142 9 JULY 2021 • VOL 373 ISSUE 6551 sciencemag.org SCIENCECREDITS: (ILLUSTRATION) V. ALTOUNIAN/SCIENCE; (IMAGES) W. SURYA,BIOCHIM. BIOPHYS. ACTA(2018); D. WRAPP,SCIENCE,(2020); E.O. SAPHIRE,SCIENCE, (2001); ORIENTATIONS OF PROTEINS IN MEMBRANES DATABASEO
ther than running a placebo-
controlled clinical trial lasting many
months and involving tens of thou-
sands of people, is there any way
to be sure a COVID-19 vaccine will
work? Many researchers say stud-
ies of existing vaccines point to a shortcut:
Simply gauge a new vaccine’s ability to elicit
so-called neutralizing antibodies, which
bind to the virus and prevent it from enter-
ing cells. But several recent studies point to
other “correlates of protection”: “binding”
antibodies—which latch on to the virus but
don’t block entry—and another set of im-
mune warriors called T cells.Vaccine decisions may soon depend on a
better understanding of these supporting ac-
tors. Several manufacturers are developing
updates of their COVID-19 vaccines that are
tailored to protect against new viral variants
and could be used as booster shots. The com-
panies hope regulatory agencies won’t re-
quire evidence of efficacy in big clinical trials,
which are time-consuming, expensive, and
increasingly ethically fraught because some
of the participants receive a placebo even
though proven vaccines are now available.
Instead, developers would like to give an
updated vaccine to a much smaller group of
participants and then check whether they
produce the telltale immune responses.
(That’s how the annual updates of flu vac-cines are approved.) Health officials may also
turn to correlates when they compare the
powers of existing COVID-19 vaccines, autho-
rize new “mix and match” combinations, or
even when making decisions about entirely
new vaccines.
But finding robust correlates has been
challenging. During the megatrials that led
to the authorization of COVID-19 vaccines,
investigators monitored antibody responses
and tried to compare them with the odds
of participants getting sick. Different tri-
als, however, used different antibody assays
and different definitions of mild COVID-19,
the main endpoint in the trials. Many trials
lacked the statistical power to measure pro-
tection from hospitalization and death, argu-
ably a COVID-19 vaccine’s most important
task. “It’s anarchy because it’s always been
anarchy,” says John Moore, an immunologist
at Weill Cornell Medicine. “You’re dealing
with different academic labs and different
companies, and companies tend not to talk to
each other.” Few trials even looked carefully
at T cells, which are cumbersome to measure.
Still, two studies—first published as pre-
prints in March—confirmed the prediction
by Moore and many other scientists that neu-
tralizing antibodies (“neuts”) play a key role.
To “normalize” the different assays used in
the trials, they compared levels of antibody
elicited by each vaccine with those found in
people who naturally became infected in the
trial’s placebo group. In both analyses, the
vaccines that triggered higher levels of neuts
than the ones typically seen in recovered
people offered the best protection—strong
evidence of a correlation, Moore says.
“That’s a great relief to me,” says Penny
Moore (no relation to John Moore ), a viro-
logist at the National Health Laboratory
Service in South Africa, who helped measure
immune responses in different vaccine trials
and was “really puzzled” by the results. But
she and others say neuts are not the whole
story. “I just cannot work out for the life of
me how much [other immune responses] are
contributing and where they’re contributing,”
she says.
During the efficacy trials of the messenger
RNA (mRNA) vaccines made by the Pfizer-
BioNTech collaboration and Moderna, for
example, the first shot triggered barely mea-
surable levels of neutralizing antibodies, but
still offered substantial protection. “It sug-
gests there’s more than neutralizing anti-
bodies going on here,” says David Montefiori,
an immunologist at Duke University who
runs a lab that measures neuts for a hand-
ful of COVID-19 vaccine trials. Neuts sky-
rocketed only after the second mRNA shot,IN DEPTH
An antibody (red/pink) latches on to the surface
protein of SARS-CoV-2 (green).Can immune responses predict
which vaccines work best?
Elusive “correlates of protection” could lead to approvals
of boosters or new vaccines without big clinical trials
COVID-By Jon Cohen