vaccines

COVID More Deadly Than Flu For Kids

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

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

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

Mortality in kids


A Single Gene Doubles Risk Of COVID Death

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

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

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

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

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

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

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Why Don’t The COVID Vaccines Last Longer?

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

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

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

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

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

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

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

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

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

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

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

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Updated: Over 65? Roll Up Your Sleeve Again

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

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

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

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

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

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

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

 

 


Son Of Omicron

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Harry Became Severely Disabled After The Vaccine

Does the crowing of a rooster cause the sun to rise?

Harry: A follower of this blog, recently wrote to me about the experience of his senior friend, Harry. With permission, I relay the story here and add some thoughts.

Harry was 80 years old and living a healthy, robust life. He did his own home improvement projects, he was mobile and drove everywhere--he lived an active life. His only health concern was a bit of a problem with high blood pressure (who doesn’t at his age?) that was well controlled with a statin drug.

But, soon after his third shot (booster), his shoulder in the non-injection arm began stiffening. After that, one side of his groin became very painful and the pain migrated to the other side and then began shooting into his legs. Within weeks, he was unable to walk, relying on a walker or wheelchair. He became home-bound. His painful arm is now useless—he needs to hoist it with his other hand to get dressed. Same with both legs. Harry gets by each day on pain meds, but he is reluctant to take a higher dosage to fully control the pain as it makes him too groggy, so he only sleeps an hour or two at night due to the pain, then catnaps in his recliner throughout the day.

This sudden and quick decline began about a month after his booster shot so he was convinced his new maladies were a consequence of the vaccine.

VAERS: Harry’s case is the sort of case that is reported to the CDC’s Vaccine Adverse Effects Reporting Site or VAERS. When someone begins experiencing untoward health problems soon after vaccination they or their doc can easily report it on the VAERS site, which has served as an early warning system for identifying rare side effects of vaccines since 1990. Thousands of people have reported post-vaccination symptoms, and the site is accessible to anyone. Hence, there is a CDC database listing thousands of reports of health problems following COVID vaccination that you can pull up after a few clicks.

The CDC uses this uncorroborated raw anecdotal information to look for patterns that could point to previously unknown side effects of vaccines. This is common practice for all medicines after they have been approved for use. Data from clinical trials that form the basis for approval or rejection of a new medicine or vaccine only include results from ~40,000 test subjects. That is enough to discover very significant and fairly common side effects. But, after the medicine gets on the market, patient data still are collected in order to see if there are serious side effects that only appear in, say, one out of 250,000 people and that would not be found during the clinical trial on just 40,000 subjects. Remember the COX-2 anti-inflammatory drugs that were widely used in the 90s but were pulled because they were found to cause rare, but serious cardiovascular problems? This was found by collecting post-approval data from a few million people who had taken the drugs. Evaluating data collected after a medicine is on the market is referred to as post-market or Phase IV research. This is what the CDC uses the VAERS database for.

The CDC then digs into the raw VAERS reports to make sense of them. They first confirm the reports and then to see if they are just correlations or causative. Scientists look at further health data on the patients, and look for similar recurring problems in other patients. This also means that the raw data reported on the VAERS site are just that—raw. The raw data you can see on the site have not been confirmed or determined to have actually arisen from a vaccine side effect. In fact, the VAERS web site carries this clear disclaimer:

“VAERS reports alone cannot be used to determine if a vaccine caused or contributed to an adverse event or illness. The reports may contain information that is incomplete, inaccurate, coincidental, or unverifiable. In large part, reports to VAERS are voluntary, which means they are subject to biases. This creates specific limitations on how the data can be used scientifically. Data from VAERS reports should always be interpreted with these limitations in mind.”

The task for the CDC then is to separate health complaints that are just coincidental (i.e., that would have happened anyway without the vaccine) from those that are causal (i.e., that were caused by the vaccine). The fact alone that someone vomited a day after being vaccinated cannot be taken as proof that the vaccine caused the vomiting. There is a big difference between correlation, i.e., when two unrelated things happen together, vs causation when one thing leads to the other thing.

But, this is what the vaccine naysayers are doing—they look at the VAERS site and believe that all those raw reports are causative reports showing that the vaccines harm people. In other words, they completely ignore (or do not even read) the CDC disclaimer that the VAERS data are very incomplete and require further investigation before any conclusions can be drawn. When you hear someone on social media, TV, or the radio claim that tens of thousands of people have been seriously hurt by the vaccines, they are basing that claim on an incompetent (and possibly dishonest) use of the raw, uncorroborated VAERS data. I know this because every time I ask someone to back up their claim that the vaccines have injured tens of thousands of people, they eventually cite the VAERS database. When I quiz them further, most clearly have not even looked at the complicated VAERS web site, but are reporting second hand what they have heard elsewhere.

The truth is that few of the VAERS reports have been confirmed to be related to vaccination. Furthermore, the side effects mostly are of the “sore arm” variety, while serious health effects are vanishingly rare. Only about 200 people have actually died from the vaccines. All this compares to the almost 900,000 deaths (and counting) from COVID, and the ~20 million (and counting) cases of long term debilitation from long COVID. Remember, both the deaths and long COVID are prevented by the vaccines.

Back to Harry: Harry developed his debilitating conditions shortly after his third shot and attributed his woes to the vaccine. That is a temporal correlation—the debilitation happened shortly after the vaccine. But, is there anything that proves the vaccine caused Harry’s debilitation?  Well, a deep dive into Harry’s medical condition, like the CDC does into the data in its VAERS data, proves the vaccine did not cause Harry’s condition.

Sadly, a couple of days ago my blog friend told me that recent scans showed a mass on Harry’s lung. He has end-stage lung cancer that has spread to his pelvic bones and shoulder causing severe bone lesions and the pain. He will soon die from untreatable advanced cancer. It seems that Harry has a 50+ history as a smoker. But, he, as well as folks who abuse the VAERS system, totally ignore that kind of history and jump on the less-likely correlation between vaccination and diminishing health as proving a cause and effect relationship between the two. In doing this, people must assume that there could be no other causative factor for any malady that appears shortly after vaccination. Harry himself, ignored his long history of smoking, which is, by far, the leading cause of lung cancer, while the vaccines have been associated with zero cases of cancer.

This is a sad example of the mental gymnastics anti-vaxers resort to in order to confirm their bias against the vaccine. Real data be damned once they see a simple correlation that fits their bias.

Bottom line: Just as the vaccine did not cause Harry’s cancer, the crowing of the rooster does not cause the sun to rise. Both are correlations of events only temporally, not causally related.

Do not buy into the claims that the VAERS shows that people are suffering by the thousands from the vaccines. It is not true.


Has Omicron Rendered Vaccines Ineffective?

Early in the pandemic, when we realized that the CoV-2 virus was quickly producing mutated progeny, some of which were becoming more deadly and transmissible, some (including your humble blogger) warned that viral mutation could feasibly give rise to a variant that ignored immunity to previous iterations of the germ—in other words able to ignore the current vaccines. We have arrived—almost.

The so-called omicron variant partly avoids immunity conferred by the current vaccines (and by prior infection), meaning that we are seeing “break-through” infections in fully and partially  immune people. Popular news sources are running headlines declaring that vaccinated patients with COVID are filling hospital beds, leading many to leap to the conclusion that the vaccines have failed.

But, that is not fully accurate. Many vaccinated people are indeed getting infected with omicron, yet the vaccines are still quite effective, and much better than no vaccine. Let me explain.

First, about two-thirds of Americans are vaccinated—a definite majority of the population. This means that for a hypothetical virus that can fully evade immunity, there are more vaccinated than unvaxed viral “targets” available; meaning more vaccinated than unvaccinated people will be infected. The reality, however, is that the vaccines are still partly protective so that many vaccinated people still catch omicron COVID. Yet, compared to vaxed people, unvaccinated people remain at significantly greater risk of infection, hospitalization, and death. Numbers in my State of Wisconsin, bear this out.

Currently, 69% of the State adult population is vaccinated. According to the latest data* (as of January 15, 2022), out of 100,000 vaccinated people, 1573 caught COVID, 18.5 were hospitalized, and just under 4 died. In contrast, out of 100,000 unvaccinated people, 4,746 got infected, 176 were hospitalized, and 51 died. In other words, many more unvaccinated adults are feeling the effects of COVID, despite representing only 30% of the State population. Clearly, there were breakthrough infections in vaccinated people, but just as clearly, unvaccinated people fared way worse than they would have if they had the shot.

Yet, the headlines persist, proclaiming things like, “Similar numbers of vaccinated and vaccinated people hospitalized for COVID.”   Does this not show that the vaccines are no longer effective? Not at all. Because many more people are vaccinated and partly susceptible to the virus, more and more vaccinated people are showing up with infection, but at a much lower rate than unvaccinated people do. The graphic below illustrates how this works.

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The benefits of the vaccines also are reflected in national and world-wide numbers. The US has one of the lowest vaccination rates among developed countries such as the UK, Canada, Norway, Denmark, etc. And despite omicron’s “milder” nature, which means it kills fewer people but still kills, the COVID death rate in the less vaccinated US is greater than seen in more vaccinated countries, attesting to the efficacy of the shots. Also, new hospital admissions in the US have now reached an all-time high and far exceeding hospitalization rates in better vaccinated countries. Current data from New York State shows that hospitalization among the unvaccinated is 14x higher than among fully vaccinated people.

All of this demonstrates how effective the vaccines remain at preventing infection, hospitalization, and death from omicron-driven COVID. Places with higher vaccination rates, such as the UK and Canada, are not experiencing an increase in base case rates of patients admitted to the ICU or deaths, even with omicron cases skyrocketing. The US is.

Get your Fauci boo boo.

*Note on Wisconsin State data sources: State data mentioned here are from the Wisconsin Department of Health Services, Public Health Madison and Dane County, and the Wisconsin Hospital Association as reported Jan 15, 2022 in the Wisconsin State Journal.


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.