vaccines

Take Your Vaccine Skepticism To A Cemetery

“Still a man hears what he wants to hear and disregards the rest”

            --Paul Simon, in The Boxer

They say you won’t find an atheist in a foxhole. Well, perhaps you shouldn’t find a vaccine skeptic in a cemetery, either. Bear with me and I will explain.

I have been reading about how vaccine skepticism is growing beyond the COVID vaccine to include other common vaccines against flu, measles, chicken pox, polio, etc. Perhaps this all began with parental resistance to Gardasil, a vaccine against human papillomavirus, or HPV, introduced in 2006. HPV is a sexually transmitted virus that causes genital, anal, and oral cancers. It is the most common cause of cervical cancer. In order to confer maximal and lasting protection, it is recommended that children around 11 and 12 years old be vaccinated. Some parents have railed that this promotes promiscuity. They fret that the vax licenses licentiousness in children, akin to giving them condoms with illustrated instructions in their use. Balderdash!  

While that medical insurrection continues to smolder, along came COVID and the anti-COVID mRNA vaccines accompanied by the surprising resistance of many people against the shots. It is a resistance that seems to be growing and spreading to vaccines in general including those listed above that have long been commonly accepted.

This is concerning because it portends that in the near future, kids will begin coming down with diseases that we have pretty well controlled. In fact, in the last year or so, de novo cases of polio have appeared in the US in unvaccinated people. Before this incipient vaccine resistance, polio had been eradicated in North America, thanks to the vaccine.

It is safe to expect that vaccine resistance will persist, and probably increase as new vaccines are developed to treat cancer and better protect against flu. The mRNA vaccine technology is being used to develop new vaccines against the deadly skin cancer melanoma, and research is underway to also develop vaccines to prevent breast, liver, prostate, and other cancers. This use of modern vaccine technology to prevent cancer is a very novel and promising approach to dealing with malignancy. Anti-cancer vaccines are a potentially exciting new weapon in the armamentarium for the war on cancer. Too bad for those who would reject an effective cancer-preventing vaccine. At least they can fall back on the standard harsh radiation and chemo therapies.

mRNA vaccine technology also is being used to try to develop a universal vaccine against the flu. Flu is a highly malleable virus because there are many strains out that that can mix and shuffle their genetic material. This means that every year, it is a guessing game as to which combination of flu we will contend with—hence the changing flu numbers each year-- H1N3, H2N4, H3N1, etc. Since the Southern Hemisphere’s flu season precedes ours in the North, flu sleuths follow what goes on down there and track which strains make their way Northward, often via migrating birds, and try to predict what flu strains will be prevalent here each year. Then flu vaccines are made based on the best predictions. Usually, the annual flu vaccine is a mix of 2-3 of the flu strains that we are most likely thought to encounter. Some years we better predict which flu strains to vaccinate against than in other years, hence the efficacy of the vaccine can vary from year to year. Therefore, the advantage of a universal vaccine effective against all strains would be to remove this uncertainty and variability. That is the goal of using mRNA technology to take genetic material that is common to all flu strains and package it into lipid particles as pseudo-viral particles to trick the immune system to make an immune response to these parts of the viruses. If successful, this would protect against all flu strains and eliminate the need to guess which strains to vaccinate against. Theoretically.

The point is, vaccine science is moving forward and continues to offer great promise to prevent diseases that have proven very difficult to treat. The vaccine naysayers will miss the boat if they continue their misguided dissent. I suggest that they test their skepticism in a cemetery.

Go to an old cemetery and find the graves of people who died in the 1950s and earlier. See how many headstones belong to children.

Then go to the part of the cemetery where the grave stones are for people who died in the 60s and later and see how many graves are occupied by children.

The sharp drop in the number of childhood deaths after the 60s can largely be attributed to vaccines. Vaccines prevent serious disease and death in children who used to die from meningitis, pneumonia, dysentery, small pox, flu, and other diseases, but now do not. And to those who think that the vaccines are killing people, where are their headstones?

It is always better to prevent disease than to treat it. Vaccines prevent disease. Avoid vaccines if you wish. Darwin might approve.


The Latest On Long COVID (So Far)

“After all, tomorrow is another day.” Gone With the Wind

In these pages, your humble bloggeur (me) has followed the evolution of what we know about the odd condition known as long COVID. You can find seven previous blog posts on the topic here. Because we were just learning what long COVID was all about, many of those posts ended with the disclaimer, “we will see.”

Well, we have seen and continue to see. Here is what we now know after over 2 years of experience with this complication. But, tomorrow is indeed another day.

The risk of death from COVID is now about the same as the risk of death from flu, which can vary from year to year, thanks to vaccines, natural exposure, and developing therapies. One study in Lancet found that people with COVID had a 3-fold greater chance than uninfected people of dying each year. But, as I explained before, mortality is only part of the story. There also is morbidity. Long COVID is "the rest of the story" as Paul Harvey used to drone. Some 54 studies on long COVID, involving 1.2 million people, have been reviewed and it was reported that about 6% of people with symptomatic COVID infection wind up with long COVID. This agreed with a massive Swedish study of COVID patients done between 2020-21. According to the new Census Bureau Household Pulse Survey, some 16 million working age Americans now suffer from long COVID, which creates a huge burden on our health system. Up to 4 million of these are unable to work, which is a major drain on a labor market already short of workers. The annual cost in lost wages is up to $230 billion! The total economic cost of long COVID in the US so far has been an astounding $3.7 trillion!!

And as the virus evolves, reinfections with new CoV-2 variants are becoming more and more common. Unfortunately, a large VA study on reinfections suggests that you want to avoid them. A second or third infection is associated with worse disease and increased chance for long COVID. And a large German study including nearly 12,000 children with COVID concluded that long COVID “cannot be dismissed among children and adolescents.”

A sobering study of medical records from millions of US military veterans in the VA medical system published in Nature Medicine found that 7% more COVID patients (compared to uninfected veterans) had lasting brain or neurological disorders. This extrapolates into about 6.6 million Americans with long-term brain impairments linked to COVID. Memory impairment was the most common brain malady. But those with a history of COVID also were at greater risk of ischemic stroke, seizures, anxiety and depression, and movement disorders.

The good news is that vaccines reduce the risk of long COVID—how much is still debatable at this point. The anti-COVID medicine, Paxlovid, reduces long COVID risk by 25% according to one study. And the Omicron CoV-2 variant shows a reduced risk of long COVID compared to the more pathogenic Delta variant.

Assessing the risk: How much should the risk of catching long COVID affect one’s daily decisions? Should I go to the concert? Graduation? Grocery store? Wear a mask everywhere? That is hard to say definitively. Perhaps it would help to compare COVID risk to other risks we face every day.

  • The annual risk of getting in a car accident is about 1 in 30 per year. Of those, ~43% involved injuries and ~10% of those cause permanent impairment. This makes the annual risk of permanent injury from an auto accident about 1 in 700.
  • The annual risk of serious injury in a house fire is ~1 in 20,000.
  • The risk of needing reconstructive surgery after a dog bite is 1 in 400 annually.
  • The risk of catching the Omicron variant (symptomatic or asymptomatic disease) is ~1 in 2 annually (it was 1 in 4 before Omicron). Say 3% of those get long COVID, and ~18% of them are so sick they are unable to work for an extended period. This makes the annual risk of severe long COVID about 1 in 370.

So, the risk of debilitating long COVID is about twice the risk of serious injury from driving and about the same as getting a serious dog bite. The risk of severe long COVID is much higher than being injured in a house fire. Of course, all of these risks are affected by our personal behaviors. We don’t drive drunk and wear seat belts (hopefully). We replace the batteries in home smoke detectors every year and avoid growling curs. And if we are smart, we vaccinate and stay home when we are not feeling well.

At least those are things that responsible people do to reduce the risks of life.


Pandemic History: Long COVID

"We learn from history that we learn nothing from history."
--George Bernard Shaw

Let’s hope GBS is wrong about what we learn from the recent pandemic. As it recedes in our rear view mirrors, scientists are looking to all the data and information collected to retrospectively see what we learned about this new virus and disease. This is especially true for that totally unexpected disease phenomenon called “long-COVID.” As we became aware that some COVID survivors continued to suffer from a strange constellation of symptoms, referred to as long COVID, I wrote in these pages about what that affliction entailed, and what we were seeing and discovering about it. You can find several other blog posts on that topic by looking under “long COVID” in the "Categories" listed to the side of this post.

Long COVID was particularly difficult to study since, by definition, it lasts months, maybe even years in some people. That means that discerning how it manifests itself, and how to effectively treat it would take months to flesh out. We have gleaned a bit about that and also have identified areas we need to look at more closely in order to fully understand this part of the disease.

A Scottish study of about 100,000 participants began while the pandemic fulminated, and the results of that study are just being released. The study helps clarify how to diagnose long COVID, which earlier had vexed physicians who had no idea what they were looking at. Long COVID presented doctors with a hodge-podge of seemingly unrelated symptoms—was it a single disease? Different disease manifestations? Psychosomatic? What it then was was a head scratcher. The Scottish study helps confirm that it is a real COVID-associated problem, and the most common symptoms include breathlessness, palpitations, chest pain and “brain fog” or reduced mental acuity. We also learn from the study that the risks of acquiring long COVID is greater in women, older people and economically disadvantaged people. Also, people already dealing with other physical and mental health problems, such as respiratory problems or, surprisingly, depression, are more prone to long COVID. Why is that? The study also found that 1 in 20 people had not recovered up to 18 months after coming down with COVID. It also reported that people with asymptomatic infections were unlikely to suffer long-term effects, which helped confirm what we expected, that it probably is not the virus that causes long COVID, but the culprit is some people’s immune response to the virus. Who are those people susceptible to long COVID, and what is different about their immune response? It also seems that vaccination protects a bit against long COVID, but not as much as previously thought. But, this observation complicates things. The vaccine is designed to stimulate an anti-virus immune response without the risk attendant to an infection. Why doesn't this immune response cause long COVID symptoms like the immune response to the actual infection? Basically, how it all works still is not well known, but that bit of new information scientists are gleaming from the data moves us gradually closer to finding out.

Looking at other data collected since the pandemic reared its ugly head, the WHO estimates that about 10-20% of COVID survivors have lasting symptoms that reduce their quality of life to varying degrees.

The Washington Post reports that somewhere between 7-23 million Americans currently suffer from long COVID. One million of these are unable to work. People are not dying from long COVID, but they often are considerably impaired and that makes them heavy consumers of expensive medical care, and often unable to work at full capacity, which adds to the personal and social costs of the chronic complication.

Anthony Fauci, in an interview with The Guardian, cautions that even though COVID deaths and hospitalizations are declining, it is premature to declare victory over COVID since we continue to deal with the insidious chronic sequelae of the disease. Furthermore, all indications suggest that COVID will be a recurring problem for the world and as it regularly sweeps across the globe, it will continue to create new cases of long COVID. This means that we still need to remain vigilant to avoid the virus when possible, and to make sure that vaccinations are effective and available to the population. Other therapies continue to be explored, but, unlike, antibiotics that fight bacteria, safe anti-viral drugs are very hard to develop because they often come with too extreme side effects.

Continued research into the virus and disease by medical scientists, and further examination of the pandemic history by epidemiologists hopefully will lead to a better understanding of the causes of long COVID, how to more definitively diagnose it, and ultimately how to effectively treat, or even prevent it. Toward these ends, Fauci’s National Institute of Allergy and Infectious Diseases recently launched a $1.15 billion initiative to achieve these goals. The CDC also recently began its own major study of the problem.

Stay tuned for changes in how we deal with the virus and with long COVID as we learn more about it. That is how science works.


The Next Pandemic Is Here

Who ya gonna call?  --“Ghostbusters”

We seem to have mostly weathered two-plus years of a pandemic like the world has not seen in our lifetimes. It raced across the globe killing and maiming people, and overwhelming health care capabilities. Sure, we have read the history about the black plague, small pox, and the Spanish flu pandemics, but vicarious experience through books and film is no substitute for first-hand experience. We now have that experience. It was sobering to see the novel SARS-CoV-2 virus ravage country after country while medical experts played a desperate game of catch-up to learn how to retard the spread of a brand new virus and how to treat the brand new COVID-19 disease it spawned. It was sobering seeing and hearing about people we know get very ill and sometimes die, and sobering reading the statistics of millions of deaths that occurred worldwide.

While most of us today have not seen such a pandemic wild-fire before, we have seen other, more smoldering pandemics that do not spread as fast. HIV is a good example. It too is a world-wide disease that, for many years was a death sentence for those who were infected. Now it is a well-managed chronic disease, thanks to medical science.

The world was not as frantic over HIV and AIDS as we were over CoV-2 and COVID. The reasons for this are probably two-fold: First, it was quickly recognized that AIDS was largely limited to homosexual men and IV drug users and, therefore, was not an eminent threat to most of us. It was not necessary to quarantine, mask up, and shut down businesses and schools in order to prevent catching the “gay disease.” Second, despite the world-wide spread of AIDS, it is not easy to catch. You must be in very intimate contact with an infected person to catch it—it is not caught by simply breathing the same air as an infected person like COVID is. Clearly, not all pandemics are created equal. Some smolder like AIDS, others fulminate like COVID. What will our next pandemic be like?

As the global population grows, as the climate changes, as humans push into spaces occupied by wild animals, and as we continue enjoying our ever increasing global connectedness, future pandemics become more likely. We are not guaranteed the luxury of facing just one a century, or even one at a time. As greatly encouraging, even exciting as it was to watch the post-molecular BioX science, as I have called it, roar into life to produce several effective and novel anti-CoV-2 vaccines in record time, there is no guarantee BioX can save us next time.

Well, the “next pandemic” already is upon us and BioX is struggling to deal with it. This pandemic is not as volatile as COVID or the Spanish flu. In fact, compared to COVID, it is a “slow mo’” pandemic, more like AIDS. But, it promises to be more difficult than COVID, even for BioX, to mitigate. It currently kills about 700,000 people annually around the world, but threatens to kill 10 million people a year by 2050 (in contrast, COVID killed ~6 million around the world in 2.5 years).

The problem

 In March 1942, Anne Miller of New Haven, Connecticut, was near death. A bacterial infection had made its way into her bloodstream, which was a death sentence at that time. Desperate to save her, doctors administered an experimental drug called penicillin, which Alexander Fleming accidentally discovered 14 years earlier. In just hours, she recovered, becoming the first person to ever be saved by an antibiotic. Rather than dying in her thirties, Mrs. Miller lived to be 90 years old and Fleming went on to win the Nobel Prize for his inadvertent discovery.

Today, decades later, germs like the one that infected Mrs. Miller, but easily eradicated with antibiotics, are increasingly becoming resistant to penicillin and the many other antibiotics that have since been developed. There is a very good chance that right now, you have such a “superbug” in or on your body—a resistant germ that, given the opportunity could enthusiastically sicken you leaving medical people at a loss on how to treat you. You would be at the mercy of the bug just as all patients with a microbial infection were before Mrs. Miller.

We are not talking about a new, exotic germ like CoV-2 suddenly appearing and ravishing the world. The antimicrobial resistance crisis stems from the simple fact that new antibiotic development cannot keep pace with the rate that common microbes become resistant to antibiotics. This very slowly growing pandemic we are now in involves run-of-the-mill pathogens, bacteria and fungi that have caused disease since humans first dragged their knuckles on the earth. These are bugs which we had well controlled with antibacterial and antifungal drugs, but there is a very definite trend toward these germs becoming resistant to ALL known antimicrobial medicines we have. Infection with multidrug resistant pathogens is the slow moving pandemic that already is among us but that is growing at a logarithmic rate.

Since multi-drug-resistant infections do not respond to our antibiotics, treatment increasingly involves surgically removing an infected organ. For example, in the case of drug-resistant Clostridioides difficile (aka, “C-diff) colitis, an emergency colectomy is performed when patients no longer respond to antibiotic therapy. CDC data show C-diff infections occur in half a million patients each year, and at least 29,000 die within one month of initial diagnosis. Up to 30% of patients with severe C-diff colitis develop sepsis require emergency surgery, and still their mortality remains high.

As of 2019, about 18 drug resistant pathogens affected >3 million people in the US, causing 48,000 deaths. These bugs cause pneumonia, septic shock, various GI problems, STDs, urinary tract infections, typhoid fever, TB, and infection with the so-called “flesh eating bacteria.” Compared to COVID, this has received relatively little attention in the popular press, but has been a frequent topic in medical lectures and conferences for the last 20 or more years. These infectious disease lectures tend to scare the bejeebers out my colleagues and me. This smoldering pandemic is that serious.

And it is not just antibiotic-resistant bacteria we have to worry about. Certain fungi, especially of the Candida genus, cause various serious ailments in people. Recently, for the first time, the CDC reported five unrelated cases (two in DC and three in Texas) of people infected with fungi that showed “de novo” resistance to all drugs. Usually, drug resistant fungi only appear after infected patients have been treated with antifungals. But, the patients in these five de novo cases had no prior exposure to antifungal drugs. The fungi were already drug-resistant when they infected the patients; they were picked up from the environment already resistant to our medicines.

Antibiotic resistance is now one of the biggest threats to global health. It occurs naturally in naturally occurring pathogens, but is accelerated by overuse of antibiotics in humans and animals, especially farm animals. What happens is that upon treatment with an antibiotic, a single infectious bug out of a population of millions or billions fortuitously mutates and becomes resistant to the antibiotic. The antibiotic then kills off all the non-resistant population, including beneficial bacteria, opening the door for the drug-resistant pathogen to take over. This resistance can occur via many different mechanisms. The bacteria or fungal cell can stop taking up the drug, it can spit out the drug if it is taken up, it can neutralize the drug once it takes it up, or it can change its internal machinery so that it no longer responds to the drug. This problem can be further exacerbated since bacteria and fungi can pass along their mutations by sharing mobile genetic material with their progeny and even with other bugs in their immediate environment that have never been exposed to the antibiotic. They can even pass along this DNA to microbes of different species. Bacteria can also pick up DNA remnants left over from dead germs. Thus, DNA that confers resistance to anti-microbial drugs can spread to the environment even in treated human and animal waste contaminating lakes and streams and ground water.

Currently, the major problem with drug resistant infections occurs in in-patient clinical settings—perhaps you have seen the heightened infection control efforts (gowns, gloves, masks, and isolation) in hospitals designed to prevent the spread of untreatable pathogens. People receiving health care, especially those with weakened immune systems, are at higher risk for getting an infection. Routine procedures, such as bladder catheterization or kidney dialysis are common ways to introduce drug resistant germs into clinical patients. But, infection can happen in any surgical or invasive procedure. Treatment of diabetes, cancer, and organ transplantation can weaken a person’s immune system making them even more susceptible for infections that either are, or that can become drug resistant.

But, antibiotic infections can also occur in the community outside of clinical settings. There is the case of Mike who needed a month long hospital stay for kidney failure after bringing home a new puppy from which he caught a multidrug-resistant Campylobacter infection. He was one of 113 people across 17 states who was part of an outbreak linked to pet store puppies. He recovered after surgery to remove a dead section of his stomach.

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The NIH Hospital Experience. About 10 years ago, the NIH Clinical Center in Bethesda was hit with an epidemic of drug resistant infections that killed a number of patients in just a few months. It was such an intractable problem that NIH finally had to gas rooms with a disinfectant, rip out plumbing, and build a wall to isolate infected patients. Still, over a period of six months it reached 17 patients, 11 of whom died. In this case, the bug was Klebsiella pneumoniae, which arrived in June 2011 with a 43-year-old female lung transplant patient who had just transferred from New York City. NIH nurses noted something startling in her chart: She was carrying an antibiotic-resistant infection.

Desperately trying to contain the superbug before it could spread, the NIH staff quickly isolated the woman in the ICU. Staff members donned disposable gowns and gloves before entering her room and her nurses cared for no other patients. After a month, the patient was discharged and the staff believed that their containment measures had worked. There were no signs that the bacteria had spread. But a few weeks later, they were shocked when a second patient tested positive for resistant Klebsiella. A third and fourth soon followed and all these patients died.

This pattern was baffling since, if the bug had not been cleared, it should have reappeared sooner. Even though it was the same type of bacteria, K. pneumoniae, perhaps it had spontaneously arisen anew in the other three patients. But by reading the genomes of the bacteria isolated from each patient, including the NYC transfer, scientists at NIH’s National Human Genome Research Institute saw that the bacteria in the subsequent patients came from the New York patient.

That meant two unsettling things: The bacteria lingered for weeks unnoticed in the hospital environment; and the hospital’s infection control measures for the New York patient failed. A further search for the bacteria found it on a ventilator that had been bleached twice. They also found it in a sink drain in a patient’s room, so they tore out all the plumbing. Yet, it began popping up it in more patients, at a rate of about one per week.

As hospital staff desperately raced to stanch the outbreak, they also struggled to treat the infected patients. Out of desperation, doctors battling the deadly, drug-resistant superbug turned to colistin, an antibiotic of last resort. It is not a new drug, having been discovered in 1949 in a beaker of fermenting bacteria in Japan. It had quickly fallen out of favor then since it causes significant kidney damage. The fact that the doctors resorted to such an old, dangerous drug highlights the lack of new antibiotics coming out of the pharmaceutical pipeline even in the face of a global epidemic of hospital-acquired bugs that quickly grow resistant to our toughest drugs.

While colistin defeated the superbug in a few patients, in at least four, the bacteria evolved so rapidly it outran colistin, too. Those four died. This was when the wall was built and all new Klebsiella-positive patients were moved into a new isolation unit behind the wall. Blood pressure cuffs and other normally reusable gear were tossed after one use. Clinical monitors were hired to follow doctors and nurses around to ensure that they were donning gowns, gloves and masks, and scrubbing their hands after seeing each patient.

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Among the most concerning mutating bacteria are carbapenem-resistant Enterobacteriaceae (CRE). Enterobacteriaceae are a large family of more than 70 bacteria that includes the common E. coli, that normally live in the digestive system and help digest food. But, if conditions allow the bacteria to leave the digestive system, they can cause serious disease that needs to be treated with antibiotics. They too can quickly develop resistance to front-line drugs and become a serious problem.  Carbapenem is an antibiotic "drug of last resort" used to treat disease caused by bacteria resistant to other front line antibiotics. Therefore, CRE are resistant to all or nearly all antibiotics and kill up to half the >13,000 patients who get bloodstream infections from them. The CDC first detected this type of antibiotic-resistant bacteria in 2000. Since then, it has been reported in 41 states. In the 10 years between 2001 and 2011, the percentage of Enterobacteriaceae resistant to antibiotics increased almost fourfold according to the CDC. Recently, the CDC tracked one type of CRE from a single health-care facility to facilities in at least 42 states.

The cause

The antimicrobial resistance crisis stems from the simple fact that new antibiotic development cannot keep pace with the rate that bacteria become resistant to antibiotics. Between 1945 and 1968, drug companies invented 13 new categories of antibiotics. Between 1968 and today, just two new categories of antibiotics have arrived. In 1980, the FDA approved 4-5 new antibiotics a year, but now only about 1-2 new drugs are submitted annually for approval. Hence, the solution appears quite simple: Develop more novel antibiotics. However, this is quite complicated since BioX science, which led to the rapid development of the novel mRNA anti-COVID vaccines, has not quite caught up to novel antibiotic development. There are two general reasons for this. First, finding a drug that disrupts the metabolism of bacteria or fungi, but that does not interfere with mammalian biochemical pathways is a difficult and narrow path. Second, so far, the market for novel antibiotics has been comparatively small, meaning that the profit incentive for pharma companies has not been large compared to that for so-called lifestyle medications. While a new antibiotic may bring in a billion dollars over its lifetime, a drug for heart disease may net $10 billion. Drugs to treat depression and erectile dysfunction are typically taken for years making them much more profitable than antibiotics that are used short-term.

Development of bact resistance

Even if we could develop new antibiotics faster, their overuse is the primary driver of antibiotic resistance. According to the CDC, in 2018 seven antibiotic prescriptions were written for every 10 Americans. Of these, one-third were unnecessary, and very often were prescribed for viral illnesses that do not respond to antibiotics. Clinicians writing these prescriptions argue that the antibiotic can help prevent the primary viral infection from leading to a secondary bacterial infection. In other words, many antibiotics are prescribed for prophylaxis rather than treatment.

Time to resistance

The number of new antibiotics that the FDA approves annually has slowed to a trickle, while the rate of bacterial mutation has grown exponentially. It used to take 21 years on average for bacteria to become resistant when antibiotics were first used. Now it takes just 1 year for bacteria to develop drug resistance because antibiotics are so readily prescribed and used. Today, the CDC lists 18 different types of antibiotic-resistant bacteria, five of which are classified as urgent threats to human health.

Physician-prescribed antibiotics, however, are not the only, or even main, source of our antibiotic resistance crisis. In the U.S., 70%-80% of all antibiotics are given to animals, especially farm animals destined for human consumption.  Drug-resistant pathogens from farm animals can spread to the environment providing a gateway through which drug resistant germs can quickly spread across our communities, food supply, and even our soil and water around the world.

Surprisingly, antibiotic use is even rampant in salmon and other fish farms, which is especially concerning, considering that 90% of fresh salmon eaten in the U.S. comes from such farms. Antibiotic-resistant infections also affect petting zoo animals, which can then transfer the germs to people.

The solution

Antibiotics clearly have been miracle medicines, saving countless lives; however, anytime they are used, they drive the development of antibiotic resistant pathogens that ultimately defeat their purpose.  Developing new antimicrobial drugs to counter the growing resistance to current drugs is not working; it is not keeping pace with the appearance of new antibiotic resistant germs. Without drastic changes in the science and economics behind antibiotic development and business, this will only be a partial solution to the growing pandemic. However, what we can do now is resort to low-tech, less expensive, and more innovative mitigation measures. These include alternative prevention steps such as more judicious use of antibiotics and increased use of isolation and sanitation measures (where have we heard this before?). Isolation and sanitation defenses against infectious diseases have been part of our disease fighting repertoire since the earliest awareness that contagions can spread through communities. It is an ancient remedy, but still the most effective way to protect ourselves against contagious diseases worldwide. Between 2013-2019, these mitigation measures led to an 18% reduction in US deaths from drug resistant infections. It always is better to prevent than treat.

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Alternative medical treatment and prevention options.  Besides the obvious masks, gloves, sanitation, and quarantine measures, there are other alternative medical (i.e., non-antibiotic) options that can be used to prevent and control drug resistant infection. In fact, these methods are often preferable to using antibiotics, which also deplete the microbiome of “good bacteria” that are critical for good health. These options include vaccines, therapeutic antibodies, and bacteriophages.

From 2000 to 2016, members of the WHO increased the use of the pneumococcal vaccine around the world, thereby decreasing antibiotic use which slowed the development of antibiotic resistant S. pneumoniae saving ~250,000 children from death. Pneumonia caused by secondary infection with other bacteria is a leading cause of complications and death in patients who get the flu. Therefore, the influenza vaccines also are effective tools to decrease the risk of drug-resistant bacterial pneumonias by preventing viral influenza. Since patients with COVID can also develop secondary complications from bacterial pneumonia, COVID vaccination now is another important weapon in the arsenal to prevent the development of antibiotic resistant bacterial lung infection.  

In recent years, healthcare providers also have been increasingly using therapeutic antibodies to treat viral and bacterial infection. For example, antibody therapy is often used to treat recurrent C-diff GI infections, and antibodies to prevent and treat bacterial associated pneumonia also are being developed. So far, we have not seen bacteria develop resistance to antibodies.

Finally, a different and very novel approach to dealing with untreatable bacterial infection has recently taken advantage of bacteriophages, which are viruses that can specifically infect and kill bacteria. There are a few cases in which phage therapy has been used to cure people dying of multidrug-resistant bacterial infections.  According to Pew Charitable Trusts, as of June 2019, 29 non-antibiotic products like therapeutic antibodies and phages were in clinical development and seven were in Phase 3 clinical trials. 

Perhaps BioX is indeed coming to rescue us from the growing pandemic of drug-resistant pathogens.

Notes: 1) By way of disclaimer, your correspondent has consulted for a biotech company that engages in “big genome” research to search for novel antibiotic molecules produced by everyday bacteria and fungi that grow in the soil under your feet. Something like this could be part of the future of novel antibiotic development. 2) In order to have blog updates delivered to your email, see the simple Subscription Instructions here. Remember, you can easily unsubscribe when you want. But, you can’t beat the price.


COVID More Deadly Than Flu For Kids

In the US, nearly six times more kids and teens died from COVID in one year than did from the flu, according to a new analysis of pediatric mortality data. According to CDC data, childhood flu deaths have ranged from 39 to 199 per year since 2004. Meanwhile, in 2021 alone, more than 600 children died from Covid-19, according to an analysis done by researchers at the Harvard University Medical School and at Brigham and Women’s Hospital in Boston.  The analysis used data from the CDC to compare COVID deaths during the pandemic to flu deaths over the last decade (see figure below).

Of the known respiratory viruses, only CoV-2 has ever killed more than 100 US kids in a single month since the middle of the 20th century. Much of that is because we have long had vaccines for other viruses that cause human respiratory disease, but have yet to widely vaccinate children against COVID-19. Hopefully, new vaccines will also render COVID less deadly for kids like vaccines have done for several other respiratory diseases.

Throughout the pandemic, some have argued that COVID poses little health risk to kids aside from a few days of sniffles. Though kids often experience less-severe symptoms than adults, COVID is still a very real risk. An estimated half a million kids now deal with long COVID, a number that experts say is likely an undercount because its myriad symptoms make it tricky to diagnose.

Mortality in kids


A Single Gene Doubles Risk Of COVID Death

“Nothing shocks me. I’m a scientist.” —Indiana Jones

British scientists recently identified an allele, or a version of a gene, that portends lung failure and death in COVID-19 patients. Research recently published in the journal Nature Genetics, found that a poorly studied gene expressed in lungs, designated LZTFL1, has a variant form that does not differ in its coding sequence. That is, the different alleles of the gene express the same protein sequence. They do differ, however, in their non-coding sequences that regulate expression of the gene. When expressed, the gene product prevents cells lining airways and the lungs from responding properly to the CoV-2 virus. The lining of the lung essentially transforms into less specialized cells which affects their normal function.

Previous work had identified a stretch of DNA on human chromosome 3 that doubled the risk of death from COVID. Using an artificial intelligence algorithm to analyze millions of genetic sequences from hundreds of cell types from all parts of the body, the Oxford University Howard Hughes research team honed in on the lung-specific genetic off-on switch. This is another example of what I previously labeled "BioX," the new frontier of bioscience, or post-molecular biology science.

Importantly, the variant allele that augurs a worse lung response to infection does not affect the immune system. Therefore, the it is probable that vaccination remains the best way to protect these at-risk patients. Finding this new allele could also lead to novel therapies to target the pathway affected by this genetic variant to provide targeted treatment for at-risk populations.

The troublesome variant is mostly found in people of South Asian ancestry—some 60% of whom carry the allele—which partly explains the severe devastation from COVID seen in the Indian subcontinent. In contrast, 15% of those with European ancestry and 2% of Afro-Caribbean people carry the risky allele.

It will be interesting to see if this lung-specific gene also affects the course of other respiratory infectious diseases.

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Why Don’t The COVID Vaccines Last Longer?

The FDA just authorized a second booster shot of the Pfizer-BioNTech and Moderna coronavirus vaccines for people over 50 and the CDC has approved it. A second booster has already been approved in the U.K., Sweden, Israel and Denmark.

Why do we need a second booster only months after the first booster, which came only months after most of us received two jabs of either the Pfizer-BioNTech or Moderna mRNA vaccines? Are the vaccines not very good? After all, we get small pox or measles shots that last a lifetime. Others, like the vax for tetanus, last for ~10 years. Why can’t we get a more durable coronavirus vaccine?

The answer is complicated and largely rooted in both viral biology and vaccine immunology.

Viral biology. The simplest answer is that viral mutation can change the molecules the vaccine immune response is trained to recognize, causing vax immunity to decay as viruses mutate. The coronavirus vaccines are directed against the spike protein expressed on the original CoV-2 that first appeared in Wuhan, but that ancestral bug has spawned mutated progeny that look a bit different to the immune system. In other words, viral variants created by “antigenic drift” become less recognizable to the immune system. That is why the vaccines are somewhat less effective against the Omicron variant that carries numerous point mutations in its spike protein. The current vaccines are still pretty effective against current viral variants, but continued antigenic drift along with the selection of variants that can better avoid vaccine immunity will likely require new vaccines in the future.

So, why do we need new flu vaccines every year, and need frequent CoV-2 vaccines, but we don’t similarly need new measles vaccines? Measles, mumps, flu, COVID, and other diseases are caused by viruses, but the different viruses behave quite differently. Viruses carry relatively little genetic material that tends to mutate as they replicate and spread. Some viruses, like flu, also have a “segmented genome” meaning that their genetic material is carried on several separate genetic molecules, making it easy to shuffle their genomes like a deck of cards when different flu strains infect the same animal. Other pathogens carry all their genetic material on a single DNA or RNA molecule making such gene shuffling between strains less likely, but it still happens. Also, the mutation rate of a pathogen’s genome is a function of its replication rate; hence, each time a bug copies its genome, small random errors are inserted into its genetic code. The more the bug replicates, the more mutations will accumulate in its genome and the faster replicating bugs will more rapidly create new variants. Thus, the measles virus is pretty stable since it does not replicate as much as a coronavirus or a flu virus, so it is not surprising that vaccine immunity to measles is much more durable. Smallpox and polioviruses also have relatively low replication rates and vaccine immunity to them also is long-lasting. In contrast, flu and coronaviruses replicate rapidly and pass back and forth between humans and animals. This means that they mutate rapidly and need frequent vaccine updates.

Other vaccines, such as the TB vax, target bacteria not viruses. Bacteria carry larger genomes that are not so changeable, so anti-bacteria vaccines also are pretty long-lasting compared to many anti-viral vaccines.

Yet other vaccines, such as those against tetanus, diphtheria, and pertussis do not even target the pathogen at all, but target toxins produced by the bugs. Vaccinated people produce antibodies that neutralize the toxins and this prevents disease. These vaccines do not forestall infection, they simply prevent the ill effects of the pathogen. Therefore, for these toxoid vaccines, there is no immunological selective pressure to select pathogen variants that can avoid vax immunity. Vaccines against these toxins also tend to be among the longest-lived vaccines.

Vaccine immunology. Vaccines aim to mimic natural immunity we develop to infection with pathogens. By exposing the body to harmless imitations of a pathogen, vaccines create an immune response and immune memory against pathogens, while avoiding the disease caused by the bugs. When an infection does occur in a vaccinated person, a rapid and robust immune response is mounted, first with B-cell generated antibodies that latch onto the invaders and prevent them from spreading and causing illness. Then T-cells secret cytokines that further ramp up the inflammatory response, and other T cells attack pathogen-infected cells. As explained earlier in these pages, antibody responses tend to linger only a few weeks to a few months and then gradually decay. This is good; otherwise your blood serum would be like syrup from all the antibodies against all foreign things you encountered over your lifetime. While antibodies circulating in your blood are good for quickly attacking infections shortly after infection, they do not confer long-term immunity. What confers long-term protection is what are called memory cells. These are a relatively few T and B cells that go dormant after fighting an initial infection or responding to a vaccine, but hang around awaiting a new infection to signal them to quickly roar back to life and mount a vigorous response against their cognate pathogen. This secondary response to a previously seen pathogen is much faster and usually nips the bug in the bud so you don’t even know you were infected.

When we hear that CoV-2 immunity decays only a few months after vaccination, the reports usually refer to declining levels of anti-CoV-2 antibodies, which happens naturally. Such announcements do not take into account your immune memory, which is harder to measure, but which is a better metric of your long term immunity. The problem also is that we simply have not had enough time with the vaccines to know how long their immune memory persists. It seems relevant that a study published in July 2020 reported that people who were infected with SARS in 2003 maintained robust T cell immunity 17 years later. So far, indications are that even though antibody levels fall over time, immunological memory after vaccination also remains robust. This is seen by the continued protection from serious disease and death in vaccinated people with low antibody levels. The vaccines and the immune memory they stimulate are working. How long that memory persists is unknown. Time will tell.

So why are we getting the booster shots? In the face of a raging pandemic caused by a novel pathogen, the cautious approach is to keep antibody levels at a protective level in vaccinated people until we better understand the extent of long-term protection brought on by our immune memory. The boosters, therefore, represent a cautious approach to maintain an effective antibody defense during these still early months of a novel pandemic. We likely will reach a time where world-wide immunity from vaccination and natural infection will give us baseline protection that will render COVID-19 mostly a bothersome disease rather than a life threatening infection. Until then, the boosters are a good idea to help us maintain an effective antibody defense against serious disease.

The natural pathology of measles is instructive here. Even though antibody levels typically decline after most immunizations, antibodies produced after a measles vaccine persist for many years. This happens with some other, but not all, vaccines too, but why? In countries where the measles virus is endemic, repeated infection of vaccinated people keeps the antibody immune response in continual high gear. That is not the case with the flu virus which changes rapidly and bypasses last years shot. Interestingly, measles has been eradicated from the US and Western Europe, so vaccinated people are not continually exposed and re-exposed to the virus and, unlike for those who live in endemic areas, our anti-measles antibody levels decline. Therefore, our long-term protection against the virus is due to our immune memory and not due to antibody levels.

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Updated: Over 65? Roll Up Your Sleeve Again

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The Washington Post just reported that Pfizer and its partner-in-vax, BioNTech, plan to seek emergency authorization for a second CoV-2 booster for those of us 65 and older (you know who you are). It is intended to beef up immunity that wanes a bit a few months following the previous booster.

US data show protection against severe COVID illness is robust after the first booster, but falls somewhat from 91 percent effective in preventing severe illness to 78 percent effective over several months. Still, 78% protection is very good, but given how transmissible Omicron is, and the possible emergence of the Son-of-Omicron, which might be even more infectious and virulent, the idea behind a second booster is to offer people the chance to acquire the greatest level of protection possible. Not a bad idea.

The data that will be submitted to the FDA in support of the 2nd booster probably will include real-world data collected in Israel, which has already rolled out the second shot, and has reduced infections and serious illness in people older than 60. This will likely not be the last CoV-2 vax we will see. Pfizer and BioNTech are also working on a vaccine more effective against all variants and provide more lasting protection. That remains on the horizon, so stay tuned.

For those of us 65 and older, we (at least the males in that demographic) remember draft cards. As we entered our later years, the draft card, if unburned, was replaced in our wallets with our AARP cards, and then accompanied with our Medicare cards. Now we need a new wallet pocket to accommodate our vax card.

On a personal note about cards, your maturing and slowing bloggeur admits favoring a certain grocery store in town because they still card him when he buys his bottles of 80 proof anti-vax remedies.

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Update: Three days after this was first posted, Moderna announced that it also has asked for FDA approval for a second booster. However, they ask that the booster be approved for all adults over 18, and not just for those over 65 as Pfizer/BioNTech have done. This request, like the one submitted by Pfizer/BioNTech is largely based on recent data from Israel

Moderna made a strategic decision to request approval for all adults in order to give the FDA flexibility in deciding which patients would be good candidates for the booster. In other words, they could decide that it also would benefit under 65 and so recommend.

 

 


Son Of Omicron

“A rose is a rose is a rose.” –Gertrude Stein

Omicron is Omicron is Omicron (except when it becomes something different).

Two-plus years into the pandemic, many Americans are ready to declare the COVID crisis over. But, we have been at this juncture before—at the end of the very first surge (remember “flattening the curve?”), and again as Delta faded. Each time, a new virus variant came roaring back. Why should it be different now?

There are reports of two new sons of Omicron circulating in the world. The original Omicron, or BA.1 has spawned BA.2 and BA.3. While little is known about BA.3 at this time, very early indications are that BA.2 represents an even more infectious variant of Omicron, and it is spreading around the world and the US. This variant of a variant seems to be about 30% more infectious than Omicron BA.1. It quickly overtook BA.1 in South Africa and other countries and has caused a second Omicron surge in Denmark. BA.2 has been detected in 74 countries, and has become dominant in at least 10 of them: Bangladesh, Brunei, China, Denmark, Guam, India, Montenegro, Nepal, Pakistan and the Philippines, according to the World Health Organization's weekly epidemiological report.

In the US, BA.2 has been reported in 47 states and accounts for ~4% of all new infections according to the CDC, and it appears to be doubling fast. Samuel Scarpino, director of pathogen surveillance at the Rockefeller Foundation says that if infections double again to 8%, we will be in another exponential growth phase, or the fifth wave of the pandemic. In other words, BA.2 seems to be quickly backfilling the vacuum left as BA.1 peters out.

While BA.2 clearly arose from BA.1, it carries dozens of additional gene changes, making BA.2 as distinct from BA.1 as the Alpha, Beta, Gamma and Delta variants were from each other. This suggests that BA.2 might soon be given its own unique Greek letter designation.

What does BA.2 augur? While vaccination and prior infection still appear to protect fairly well against BA.2, this variant still seems more adept at skirting the immune system then the original Omicron. An early report also shows that vaccine induced antibodies often fail to neutralize BA.2 in tissue culture, and that the virus better replicates than BA.1 in nasal epithelial cell cultures. Nevertheless, those who have been vaccinated and boosted are 74% less likely to become ill from BA.2.

Hopefully, this reduced immunity will still be enough to provide an immunological redoubt against extensive spread of BA.2. The best thing that could happen is that as we become increasingly immunized by vaccine and infection, it might be enough to continue the drop in BA.1 Omicron infections, and check any surge from the new BA.2 variant. This is speculation at this point, and one thing we have learned over the last 2+ years is that the virus does not often respond as expected.

Then there is this: Very preliminary laboratory data hint that BA.2 might cause more severe disease than BA.1, and it appears capable of foiling some of the key weapons we have against COVID-19. In initial lab studies, a Japanese team reported that BA.2 has structural features that might make it as virulent as Delta was. This prediction of increased virulence was supported by hamster infection experiments, but this has yet to be confirmed or refuted in real-life epidemiological studies. Rest assured, those studies are underway, so we will see.

BA.2 also is almost completely resistant to some COVID treatments, such as sotrovimab, a monoclonal antibody therapy that is currently used against Omicron.

Bottom line: During the Spanish flu, as people wearied of the social restrictions designed to prevent the spread of the virus (there were no vaccines or drugs for flu then), many pushed back against the restrictions, which led to premature relaxation of the mandates. Cities like Denver and Philadelphia, which lifted their mandates early paid a hefty price. Other cities like St. Louis, which took a more cautious approach were relatively unscathed. Let’s hope that we are not relaxing and entering a “control phase” too quickly.

What’s ahead of us is not COVID’s end, but might be the start of a phase in which we continue to invest in measures to continue to shrink the virus’s burden. Success in this is not entirely up to us. The virus will have a say too. Our future will depend both on the virus’s continued and unpredictable evolution and on our responses, both immunological and social. The goal is to get ahead of any new variants with wide spread immunity and a growing formulary of antibody and drug treatments, and, yes, this might also require renewed mandates.

A detailed report  looking at past suspected coronavirus pandemics (e.g., the Russian “flu”of 1889, which was probably a coronavirus) published last August in the journal Microbial Biotechnology, suggested plausible scenarios in which elevated levels of COVID-19 deaths could last another five years or longer. This of course depends on what happens to and after BA.2.

It probably is not quite time to relax all mask mandates or let up on the push to vaccinate.

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