20 MARCH 2020 • VOL 367 ISSUE 6484 1297The virus can clearly transmit in warm, hu-
mid climates: Singapore already has more
than 240 cases. Two new papers published
on preprint servers last week come to op-
posite conclusions. One, co-authored by
Lipsitch, looked at COVID-19 spread in
19 provinces across China, which ranged
from cold and dry to tropical, and found sus-
tained transmission everywhere. The second
study concludes that transmission appears
to occur only in specific bands of the globe
that have average temperatures between 5°C
and 11°C and 47% to 70% relative humidity.
The other coronaviruses may be more
susceptible to seasonal changes in the en-
vironment simply because they’ve been
infecting people for much longer. Once a
high percentage of the population develops
immunity, an unfavorable environment can
provide the extra push needed to temporar-
ily exile those viruses. But that’s not the sit-
uation with COVID-19. “Even though there
might be a big seasonal decline, if enough
susceptible people are around, it can coun-
ter that and continue for a long time,”
Martinez says. Lipsitch doesn’t think the
virus will go poof in April either. Any slow-
down “is expected to be modest, and not
enough to stop transmission on its own,” he
wrote in a recent blog post.
IN SURREY, MARTINEZ is investigating a dif-
ferent factor that might eventually affect
COVID-19 incidence. Her subjects have re-
turned to the clinic repeatedly—at the win-
ter and summer solstices and again at the
spring and fall equinoxes—so the research-
ers can evaluate how their immune system
and other physiology change over the course
of the day and from season to season.
She doesn’t expect to show that our immu-
nity is, say, weaker in the winter and stronger
in the summer. But by counting different
immune system cells, assessing metabolites
and cytokines in the blood, deciphering the
fecal microbiome, and measuring hormones,
Martinez’s team hopes to learn whether the
seasons “restructure” the immune system,
making some types of cells more abundant
in certain parts of the body, and others less,
in ways that influence our susceptibility
to pathogens.
Animal studies support the idea that im-
munity changes with the seasons. Ornitho-
logist Barbara Helm from the University of
Groningen and her colleagues, for example,
studied European stonechats, small song-
birds that they caught and then bred in cap-
tivity. By taking multiple blood samples over
the course of 1 year, they found that the birds
ramp up their immune systems in the sum-
mer, but then tamp them down in the fall,
the time they migrate, presumably because
migration is a big drain on their energy.
SCIENCE
Melatonin, a hormone primarily secreted
at night by the pineal gland, is a major driver
of such changes. The hormone keeps track
of the time of day but is also a “biological cal-
endar” for the seasons, says Randy Nelson,
an endocrinologist at West Virginia Univer-
sity who specializes in circadian rhythms.
When nights are long, more melatonin is re-
leased. “The cells say, ‘Oh, I’m seeing quite a
bit of melatonin, I know, it’s a winter night.’”
In studies of Siberian hamsters—which, like
humans, are diurnal—Nelson and his co-
workers have shown that administering mel-
atonin or altering light patterns can change
immune responses by up to 40%.
The human immune system, too, seems
to have an innate circadian rhythm. For
instance, a vaccine trial in 276 adults by
researchers at the University of Birming-
ham randomly assigned half to receive an
influenza vaccine in the morning and the
other half in the afternoon. Participants inthe morning group had significantly higher
antibody responses to two of the three flu
strains in the vaccine, the researchers re-
ported in 2016.
There’s evidence of seasonal variation
in the actions of human immune genes as
well. In a massive analysis of blood and tis-
sue samples from more than 10,000 people
in Europe, the United States, Gambia, and
Australia, researchers at the University of
Cambridge found some 4000 genes related
to immune function that had “seasonal ex-
pression profiles.” In one German cohort,
expression in white blood cells of nearly
one in four genes in the entire genome dif-
fered by the seasons. Genes in the North-
ern Hemisphere tended to switch on when
they were switched off south of the equa-
tor, and vice versa.
Just how these massive changes might af-
fect the body’s ability to fight pathogens is
unclear, however, as immunologist Xaquin
Castro Dopico and colleagues explain in
a 2015 paper describing the findings. And
some changes could be the result of an in-
fection, instead of the cause. The team tried
to eliminate people who had acute infec-
tions, but “of course a seasonal infectious
burden likely plays a part,” says Dopico,who is now at the Karolinska Institute.
And seasonal immunity changes could not
explain all the complex variation in season-
ality that diseases show. “They’re all out of
sync with each other,” Nathanson points
out. He’s also skeptical that a seasonal im-
mune system change could be large enough
to make a difference. “It would have to be
pretty markedly different.”
Martinez, however, says she has found
intriguing hints. Early analyses from her
Surrey study, which collected its final data
in December 2019, don’t reveal anything
about seasonality yet, but they do show
that specific subsets of white blood cells
that play central roles in immune system
memory and response are elevated at cer-
tain times of day. She hopes to firm up the
finding by launching a similar but larger
study next year.
Martinez cautions that artificial light may
play havoc with natural circadian rhythms,
with unpredictable effects on disease sus-
ceptibility. To explore possible impacts, she
has a separate study underway, with Helm,
in both urban and rural parts of New York
and New Jersey. They have installed light
sensors on trees and poles and outfitted
participants with devices that monitor light
exposure and body temperature. “The fact
that people really are just kind of washing
out the rhythms in light exposure can be
problematic,” she says.“EXPERIMENTS OF NATURE” could also of-
fer insights into the factors affecting dis-
ease seasonality, Dowell suggested in his
2001 paper. People from the Southern and
Northern hemispheres who have adapted
to different seasons regularly mix on cruise
ships or at conventions, where they are con-
fronted by the same pathogens—witness the
massive COVID-19 outbreak on the Diamond
Princess, which was docked and quaran-
tined in Yokohama, Japan, for 2 weeks last
month. Researchers could potentially analyze
whether they were infected at different rates.
Whatever the answers, they might even-
tually bring important public health ben-
efits, Martinez says. For example, “If we
know how best to administer vaccines, in
terms of what time of year and the best time
of day to take advantage of our immune sys-
tems, then we can get a lot more bang for
our buck,” she says.
The global COVID-19 emergency may
bring more attention to the research and
help speed discoveries, she says. But for
now, no one knows whether rising humid-
ity, longer days, or some as-yet-unsuspected
seasonal effect will come to the rescue—or
whether humanity must confront the pan-
demic without any help from the seasons.
Time will tell. j“If we knew what suppressed
influenza to summertime
levels, that would be a
lot more effective than any of the
flu vaccines we have.”
Scott Dowell, Bill & Melinda Gates Foundation