This is a republication of the article “What If COVID Reinfections Wear Down Our Immunity?”, with the title above.
Dr. Anthony Leonardi is a lightning rod for debate. If he’s right, this pandemic poses a greater threat than widely assumed.
The Tyee
Andrew Nikiforuk
7 Nov 2022
Nearly three years into the pandemic, it’s clear early expectations about the behaviour of the coronavirus and its toll on our bodies have proven overly optimistic.
Recall those early days when experts broadly assumed that once we’d withstood an infection our immune systems would adjust and fully resist another reinfection.
And then hopes rose that mass vaccination would provide the path out of the pandemic. Although vaccines did reduce deaths and hospitalizations, the effort failed to produce herd immunity.
But researchers saw further promise in what they called hybrid immunity:
people who had been infected with COVID and then received mRNA vaccines would, it was assumed, develop a formidable protection through raised levels of antibodies (proteins made by the immune system to battle infection).
However variants emerged, capable of evading those antibodies.
Many people who had been vaccinated or already had endured a bout of COVID were experiencing “breakthrough infections.” What could put the brakes on this ever-evolving virus, which can kill, damage organs and linger for months?
The answer from many scientists has been T cells — our bodies’ line of immune defence after antibodies. T cells can spot and attack viruses and even remember previous invaders. As virologist Vincent Racaniello titled one of his articles: “T cells will save us from COVID-19.”
But what if COVID wears down T cells in people who get it, and does so increasingly with each reinfection?
That concern lies at the heart of a rolling, rancorous scientific debate, a lot of it conducted on Twitter.
A person at the centre of the storm, sounding alarms about T cell “dysregulation” since the early days of the pandemic, has been a U.S. immunologist named Anthony Leonardi.
A person at the centre of the storm, sounding alarms about T cell “dysregulation” since the early days of the pandemic, has been a U.S. immunologist named Anthony Leonardi.
By dysregulation Leonardi means three effects of COVID:
- The hyperactivation of many T cells, which can prematurely age them
- The exuberant function of those hyperactivated T cells, which can then cause organ damage
- The exhaustion of those hyperactivated T cells, which implies they aren’t winning the battle against viral proteins they are supposed to defeat.
In other words, argues Leonardi, T cells are becoming hyperactivated by SARS-CoV-2 and are prematurely aging, harming organs, and becoming exhausted trying to rid the body of an immune-evasive virus.
In other words, argues Leonardi, T cells are becoming hyperactivated by SARS-CoV-2 and are prematurely aging, harming organs, and becoming exhausted trying to rid the body of an immune-evasive virus.
If he is right, then no, we cannot assume that T cells will save us — not as thoroughly, at least, as we’ve been led to believe.
If he is right, then no, we cannot assume that T cells will save us — not as thoroughly, at least, as we’ve been led to believe.
Which is why The Tyee decided Anthony Leonardi and his controversial assertions merit a deep dive.
Leonardi’s critics say he paints too dire a picture. Some prominent researchers have accused him of being misguided, their tweeted insults scathing.
Reached by The Tyee, Leonardi did not apologize for the pessimistic edge to his warnings. “Optimism sells and optimism around T-cell memory sold well too.” Rather than practice a “passive conventionalism” that pretends the pandemic is over, he said, public health officials “need to be candid with the public.”
In a recent tweet Leonardi punched back at his most vociferous attackers, saying:
“All I have done is warn people and people find the warnings unpalatable. Not only that, people have given opinions on the trajectory of the virus and the immunology and have been blatantly wrong and are seeking a pound of flesh out of anger.”
To understand why Leonardi is such a lightning rod requires a bit more discussion about how the human immune system works. It is composed of two complementary branches: one directed by antibodies and another mediated by T cells.
T cells are one of two white blood cells that defend the body against foreign invaders. (The other are B cells, which make antibodies.)
The human body supports millions of both T and B cells.
T cells, which originate in bone marrow and then mature in the thymus, perform multiple different roles as the human body matures and ages.
Some T cells, for example, regulate the immune response while others directly bind to and kill cells infected by cancer or viruses. Others survey the body for signs of cancer. And some are simply “naive”: young cells not yet stimulated by an antigen.
Another group known as memory T cells can remember a foreign invader and lead the charge against reinfection.
T cells can also secrete chemicals that help B cells produce antibodies. As a general rule T cells protect against reinfection by providing durable memory of past invaders.
Which is why it’s a big deal if Leonardi is correct in his belief that COVID exhausts, ages and cumulatively wears down the immune system with each infection.
So who is Leonardi and how has he arrived at his convictions?
Leonardi will be the first to say he is no expert on COVID. The soft-voiced Californian, scientist, public health student and water polo player, wrote his PhD thesis on T cells in 2017 while working for the U.S. National Institutes of Health.
Leonardi will be the first to say he is no expert on COVID. The soft-voiced Californian, scientist, public health student and water polo player, wrote his PhD thesis on T cells in 2017 while working for the U.S. National Institutes of Health.
In particular his thesis looked at how T cells can be cultivated and fine-tuned to battle cancer.
He spent years studying healthy and unhealthy T cells.
So he knows a thing or two about how T cells work and how they regulate the immune system. And he has learned that science debates can be as rough and tumble as a water polo game.
He spent years studying healthy and unhealthy T cells.
So he knows a thing or two about how T cells work and how they regulate the immune system. And he has learned that science debates can be as rough and tumble as a water polo game.
And then along came the pandemic.
In the Twitterverse he was one of the first scientists to openly speculate about COVID’s ability to disarm the immune system.
He reasoned that a weakened immune system would have profound implications for the severity of disease, the effectiveness of vaccines and the health of the elderly over the course of the pandemic.
Given nearly five years of work on T cells, Leonardi got a bad feeling while reading a Lancet study that appeared at the beginning of the pandemic.
The study described the unhealthy state of the first patients in Wuhan, China.
Scientists noted that the virus had diminished the patient’s white blood cells — the ones responsible for fighting infection.
Moreover descriptions of the patients suggested that a blood infection might be contributing to shock and death.
That profile looked like a super antigenic infection whereby a particular molecule has set off an extreme immune response.
As a result the immune system began to attack the body, it appeared to Leonardi.
Lots of viruses can set off autoimmune reactions in select populations, but Leonardi thought COVID might have the potential to unsettle the general health of the globe, and even change life expectancy patterns.
Readings on the long-term health impact of the original SARS virus and its cousin MERS also alarmed Leonardi.
These pathogens also disrupted the immune system. MERS, for example, not only infected and killed the cells lining blood walls but T cells as well. Both SARS and MERS could overcome the defences of the immune system, and result in prolonged chronic illness that lasted years.
To Leonardi the ramifications seemed highly significant. It meant that repeated waves of COVID infection might not leave durable or competent memory to fight reinfection or to clear the virus. Repeat infections could get worse over time resulting in more death, organ damage and long-term disability. He started writing letters to school boards and issuing warnings about his conclusions based on his extensive readings.
As Leonardi gained more followers (and detractors) on Twitter, someone created a “Dr. Leonardi’s translate bot.” Its tweets offered translations of the medically esoteric language Leonardi often employs. “Good afternoon humans, powered up and ready to parse some Leonardi,” reported the bot.
Meanwhile Leonardi’s Twitter account went from nothing to more than 70,000 followers, and became a battleground of debate between those who said we were on the downside of the pandemic and taking appropriate measures and those who said our attitudes and policies were dangerously cavalier. The dispute is far from decided.
The uproar reached a fever peak this year when Leonardi speculated that repeated COVID infections could exhaust T cells in people 50 years or older leading to a blunted immune response. (Chronic infections such as HIV or Epstein-Barr virus typically exhaust T cells.)
Leonardi first offered this opinion in August 2020 but it gained currency as reinfections skyrocketed with Omicron.
So, too, did the naysaying. Early this year, Vincent Rajkumar, the editor of Blood Cancer Journal, called the idea “nonsense,” as did U.S. virologists Vincent Racaniello and Amy Rosenfeld.
In January, sociologist and New York Times writer Zeynep Tufecki implied Leonardi was a solo outlier not to be trusted, tweeting:
“Reminder that not every crank is Galileo. Yes, experts can be wrong, even a field can be wrong — we saw with airborne — but challenges involve *groups* of actual working, publishing scientists.”
One of the barbs often tossed at Leonardi by critics is that he is not ensconced in a lab churning out results from experiments, so he doesn’t really belong to the club of researchers seriously trying to crack COVID.
Leonardi is in fact a PhD accredited immunologist currently pursuing a master’s degree in public health.
One high-profile T cell expert among Leonardi’s harshest critics is Duke University scientist Antonio Bertoletti, who often ends his Twitter posts with “Go T Cells Go.”
On Twitter he posted a Nature study on health-care workers claiming that it showed that “exposure [to COVID] broadens T-cell repertoire,” and that there was no problem with exhaustion.
However, the paper only looked at working age people and did not include individuals with long COVID in which chronic and persistent infection inflames the immune system.
And so the debate, like the pandemic, keeps rolling along.
Among Leonardi’s defenders is University of Guelph evolutionary biologist T. Ryan Gregory, who calls him a “brave” voice, sober and brilliant.
“His arguments threatened to undermine the narratives of those people minimizing the pandemic,” Gregory told The Tyee. “If previous infection dampens the immune system and does not strengthen it, it undermines the popular notion that we should let the virus rip.”
Yaneer Bar-Yam, an acclaimed complexity scientist, pandemic expert and director of the World Health Network, agrees.
“The reasons Anthony was so broadly attacked was because he undermined the position that once you’ve been infected, you don’t have to worry again.”
Added Bar-Yam: “He recognized early on that our idea of how the immune system should work with a virus, wasn’t going to be the case with COVID, and he was right.”
Toronto emergency physician Kashif Pirzada has been following Leonardi’s take on COVID and initially didn’t want to believe his predictions on T cells.
“But they have stood the test of time and are now being confirmed by multiple lab studies.”
LEONARDI’S TRACK RECORD
So how valid are Leonardi’s warnings proving to be as research on COVID and immune responses has mounted? Let’s look at six key issues, comparing his statements with what the scientific literature now says or suggests.
For starters, Leonardi warned that the virus undermined and aged the immune system by hyperactivating and exhausting T cells. This overstimulation could in turn damage organs including the heart, brain and kidneys.
He predicted that the pandemic would reduce life expectancy around the world, most harming people aged 50 and over.
He hypothesized that the virus, by harming the immune system, could make people more vulnerable to other infections and cancers.
He speculated that COVID reinfections could be big trouble and should be avoided.
Given the virus’s ability to undermine and age the immune system, he argued that exposing children repeatedly to a virus that impairs the immune system and causes vascular disease and brain shrinkage was bad policy.
And, very early in the pandemic, he argued that herd immunity was wishful thinking and could not be achieved.
- 1.Immunity and exhausted T cells
- 2. Vulnerability related to age
- 3. The ‘Leonardi Effect’ for other pathogens
- 4. Repeated reinfections
- 5. Suffer the children
- 6. Herd immunity
1.Immunity and exhausted T cells
When many experts presented COVID as another flu-like bug that only dispatched the old or unwell, Leonardi posited a radically different take. In 2020 he offered a controversial explanation for the acute disease and organ damage seen in some adults and children with multisystem inflammatory syndrome. He suspected that the virus was hyperstimulating T cells in a number of ways. As a result, the virus was somehow causing the immune system to attack the internal organs.
In 2020 Leonardi wrote the first of several peer-reviewed papers for Frontiers in Immunology and elaborated on his hypothesis, positing that COVID is a “lympho-manipulative pathogen, which… creates a dysfunctional immune response.” In other words the virus damages T cells so severely that COVID not only undermines the immune response for COVID but perhaps other pathogens as well.
Or as the “Dr Leonardi translator bot” put it: “Dr. AJ’s followers understand that T cells are a valuable part of the human immune arsenal, but COVID distorts their function to induce autoimmunity.”
The widely read paper attracted much scorn but also thoughtful attention and calls for further exploration. “If proven right, it may provide some serious jolts to our understanding of immune responses against the SARS-CoV-2 virus and may have some serious implications as far as protection against severe COVID-19 is concerned,” wrote two researchers in the Expert Review of Vaccines in 2022.
So what does the evidence now say?
One of the first hints that COVID could severely mess with the immune system, particularly in severe cases, came in a small study that autopsied 11 people who died of the infection in the summer of 2020. The dead didn’t have so-called germinal centres or places in the spleen and lymph glands where immune cells learn how to mount a long-lasting attack against a biological invader.
In other words the immune system didn’t do what it is supposed to do: successfully defeat the infection.
In 2021 the Journal of Clinical Investigation confirmed that changes in T-cell activation and exhaustion were notable in non-hospitalized patients. Moreover the evidence suggested “a prolonged period of immune dysregulation” after infection.
In November 2021 a group of Italian researchers studied the immunological character of patients recovering from acute disease after hospitalization. They, too, found what Leonardi predicted in 2020: exhausted T cells. In fact the immune system of these patients was not only beat up but suffered a number of other abnormalities that the researchers characterized as a “deranged immune profile.” This immune weakness persisted months after infection but could be restored with the administration of a protein called PD-1 Blockade.
Other scientists found that mild COVID infections can damage the immune system. British and U.S. researchers looked at the state of T cells in patients who had mild, severe and no COVID. What they discovered surprised them and appears counterintuitive. Patients with severe disease appeared to have competent T cell memory to fight off reinfection while mild cases suffered from T cell exhaustion. Exhausted T cells lose their ability to fight off viruses or cancer for that matter.
“People who have severe disease are likely to end up with a good number of memory cells,” said Dr. Pandurangan Vijayanand at the La Jolla Institute for Immunology. “People with milder disease have memory cells, but they seem exhausted and dysfunctional — so they might not be effective for long enough.”
Australian researchers have reported similar intriguing findings after looking at the blood profiles of patients suffering from long COVID and comparing them to healthy controls. They found that “immunological dysfunction persisted for eight months after mild to moderate” infection including indicators of “chronic T cell activation and potentially exhaustion.” They also found that people with long COVID were missing naive T cells, just as Leonardi had warned.
Nobel laureate and Australian immunologist Peter Doherty speculated that these preliminary findings “could reflect a continuing confrontation between persistent virus and immune cells and antibodies that are trying to eliminate it from our bodies, but are not quite succeeding in doing so.”
In 2022 a Chinese study reported that COVID infects and kills T cells contributing to immune dysfunction that favours viral persistence in the body. Two researchers commenting on the study’s implications noted that infected T cells “are not only compromised in their ability to control viral infection, but they can also transport viruses to other parts of the body through the bloodstream, causing the spread of infection, affecting various organs and parts of the body.”
Other prominent immunologists have begun to explore the same territory.
Yale immunologist Akiko Iwasaki has hypothesized that long COVID can be caused by persistent virus infection, viral remnants or an autoimmune reaction. In a recent study that closely looked at the immune systems of 99 patients with long COVID, Iwasaki’s team found exactly what Leonardi had first hypothesized: exhausted T cells that suggested the patients were fighting an active chronic infection. The strength of T-cell exhaustion also corresponded with the reactivation of Epstein-Barr virus in patients.
In many respects people with long COVID closely resemble patients with chronic fatigue syndrome — another form of immune dysregulation brought on by chronic viral infection.
Just last month Swedish researchers confirmed again what Leonardi speculated about two years ago: that people with severe COVID showed long-lasting effects on the immune system for seven to eight months. “The effects on the T cells of the immune system are interesting and mixed,” reported virology professor Marie Larsson in the department of biomedical and clinical sciences at Linköping University, and leader of the study.
“Some of them are still activated long after the disease episode, while others are ‘fatigued’ and cannot function normally. We see similar effects on patients with a chronic HIV infection. The question is: why are these effects still present after so long?” asked Larsson.
The drug company Merck now lists COVID as a major cause of lymphocytopenia: the destruction of white blood cells including T cells.
Last June a trial of a new drug Abatacept, which directly blocks the activation of T cells, prevented deaths in severe COVID patients.
Even Leonardi-slamming Antonio Bertoletti recently offered a more nuanced perspective on T cells and COVID in the publication Immunity than he has on Twitter.
“
It is therefore possible that mechanisms of functional dysregulation in T cells might drive the exacerbated inflammatory events that characterize severe COVID-19 and even some aspects of the prolonged pathology observed in some COVID-19 convalescents.” He does not mention Leonardi.
2. Vulnerability related to age
In July 2020, six months before COVID vaccines became available and long before we learned the virus would evolve to achieve “breakthrough infections” despite vaccines, Leonardi voiced this grim concern:
“
In the worst case scenario, in a situation where this virus sufficiently mutates and perpetuates, I fear a world where most of the aged succumb to complications of COVID.”
Many life expectancy experts said such speculation was ridiculous. (They have since deleted their tweets.) At the time they argued that a virus that resembled flu couldn’t do that kind of population-level damage.
But Leonardi reasoned that COVID caused more death than flu, and he noted that the immune system performed at its peak when people are in their 30s declined when people entered their 50s. COVID’s impact on the elderly was worrisome, he noted in 2020, “because as we age, we don’t produce many, if any, T cells…. You can’t turn the clock back on T cells. Too many challenges, and they exhaust and senesce. Not to mention, the virus will mutate and escape without vaccines.”
Turns out that Leonardi was right again.
A recent and prominent scientific paper confirmed that the age of 50 is indeed an inflection point for COVID deaths. It posited that the loss or narrowing of T cell diversity in response to infections might explain why.
In one recent tweet Leonardi asked his readers, “Do you all have any idea of what you’ve lost. So goodbye to the golden years…. I told you so.”
3. The ‘Leonardi Effect’ for other pathogens
If COVID can dampen an efficient immune response and activate other latent pathogens (everything from shingles or Epstein-Barr virus), could it impair a person’s ability to fight other pathogens as well? Leonardi wondered this in 2020.
In other words, might the pandemic have the unwanted effect of suppressing immune systems generally resulting in greater vulnerability to other viral, bacterial or fungal infections — and as a result accelerating their spread?
Dr. David Joffe, an Australian physician, dubbed the idea the “Leonardi Effect.” He thought it explained “the widespread availability of previous quiescent diseases, more available in lots of flavours.”
The evidence shows the idea is not far-fetched. In fact the scientific literature brims with accounts of viruses and bacteria behaving strangely in the wake of the COVID-19 pandemic. The U.S. Centers for Disease Control and Prevention, for example, noted a recent increase in severe respiratory illness requiring hospitalization in children caused by a normally benign enterovirus. U.S. hospitals have also reported admitting children with an unusual array of two and even three respiratory infections — all at once. They also appear more tenac