Coronavirus news & views

While SARS-CoV-2 And Our Immune Systems Do A Dance, We Get Re-Infected

Note: Artificial intelligence wrote nary a word of the following article, which was fully composed by the natural intelligence of a certain human.

Your sometimes humble blogger remembers how immunology science first beguiled him. It was during senior year in high school in the Virginia suburbs of Washington, DC. More specifically it was during a lunch break while working at a People’s Drug Store that had a lunch counter. Your then nascent blogger grabbed the recent issue of Scientific American from the magazine rack and opened it to an article that was way above his green scientific understanding but, he, nevertheless, gleaned from the article that the immune system could make antibodies to just about any molecule in the universe, even ones newly created in a lab that the universe had never seen. Amazing!

Your immune system would also make antibodies against the cells and tissues of your best friend and everyone else in the world, and vice versa, but you and your best friend, et al., would not make antibodies against the same cells and molecules in your own bodies! What?

“Holy cow!” I thought. How in the world can the immune system do all that? How can it respond to something the world had never seen and secern friend from foe? At that moment, at that lunch counter over a burger, Coke and an article I barely understood, an immunologist was made. And I did indeed go on to earn a PhD in immunology and I indeed have studied how the immune system recognizes viruses and have done vaccine research. What a pivotal lunch break that was for me.

The question about antibody discrimination clearly fascinated me. That mystery has been solved and a few Nobel prizes awarded for its elegant solution, but related spin-off questions about how antibodies protect us keep coming up in different ways. It did so most recently during the COVID pandemic. Why weren’t the antibodies we generated via vaccination or via natural infection more protective against subsequent infection? In a twist in the plot of biology, it turns out that we have learned that the answers to these questions center around a complicated dance performed between both the virus and immune biological systems.

Biology is so doggone interesting!!

COVID Vaccine generated immunity: The several vaccines we now have against the SARS-CoV-2 virus are effective and provide examples of how vaccines are very good at getting the immune system to respond to what it detects as foreign invaders. But the vaccines are just designed to tell our immune systems to make antibodies against just a very small fragment of the spike protein. In contrast, the virus is constructed of several large proteins each of which has many different regions that the immune system can separately recognize as foreign. In other words, if the virus is like a brick building, your system theoretically can make a different antibody that specifically recognizes each brick of the building. So, the vaccine is like exposing the immune system to about 2-3 bricks of the whole building and trusting the resulting immune response against those few bricks to bring the whole building down.

The immune system was very good in generating antibodies to a small portion of the virus, yet many vaccinated people still were infected and caught COVID. Does that mean, as many vax naysayers claim that the vaccines were ineffective? Not at all, as I have discussed here before. While the CoV-2 vaccines did a good job at protecting against serious disease and death they were not very good at preventing the spread of the virus. These vaccines effectively generated a systemic immune response, meaning that you had anti-viral antibodies circulating in your blood, which did do a very good job preventing serious disease once the virus got inside you. But, it still got inside. You still got infected and got mildly sick.

We now know that the virus enters via mucous membranes in your nose, sinuses, mouth, throat and eyes. It has to first cross mucous membranes in order to infect you and that is where it needs to be stopped in order to actually prevent infection and further spread to others. The problem is that mucosal immunity is caused by a different type of antibody than what circulates in the blood and by what is generated by a typical vaccine that is given by an injection in the arm. To generate mucosal immunity, you need a vaccine that you spray in your mouth or nose, which then should generate the type of antibodies that provide mucosal protection and better protect you from infection via that route and better prevent the virus from spreading through a population.

At the beginning of the pandemic, we were faced with a brand new pathogen for which we knew nothing about how it behaved or how it infected and spread between people. At that point, we reasonably chose to quickly make the most common type of vaccine--a shot. While it didn’t fully protect against getting infected, it nevertheless was very effective at protecting against serious disease. So, it did a good job. Current efforts are underway to develop a mucosal vaccine. But, we must also deal with other complications we have learned about the dance between the virus and the immune system to make sure that vaccine will be maximally effective at preventing infection. Read on.

“Natural” COVID immunity: As it became clear that vaccinated people were still getting infected, the vaccine dissenters and dissemblers proclaimed loudly, and still do, that the vaxes failed miserably. They ignored the survival data and only focused on the infection data. They then began touting “natural immunity,” which is the immunity one usually gains after being naturally infected. But, that can be uncertain given the fact that the route of infection and the dose of virus can vary wildly and confer different levels of protection, as I reported earlier. Plus, with natural infection, one runs the risk of serious disease and death from the disease.

Then, to the chagrin of the “natural immunity” enthusiasts it turned out that they also were getting re-infected! And this re-infection occurs despite the fact that natural immunity occurs after infection across the mucous membranes that should, as discussed above, generate an immune response that would stop an infection! This is the dance.

Therefore, we now know that neither vaccine immunity, nor infection immunity fully protects against future infection with the CoV-2 virus (there is partial protection, but I won’t go into that here).

As we learned as recently as last April, from a Harvard study published in the journal Science, despite the fact that a natural infection presents the immune system with the full viral “building and all its bricks” potentially recognizable by antibodies, it turns out that only a few of the “bricks” are in fact actively “seen” at any time by the immune system.

This immuno-dominance of a small part of a larger pathogen that has thousands of sites or bricks the immune system can recognize is not unusual. It is like a large building consisting of thousands of bricks, but having a very attractive window that draws your attention. While you know an entire building is there, your attention is mostly drawn to the window. So can the focus of the immune system be preferentially drawn to a small part of a larger edifice. The immune system is perfectly capable of seeing the rest of the “building,” but it prefers to direct its attention to a small part of it. However, if you take away the part it prefers to focus on, the immune system will easily recognize something else. This immuno-dominance in what the immune system “sees” has several causes that are way too complicated to go into here without writing a textbook (an interested reader might try Paul’s Fundamental Immunology. My rather old edition of that book runs about 1500 pages!). Suffice it to just know that this sort of immuno-dominance often happens where only a small part of a large pathogen is preferentially recognized by the immune system.

Thus, the immunity developed after a natural infection is mostly only directed at a small portion of the virus, much like the antibody response after vaccination with just a small part of the virus. The natural immune response, like the vaccine immune response, is robust and effective, yet both are only directed against a very small portion of a big pathogen, and both are very leaky in that one can still get infected again! What gives?

Mutation gives.

How the virus escapes immunity: The SARS-CoV-2 virus is highly mutable unlike the other viruses like polio and small pox we vaccinate against and maintain long term immunity against. Thus, the virus quickly mutated, or changed, the “bricks” against which the vaccines were made rendering the immune response less and less effective over time as new viral iterations appeared. That is why the many boosters we got were necessary to keep vaccination immunity up with viral changes.

And that also is how someone who became immune after natural infection also became re-infected. The virus did a two-step and mutated the small region recognized by the immune system. It was pretty easy for the virus to do since it only had to change a couple of “bricks” in its facade that the antibodies were mostly attacking. That means that upon re-infection with a slightly mutated virus, the immune systems have to be re-educated to recognize a new intruder, and that takes time, which allows a new infection to settle in. Thus, in this dance, the gentleman virus leads and the dame immune system follows.

New vaccines continue to be developed that scientists hope will solve these problems unique to SARS-CoV-2. Most of the new vaccines are being built on the mRNA platform, but using novel approaches to 1) develop vaccines that can be given as a nasal spray in order to generate the mucosal immunity that hopefully would be more effective at actually preventing COVID. If this works, it might even be possible to hinder COVID spread. 2) But in order to block CoV-2 spread on a population level, we need to find other regions of the virus that are not so highly mutable. These would conceivably be regions of COVID proteins critical for viral function that tolerate little change in structure because that change would destroy the proteins' critical function and essentially kill the virus. Alternatively, new vaccines could incorporate multiple "bricksl" from different regions of the edifice assuming that it would be nigh impossible for all those sites to simultaneously mutate. If such regions are accessible to the immune system, then the resulting immunity would be expected to be impervious to viral mutation, thus ending the dance on a sour note.

It is even possible that such a vaccine could protect against a wide range of coronaviruses, thereby preventing future health problems arising from new coronaviruses. Remember SARS that also popped up in China a couple of decades ago? That virus has some genome similarity to the virus that caused the COVID pandemic, and both are distantly related to the virus that caused MERS that arose in the Middle East. If a pan-coronavirus vaccine can be developed, it could feasibly prevent many future epidemics and pandemics.

We shall see.

This is all part of a new biology that I earlier dubbed BioX. Biology is so doggone interesting!!

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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.

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.

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.

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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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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Lions And Tigers And…Deer? Oh My!

First it was bats and humans, then domestic cats and dogs, farmed mink, and big zoo cats; now gorillas, hippos, and wild deer that have been infected by the SARS-CoV-2 (CoV-2 for short) virus. Many of these animals have become ill and several have died of COVID-19, most recently three snow leopards in South Dakota and Nebraska zoos. This is quite a wanton virus.

Of course, before CoV-2 and COVID-19 were known to the world, we knew that bats, humans and a few other animals, notably civets and even camels, were ready hosts of several different strains of “‘rona” viruses. We also knew that domesticated animals are also susceptible to their own coronavirus diseases—in fact veterinary coronavirus vaccines have been in use for years. Humans are known hosts for several coronaviruses, including those that cause the common cold, as well as the viruses that cause SARS, MERS, and now COVID-19. And we know that humans often catch these germs from bats and other intermediate hosts as diverse as civets and camels. After we genetically identified CoV-2 and were able to follow its spread, we quickly noticed that domestic pets also could be infected. This was closely followed with news that seven big cats at the Bronx zoo had become infected, and that mink farms across Europe were hotbeds for CoV-2 spread between humans and the animals and back. In fact, mink farms became such a hotbed of CoV-2 zoonotic spread that a couple of European countries completely shut down mink farming and culled all their animals. Several US states have also sharply curtailed mink farming. PETA probably applauds.

More recently two snow leopards at the Lincoln, NE children’s zoo and one in a zoo in South Dakota died from COVID. The Lincoln zoo also had two infected Sumatran tigers who recovered after being treated with steroids and antibiotics to prevent secondary infections and pneumonia. How the animals were infected is uncertain, but the most likely scenario is that they caught the virus from a caretaker. The problem is, none of the caretakers tested positive for the virus. Bats? Something else?

Since April 2020, when a tiger tested positive at the Bronx Zoo, dozens of other animals in zoos around the world have caught COVID. This month, the Denver Zoo reported the first coronavirus cases in hyenas, and the St. Louis Zoo found eight positive cases among its big cats, including two snow leopards. Abroad, the virus has killed a lion in India and two tiger cubs in Pakistan. Big cats seem especially susceptible since three other snow leopards at the Louisville Zoo were infected last December, and another snow leopard tested positive at the San Diego Zoo in July. The virus doesn’t just infect our fuzzy friends either; two hippos, named Imani and Hermien, at a zoo in Antwerp recently tested positive for COVID-19. Zoo keepers were first alerted to a potential problem when they noticed that the colossi had “runny noses.”  One reckons that a runny nose for a hippo is a big deal. One also wonders who gets to dab that nasal maw in order to test for the virus.

In fact, zoo and domestic animal infections have become so prevalent that an animal COVID vaccine developed by Zoetis, a NJ-based veterinary pharma company and former Pfizer subsidiary, has been authorized by the USDA for experimental use. The Cincinnati Zoo, for one, has vaccinated  80 animals, from giraffes to apes, against COVID.

Deer too. Oh my! It is one thing for zoo animals to acquire COVID—their captivity makes it easy to limit their interaction with other animals and humans to prevent spread of contagions, and they seldom complain that their rights are being infringed when they are quarantined. However, COVID in wild animals is a different story, as we have seen with bats and how easily they transmit the virus to humans. Scientists now have evidence that CoV-2 also readily propagates in white-tailed deer. In fact, the virus is already widespread in cervids across the US, which likely has significant implications for the long-term course of this pandemic.

In September of last year, genetic analysis of the gene that encodes the ACE2 protein (i.e., the viral receptors expressed on many cells in the body) in many different animal species suggested that CoV-2 could easily infect deer (and several other animals too). A survey of white-tailed deer in the Northeast and Midwest found that 40% had antibodies against the CoV-2 virus, indicating prior exposure. Between April and December 2020, veterinarians at Penn State found active CoV-2 infections in ~30% of deer tested across Iowa. Then during the winter COVID surge in humans from Nov. 23, 2020, to Jan. 10 of this year, ~80% of the tested deer were infected. The prevalence of the virus in deer was 50 to 100 times greater than in Iowa residents at the time (and the deer reportedly did not wear face masks). The study, published about two months ago, indicates that white-tailed deer have become a permanent reservoir for CoV-2. While it is not fully understood how the virus entered the deer population, genetic sequence analysis of nearly 100 viral samples found that the variants circulating in deer matched the variants circulating in people. This suggests that deer caught the virus from people multiple times in Iowa alone. How that happens is not known since people usually do not have close contact with live deer. More concerning is whether viral variants arising in deer readily pass back to people.

Bottom line. Clearly, a lot of different animal species can catch Cov-2 and spread it. It is clear that people can spread coronaviruses to pets and other animals, but the FDA says that the reverse, animal-to-human virus transmission, is not common. But, it clearly happens as we have seen with this pandemic, and with many other viruses that cause SARS, MERS, AIDS, Ebola, flu, etc., that spread from animals to humans. The prevalence of CoV-2 infection in so many species of mammals, especially in animals that have close contact with humans, suggests that several animal species, not just bats, can serve as permanent reservoirs for the virus and the jump to humans is something that can happen over and over. This is not unprecedented. It is what we see with influenza, which is carried back and forth between the Northern and Southern hemispheres with migratory birds, in which different flu viruses shuffle their genomes to create the new strains of flu for which we have to vaccinate against each year. This animal reservoir for flu makes it next to impossible to eliminate influenza, and similar animal hosts for CoV-2 likely would make it nigh impossible to eliminate COVID too. I raised this specter some months ago in these pages when reporting that pet dogs and cats can carry the virus. Our furry friends represent a viral reservoir that is in even closer contact with people than bats, deer, and fortunately, hippos and leopards.

We also have to be worried about the CoV-2 virus mutating in the different animal species that harbor and spread it. We know that happens in bats, which makes it almost certain that new strains of the virus will arise in deer and dogs too. We have already seen this on mink farms in the Netherlands and Poland. Farmworkers passed the virus to captive animals where it spread, mutated, and then spilled back into humans. In fact, zoonotic transmission from animals to humans probably happens thousands of times a year. Researchers from the EcoHealth Alliance and from Duke-NUS Medical School in Singapore, estimate that each year many people are newly infected with SARS-related coronaviruses. Many may get sick, but there are many reasons why most of these infections never grow into noticeable outbreaks (for example see my earlier blog post about unusual respiratory infection clusters in China and Los Angeles just before COVID). The researchers also created a detailed map of Asian habitats of 23 bat species known to harbor SARS-related coronaviruses then overlaid it with data on where humans live to create a map of potential infection hot spots. They found that close to 500 million people live in areas where bat-to-human transfer is likely, and this risk is highest in southern China, Vietnam, Cambodia, and Indonesia. Other surveys done before COVID-19 showed that many people in Southeast Asia harbor antibodies against other SARS-related coronaviruses. Blending these data with data on how often people encounter bats and how long antibodies remain in the blood, the researchers calculated that ~400,000 undetected human infections with these viruses occur each year across the region.

That is just for bat-to-human transfer in Southern Asia. It now looks like we will have to also concern ourselves with zoonotic coronavirus transfer from Buddy and Bambi too.

For this reason, researchers are working to develop a universal coronavirus vaccine that will be effective against most viral strains and variants. I will write about this soon. Stay tuned.

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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.