When Vanessa Bryant recently managed to dodge COVID-19 despite the rest of her young family getting infected, she felt fortunate — but not entirely surprised.
"As an immunologist, I know there's a bit of luck to it," said Dr Bryant, who leads the Immunogenetics Research Laboratory at the Walter and Eliza Hall Institute of Medical Research 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.
Scientists, including Dr Bryant, want to know why.
Dr Bryant is part of an Australian research team investigating how COVID-19 spreads in households, and why some people — like herself — don't test positive at all.
"We can gain a lot of knowledge from the people who are resistant genetically and immunologically," she said.
"Obviously, that's going to have implications for understanding the critical components that are necessary for COVID-19 protection.
"It's also going to really pinpoint the essential therapeutic targets for [the treatment of] other people."
COVID-19 immunity is influenced by multiple factors
At the beginning of the pandemic, scientists focused intensely on understanding what makes people more vulnerable to severe COVID-19 — which we've since learnt includes factors like old age, underlying health conditions, and obesity.
These days, an increasing amount of research is being devoted to the other side of the coin: why do some people seem to never get sick?
"Everyone's immune system is slightly different," Dr Bryant said.
"Some people might generate an immune response that just makes better antibodies … and we do think this is largely genetic."
Vaccination, of course, is an essential tool in our armour against COVID-19, and the most sure-fire way to protect yourself from becoming unwell.
"If you've just recently completed your vaccination and had a boost, you're going to have the highest immunological protection," Dr Bryant said.
"That's when you've got lots of circulating protective antibodies … that can really mop up and neutralise the virus before it has a chance to even infect cells."
But the effectiveness of COVID-19 vaccines wanes over time, most notably against infection and symptomatic disease.
The speed at which this happens — and when a person might become vulnerable to a breakthrough infection — depends on the vaccine, the variant and the individual.
"We can sort of generalise and say what that [waning] looks like at the community level, but when you home in on the individual level, it's really highly variable," Dr Bryant said.
When considering why someone might not have tested positive for COVID-19, it's also important to look at how likely it is they were exposed, and the nature of that exposure.
Immunologist Stuart Tangye from the Garvan Institute of Medical Research said the length and location of virus exposure were important, as well as potential viral load.
"Being outside is one big environmental factor that mitigates person-to-person transmission, in addition to all the sanitation, mask-wearing, and social distancing," Professor Tangye said.
Previous infection can play a role
Adding to that complex picture of individual protection and risk is the possibility of previous infection.
Professor Tangye said it was likely that many Australians had been infected with COVID-19 without realising it.
"When we first started doing PCR testing, it was really done on symptomatic people … so we were obviously missing a lot of those asymptomatic people," Professor Tangye said.
The sensitivity of rapid antigen tests, which many of us now use to diagnose COVID-19, is not as high as PCRs — another factor in why some cases were likely missed.
It's not just previous COVID-19 infections that might impact levels of immunity, either.
Research has found that people with higher levels of memory T-cells from other coronavirus infections — i.e., those responsible for common colds — 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 is possibly some pre-existing immunity that's effective against SARS-CoV-2 infection," Professor Tangye said.
But it's not clear why some individuals maintain a level of cross-reactive immunity, while others don't.
Do some people have an innate advantage?
Putting aside environmental factors and protection induced by vaccination (and previous infection), experts say there may be particular genetic and immunological features that mean some people are naturally more resistant to COVID-19.
Earlier this year, UK researchers deliberately exposed a group of 36 young, healthy individuals — with no evidence of previous infection or vaccination — to COVID-19, in what's known as a human-challenge trial (the first of its kind for SARS-CoV-2).
According to their preliminary findings, only half of the volunteers actually became infected with the virus (defined as two consecutive positive PCR tests).
Of those who didn't develop an infection, around half briefly tested positive for low levels of the virus, suggesting their immune system rapidly shut the infection down.
"There's probably a few people like that, who would have a really strong innate immune response [that] just quells the infection, without enabling the virus to get too far ahead."
But Professor Tangye said there was likely to be an even smaller group of people who carry a genetic resistance to SARS-CoV-2 that stops the virus from gaining a foothold altogether.
"There are going to be people who are less susceptible to viral infection because they have differences in their genes, such as genes that are important for viral entry into your cells."
He said the notion of genetic resistance to infectious diseases was not without precedent.
"With HIV, for example, there is a very, very small number of people who are genetically resistant to infection," Professor Tangye said.
"That's because they have naturally occurring genetic mutations in a certain gene so the virus can't physically infect their T cells."
Viruses on their own are pretty useless — they need to hijack the cellular machinery of their host in order to replicate.
"In the case of HIV, that's a T cell, but they physically can't find the door to knock on and sneak in."
While Professor Tangye said genetic resistance to COVID-19 was likely rare overall, researchers hoped that identifying key genetic changes in people who are resistant could lead to the development of more effective drug therapies.
He is part of an international consortium of experts called the COVID Human Genetic Effort, who are seeking to understand the genetic and immunological factors that influence SARS-CoV-2 infections.
It will study hundreds of unvaccinated people who had not yet had the virus, but were exposed to a COVID-positive person over an extended period of time — and still didn't test positive or mount an immune response.
Some preliminary research has shown rare mutations thought to affect the body's ACE2 receptors — essential for the virus slipping into our cells — may influence susceptibility to COVID-19.
"[Researchers] are finding changes at the genetic level [that] are altering the structure of the ACE2 protein … so the ability for SARS-CoV-2 to use it as an entry into the cell is reduced," Professor Tangye said.
Solving genetic and immunological mysteries
Dr Bryant said research previously done by the COVID Human Genetic Project on why some people were — conversely — genetically susceptible to severe disease had already led to improved understanding and treatments.
In 2021, researchers discovered that individuals with genetic mutations that disrupt the activity of proteins critical to fighting off 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" that attack and block their own type 1 interferons.
"If we can understand that, that will be transformative in the way we develop therapeutics to combat disease."
In addition to solving some of COVID-19's genetic mysteries, Dr Bryant said 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 neutralising antibodies are important. But they're just one part of the story," she said.
"We've also got 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 that information to inform public health responses on issues such as the frequency of boosters."
