SCIENCE sciencemag.org 9 JULY 2021 • VOL 373 ISSUE 6551 143when protection rose to more than 90%.
T cells, which coordinate the B cells that
produce antibodies but also clear infected
cells when neuts falter, appear to bolster the
defense. In a study published in February that
included 12 patients whose COVID-19 ranged
from mild to fatal, a team led by immuno-
logist Antonio Bertoletti of the Duke–
National University of Singapore Medical
School reported that patients who early on
had the highest levels of immune system
messengers that kick T cells into action—an
indirect, but relatively simple, way to mea-
sure their presence—had milder disease be-
cause they cleared the infection faster.
Penny Moore and colleagues also found
support for a role for T cells. In an 11 June
preprint, they reported that 96% of partici-
pants in an efficacy trial of the COVID-
vaccine produced by Johnson & Johnson
(J&J) made antibodies that neutralized a
viral strain from early in the pandemic but
only 19% had antibodies that neutralized the
Beta variant, which is widespread in South
Africa and infamous for dodging neuts. Yet
the vaccine remained protective against
moderate and severe COVID-19. “I think it’s
entirely plausible ... that T cells
are doing something really useful
here,” Moore says. A monkey study
with the J&J vaccine published in
Nature last year also showed that
T cells contributed to control of
the virus if neut levels weren’t high
enough to do the job.
Binding antibodies may also be
more important than researchers assumed.
A 24 June preprint by researchers from the
University of Oxford reported that high levels
of neuts correlated with the 80% protection
seen 28 days after U.K. participants received
two shots of the vaccine the team developed
with AstraZeneca. But digging more deeply
into the data revealed that binding antibodies
were as good as a correlate—if not better.
It’s not clear exactly why, because binding
antibodies don’t directly block the infection
process. One possibility is that they make the
virus more susceptible to being gobbled up
by macrophages or other cells that ingest in-
truders. This mechanism, called phagocyto-
sis, protected children from severe COVID-19,
immunologist Galit Alter of the Ragon Insti-
tute of MGH, MIT, and Harvard reported in
Nature Medicine in March. Then again, it
may be that binding antibodies are produced
in lockstep with neuts, but at higher levels,
and are simply a surrogate marker.
A study of the immune reactions of
24 COVID-19 patients whose disease ranged
from mild to fatal, by virologist Shane Crotty
and Alessandro Sette of the La Jolla Institute
for Immunology, showed that people handle
SARS-CoV-2 most effectively if they have T
cells and antibodies working in sync. “The
immune system figures out how to use all the
weapons at its disposal,” Crotty says.
South Africa, where fewer than 1% of the
population is fully vaccinated amid an ex-
ploding epidemic, has shown the potential
pitfalls of overemphasizing neuts. In Febru-
ary, the country abandoned the AstraZeneca-
Oxford vaccine after it had a disappointing
22% efficacy against mild disease in a large
trial. Test tube analyses seemed to support
the decision: Antibodies triggered by the vac-
cine had far less neutralizing power against
the Beta variant, which then accounted for
nearly all infections. But Penny Moore’s study
of the J&J vaccine has subsequently shown
that disappointing levels of neutralizing an-
tibodies don’t keep a vaccine from provid-
ing good protection against severe disease.
“Our obsession with neuts may mean that we
missed an opportunity here for AstraZeneca,”
she says.
Other scientists counter that it makes
sense to use neuts as a gauge to rank the
relative powers of different vaccines, but
acknowledge that this will require standard-
ized assays. “This has not been the most im-
portant priority, but it’s going to
become one if we move away from
phase 3 trials,” John Moore says.
With the picture still muddy, reg-
ulators need to decide whether cor-
relates of protection should offer
vaccinemakers a shortcut to bring-
ing improved products to market.
Pfizer and Moderna are developing
candidates designed to create high levels of
neutralizing antibodies against the Beta vari-
ant, and the U.S. Food and Drug Administra-
tion (FDA) has signaled it will accept this
correlate of protection for approval decisions.
But Alter worries relying on neuts might lead
regulators to approve unnecessary booster
shots simply because they outdo existing
shots on that measure. “If [regulators] don’t
adapt, we’re going to end up overboosting,
and we’re going to be making the drug com-
panies really happy,” she says.
It’s also unclear whether a convincing cor-
relate from a vaccine that uses, say, mRNA,
applies to one that uses a different technol-
ogy. “We’re hoping to have more immune
correlate of protection information before
updates on that,” says Peter Marks, who
heads FDA’s vaccine division.
With more than a dozen vaccines now in
use, that information may arrive soon, Sette
says. Companies typically control the data
from clinical trials, but academic labs can
now compare recipients of different vaccines,
he says. “In the next few months ... a large
amount of data will be generated in academic
labs,” Sette says. “There’s going to be a funda-
mental wealth of information.” jNEWSScience’s
COVID-
reporting is
supported
by the
Heising-Simons
Foundation.A
lmost 200 years ago, the renowned
U.S. naturalist John James Audubon
hid a decaying pig carcass under a
pile of brush to test vultures’ sense
of smell. When the birds overlooked
the pig—while one flocked to a nearly
odorless stuffed deer skin—he took it as
proof that they rely on vision, not smell, to
find their food. His experiment cemented a
commonly held idea. Despite later evidence
that vultures and a few specialized avian
hunters use odors after all, the dogma that
most birds aren’t attuned to smell endured.
Now, that dogma is being eroded by find-
ings on birds’ behavior and molecular hard-
ware, two of which were published just last
month. One showed storks home in on the
smell of freshly mowed grass; another docu-
mented scores of functional olfactory recep-
tors in multiple bird species. Researchers are
realizing, says evolutionary biologist Scott
Edwards of Harvard University, that “olfac-
tion has a lot of impact on different aspects
of bird biology.”
Forty years ago, when ethologist Floriano
Papi proposed that homing pigeons find their
way back to a roost by sniffing out its chemi-
cal signature, his colleagues scoffed at the
idea. They pointed out that birds have several
other keen senses to guide them, including
sight and, in the case of pigeons and some
other species, a magnetic sense. “By then,
biological textbooks already stated unequiv-
ocally that birds have little to no sense of
smell, and many people still believe it—even
scientists,” says Danielle Whittaker, a chemi-
cal ecologist at Michigan State University.
Still, contrary evidence was already ac-
cumulating. In the 1960s, ornithologist
Kenneth Stager found vultures were at-
tracted to boxes with a carcass hidden
inside and fans that vented the odors—as
long as this bait wasn’t too decomposed, as
was likely the case in Audubon’s experiment.
Researchers also found that albatrosses,
shearwaters, and some other seabirds findSmell proves
powerful sense
for birds
New studies highlight
underappreciated role
of avian olfaction
ANIMAL BEHAVIORBy Elizabeth Pennisi