Why Some People Don't Get Covid?
We all know a "Covid virgin," or "Novid," someone who has defied
all logic in dodging the coronavirus. But beyond judicious caution,
sheer luck, or a lack of friends, could the secret to these people's
immunity be found nestled in their genes? And could it hold the key
to fighting the virus?
In the early days of the pandemic, a small, tight-knit community
of scientists from around the world set up an international
consortium, called the COVID Human Genetic Effort, whose goal
was to search for a genetic explanation as to why some people were
becoming severely sick with Covid while others got off with a mild
case of the sniffles.
After a while, the group noticed that some people weren't getting
infected at all-despite repeated and intense exposures. The most
intriguing cases were the partners of people who became really ill
and ended up in intensive care. "We learned about a few spouses
of those people that-despite taking care of their husband or wife,
without having access to face masks-apparently did not contract
infection," says Andras Spaan, a clinical microbiologist at
Rockefeller University in New York.
Spaan was tasked with setting up an arm of the project to investigate
these seemingly immune individuals. But they had to find a good
number of them first. So the team put out a paper in Nature
Immunology in which they outlined their endeavor, with a discreet
final line mentioning that "subjects from all over the world are
The response, Spaan says, was overwhelming. "We literally received
thousands of emails," he says. The sheer volume rushing to sign up
forced them to set up a multilingual online screening survey. So far,
they've had about 15,000 applications from all over the world.
The theory that these people might have preexisting immunity is
supported by historical examples. There are genetic mutations that
confer natural immunity to HIV, norovirus, and a parasite that causes
recurring malaria. Why would Covid be any different, the team
rationalized? Yet in the long history of immunology, the concept
of inborn resistance against infection is a fairly new and esoteric
one. Only a few scientists even take an interest. "It's such a niche
field, that even within the medical and research fields, it's a bit
pooh-poohed on," says Donald Vinh, an associate professor in the
Department of Medicine at McGill University in Canada. Geneticists
don't recognize it as proper genetics, nor immunologists as proper
immunology, he says. This is despite there being a clear therapeutic
goal. "If you can figure out why somebody cannot get infected, well,
then you can figure out how to prevent people from getting infected,"
But finding immune people is an increasingly tricky task. While many
have volunteered, only a small minority fit the narrow criteria of
probably having encountered the virus yet having no antibodies
against it (which would indicate an infection). The most promising
candidates are those who have defied all logic in not catching Covid
despite being at high risk: health care workers constantly exposed to
Covid-positive patients, or those who lived with-or even better,
shared a bed with-people confirmed to be infected.
By the time the team started looking for suitable people, they were
working against mass vaccination programs too. "On the one hand,
a lot of people were getting vaccinated, which is great, don't get me
wrong," says Vinh. "But those are not the people we want." On the
other hand, seeking out the unvaccinated "does invite a bit of
a fringe population." Of the thousands that flooded in after the
call, about 800 to 1,000 recruits fit that tight bill.
Then the highly infectious Omicron variant arrived. "Omicron
has really ruined this project, I have to be honest with you," says
Vinh. It dramatically reduced their pool of candidates. But Spaan
views Omicron's desecration in a more positive light: that some
recruits survived the Omicron waves really lends support to the
existence of innate resistance.
Across the Atlantic, in Dublin, Ireland, another member of the
group-Cliona O'Farrelly, a professor of comparative immunology
at Trinity College Dublin-set about recruiting health care workers
at a hospital in Dublin. Of the cohort she managed to assemble,
Omicron did throw a wrench in the works-half of the people whose
DNA they had sent off to be sequenced ended up getting infected
with the variant, obliviating their presumed resistance. To spread
awareness of their research and find more suitable people, O'Farrelly
went on the radio and expanded the call to the rest of the country.
Again, enthusiasm abounded: More than 16,000 people came forward
who claimed to have defied infection. "We're now trying to deal with
all of that," she says. "I'm hoping that we'll have one or two
hundred from those, which will be unbelievably valuable."
Now that they have a substantial cohort, the group will take
a twofold approach to hunting for a genetic explanation for
resistance. First, they'll blindly run every person's genome through
a computer to see if any gene variation starts to come up frequently.
At the same time, they'll look specifically at an existing list
of genes they suspect might be the culprits-genes that if different
from usual would just make sense to infer resistance. An example
is the gene that codes for the ACE2 receptor, a protein on the
surface of cells that the virus uses to slip inside.
The consortium has about 50 sequencing hubs around the world, from
Poland to Brazil to Italy, where the data will be crunched. While
enrollment is still ongoing, at a certain point, they will have
to decide they have enough data to move deeper into their research.
"That's going to be the moment we have people with clear-cut
mutations in the genes that make sense biologically," says Spaan.
Once they come up with a list of gene candidates, it'll then be
a case of narrowing and narrowing that list down. They'll go through
the list one by one, testing each gene's impact on defenses against
Covid in cell models. That process will take between four to six
months, Vinh estimates.
Another complication could arise from the global nature of the
project; the cohort will be massively heterogeneous. People in
Slavic countries won't necessarily have the same genetic variation
that confers resistance as people of Southeast Asian ethnicity.
Again, Spaan views this diversity as a plus: "This means that we
can correct for ethnic origin in our analysis," he says. But it also
means, Vinh says, that they're not just looking for one needle in
one haystack-"you're looking for the golden needle and the silver
needle and the bronze needle, and you're looking in the factory
It's unlikely to be one gene that confers immunity, but rather an
array of genetic variations coming together. "I don't think it'll
come down to a one-liner on the Excel sheet that says, 'This is
the gene,'" says Vinh. "If it happens to be a single gene, we will
After all this work is done, natural genetic resistance will likely
turn out to be extremely rare. Still, should they find protective
genes, it could help to inform future treatments. There's good reason
to think this: In the 1990s, a group of sex workers in Nairobi,
Kenya, defied all logic in failing to become infected with HIV
during three years of follow-up testing. It was discovered that some
were carrying a genetic mutation that produces a messed-up version
of the protein called the CCR5 receptor, one of the proteins that HIV
uses to gain entry to a cell and make copies of itself. Having the
mutation means HIV can't latch onto cells, giving natural resistance.
This then inspired maraviroc, an antiretroviral used to treat
infection, as well as the most promising "cure" for HIV, where two
patients received stem cell transplants from a donor carrying the
mutation and became HIV free.
It's also possible that genetics doesn't tell the full story of those
who resist infection against all odds. For some, the reason for their
protection might rest instead in their immune system. During the
first wave of the pandemic, Mala Maini, a professor of viral
immunology at University College London, and her colleagues
intensively monitored a group of health care workers who
theoretically probably should have been infected with Covid,
but for some reason hadn't been. The team also looked at blood
samples from a separate cohort of people, taken well before the
pandemic. On closer inspection of the two groups' samples, Maini's
team found a secret weapon lying in their blood: memory T
cells-immune cells that form the second line of defense against
a foreign invader. These cells, lying dormant from previous
dalliances with other coronaviruses, such as the ones that cause
the common cold, could be providing cross-protectivity against
SARS-CoV-2, her team hypothesized in their paper in Nature
in November 2021.
Other studies have supported the theory that these cross-reactive
T cells exist and may explain why some people avoid infection.
Maini compares the way these memory T cells might quickly attack
SARS-CoV-2 to driving a car. If the car is unlike one you've ever
driven before-a manual for a life-long automatic driver-it would
take you a while to get to grips with the controls. But assume the
pre-existing T cells are accustomed to automatics, and a SARS-CoV-2
encounter is like hopping into the driver's seat of one, and you can
see how they would launch a much quicker and stronger immune
A previous seasonal coronavirus infection or an abortive Covid
infection in the first wave-meaning an infection that failed to take
hold-could create T cells that offer this preexisting immunity. But
Maini points out a crucial caveat: This does not mean that you can
skip the vaccine on the potential basis that you're carrying these
More recently, Maini and her colleague Leo Swadling published
another paper that looked at cells from the airways of volunteers,
which were sampled and frozen before the pandemic. They figured,
if the infection is getting shut down so quickly, then surely the cells
responsible must be ready and waiting at the first site of infection.
The cohort in the study was small-just 10 people-but six out of the
10 had cross-reactive T cells sitting in their airways.
Off the back of her research, Maini is working on a vaccine with
researchers at the University of Oxford that induces these T cells
specifically in the mucus membranes of the airway, and which could
offer broad protection against not only SARS-CoV-2 but a variety
of coronaviruses. Such a vaccine could stop the Covid virus wriggling
out of the existing vaccines' reach, because while the spike
protein-the focus of current vaccines-is liable to mutate and change,
T cells target bits of viruses that are highly similar across all human
and animal coronaviruses.
And a mucosal vaccine could prepare these T cells in the nose and
throat, the ground zero of infection, giving Covid the worst shot
possible at taking root. "We're quite optimistic that that sort of
approach could provide better protection against new emerging
variants, and ideally also against a new transfer of a new animal
zoonotic virus," says Maini.
As for Spaan and his team, they also have to entertain the
possibility that, after the slog, genetic resistance against
SARS-CoV-2 turns out to be a pipedream. "That's our fear-that
we will do all this and we will find nothing," says Vinh. "And that's
OK. Because that's science, right?" O'Farrelly, on the other hand,
has undeterred optimism they'll find something. "You just can't
have people die and not have the equivalent at the other end
of the spectrum."