Article: The people with hidden immunity against Covid-19

While the latest research suggests that antibodies against Covid-19 could be lost in just three months, a new hope has appeared on the horizon: the enigmatic T cell.

By Zaria Gorvett

19th July 2020

(Image credit: Getty Images)

A scientist testing a Covid-19 vaccine on some cells (Credit: Getty Images)

The clues have been mounting for a while. First, scientists discovered patients who had recovered from infection with Covid-19, but mysteriously didn’t have any antibodies against it. Next it emerged that this might be the case for a significant number of people. Then came the finding that many of those who do develop antibodies seem to lose them again after just a few months.

In short, though antibodies have proved invaluable for tracking the spread of the pandemic, they might not have the leading role in immunity that we once thought. If we are going to acquire long-term protection, it looks increasingly like it might have to come from somewhere else.  

But while the world has been preoccupied with antibodies, researchers have started to realise that there might be another form of immunity – one which, in some cases, has been lurking undetected in the body for years. An enigmatic type of white blood cell is gaining prominence. And though it hasn’t previously featured heavily in the public consciousness, it may well prove to be crucial in our fight against Covid-19. This could be the T cell’s big moment.

When researchers tested blood samples taken years before the pandemic started, they found T cells which were specifically tailored to detect proteins on the surface of Covid-19

T cells are a kind of immune cell, whose main purpose is to identify and kill invading pathogens or infected cells. It does this using proteins on its surface, which can bind to proteins on the surface of these imposters. Each T cell is highly specific – there are trillions of possible versions of these surface proteins, which can each recognise a different target. Because T cells can hang around in the blood for years after an infection, they also contribute to the immune system’s “long-term memory” and allow it to mount a faster and more effective response when it’s exposed to an old foe.  

Several studies have shown that people infected with Covid-19 tend to have T cells that can target the virus, regardless of whether they have experienced symptoms. So far, so normal. But scientists have also recently discovered that some people can test negative for antibodies against Covid-19 and positive for T cells that can identify the virus. This has led to suspicions that some level of immunity against the disease might be twice as common as was previously thought.

Most bizarrely of all, when researchers tested blood samples taken years before the pandemic started, they found T cells which were specifically tailored to detect proteins on the surface of Covid-19. This suggests that some people already had a pre-existing degree of resistance against the virus before it ever infected a human. And it appears to be surprisingly prevalent: 40-60% of unexposed individuals had these cells.Aids is primarily a disease of T cells, which are systematically eliminated by HIV in patients who are infected by the virus (Credit: Martin Keene/PA)

Aids is primarily a disease of T cells, which are systematically eliminated by HIV in patients who are infected by the virus (Credit: Martin Keene/PA)

It looks increasingly like T cells might be a secret source of immunity to Covid-19.

The central role of T cells could also help to explain some of the quirks that have so far eluded understanding – from the dramatic escalation in risk that people face from the virus as they get older, to the mysterious discovery that it can destroy the spleen.

Deciphering the importance of T cells isn’t just a matter of academic curiosity. If scientists know which aspects of the immune system are the most important, they can direct their efforts to make vaccines and treatments that work.

How immunity unfolds

Most people probably haven’t thought about T cells, or T lymphocytes as they are also known, since school, but to see just how crucial they are for immunity, we can look to late-stage Aids. The persistent fevers. The sores. The fatigue. The weight loss. The rare cancers. The normally harmless microbes, such as the fungus Candida albicans – usually found on the skin – which start to take over the body.

Over the course of months or years, HIV enacts a kind of T cell genocide, in which it hunts them down, gets inside them and systematically makes them commit suicide. “It wipes out a large fraction of them,” says Adrian Hayday, an immunology professor at King’s College London and group leader at the Francis Crick Institute. “And so that really emphasises how incredibly important these cells are – and that antibodies alone are not going to get you through.”

During a normal immune response – to, let’s say, a flu virus – the first line of defence is the innate immune system, which involves white blood cells and chemical signals that raise the alarm. This initiates the production of antibodies, which kick in a few weeks later.

“And in parallel with that, starting out about four or five days after infection, you begin to see T cells getting activated, and indications they are specifically recognising cells infected with the virus,” says Hayday. These unlucky cells are then dispatched quickly and brutally – either directly by the T cells themselves, or by other parts of the immune system they recruit to do the unpleasant task for them – before the virus has a chance to turn them into factories that churn out more copies of itself. There's growing evidence that some people might have a hidden reservoir of protection from Covid-19 (Credit: Getty Images)

There’s growing evidence that some people might have a hidden reservoir of protection from Covid-19 (Credit: Getty Images)

The good and bad news

So, what do we know about T cells and Covid-19?

“Looking at Covid-19 patients – but also I’m happy to say, looking at individuals who have been infected but did not need hospitalisation – it’s absolutely clear that there are T cell responses,” says Hayday. “And almost certainly this is very good news for those who are interested in vaccines, because clearly we’re capable of making antibodies and making T cells that see the virus. That’s all good.”

In fact, one vaccine – developed by the University of Oxford – has already been shown to trigger the production of these cells, in addition to antibodies. It’s still too early to know how protective the response will be, but one member of the research group told BBC News that the results were “extremely promising”. (Read more about the Oxford University vaccine and what it’s like to be part of the trial).

There is a catch, however. In many patients who are hospitalised with more serious Covid-19, the T cell response hasn’t quite gone to plan.   

“Vast numbers of T cells are being affected,” says Hayday. “And what is happening to them is a bit like a wedding party or a stag night gone wrong – I mean massive amounts of activity and proliferation, but the cells are also just disappearing from the blood.”

One theory is that these T cells are just being redirected to where they’re needed most, such as the lungs. But his team suspects that a lot of them are dying instead.

“Autopsies of Covid-19 patients are beginning to reveal what we call necrosis, which is a sort of rotting,” he says. This is particularly evident in the areas of the spleen and lymph glands where T cells normally live.

Disconcertingly, spleen necrosis is a hallmark of T cell disease, in which the immune cells themselves are attacked. “If you look in post-mortems of Aids patients, you see these same problems,” says Hayday. “But HIV is a virus that directly infects T cells, it knocks on the door and it gets in.” In contrast, there is currently no evidence that the Covid-19 virus is able to do this.

“There are potentially many explanations for this, but to my knowledge, nobody has one yet,” says Hayday. “We have no idea what is happening. There’s every evidence that the T cells can protect you, probably for many years. But when people get ill, the rug seems to be being pulled from under them in their attempts to set up that protective defence mechanism.”T cells can lurk in the body for years after an infection is cleared, providing the immune system with a long-term memory (Credit: Reuters/Alkis Konstantinidis)

T cells can lurk in the body for years after an infection is cleared, providing the immune system with a long-term memory (Credit: Reuters/Alkis Konstantinidis)

Dwindling T cells might also be to blame for why the elderly are much more severely affected by Covid-19.  

Hayday points to an experiment conducted in 2011, which involved exposing mice to a version of the virus that causes Sars. Previous research had shown that the virus – which is also a coronavirus and a close relative of Covid-19 – triggered the production of T cells, which were responsible for clearing the infection.

The follow-up study produced similar results, but the twist was that this time the mice were allowed to grow old. As they did so, their T cell responses became significantly weaker.

However, in the same experiment, the scientists also exposed mice to a flu virus. And in contrast to those infected with Covid-19, these mice managed to hold onto their T cells that acted against influenza well into their twilight years.

“It’s an attractive observation, in the sense that it could explain why older individuals are more susceptible to Covid-19,” says Hayday. “When you reach your 30s, you begin to really shrink your thymus [a gland located behind your sternum and between your lungs, which plays an important role in the development of immune cells] and your daily production of T cells is massively diminished.”

What does this mean for long-term immunity?

“With the original Sars virus [which emerged in 2002], people went back to patients and definitely found evidence for T cells some years after they these individuals were infected,” says Hayday. “This is again consistent with the idea that these individuals carried protective T cells, long after they had recovered.”

The fact that coronaviruses can lead to lasting T cells is what recently inspired scientists to check old blood samples taken from people between 2015 and 2018, to see if they would contain any that can recognise Covid-19. The fact that this was indeed the case has led to suggestions that their immune systems learnt to recognise it after being encountering cold viruses with the similar surface proteins in the past.   

This raises the tantalising possibility that the reason some people experience more severe infections is that they haven’t got these hoards of T cells which can already recognise the virus. “I think it’s fair to say that the jury is still out,” says Hayday.

Unfortunately, no one has ever verified if people make T cells against any of the coronaviruses that give rise to the common cold. “To get funding to study this would have required a pretty Herculean effort,” says Hayday. Research into the common cold fell out of fashion in the 1980s, after the field stagnated and scientists began to move to other projects, such as studying HIV. Making progress since then has proved tricky, because the illness can be caused by any one of hundreds of viral strains – and many of them have the ability to evolve rapidly.   While antibodies are still important for tracking the spread of Covid-19, they might not save us in the end (Credit: Reuters)

While antibodies are still important for tracking the spread of Covid-19, they might not save us in the end (Credit: Reuters)

Will this lead to a vaccine?

If old exposures to cold viruses really are leading to milder cases of Covid-19, however, this bodes well for the development of a vaccine – since it’s proof that lingering T cells can provide significant protection, even years after they were made.

But even if this isn’t what’s happening, the involvement of T cells could still be beneficial – and the more we understand what’s going on, the better.

Hayday explains that the way vaccines are designed generally depends on the kind of immune response scientists are hoping to elicit. Some might trigger the production of antibodies – free-floating proteins which can bind to invading pathogens, and either neutralise them or tag them for another part of the immune system to deal with. Others might aim to get T cells involved, or perhaps provoke a response from other parts of the immune system.

“There really is an enormous spectrum of vaccine design,” says Hayday. He’s particularly encouraged by the fact that the virus is evidently highly visible to the immune system, even in those who are severely affected. “So if we can stop whatever it’s doing to the T cells of the patients we’ve had the privilege to work with, then we will be a lot further along in controlling the disease.”

It seems likely that we are going to be hearing a lot more about T cells in the future.

Paper: Do Your Genes Predispose You to COVID-19?

Individual differences in genetic makeup may explain our susceptibility to the new coronavirus and the severity of the disease it causes

By Loïc Mangin on April 30, 2020

Do Your Genes Predispose You to COVID-19?
Determining blood type in the ABO group system. Credit: Getty Images

Since the start of the COVID-19 pandemic several months ago, scientists have been puzzling over the different ways the disease manifests itself. They range from cases with no symptoms at all to severe ones that involve acute respiratory distress syndrome, which can be fatal. What accounts for this variability? Might the answer lie in our genes?

Coronaviruses have raised such questions for more than 15 years. In researching the 2003 outbreak of severe acute respiratory syndrome (SARS), Ralph Baric and his colleagues at the University of North Carolina at Chapel Hill identified a gene that, when silenced by a mutation, makes mice highly susceptible to SARS-CoV, the coronavirus that causes the disease. Called TICAM2, the gene codes for a protein that helps activate a family of receptors, called toll-like receptors (TLRs), that are involved in innate immunity, the first line of defense against pathogens.

Attention has now shifted to SARS-CoV-2, the new coronavirus that causes COVID-19. And TLRs have once again drawn researchers’ interest—this time to help explain the excess number of men who suffer from severe infections.

Men made up 73 percent of severe cases of COVID-19 in intensive care in France, according to a national survey published April 23. Behavioral and hormonal differences may be partially responsible. But genes may also factor into the mix. Unlike men, women have two X chromosomes and so carry double the copies of the gene TLR7, a key detector of viral activity that helps boost immunity.

The genetics of blood groups may offer some insight into whether you are liable to be infected with the virus. In late March Peng George Wang of the Southern University of Science and Technology in China and his colleagues released the results of a preprint study—not yet peer-reviewed—that compared the distribution of blood types among 2,173 COVID-19 patients in three hospitals in the Chinese cities of Wuhan and Shenzhen with that of uninfected people in the same areas. Blood type A appears to be associated with a higher risk of contracting the virus, whereas type O offers the most protection for reasons that have yet to be determined.

<See the link below for the rest of the article>

Edmond Sun: Investigator unraveling mystery of COVID-19 genetic markers and virus susceptibility

Local genome researcher Daniel Brue investigates why some people are more susceptible to COVID-19 while others are not. As an inventor and the founder of General Genomics, he has established a group of people in an attempt to find more information and correlations between genetic markers and virus susceptibility of COVID-19.

Investigator unraveling mystery of COVID-19 genetic markers and virus susceptibility

The findings could potentially reveal effective methods of treatment against the virus.

“What we do know now is that there is a significant part of the population A-symptomatic to COVID-19,” said Brue, P.h.D. “So they are carriers, but they don’t know that they’re ill.”

Brue is part of a group whose focus is to increase the effectiveness and preventiveness of treatments and illnesses by warning people to understand what they may be susceptible to, based on their genetic information.

Brue said a large population of participants in companies such as 23andMe and have been receiving reports about their genetic information.

“What I would like to track is how a disease effects people of different genetic dispositions,” Brue said.

A clearer picture of genetic markers linked to disease is forming from incoming information and volunteer participants. Brue correlates the effectiveness of treatments participants have received based on their genetic bands.

COVID-19 is becoming one of the best documented cases of a pandemic, and it is Brue’s hope that the group’s findings will apply to a bigger picture, triggering further scientific research of other disease processes as well.

“What I would want people to know is we have greater capacity to understand what is happening than we have ever had before,” Brue said. “If we didn’t take advantage of learning as much as we possibly can, we would be horribly remiss in not using data that we have on hand to try to improve people’s health care, and understand on the onset, what is the most effective treatment for those who are ill.”

The three inventors of the new program combine expertise in several disciplines. Ultimately they want to save lives.

Brue has an extensive background in physics and artificial intelligence/machine learning, and medical image processing. He earned his doctorate at the University of Oklahoma. Brue said he understands how sensors work and how to get the best information from them.

“What I know very well is how to extract information from measuring apparatuses that we’re using,” he said. 

Warren Gieck, of Calgary, Alberta, is an entrepreneur and industrial engineer, with experience in software development, artificial intelligence, robotics, mechatronics, and product development. 

“Our motivation is the suffering of our friends and society around us. And just as importantly, we are dads whose kids just want to go back to school,” Gieck said. “With extensive scientific and engineering expertise, we have built solutions using similar technologies for industrial applications, and we saw how we could help solve the uncertainty around the Covid-19 virus.

“Ultimately our goal is to allow people who are low risk to get back to their lives.”

A.J. Rosenthal of Midland, Texas, has a background in multi-disciplinary engineering solutions, nuclear engineering technology, and finance. Kyrie Cameron, attorney at Patterson + Sheridan, has assisted these inventors in filing their patent applications.   

“I want to figure out a way that we can better identify what people should be looking for in their own health care,” Brue said.

The goal is provide people a better understanding of how to take care of their personal health. By understanding individual risks, individuals would be able to provide care providers a better understanding of how they should be treated should they be in poor health, Brue said. As a result, physicians would have more concrete information to work with in patient care.

Brue said one of the worst aspects of what anyone goes through when they become sick is their uncertainty. A lot of people are concerned and scared of COVID-19.

“I have lived through enough personal losses to see how much the damage is on not just the person who’s ill, but their entire family around them,” Brue said.

His goal is to reduce anxiety by educating people about disease processes.

“It’s personally important to me,” Brue said.

Houston Chronicle: Midlander creates algorithm to predict likelihood of infection

Determination would be made using person’s genetic make-up, medical history

By Caitlin Randle, Reporter-Telegram Published 9:11 pm CDT, Thursday, April 16, 2020

A Midland data scientist and his two partners have created an algorithm that uses a person’s genetic markers and medical history to predict someone’s likelihood of becoming infected with the coronavirus and suffering complications from it.

Midlander A.J. Rosenthal and his partners, Dan Brue of Oklahoma and Warren Gieck of Alberta, Canada, filed patents this week related to the algorithm.

Rosenthal said it could use a person’s genetic make-up in combination with various factors, such as their medical history and types of exposure they’ve had (i.e. a miner exposed to coal dust), to determine someone’s risk factor and assign them a correlating score.

“We’re describing potentially where a person would fall, give them a score, and that score allows them to either start going back to the workplace because they’re not going to succumb to the disease, or they won’t even be susceptible to it,” he said.

The algorithm would use the medical histories of those who have been hospitalized with COVID-19 to determine what markers could put a person at risk, Rosenthal said. He described inputting the data from past patients as “training the algorithm.”

The goal of this project is for the information to be widely accessible, Rosenthal said. He said the algorithm could potentially be on a website where a person could enter their medical information after signing a HIPPA privacy release.

“What we’re trying to do is if people want this – and we’re hoping they do – is to make it easier for them to feel comfortable and safe going back out,” he said. “Because they’ve now been locked in their houses for weeks … they don’t know if they’re going to get sick. They don’t know if they’re even susceptible to it.”

The algorithm could also be applied to other viruses and diseases, Rosenthal said, but the trio has chosen to focus on COVID-19 because there’s an immediate need.

The project’s success is contingent on partnerships with other entities – primarily, with medical providers who would give access to the medical histories of past COVID-19 patients. HIPPA laws prevent that data from being publicly available.

Rosenthal pointed to studies linking ACE2 receptors in the lungs to COVID-19 as evidence that a person’s DNA could be used to predict their risk of being infected. Some studies have found the coronavirus uses these receptors to infiltrate cells in the body.

“When the coronavirus attaches, it has a certain type of envelope that it attaches to,” Rosenthal said. “Your receptor on your lung, a lot of the coronavirus sticks to it … and from there, it propagates an infection.”

Some health entities worldwide have advised against using ibuprofen to treat COVID-19 because it’s thought to increase the number of ACE2 receptors in the body, but there’s no clear consensus among the scientific community about whether more of these receptors create a higher risk of contracting or having complications from the coronavirus.

Rosenthal said the algorithm could determine if certain combinations of medications and genetics were frequently present in those infected with the virus and serve as a guide to those with similar DNA who are also on those medications.

A former multi-disciplinary engineer in the U.S. Navy and at General Electric, Rosenthal currently works for an oil and gas company in Midland. He said he and his partners, who met working at GE, were inspired to take up this enterprise by their kids, who want to “go back to school and go to the mall and play baseball.”

“We’re just three dads. We just want our kids to have a normal life again,” Rosenthal said.

“Maybe these three dads can help the world,” he said. “The only thing we’ve got left to lose are our jobs or the economy.”

Paper: Relationship between the ABO Blood Group and the COVID-19 Susceptibility


The novel coronavirus disease-2019 (COVID-19) has been spreading around the world rapidly and declared as a pandemic by WHO. Here, we compared the ABO blood group distribution in 2,173 patients with COVID-19 confirmed by SARS-CoV-2 test from three hospitals in Wuhan and Shenzhen, China with that in normal people from the corresponding regions. The results showed that blood group A was associated with a higher risk for acquiring COVID-19 compared with non-A blood groups, whereas blood group O was associated with a lower risk for the infection compared with non-O blood groups. This is the first observation of an association between the ABO blood type and COVID-19. It should be emphasized, however, that this is an early study with limitations. It would be premature to use this study to guide clinical practice at this time, but it should encourage further investigation of the relationship between the ABO blood group and the COVID-19 susceptibility.