Feature

ARE REPEAT
COVID INFECTIONS
DANGEROUS?
WHAT THE
SCIENCE SAYS
Researchers disagree over how bad it is to
be reinfected, and whether COVID-19 can
cause lasting changes to the immune system.
By Cassandra Willyard

W
hen the coronavirus pan-
demic began in early 2020, the
SARS-CoV-2 virus was a strange
and terrifying adversary that
plunged the world into chaos.
More than three years later,
the infection’s symptoms are
all too familiar and COVID-19
is here to stay — part of a long list of common
diseases that infect humans. Experts esti-
mate that the majority of the world’s popu-
lation has been infected at least once; in the
United States, some estimates suggest that
as many as 65% of people have had multiple
infections1. And it’s likely that in the decades
to come, we’re all destined to get COVID-19
many more times.
Just how much harm repeat infections will
cause is a matter of debate. “There are some
almost pathologically polarized opinions
evidence. What do the data say about the risks
of reinfection and the potential for COVID-19
to cause lasting consequences?
How common is reinfection,
and what are the risks?
First, reinfection so far seems to be relatively
rare in studies that tested people for the
virus over time. The latest data from various
countries suggest rates ranging from 5%2 to
15%3, although this proportion is expected to
increase as time passes.
When reinfection does occur, the good news
is that the immune system seems primed to
respond. In a preprint posted in March4,
researchers examined reinfections in US
National Basketball Association players, staff
and their families. They found that people who
became reinfected cleared the virus faster — in
about five days, on average, compared with
infection5. And two large studies suggest that
reinfections tend to be less risky than the ini-
tial one. In one study6, researchers compared
two groups of unvaccinated people in Qatar
— around 6,000 who had been infected once
and 1,300 who had been reinfected. The odds
of severe, critical or fatal disease at reinfection
were almost 90% lower than that for a primary
infection.
The other study 7, which looked at
3.8 million first infections and 14,000 rein-
fections in England, found that people were
61% less likely to die in the month following
reinfection than in the same period after a first
infection, and 76% less likely to be admitted to
an intensive care unit.
But reinfection isn’t risk free. Those who are
most vulnerable to severe disease during a first
infection continue to be the most vulnerable,
even if their risk of hospitalization or dying
CREATIVE TOUCH IMAGING/NURPHOTO VIA GETTY

out there,” says Danny Altmann, an immunol-
ogist at Imperial College London. One side
argues that SARS-CoV-2 is a run-of-the-mill
respiratory virus, no worse than the com-
mon cold, especially for those who have been
vaccinated. Others have said that repeatedly
getting COVID-19 is a gamble. Each bout comes
with a risk of damage — or at least changes —
to the immune system, and long-term health
repercussions. Both groups are armed with
about seven days for a first infection. People
who had a vaccine dose between their first and
second infection cleared the virus the fastest,
says Stephen Kissler, an infectious-disease
researcher at the Harvard T.H. Chan School
of Public Health in Boston, Massachusetts, and
a co-author of the paper.
Other studies have shown that people who
experience mild symptoms with their first
infection will probably have a mild subsequent
diminishes. In a January preprint5, researchers
analysed data from the National COVID Cohort
Collaborative in the United States, which
contains clinical information on more than
16 million people. The vast majority of those
who got reinfected — more than three-quar-
ters — had a mild illness both times. A small
proportion of people who weren’t hospital-
ized the first time did end up in the hospital
on reinfection. But a severe second infection

650 | Nature | Vol 616 | 27 April 2023

©
2
0
2
3
S
p
r
i
n
g
e
r
N
a
t
u
r
e
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 People crowd onto a ferry boat in Toronto,
Canada, in July 2022, as the Omicron
variant prompted a surge in cases.

physician at the University of Michigan in Ann

Arbor. But, she adds, “getting COVID a second
or third time isn’t good for anyone.”

Can reinfection boost

the risk of long COVID?
That every new bout of COVID-19 carries some
risk wasn’t a shock to Al-Aly. What did come
as a revelation is that the risks associated
with reinfection extend beyond the acute
phase. Even six months after reinfection, the
researchers found an excess risk of outcomes
such as heart disease, lung problems, diabetes,
fatigue, neurological disorders. “If you dodged
the bullet that first time and did not get long
COVID, upon reinfection you could still get
long COVID,” Al-Aly says.
The latest data (go.nature.com/3h6vl67)
from the UK Office of National Statistics,
however, suggest that the risk of long COVID
diminishes with subsequent infections. Adults
had a 4% risk of developing long COVID after a
first infection, and that declined to 2.4% after
reinfection. For children and young people,
the long-COVID risk after a first infection was
1% and didn’t decline much.
For people who already have long COVID,
reinfection seems to exacerbate symptoms. In
a survey of nearly 600 people with long COVID
(go.nature.com/3a0aadc), conducted by the
charity Long Covid Kids & Friends, based in
was much more common in people who had Salisbury, UK, 80% reported that reinfection
a severe first infection. Of the people who worsened at least some of their symptoms.
had to be put on a ventilator during their first Only 15% reported that reinfection had no

GETTING COVID A
infection, 30% ended up back in the hospital impact on symptoms.
on reinfection. “They should have some degree

of concern,” says Richard Moffitt, a biostatis-
tician at Emory University School of Medicine
in Atlanta, Georgia.
One reinfection paper that garnered a lot of
media attention looked at electronic health
records from the US Department of Veterans
Affairs8. In the database, the researchers found
nearly 500,000 people who were infected by
SARS-CoV-2 once, and about 41,000 who had
2 or more confirmed infections. The paper
did not compare the severity of first and sub-
sequent infections. Instead, the researchers
compared the outcomes of people infected
once with those who had two or more infec-
tions. At the time, Ziyad Al-Aly, an epidemi-
ologist at Washington University School of
Medicine in St. Louis, Missouri, was seeing
people who had been both vaccinated and
infected. They felt bulletproof. “People in
the press started referring to these patients
as ‘super immune’.” Al-Aly wanted to know if a
second infection would even matter for those
individuals.
The study showed that it did (see ‘Reinfec-
tion risks’). Having COVID-19 more than once
SECOND OR THIRD
TIME ISN’T GOOD
FOR ANYONE.”
is worse than having it just once. “It’s not really
surprising,” Al-Aly says. If you get hit in the
head twice, he says, it will be worse than one
blow. People with repeat infections were twice
as likely to die and three times as likely to be
hospitalized, have heart problems or experi-
ence blood clots than were people who were
infected only once. In a surprising twist, vac-
cination status didn’t seem to have an impact
— although other studies show vaccines to be
protective. Whether these results hold true for
the general population is up for debate. The
Veterans Affairs cohort was made up mostly of
older white men, which is not representative
of the wider population.
It might be impossible to avoid infection alto-
gether, says Preeti Malani, an infectious-disease
Does COVID-19 alter
the immune system?
There’s another reason why some scientists
think that a SARS-CoV-2 infection — whether
first or fourth — is worth avoiding. Some argue
that even mild cases of COVID-19 can cause
lasting damage to the immune system, which
could make people more susceptible to other
kinds of infection. This has been floated as an
explanation for the surge in cases of influenza
and other respiratory illnesses in the Northern
Hemisphere beginning in October last year.
Such evidence “dispels the myth that repeated
brushes with the virus are mild and you don’t
have to worry about it”, says Rambod Rou-
hbakhsh, a physician at the Forrest General
Hospital in Hattiesburg, Mississippi, in a press
release. “It is akin to playing Russian roulette.”
Many immunologists, however, say that
evidence for that hypothesis is lacking.
Immune abnormalities do seem to accom-
pany long COVID and linger after severe cases
of COVID-19, but for most people who have
recovered, there is no sign that the virus causes
a long-lasting immune deficiency. “We know

Nature | Vol 616 | 27 April 2023 | 651

©
2
0
2
3
S
p
r
i
n
g
e
r
N
a
t
u
r
e
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
Feature
REINFECTION RISKS by a return to the baseline. In one small study
Does getting COVID-19 more than once increase your risk of health problems or of hospitalization? In an analysis published in January11, researchers assessed
of around 265,000 people who had at least one bout of COVID-19 and were followed over a year, reinfection was
this by looking at whether COVID-19 changes
not harmless: the cumulative risks increased the more often someone had COVID-19. The excess burden indicates
how many more people per 1,000 had each health problem after infection compared with no infection. the immune system. The researchers recruited
33 people who were infected with SARS-CoV-2
One infection (234,990 people) Two infections (28,509 people) Three or more infections (1,023 people)
early in the pandemic and took blood samples
for several months, before and after they got
Hospitalization their flu shots. When they compared those
individuals to people who had their flu shot
without having had COVID-19, they found
Cardiovascular disease
differences that they weren’t expecting
between male and female participants. Typ-
Pulmonary disease ically, the female response to a flu vaccina-
tion is stronger. “In this case, we saw the flip,”
says John Tsang, a systems immunologist at
Fatigue the Yale School of Medicine in New Haven,
Connecticut, who co-authored the study while
Kidney disease
in his post at the National Institutes of Health
in Bethesda, Maryland.
“It may not be that we’ve made things better
Diabetes or worse, we’ve just made it a little bit differ-

0 1 5 15
Excess burden per 1,000 people (95% confidence interval)
what immunodeficiency really looks like,”
says Sheena Cruickshank, an immunologist
at the University of Manchester, UK. Only a few
common viruses have the ability to suppress
the immune system: HIV infects and destroys
immune cells such as T cells, leaving people
more vulnerable to other types of infection;
measles infects immune memory cells, making
them targets for destruction and prompting
the immune system to forget pathogens it has
previously met.
Nonetheless, a handful of studies have found
immunological changes that last weeks or even
months after the initial SARS-CoV-2 infection —
even in people who had a mild illness and seem
to have fully recovered. Several studies have
looked at different immune markers, such as
inflammatory proteins and various immune
cells, and have observed changes that linger.
A paper published earlier this year that
raised concerns compared the T cells of peo-
ple in three groups: those who were infected
with SARS-CoV-2 but never vaccinated, those
who were vaccinated but never infected and
those who were infected and then vaccinated9.
The researchers observed marked differences
in the number and activity of killer T cells,
which seek out and destroy infected cells. In
the group that was infected then vaccinated,
the vaccine prompted a weaker killer-T-cell
response than it did in the group that had been
vaccinated but never infected. The fainter
response is “cause for concern”, the authors
write, because it might mean that people are
vulnerable to repeat infections or other health
issues even if they have been vaccinated.
But the significance of any of the changes
seen so far isn’t entirely clear. “We don’t know
how they read out in terms of people’s lives,”
Altmann says.
50 200
Marc Veldhoen, an immunologist at the
University of Lisbon, bristles at the descrip-
tion of these changes as immune dysfunction
or dysregulation. Much of what these papers
describe is the tail end of a normal physio-
logical response to a new infection, he says.
Roughly speaking, SARS-CoV-2 “behaves like
all the other viruses we are familiar with”,
he says. “We haven’t discovered something
magical about this virus.”
Some papers that find no immune dysfunc-
tion have been taken as evidence that it does
in fact exist. Margarita Dominguez-Villar, an
immunologist at Imperial College London, and
her colleagues published a study10 showing
that monocytes — a type of immune cell that
serves as a first line of defence against patho-
gens — express genes linked to clot formation
after a SARS-CoV-2 infection. The study looked
only at acute infection, and didn’t show evi-
dence of immune damage. But on Twitter, the
research took on a life of its own; some tweets
claimed it showed a rewiring of innate immu-
nity. “Suddenly I see my paper being retweeted
like 1,000 times,” she says. “I think it generated
a lot of panic when there shouldn’t be any.”
Are these immune changes
unique to COVID-19?
It’s hard to say. No other virus has been the
focus of such intense study using the full arse-
nal of modern tools available to researchers.
Many of the immunological changes being
observed might be present after other viral
infections, says Dominguez-Villar. “If we were
to look at, for example, influenza, as deeply
as we have been looking at COVID, we will
probably find some similarities.”
Perhaps scientists have been wrong to
assume that infection with any virus is followed
SOURCE: REF 8
ent,” says John Wherry, an immunologist at
420 the University of Pennsylvania in Philadelphia.
His own investigations of the immunological
aftermath of SARS-CoV-2 haven’t revealed any
significant changes. In a February preprint12,
his team looked at the immune response in
vaccinated people who later became infected.
“We see markers of high T-cell activation, high
B-cell activation. That all returned to baseline
levels within 45–60 days,” he says.
Many of these questions might never be
fully answered. Even as reinfections become
more common, they have become harder to
track as testing for COVID-19 has dropped
off. Furthermore, the landscape of COVID-19
immunity is becoming increasingly complex.
People vary by the number and type of vaccine
doses they’ve received, whether they’ve been
infected and with what variant and the tim-
ing of each exposure. “It’s not clean to look at
those things,” Tsang says.
Whatever the risks, COVID-19 is here to stay
— still evolving, still infecting and reinfecting
people and likely to keep on revealing secrets
of the immune system.
Cassandra Willyard is a freelance science
journalist in Madison, Wisconsin.
1. Klaassen, F. et al. Preprint at medRxiv https://doi.
org/10.1101/2022.11.19.22282525 (2022).
2. Guedes, A. R. et al. Sci. Rep. 13, 712 (2023).
3. Eythorsson, E., Runolfsdottir, H. L., Ingvarsson, R. F.,
Sigurdsson, M. I. & Palsson, R. JAMA Netw. Open 5,
e2225320 (2022).
4. Kissler, S. M. et al. Preprint at medRxiv https://doi.
org/10.1101/2023.03.03.23286775 (2023).
5. Hadley, E. et al. Preprint at medRxiv https://doi.
org/10.1101/2023.01.03.22284042 (2023).
6. Abu‑Raddad, L. J., Chemaitelly, H. & Bertollini, R. N. Engl.
J. Med. 385, 2487–2489 (2021).
7. Mensah, A. A. et al. J. Infect. 84, 542–550 (2022).
8. Bowe, B. et al. Nature Med. 28, 2398–2405 (2022).
9. Gao, F. et al. Immunity https://doi.org/10.1016/
j.immuni.2023.03.005 (2023).
10. Maher, A. M. et al. Nature Commun. 13, 7947 (2022).
11. Sparks, R. et al. Nature 614, 752–761 (2023).
12. Painter, M. M. et al. Preprint at bioRxiv https://doi.
org/10.1101/2023.02.05.527215 (2023).

652 | Nature | Vol 616 | 27 April 2023

©
2
0
2
3
S
p
r
i
n
g
e
r
N
a
t
u
r
e
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.