Reporting System (VAERS) that lists all reported adverse events and deaths that occur shortly after vaccination, whether or not they are caused by the vaccine. Seeing as how tens of millions od people in the US have been vaccinated, unrelated health problems and deaths are expected to occur by chance. If you blew kisses at 50 million people, several of them would die in the next day or two just by chance. The air kisses did not kill them. The trick is to distinguish chance deaths vs possible vaccine-related deaths.

In order to determine whether a new vax causes adverse health effects, CDC doctors look for recurring patterns. If they see a pattern of similar types of death in certain people they pay closer attention to that group and even back off vaccinating them. With one extremely rare exception with one of the current vaccines as discussed below, these kinds of patterns have not been seen with the current vaccines.

  • The COVID vaccines will not eradicate the virus any more than flu vax eradicates flu. This statement by Hotze and others is either dishonest or they are ignorant of basic virology. It ignores the fact that flu rapidly changes every season, making it very hard to eradicate. The statement also ignores the facts that small pox has been fully eradicated by vaccines, and that in the US measles and polio have been eradicated—the only cases we see here come from overseas. Whether or not the COVID vaccines can eradicate CoV-2 depends on how well they work against the viral variants, how quickly the variants arise, and how many people are vaccinated in the next few months.
  • Herd immunity caused by natural infection is better than the vaccine. This statement too betrays ignorance of the disease and of vaccinology. Natural immunity to CoV-2 comes with the cost of many deaths and with many more people suffering long-term health problems caused by COVID-19. Again, the vaccines have not been linked to deaths or to lasting health problems. Vaccines are used to confer herd immunity without running the risk of the deadly consequences of the disease. By all measures, the vaccines confer significant protection against the disease and are more reliable than natural immunity where you cannot ensure a uniform level of infection and immunity for everyone.
  • Companies are reaping great profits off their lies. Pfizer and Moderna and other vaccine producers are providing the vaccines at cost during the pandemic. They are not profiting from them. Also, Moderna has announced it will not enforce its patents on its vaccine platform, but will share its technology with other companies and researchers during the current pandemic. In contrast, Dr. Hotze and others clearly are using the pandemic for their profit.
  • Companies are withholding raw data on their vaccines. Raw data for the approved vaccines was shared with two CDC committees consisting of scientists, vaccinologists, pathologists, epidemiologists and statisticians. That raw data was the basis for the emergency authorization of the vaccines (see below). Generally, raw data are only released to CDC and FDA and not to the public. What is released to the public are data summaries in the form of peer-reviewed journal publications and these are coming out and will continue to come out over the next few years.

The above are points Hotze has made and that are often repeated by other anti-vaxers. Below, I address other criticisms and questions about the vaccines that I have heard others, but not Hotze raise.

  • The vaccines are not FDA approved. Well, I wonder then who gave the vaccines Emergency Use Authorization (EUA)! True, EUA is not full FDA approval, but EUA approval still comes from 30 FDA experts after a rigorous evaluation of all existing data for efficacy and safety. That is well above the 2-3 experts that typically review science papers for peer reviewed publications. The EUA approval for each vaccine was based on data from about 40,000 subjects enrolled in the late stage clinical trials. Since then, millions more people have been vaccinated and their data continues to be collected and reviewed. Recent reports of this "real world" data continue to support the great safety and efficacy of the vaccines.
  • Some vaccines are better than others. The Pfizer and Moderna mRNA vaccines, which were the first tested and approved, showed ~95% efficacy, while the Adenovirus-based Johnson & Johnson vaccine, which was later tested and approved, only showed around 70% efficacy. So, shouldn’t we favor the Pfizer and Moderna vaccines? No. All the currently approved vaccines, including the J&J one, are very effective. And it is impossible to compare the relative efficacy of different vaccines from data obtained in separate trials. In order to gain an accurate comparison of different vaccines, they need to be tested in head-to-head, controlled trials in order to assure that similar patient populations are being tested against the same viral variant. For example, the Pfizer and Moderna vaccines were tested before we noticed viral variants that seem to be more infectious than the original virus. And neither company tested their vaccines in South Africa where one of the more infectious variants is rampant. In contrast, J&J began testing their vaccine after the variants began spreading around the world, and they also tested their vaccine in South Africa. This means that the Pfizer/Moderna vaccines were tested against different strains of the virus than the J&J vaccine, which confounds comparing their relative efficacy.
  • Bill Gates is promoting vaccines so he can inject us with microchips to track us. [big sigh]…Yeah, and one of the America’s Frontline Doctors, a group that claims hydroxychloroquine can cure COVID-19, said there is alien DNA in some of our medicines. I don’t waste my time with tinfoil-hat comments.
  • The vaccines cause infertility. This is based on bunk-science that began circulating last December. That rumor was solidly debunked by several sources, but the meme has been repackaged into new messages about de-population strategies. I give this the same attention I give to the silly notion that Bill Gates is trying to use the vaccines to microchip us. The vaccines do not cause infertility.

But, what about nursing mothers? Will the vaccines affect their babies? The answer is yes, but in a good way. Since babies are born with a very immature immune system, their first line of defense against pathogens comes from their mother’s antibodies that cross the placenta and that are found in mother’s milk. This “passive immunity” is an important first line of immune defense for newborns. Lactating women who have been vaccinated do show anti-CoV-2 antibodies in their milk, which provides the newborns with a temporary defense against the virus. That is a good thing.

  • The AstraZeneca vaccine causes blood clots. Over the past few weeks, 25 patients in Europe, almost all women under the age of 55, who received the AstraZeneca vaccine developed rare blood clots and nine died. The European Medicines Academy (EMA) met to review the data and found that overall clotting in vaccine recipients was less than in the general unvaccinated population. However, there are different clinical types of blood clotting problems, and for two very, very rare types, it was expected that ~2 clotting cases would arise by chance out of the ~20 million vaccinated people. But, 17 cases were reported. This is the kind of adverse event pattern that public health officials look for, as I described above. Again, exercising an abundance of caution, more than 20 European countries paused using the vaccine. However, within a week, the WHO and the EMA had reviewed the data and found that the extremely rare risk of vaccine-associated blood clots was significantly less than the risk of serious health problems from COVID-19 disease and advised that the vaccine be continued.

Final words. The disinformation about the anti-CoV-2 vaccines is disheartening, but seems to have been spawned by the roundly discredited claims by Dr. Andrew Wakefield a few years ago that the MMR vaccine was responsible for autism in kids. For that fraudulent reporting, Dr. Wakefield's paper was retracted and his medical license was taken away. Sadly, the damage was already done and continues today against all vaccines. Vaccines are one of the greatest health protection tools in the healthcare tool box and the naysayers are indeed killing people with their illogical and emotional appeals that are bereft of facts. How to counter such disinformation was a topic in a very recent article in Scientific American. What they recommend is beyond the scope of this post, but I hope that my presentation of the facts and reasoned criticism of anti-vax rhetoric is a step in that direction.


Messenger-RNA Vaccines Are The Buzz, But The Real Technology Advance Is The Lipid Mixture That Delivers The mRNA

The back story: Messenger-RNA vaccines have been wildly successful against the coronavirus and are very safe. Expect more of them in the future, even for flu. As exciting as it is to see a simple mRNA sequence generate immunity to a pathogen, it is the less “sexy” lipid, or concoction of fat molecules that makes it possible and has been a bit of a bottleneck in manufacturing the vaccines.

Messenger RNA is a fragile molecule since there are RNA-degrading enzymes called RNases all over the place. Therefore, researchers decided to encapsulate the genetic material inside a protective shell composed of a cocktail of different types of the fatty molecules that, in a solution, will form mini-cells called lipid nanoparticles. These nanoparticles essentially mimic the lipid membrane of your cells so that when, after injection and they bump into a cell, the lipids of the nanoparticle and of the cell membrane fuse, spilling the mRNA into the cells. There, normal cellular machinery can transcribe the mRNA sequence into a viral spike protein that is expressed on the cell surface, stimulating an immune response. There also are RNase enzymes inside cells that digest the mRNA after it has done its business so the vaccine genetic material naturally disappears in a couple of days and cells cease expressing the spike protein.

Some history: Since the 70s, research has been underway into using lipid nanoparticles to deliver large, fragile bio-molecules and drugs to cells. But, but the nanoparticles are notoriously difficult to make and use. Bob Langer, now a Professor of Biological Engineering at MIT has been working with lipid nanoparticles since the 70s when he was a pioneer trying to prove you can capture and transport big, complex molecules like DNA and RNA inside tiny lipid nanoparticles without destroying them. Many people told him it was not possible and he had his first 9 grant applications rejected—and this was a time when research grants were pretty easy to get. He also could not get a faculty position because people did not believe in his research.

But, he did succeed. Today, Professor Langer has a bioengineering lab at MIT bearing his name. The lab is focused on the intersection of biotechnology and materials science. In 2010, Langer branched out and co-founded a small biotech company named Moderna where he’s still on the board. That company, like the German biotech company, BioNTech, has, over the last decade been developing mRNA vaccines for infectious diseases, cancer and rare illnesses. The Moderna mRNA vaccine, developed along with researchers at NIH, is Moderna’s first commercial product.

The lipid nanoparticle field had a watershed moment in 2018, when the FDA approved the first drug delivered via lipid nanoparticles from yet another biotech, Alnylam Pharmaceuticals based in Cambridge, Massachusetts.  Their nanoparticles were used to encapsulate and deliver a drug, Onpattro, to treat a rare genetic disease that causes nerve and heart damage. That meant that before the coronavirus pandemic, regulators already had some familiarity and comfort with using lipid nanoparticles to deliver therapeutic molecules. The technology is not brand new as some vaccine naysayers like to claim.

Another scientist, Thomas Madden, worked for years with Alnylam on developing that pioneering lipid delivery system. However, before the FDA approved Alnylam’s delivery system, Madden had moved on to his own Vancouver-based company, Acuitas Therapeutics, which hoped to develop mRNA therapeutics for different diseases. Madden recalls an epiphany in 2011, when he realized that in order to successfully use mRNA for therapeutic purposes; they needed a better delivery system to protect the mRNA from the ubiquitous RNases that quickly digest any mRNA found circulating outside of cells.

To prevent that from happening, he adapted the lipid-packaging technology developed at Alnylam, thinking that if the mRNA could be packaged inside the artificial lipid membranes it  would protect the fragile genetic mRNA from the ubiquitous RNase enzymes. This became the basis for the technology behind the Pfizer/BioNTech and Moderna mRNA vaccines. The mRNA in Covid shots sits inside a lipid shell composed of four lipids. After protecting the mRNA on its journey into a person’s arm, the nanoparticle gets taken up into a cell and the mRNA is released inside the cells. Once inside the cell, the mRNA instructs the cell to produce copies of the coronavirus spike protein, which is then recognized by the body’s immune system.

Moderna has designed its own lipids used to create the nanoparticles, while Pfizer has licensed the Acuitas lipid delivery technology. Yet another mRNA vaccine is being developed by another biotec, CureVac, which also is using the Acuitas lipid technology. Each of these companies was engaged in early clinical trials of other mRNA therapeutics before the pandemic and CoV-2 burst onto the world stage. They all pivoted their efforts to develop several novel vaccines against the novel coronavirus in record time.

When Covid-19 emerged, Madden, from Acuitis Therapeutis, flew to Germany to talk to regulators and BioNTech officials about how they could most quickly commence clinical trials of mRNA COVID-19 shots. They decided to repurpose the lipid nanoparticle from a very new rabies vaccine recently developed by CureVac, since it had proven effective in people. This gave regulators further confidence on the safety and potential for lipid delivery of the coronavirus spike protein mRNA.

In a nut shell, that is how we got to this point so quickly. An important take-home message is that the mRNA vaccine technology and lipid nanoparticle delivery system are not new concepts. The vaccines are the product of decades of research and trials conducted by several academic and biotechnology labs. The lipid nanoparticle delivery system has proven effective and safe for delivering other vaccines and drugs.

In an earlier blog post, I dubbed this amazing new biology, BioX, after the name of the new and amazing space enterprise known as SpaceX.

New challenges: As Moderna and Pfizer have, almost overnight, greatly ramped up production of their lipid nanoparticle delivery systems, supply chain issues became evident. Soon after getting its mRNA vaccine approved, Pfizer announced it was scaling back the number of doses it would deliver due to difficulty obtaining the raw chemical materials needed to make the necessary lipid compounds. Until a year ago, the German biotech company, BioNTech, that partnered with Pfizer, purchased only a few grams at a time of the needed chemicals to produce its lipids for a cancer vaccine research program. Now the company is tapping huge German chemical conglomerates like Merck and Evonik Industries for barrels of the stuff in order to manufacture 2 billion vaccine doses this year. Moderna also has dramatically scaled up its need for chemicals to produce the lipids that go into its promised one billion vaccine doses. Other mRNA vaccines are also being developed by CureVac NV and Sanofi, both of which will require massive amounts of the raw materials. Lipids have leaped to the top of the world’s health-care supply-chain priority list.

Major drug and chemical makers have taken notice of the new demand for the lipid chemicals. In early February, Germany’s Merck agreed to speed up the supply of lipids to BioNTech while Evonik followed suit a week later. Evonik is repurposing tanks and vessels at two plants in Germany and buying new instruments for the purification process. Typically, in the pharma industry such large-scale manufacturing scale-up takes a year or two, but Evonik plans to do this in a couple of months in order to meet the sudden and immediate demand.

That is the German version of Warp Speed.

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Increasingly Contagious And Lethal CoV-2 Variants Are Popping Up Around The World

In September, the UK noticed a coronavirus variant that has a surprising number of genome mutations, including eight point mutations in the spike protein, which is the viral antigen targeted by most of the vaccines. In just a couple of months, the variant became the prevalent cause of COVID-2 in the UK, meaning that it spreads faster than other iterations of the virus. It also has been found in a few pockets in the US and is expected to become the dominant strain here by March. It appears that the variant is 30-50% more infectious in all age groups (down from the early 70% estimate in December). Fortunately, all indications are that the two mRNA vaccines being rolled out by Pfizer and Moderna are effective against the variant (expect two more vaccines based on different technology platforms soon, from AstraZeneca and J&J).

The bad news is that British public health officials just warned that the virus variant is just not more contagious, it also is 30-40% more lethal. Out of 1000 60-year old patients infected with the UK variant, 13-14 would be expected to die, compared to 10 deaths in patients infected with the previous virus. This warning was based on four separate UK studies.

Related, but not identical, viral variants also have appeared in South Africa and in Brazil. These variants also seem to be more contagious and, not surprisingly, share some of the same spike protein mutations as the British variant. There is no word, yet, on the lethality of these variants. However, three lab studies in South Africa have raised concerns that their variant might be resistant to the current vaccines. Pfizer studies found that their vaccine protects well against the British variant, but the South African variant seems to be more resistant to the two vaccines currently in use. It too has quickly become the dominant virus strain in that country and has been found in 22 other countries. It has not yet been found in the US, but give it time.

These new virus variants that are more contagious and more lethal are appearing in countries where a significant percentage of people have already built some immunity to the original CoV-2 strain. This raises concern that our immune responses can provide natural selection pressure that favors virus variants that avoid the specificity of our immune response. In other words, our immune systems and the vaccines might be driving the emergence of more contagious and deadly forms of the virus. If so, this would necessitate adapting the vaccines to meet the variants and establishing a regular vaccine schedule with continually changing vaccines like we do now for the flu virus.

The CEO of BioNTech, the German biotech company that spent a decade developing the mRNA vaccine platform used in Pfizer’s vaccine, said it would take only six weeks to design a new vaccine specific for new variants in the spike protein. The platform is in place and all they would need to do is swap out the spike protein mRNA for the new variant sequence. Then it would take some time to produce the new vax and get it into arms. But, again, that is similar to what we do each year for the new flu strains that pop up annually.

Hopefully, the new vax technology will let us develop new vaccines as fast as the virus mutates.

The race is on. Bet on the new vax technology, which I earlier christened, BioX.


New Coronavirus Mutation Enhances Spread

The Wall Street Journal reports that countries across Europe and beyond are banning travel from the UK in order to stem a more-infectious strain of Covid-19 that has been found in the London area. The new strain was first reported last Monday, and on Saturday, England announced that it is imposing fresh lockdowns in London and surrounding areas, which also include a ban on households mixing at Christmas. Similar restrictions have been taken across Europe with Italy announcing a complete lock down across the country. Germany and the Netherlands imposed lockdowns through Christmas, and Austria said Friday that nonessential businesses will be closed starting Dec. 26. However, it also appears that the new strain has popped up in Denmark and South Africa. Holland reported one case with the new virus variant.

Scientists believe the new strain of the coronavirus could be as much as 70% more transmissible than previous strains, but there is no evidence at this time that it is any more deadly or more resistant to the vaccines.

It seems that the virus mutated to change the spike protein on the surface of the virus, increasing the protein’s ability to cling to and chauffeur the virus into human cells. These changes allow the mutation, known as N501Y, to spread faster than other versions of the virus. Early analysis suggests the variant first occurred in September either in London—where it was identified on Sept. 21—or in the nearby county of Kent, where it was found on Sept. 20. That might explain why quarantine restrictions that have been effective elsewhere in England have not been effective in Kent. By mid-November, 28% of cases in London were attributable to the new variant. In the week starting Dec. 9, it was responsible for 62% of cases in the capital. In other words, this variant is winning the infection race against all other CoV-2 strains out there. As of December 19, there has been no evidence of the new strain in the US.

Viruses mutate all the time, but coronaviruses do so less than, say, the flu virus. Mutations happen when rare, random errors are made while cells copy millions of viral genomes. Most mutations are innocuous, but sometimes these accidental changes alter the behavior of the virus. Scientists have identified 23 genetic changes in the genome of the new variant, an unusually large number, some of which are associated with small changes in the proteins the virus makes, which, therefore, can change viral behavior. Those include changes in areas known to be associated with how the virus binds and enters cells, which probably explains why it spreads more quickly. While efforts, including quarantine measures and the new vaccines, are designed to drop the infection rate of the virus, or the R0 number, these mutations threaten to work against those efforts and increase the virus R0 value.

Two main questions are now being investigated: Is the new variant more likely to cause increased morbidity and/or mortality, and is it more likely to avoid the body’s immune responses, including those encouraged by vaccines? The provisional answers to those questions are no and no, but the research continues, so these conclusions are preliminary. We will see.

The new variant isn’t the first time a more-transmissible CoV-2 strain has emerged. As reported in these pages last summer, scientists in July described a viral variant that displaced an older strain of coronavirus to become the dominant strain in the global pandemic. Experiments showed that the variant replicated more quickly in tissue culture, but appeared to be just as susceptible to antibodies that targeted the earlier strain, and was not associated with more severe illness.

The bottom line is that as viruses replicate in cells, spread, and replicate some more, they acquire small mutations in their genome. It is like playing the lottery, an occasional mutation will be the “winner” and the ability to spread and even cause new diseases can arise. Like the lottery, the more you play the greater the chance of a winner. This is why calls for “natural herd immunity” by letting people get infected are really bad ideas--they are gambling that while spreading through a population, the virus does not become even more virulent. This also is why health professionals recommend quarantine measures to limit the reproduction-spread-more reproduction of the virus until we have vaccines that effectively block the reproduction and spread and mutation of the virus.

Otherwise, we are just playing the virus lottery.

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