When Vanessa Bryant recently managed to dodge COVID-19 despite the fact that the rest of her young family became infected, she felt lucky – but not entirely surprised.
“As an immunologist, I know there’s a bit of luck with that,” said Dr. Bryant, who heads the Immunogenetics Research Laboratory at the Walter and Eliza Hall Institute in Melbourne.
“We joke that I’m invincible, but of course that’s not true at all.”
Dr. Bryant had been boosted just 10 weeks earlier and her family took precautions against getting the virus.
But her experience is not uncommon, even among people who are much less protected – even unvaccinated.
Researchers, including Dr. Bryant, would like to know why.
Dr. Bryant is part of an Australian research team examines how COVID-19 spreads in householdsand why some people – like herself – do not test positive at all.
“We can get a lot of knowledge from the people who are genetically and immunologically resistant,” she said.
“It will, of course, have implications for the understanding of the critical components needed for COVID-19 protection.
“It will also really identify the essential therapeutic goals for [the treatment of] other people.”
COVID-19 immunity is affected by several factors
In the beginning of the pandemic, the researchers focused intensely on to understand what makes people more vulnerable to severe COVID-19 – which we have since experienced includes factors such as old age, underlying health conditions and obesity.
These days, an increasing amount of research is devoted to the other side of the coin: why do some people never seem to get sick?
“Everyone’s immune system is a little different,” said Dr. Bryant.
“Some people may generate an immune response that just produces better antibodies … and we think it’s largely genetic.”
Vaccination is of course an essential tool in our armor against COVID-19 and the safest way to protect yourself from becoming uncomfortable.
“If you have recently completed your vaccination and received a boost, you will have the highest immunological protection,” said Dr. Bryant.
“It’s when you have lots of circulating protective antibodies … that can really dry up and neutralize the virus before it has a chance to infect cells at all.”
However, the effectiveness of COVID-19 vaccines decreases over time, especially against infection and symptomatic disease.
The speed at which this happens – and when a person can become vulnerable to a breakthrough infection – depending on the vaccine, the variant and the individual.
“In a way, we can generalize and say what it is [waning] looks at the community level, but when you are at home at the individual level, it really is very varied, “said Dr. Bryant.
When considering why someone may not have tested positive for COVID-19, it is also important to look at how likely it is that they were exposed and the nature of that exposure.
Immunologist Stuart Tangye of the Garvan Institute of Medical Research said the length and location of virus exposure was important, as well as potential viral load.
“Being outside is a major environmental factor that reduces person-to-person transmission, in addition to all sanitation, mask wearing and social distancing,” Professor Tangye said.
Previous infection may play a role
Adding to the complex picture of individual protection and risk is the possibility of previous infection.
Professor Tangye said it was likely many Australians had been infected with COVID-19 without being aware of it.
“When we first started doing PCR tests, it was really done on symptomatic people … so we were obviously missing a lot of these asymptomatic people,” Professor Tangye said.
The sensitivity of rapid antigen tests that many of us now use to diagnose COVID-19 is not as high as PCRs – another factor why some cases were probably overlooked.
It is also not only previous COVID-19 infections that can affect the level of immunity.
Research has found that people with higher levels of memory T cells from other coronavirus infections – ie. those responsible for the common cold – were less likely to become infected with SARS-CoV-2.
“Studies have shown a certain amount of cross-reactivity with other seasonal coronaviruses … so there may be a pre-existing immunity that is effective against SARS-CoV-2 infection,” said Professor Tangye.
However, it is not clear why some individuals maintain a level of cross-reactive immunity while others do not.
Do some people have an innate advantage?
Putting aside environmental factors and protection induced by vaccination (and previous infection), experts say there may be special genetic and immunological traits that mean some people are naturally more resistant to COVID-19.
Earlier this year, British researchers deliberately exposed a group of 36 young, healthy individuals – with no evidence of previous infection or vaccination – to COVID-19in what is known as an experiment with human challenge (the first of its kind for SARS-CoV-2).
According to their preliminary findingsonly half of the volunteers were actually infected with the virus (defined as two consecutive positive PCR tests).
Of those who did not develop an infection, about half briefly tested positive for low levels of the virus, suggesting that their immune system quickly shut down the infection.
“There are probably a few people like that who would have a really strong innate immune response [that] just suppresses the infection without allowing the virus to get too far. “
But Professor Tangye said there is likely to be an even smaller group of people carrying a genetic resistance to SARS-CoV-2 that prevents the virus from gaining a foothold completely.
“There will be people who are less susceptible to viral infection because they have differences in their genes, such as genes that are important for viral access to your cells.”
He said that the concept of genetic resistance to infectious diseases was not without precedent.
“With HIV, for example, there are a very, very small number of people who are genetically resistant to infection,” Professor Tangye said.
“This is because they have naturally occurring genetic mutations in a particular gene so that the virus cannot physically infect their T cells.”
Viruses themselves are pretty useless – they have to hijack their host’s cellular machinery to replicate.
“In the case of HIV, it’s a T cell, but they can not physically find the door to knock and sneak in.”
While Professor Tangye said that genetic resistance to COVID-19 was probably generally rare, the researchers hoped it identify key genetic changes in people who are resistant may lead to the development of more effective drug treatments.
He is part of an international consortium of experts called COVID human genetic effortwho seek to understand the genetic and immunological factors affecting SARS-CoV-2 infections.
It will study hundreds of unvaccinated people who had not yet had the virusbut was exposed to a COVID-positive person over a long period of time – and still did not test positive or get an immune response.
Some preliminary study has shown rare mutations that are thought to affect the body’s ACE2 receptors – essential for the virus to glide into our cells – may affect the susceptibility of COVID-19.
“[Researchers] finds changes at the genetic level [that] “changes the structure of the ACE2 protein… so that the ability of SARS-CoV-2 to use it as an entry into the cell is reduced,” said Professor Tangye.
Solving genetic and immunological mysteries
Dr. Bryant said research previously conducted by the COVID Human Genetic Project into why some people – conversely – were genetically susceptible to serious illness had already led to improved understanding and treatments.
In 2021, researchers discovered that individuals with genetic mutations that disrupt activity of proteins that are essential for fighting viral infections – called type 1 interferons – have a higher risk of life-threatening disease.
Similarly, a significant proportion of people with severe COVID-19 were found to have “autoantibodies” there attack and block their own type 1 interferons.
“If we can understand that, it will be transformative in the way we develop therapeutic agents to fight disease.”
In addition to solving some of COVID-19’s genetic mysteries, Dr. Bryant that it was important to understand more about the “underlying immunological responses” to COVID-19, including how these change over time.
“We know comorbidities are important, we know age is important, we know neutralizing antibodies are important. But they are only part of the story,” she said.
“We also have our cellular memory – our memory T cells and memory B cells. These are typically long-lived cells.
“They’re harder to measure … but are something we really need to understand.”
Having a more complete picture of the immunological response, she added, would help researchers understand what factors were important for strong protection and why some people could be left vulnerable.
“We can then use this information to inform public health responses to issues such as the frequency of boosters.”
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