Coronavirus news & views

Another Jab’ll Do Ya…

“A virus is a piece of bad news wrapped in a protein coat.”

–Sir Peter Medawar (British Immunologist and Nobel Prize Winner)

Yup, looks like we should roll up our sleeves again this Fall for another COVID booster. The CDC recommends that everyone, 6 months and older receive the updated vaccine that is under development as just reported in the New York Times.

Infections are now rising across the country and this is due to a new, quite different combination of three related CoV-2 variants competing for your attention. They are collectively referred to as FLiRT. The variants are pretty effective at evading prior immune defenses and can spread faster, as we are beginning to see. Across the US COVID-related ER visits increased 15% the week ending June 15, and deaths increased 17% compared to just the previous week. Hospital COVID data are harder to come by since a CDC reporting requirement ended in May.

People “…in general do not understand how much this current virus has mutated,” said Carol Hayes, American College of Nurse-Midwives liaison to the CDC’s Advisory Committee on Immunization Practices. The Advisory Committee unanimously recommended this new round of shots.

But, again? Really?? Booster fatigue and COVID complacency seems to be a growing thing as the deep stress of the 2020-2023 pandemic fades in the review mirror. If we have been boosted a few times, and even had one or two mild COVID infections, is it really necessary to go through all this again?

Yes it is if you want to avoid serious illness. Please read on. True, at this point we all pretty much have some immunity to CoV-2 viruses, but the new boosters that keep rolling out give us important added protection to the novel virus variants that are regularly popping up like in a Whack-a-Mole game. What the boosters do is prevent you from getting serious disease that these new variants can visit on you! Realize that the vast majority of people across all age groups who were hospitalized with serious disease last fall did not get the updated booster for the current virus that was circulating.

In other words, the boosters greatly increase your chance to avoid serious illness and death that are still part of this continuing COVID tableau. Getting a shot is a heck of lot less nettlesome than being hospitalized with a serious respiratory illness. Let’s see….a prick or a ventilator???? It should be a pretty easy choice to make.

What about young people? Why vaccinate them if they don’t get very ill? Even though young adults and children do not get seriously ill as often as older people, don’t be distracted by the difference between relative risk and absolute risk (see a previous discussion on this topic here). Kids and young adults still have a real risk of serious COVID disease even if it does not happen with the frequency as it does for older people. But, that risk is absolutely real. Why chance it at all?

Also, children in particular are especially important spreaders of infectious diseases since they have the most intense social interactions of any demographic group. The intense interaction they have all day in school with classmates greatly increases their chance of infection, which they then bring home to vulnerable older people. It has been shown in epidemiology models and confirmed in real-life studies that preventing spread of infectious diseases in schools is one of the most important tools for protecting the larger population during an epidemic. Being vaccinated reduces kids’ viral burden if they do get infected and reduced viral burden means reduced virus spread. Vaccinated kids help reduce the spread of infectious disease. So, for a couple of reasons, CDC also recommends vaccinating kids this fall.

Get vaccinated.

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 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.

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.

The History Of Vaccine Mandates In The US

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As employers and the President are pushing vaccine mandates because too many have refused them, voices are crying out for their perceived rights saying “my body my choice.” They do not like their bosses or the government telling them to get vaccinated. This is a clash between individual rights and public health measures designed to save lives and to protect the larger community. Who gets to make the key decisions? How far can the government and employers go? Do individual rights trump community safety?

On Sept. 9, Biden announced the most sweeping vaccine requirements in American history, ordering that businesses with 100 or more employees ensure that all their workers are either vaccinated or get tested weekly for the coronavirus. The new rules also require vaccinations for federal workers and for federal contractors, as well as for workers at healthcare facilities that receive funding from Medicare and Medicaid. This will affect about 100 million people.

The authority for these government mandates, claims Biden, is a 1970 federal statute that gives the Secretary of Labor authority to issue a six month Emergency Temporary Standard (ETS) to protect workers from “grave danger from exposure to substances or agents determined to be toxic or physically harmful.” His move has triggered a political and legal battle, with many Republican governors vowing to fight the mandates in court. The mandates raise several new questions regarding this vague statute: Is a virus a “…toxic or physically harmful substance?” Does COVID-19 present a “grave danger?” Has the executive branch exceeded its authority in offering a solution to a problem previously reserved to the states? Do these mandates violate the 14th Amendment by depriving workers of their personal liberties? It is important to note that Biden’s mandates do not actually make vaccines compulsory: The government may levy a fine or forbid a child from attending school, but no American will be forced to get an unwanted jab. This has not always been the case.

There are historical precedents for vaccine mandates and even for forced vaccination.

In February 1991, five Philadelphia children died from measles, a disease that was mostly eradicated in the US, due to vaccination. Measles once sickened millions of kids, each year hospitalizing ~50,000 and killing close to 500 before a successful vaccine was developed in 1963. After that, cases dropped dramatically as all states mandated measles shots for school children. Vaccine hesitancy and resistance were rare because people saw the tangible success of the measles vaccine.

But, in Philadelphia that winter of 1991, the serious cases of measles came from a single source, a church cult that rejected “…all means of healing apart from God’s way.” Church members took no medicines, owned no thermometers, and saw no doctors. Rejecting all birth control, they raised large families in close quarters, a recipe for the measles epidemic, which they cooked. Trying to contain the threat to the rest of the city, officials worked through the courts to gain access to the homes of the congregants and received the authority to vaccinate the children against the wishes of their parents. In this public health emergency, defending the parents’ anti-vax actions was close to impossible. Even the ACLU took a pass.

Vaccine mandates even appeared during the Revolutionary War. George Washington mandated that all his troops be immunized against smallpox, even against their will. He described smallpox to Virginia’s Governor Patrick Henry as “more destructive to an Army in a Natural Way, than the Enemy’s Sword.” As I wrote earlier in these pages, smallpox had doomed the Colonial Army’s assault on Quebec in 1775, and it threatened Washington’s main force. Washington’s mandate proved a brilliant gambit and smallpox largely disappeared from the ranks. Some historians point to the mandate as a major factor in winning the war against the Brits.

During that war, smallpox vaccination entailed a primitive vaccination procedure known as variolation. That involved opening a lesion from an infected person and scraping its contents into the arm of a recipient. It was effective, but the vaccinated person became quite ill for a couple of weeks, and about 3% of them died from the pox. Later, in 1796, the English scientist Edward Jenner discovered a much safer method of immunization using cowpox, a virus similar to smallpox that did not cause significant disease in people. But the new smallpox vaccine got a mixed reception in the US as some resisted it for reasons of personal safety based on the variolation experience. They rationalized, “what good could possibly come from polluting the body with dangerous foreign matter?” Or, “Why challenge the plans of the Creator?” Still, Jenner’s vaccine was a clear improvement over variolation and drove a steady decline in smallpox outbreaks throughout the 19th century. States began passing laws mandating smallpox vaccinations for school children, and some forcibly vaccinated prisoners, paupers, and orphans.

In 1905, the issue of vaccine mandates reached the Supreme Court in the seminal case of Jacobson v. Massachusetts. Henning Jacobson, a Lutheran pastor in Cambridge had defied a city ordinance requiring smallpox vaccinations during an outbreak. He refused to pay a $5 fine so he was arrested. Jacobson posited that “healthy and law-abiding” people like himself (even though he was disobeying the law at the time) posed a minimal danger to the community. He argued that even if his refusal to be vaccinated led to him spreading the smallpox virus, the only victims would be others “who failed or refused to be vaccinated.” In other words, he reasoned that it would be ok to not get the vax because the vaxed would be safe, but wholly ignored the rights to safety of those who were not vaxed. 

It is an argument that is repeated today about the CoV-2 vax. Using modern science that was not available in the early 20^th century, experts have repeatedly refuted this argument, explaining that many people who want the vax cannot be fully vaccinated because they are immunocompromised, or allergic to the vaccine’s contents, or do not have access to the vaccine. Also, we now know that the more RNA viruses, like the coronavirus, are allowed to spread, the greater the chance more deadly variants can appear. Jacobson’s contention that the decision to vaccinate solely belongs to the individual, not to the state, employers, or to medical authorities remains a central tenant of today's anti-vaxers.

The Supreme Court disagreed with Jacobson. The majority opinion, written by Justice John Marshall Harlan, asserted that “the liberty secured by the Constitution does not import an absolute right in each person to be at all times, and in all circumstances, wholly freed from restraint.” Rather, he argued, the Constitution rests upon “the fundamental principle of the social compact…that all shall be governed by certain laws for the protection, safety, prosperity and happiness of the people, and not for the profit, honor or private interests of any one man, family or class of men.” Jacobson had not only broken the law, the court suggested he also had violated the principle upon which a well-ordered society depends. We are not wholly independent the court ruled. The greater good of the community can trump individual rights.

Using Jacobson as precedent, the Supreme Court in 1922, upheld a local ordinance in San Antonio requiring proof of smallpox vaccination for people entering “public schools or other places of education.”  

Later, during World War II, the US military made vaccines mandatory for a host of diseases, such as typhoid, yellow fever and tetanus, and it still mandates certain vaccines for troops in certain deployments. Soon after the war very successful vaccines were developed against several childhood diseases like polio, measles, mumps and chickenpox. Guided by the Supreme Court’s ruling in Jacobson, all 50 states put laws on the books mandating many of these vaccinations for school children. Even today, many school districts and colleges mandate certain vaccines for students and staff. Hospitals, too, often mandate certain vaccines for their staff. Until lately, vaccine mandates have not generated much angst and anger.

Why is this? Perhaps vaccines have done their job too well: Many of them have erased the tragic evidence of why they were needed in the first place. The world no longer deals with small pox, thanks to the vaccine. Almost no one in this country has seen someone ravaged by polio, or a child hospitalized with measles, or who lost his hearing due to chicken pox, all thanks to vaccines. Yet, now with COVID-19, anti-vaccine anxieties have found their way into the political mainstream, especially among conservatives. An estimated 80 million American adults remain unvaccinated against COVID and represent potential factories for producing the next deadly coronavirus variant, which is very preventable.

As I have addressed before in these pages, many factors fuel resistance to the life-saving shots, including doubts about their quick development and their possible long-term effects. But a growing distrust of professional expertise, including medical science, has also played a role, which is unwarranted. Who are you going to believe, a medical scientist like me with nothing to gain in the debate (except the safety of my friends, family, and self), or someone who read a web post from folks who are selling nostrums they claim will protect you, like Dr. Steve Hotze, or from one of America’s Frontline Doctors whose web site claimed that gynecological problems were caused by having sex with demons? Do you jump on the side of those who tout that their individual freedoms have been abridged, but who do not consider the freedoms from disease of the greater community, and whom the courts already have decided against?

Almost 300 years ago, Benjamin Franklin struggled over whether to have his sons variolated against smallpox. In his “Autobiography,” he worried that well-meaning people were tragically misjudging the calculus between the risks and benefits of the procedure, as he had once done, with a tragic result. He wrote, “In 1736, I lost one of my sons, a fine boy of four years old, by the smallpox….I long regretted bitterly and still regret that I had not given it to him by inoculation. This I mention for the sake of the parents who omit that operation, on the supposition that they should never forgive themselves if a child died under it; my example showing that the regret may be the same either way, and that, therefore, the safer should be chosen.”

Don’t Forget The Drugs: An Update

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

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

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

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

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

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

Get the vax.

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HIV And Coronaviruses: A Bad Combo

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

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

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

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

Delta: It is always better to prevent than to treat!

Previously in these pages I wrote that it was important to vaccinate kids as well as all adults, even though kids generally do not get very sick from CoV-2 infection. I also opined that it was important to get vaccines to third-world Asian and African countries that lack them. I further lamented the inability of one of the world’s leading vaccine manufacturing countries, India, to vaccinate its own population. The common reason for these exhortations in separate blog posts was the need to suppress the spread of the virus as much as possible, which I submit is just as important as protecting people from COVID-19 disease. We need to try to suppress the emergence of new viral variants since they could be more deadly and even cause significant disease in younger, healthier people. Such variants could also learn to ignore vaccine immunity and set us back to square one fighting the pandemic. As viruses replicate, they make random genetic mistakes in copying themselves. By chance, some of those mistakes can potentially make the virus more infectious or deadly. It is crucial to slow virus spread as much as possible with vaccines and social distancing measures in order to reduce the chance of such new, more deadly variants developing.

At this juncture, let me introduce the Delta variant and say, “I told you.”

Delta is more infectious. The Delta variant was first detected in October 2020 in India during that country’s long, strict shutdown. As I earlier reported, it then exploded across the country after those restrictions were lifted the following March in time for huge national  election rallies and a major religious holiday that brought hordes of Hindu worshippers to the banks of the Ganges. Delta quickly overtook previous iterations of the virus in India and has now spread to more than 100 countries, meaning that it has a significant advantage over other variants in the race to infect people. Delta was first detected in the U.S. in March and by mid-July accounted for 83% of all U.S. cases. As of the end of July, the Delta variant had caused at least 92% of the new infections in the United States, according to covariants.org, a research firm in Bern, Switzerland. The Johns Hopkins University tracker reported that daily US COVID-19 cases rose from just over 13,000 at the end of June to almost 131,000 in mid-August. almost all of which are due to Delta.

Delta has kept some of the most successful mutations found in earlier variants that first appeared in England and South Africa, but it also contains new genetic changes that, together, enable it to spread faster. In an earlier blog post, I talked about the R₀ value, or the measure of a virus’s ability to spread. For seasonal flu, R₀ is about 2, meaning that on average, an infected person will infect two others. For the original SARS-CoV-2, R₀ was ~4, which means that on average, an infected person infected four others. Now, according to the CDC, the Delta variant has an R₀ of 8-9 meaning that an infected person will, on average, pass the virus to 8-9 others. Therefore, Delta is about 4-times as contagious as the virus first identified in Wuhan. Clearly, viral variants are trending toward increased ability to spread. We can expect that the virus is not finished evolving and could become even more contagious.

How do the mutations make Delta more infectious? Research now shows that Delta has an incubation period of four days, which is the time it takes to begin spreading after infection. The original virus incubated for six days. Thus, people are becoming contagious sooner. Also, people infected with Delta are found to carry >1200-times the viral load compared to prior virus iterations. People carrying more virus pump more virus into their environment making them more infectious. With earlier variants, conventional wisdom held that you needed to be around an infected person for about 15 minutes in order to catch an infectious load of the virus. That wisdom now holds that one only needs to be in the presence of a Delta-infected person for 1-5 minutes before becoming infected. 

Some vaccinated people can also be infected and spread Delta. With any viral vaccine, the hope is that the vax will not only prevent disease, but also retard the spread of the virus, ideally reducing its R₀ value to <1. When an infected person only spreads the virus to fewer than one other person, the epidemic/pandemic would be nipped in the bud. So far, the vaccines have done a pretty good job reducing the spread of the virus; however, the Washington Post recently obtained an internal CDC document  citing a combination of recently obtained data from outbreak investigations and other studies showing that vaccinated individuals can sometimes be infected with Delta and transmit the virus as easily as those who are unvaccinated.

The data showed that vaccinated people infected with Delta sometimes had viral loads similar to infected and unvaccinated people. These data came from a July 4 outbreak in Provincetown, MA where 127 vaccinated people were infected with the Delta variant in the superspreader outbreak and they appeared to carry as much virus as unvaccinated people who also became infected. Vaccinated people with breakthrough infections only showed mild symptoms including cough, headache, sore throat, or fever. Four were hospitalized and no deaths were reported. On July 3, the day before the event, the Massachusetts Department of Public Health reported a two-week average of zero COVID-19 cases per 100,000 residents. By July 17, after the superspreader event, that number rose to 177 daily cases per 100,000. The ability of Delta to infect some vaccinated people and spread from them has been further confirmed by research published by Public Health England.

This is the reason why the CDC just recommended that all people, including vaccinated people, again don face masks when in public indoor spaces. Fortunately, the virus does not cause significant disease in this population meaning that the vaccines still protect from serious disease.

So far.

Vaccine efficacy. The CDC reports that even though the current vaccines do not fully protect against breakthrough infections, such infections only occur in about 0.1% of the 140 million vaccinated people and they still reduce the risk of severe disease 10-fold and they still reduce the risk of breakthrough infection three-fold. That is the good news.

The disappointing news is that real-world studies of vaccine efficacy indicates that the current vaccines have become somewhat less effective at preventing infection from the Delta variant than they were against earlier versions of the virus. One way to measure a virus’s ability to evade vaccines is to take antibodies from vaccinated patients and combine them with the virus in the lab, then measure how much of the virus is neutralized, or prevented from infecting cultured human cells. Dr. Akiko Iwasaki, an immunologist at Yale University, and colleagues used this technique to compare how well different coronavirus variants can withstand vaccine immunity. Iwasaki found that Delta was better at evading neutralization than earlier versions of the virus. More concerning, however, is that they also found that two other variants, Beta, first found in South Africa, and Gamma, from Brazil, were even more adept at avoiding antibody neutralization. It appears that viral mutations are being gradually selected for their ability to bypass the immunity conferred by the current vaccines. That trend is worrisome.

Other reports coming in now indicate that the early vaccine efficacy of ~95% has dropped to 70-80%. This value represents the protection a vaccinated person can expect when exposed to the virus. The increase in the number of vaccinated people who become infected suggests either that that their immunity is fading over time, or that, as mentioned above, Delta is learning how to avoid vaccine immunity. Or both. As I wrote earlier, the initial antibody response to a vaccine naturally decays over time but immunity is usually sustained via memory immune cells which serve as quick-response sentinels to subsequent exposure to the pathogen. Memory immune cells were found in another study to be robust six months following mRNA vaccination and able to efficiently respond to the known viral variants. This indicates that long-term immunity remains strong and suggests that Delta has begun to learn how to avoid vaccine immunity.

Stay tuned.

Severity of Delta disease. In India, the Delta variant caused more severe and faster illness than earlier variants, and now in the US, Delta also seems to more readily cause significant disease and do so in younger people. Currently, teens 16-17 years old are now seeing the highest rate of COVID-19 cases among all age groups in the US. That is up from a rate of 48 per 100,000 on July 10, to 200 per 100,000 people on August 14. As Delta now accounts for >95% of new COVID-19 infections and hospitalizations in the US, doctors on the front lines are reporting anecdotally that unvaccinated people in their 20s and 30s are becoming more critically ill, and faster than they did before Delta arrived. Studies in a handful of other countries confirm that Delta causes more severe disease in younger people. For example, a study in Scotland reported that patients infected with Delta ran twice the risk of needing hospitalization. Researchers in Canada confirmed this and reported that young people infected with Delta had a 4-fold increased risk of requiring ICU care and double the risk of death. Other studies out of Singapore and India further corroborated these observations.

The emergence and rise of a viral variant with enhanced infectability and increased morbidity in younger, healthier patients is a prediction I and others have made in the face of the continuing global spread of this virus.

I told you so.

What does it all mean? Breakthrough infections we are now seeing in vaccinated people could be especially worrisome. The immunity conferred by vaccination usually retards viral spread and reduced viral replication scales down the development of new, more virulent viral variants. But, when immunized people do get infected and the virus grows in their bodies, the virus has to fight the vaccine immunity to eventually develop new mutations that allow the virus to simply brush off vaccine immunity. With Delta, we might be seeing the early stage of this viral evolution in vaxed people.

Vaccine resistance by the virus can be prevented by a rapid and robust vaccination effort as a team of European scientists recently reported in the journal Nature. It is imperative to get vaccines to countries that remain largely unvaccinated, and we need to get the naysayers in countries with more robust vaccine efforts to understand how their actions perpetuate the pandemic and promote the development of dangerous variants. There is no rational reason for the vast majority of people to refuse vaccination. The ongoing pandemic is totally preventable.

Vaccines have eradicated small pox in the world and polio from most developed countries. Measles is now extremely rare in the US thanks to vaccines. Go to an old cemetery and count the number of headstones belonging to children who died before 1950, then compare that to the number of kids who died after 1950. That striking difference is a powerful testimony to the effectiveness of vaccines as preventive medicine.

It is always better to prevent than to treat!

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