SCIENCE science.org 7 JANUARY 2022 • VOL 375 ISSUE 6576 23exhibits distinct kinetics, which makes mea-
sures of such protection challenging ( 3 ). Cell-
mediated immunity has the added benefit of
conferring protection against a wide variety
of viral strains and may provide additional
protection against emerging variants ( 4 ). The
protective role of mucosal T cells, including
resident memory T cells ( 5 ), emphasizes the
importance of studying immune responses in
relevant tissue sites, not just in the blood ( 6 ).
There have been other attempts to define
COPs against SARS-CoV-2 infection and dis-
ease across a range of vaccines ( 7 , 8 ). These
studies generally support the premise that
circulating VN-Ab is a good indicator of pro-
tection, not only against severe disease but
also (if amounts are very high) against viral
replication in the mucosa (with or without
symptoms), thereby reducing transmission.
This does not mean that it is circulating an-
tibody that is causing protection: Antibody
in the serum does not normally diffuse
(or get transported) into mucosal fluids.
Protection against superficial infection de-
pends on mucosal antibodies [including im-
munoglobulin A (IgA)] and possibly on an-
tiviral T cells that reside within the linings
of the respiratory tract. T cells floating free
in the blood cannot have antiviral action;
they only act through direct contact with
infected cells. It could be that serum VN-Ab
initially correlates with protection but fades
and is replaced by other forms of immunity
(such as T cells) that become important
later. So, is the COP stable over time?
With the potential for a disconnection to
develop between a COP and the desired ef-
fect of future vaccines, such correlates require
constant scrutiny and reevaluation. For exam-
ple, the live attenuated influenza virus vaccine
that has been widely adopted for use in chil-
dren does not induce acceptable concentra-
tions of serum N-Abs. Instead, protective im-
mune responses that have been demonstrated
to result from the use of this vaccine require
techniques of site-specific mucosal monitor-
ing ( 9 ). COPs should therefore be validated
with vaccines that work in a variety of ways,
not just one type of vaccine. COPs should also
be robust in diverse settings, including after
natural infection and at delayed time points.
There are clear advantages and pitfalls to
the use of correlates and surrogates in diverse
medical fields ( 10 ). For example, measuring
viral load to determine the effect of antiviral
drugs in those living with hepatitis C or HIV
is a practical shortcut in tailoring treatment
to prevent disease and early death. The rela-
tionship between viral suppression and clini-
cal benefit is so clear that there is no need to
doubt viral load as a surrogate for long-term
benefit. However, the relationship between
a marker and the desired outcome can be
insecure or even misleading. For example,
the use of forced airflow measurements in
evaluating the reversibility of airflow ob-
struction induced by b2 agonists in patients
with asthma might distract clinicians and
patients from also treating airway inflam-
mation that is fundamental to pathogenesis.
Indeed, long-acting b2 agonists may enhance
inflammation ( 11 ) and so must be paired
with anti-inflammatory treatments, such as
inhaled steroids. Another example is in the
treatment of osteoporosis: The measurement
of bone density is widely accepted as a pre-
dictive marker of future bone fractures, but
measures that increase bone density may not
necessarily reduce fractures and might even
increase them ( 12 ).
An accurate and stable COP can save vac-
cine developers from performing large and
expensive trials to demonstrate the efficacy
of new or updated vaccines, can predict the
effects of established vaccines against new
variants of the pathogen, and may expedite
regulatory approval of updated or improved
vaccines. For example, the emergence of the
Omicron variant of SARS-CoV-2 ( 13 ) required
urgent investigation into the likely protec-
tive efficacy of existing vaccines and possibly
the redesign of vaccines to match Omicron’s
mutated spike protein. A reliable COP could
allow this to be done without large field tri-
als, accelerating vaccine rollout and saving
many lives. However, uncritical adoption of
a COP may have the perverse effect of focus-
ing future vaccine development on meeting
the correlate rather than preventing infection
and reducing disease and death. All is well
if the correlate is reliable in the face of new
viral variants and vaccines, but direct clinical
outcomes need to be kept firmly in focus. jREFERENCES AND NOTES- P. B. Gilbert et al., Science 375 , 43 (2022).
- E. G. Levin et al., N. Engl. J. Med. 385 , e84 (2021).
- J. M. Dan et al., Science 371 , eabf4063 (2021).
- Y. Pe n g et al., Nat. Immunol. 21 , 1336 (2020).
- A. Guvenel et al., J. Clin. Invest. 130 , 523 (2020).
- D. L. Faber, Nature 593 , 506 (2021).
- D. S. Khoury et al., Nat. Med. 27 , 1205 (2021).
- D. Cromer et al., Lancet Microbe 10.1016/S2666-
5247(21)00267-6 (2021). - J. Dunning et al., Mucosal Immunol. 13 , 566 (2020).
- US Food and Drug Administration, “Table of Surrogate
Endpoints That Were the Basis of Drug Approval or
Licensure” (2021); https://bit.ly/3oW1EEu. - A. I. Ritchie et al., Am. J. Respir. Cell Mol. Biol. 58 , 128
(2018). - S. Ma et al., Sci. Rep. 7 , 43399 (2017).
- World Health Organization, “Classification of Omicron
(B.1.1.529): SARS-CoV-2 Variant of Concern” (2021);
https://bit.ly/3dFgLNh.
ACKNOWLEDGMENTS
I am grateful to colleagues and collaborators, to members
of my laboratory, and to the ISARIC4C consortium for
comments. I am a scientific advisor to several vaccine
manufacturers, including Janssen, GSK, and Seqirus. I am
supported by the UK’s National Institute for Health Research
(NIHR) via Imperial’s Biomedical Research Centre, Imperial’s
Health Protection Research Unit in Respiratory Infections, the
Comprehensive Local Research Networks, and I am an NIHR
Senior Investigator (NIHR201385).10.1126/science.abn0007IMMUNOTHERAPYT cells to fix a
broken heart
In vivo eng ineered T cells
provide a promising
approach to treat cardiac
diseases
By Torahito A. Gao^1 and Yvonne Y. Chen1,2,3F
ibrosis that results from excessive ex-
tracellular matrix protein deposition
by activated cardiac fibroblasts is a
hallmark of heart disease and plays a
critical role in disease progression to
heart failure ( 1 ). However, therapies
targeting this cardiac fibrosis remain lim-
ited. On page 91 of this issue, Rurik et al. ( 2 )
describe a new approach to eliminate acti-
vated fibroblasts by harnessing the power
of engineered T cells. Lipid nanoparticles
(LNPs) carrying messenger RNA (mRNA)
that encodes a chimeric antigen receptor
(CAR) are used to generate CAR T cells in
mice, yielding a therapeutic T cell popula-
tion that is capable of ablating pathogeni-
cally activated fibroblasts and attenuating
cardiac fibrosis.
CARs are synthetic receptors that allow
immune cells—usually T cells—to recognize
targeted antigens and initiate antigen-spe-
cific immune responses ( 3 ). In conventional
CAR T cell therapy, T cells are isolated from
the blood of patients or healthy donors,
genetically modified to express a CAR tar-
geting a disease-associated antigen (e.g.,
a surface protein found on tumor cells),
and expanded ex vivo before infusion into
the patient. CAR T cell therapy has shown
substantial clinical efficacy against various
hematological malignancies, becoming the
first genetically modified cell therapy to re-
ceive US Food and Drug Administration ap-
proval ( 4 ). Following these successes, efforts
are underway to expand CAR T cell therapy
to other indications, such as infectious and
autoimmune diseases ( 5 ).
Previously, CAR T cells targeting fibro-
blast activation protein (FAP) were shown
to specifically target activated fibroblasts
and significantly reduce cardiac fibrosis in a(^1) Department of Chemical and Biomolecular Engineering,
University of California, Los Angeles (UCLA), Los Angeles,
CA, USA.^2 Department of Microbiology, Immunology, and
Molecular Genetics, UCLA, Los Angeles, CA, USA.^3 Parker
Institute for Cancer Immunotherapy Center at UCLA, Los
Angeles, CA, USA. Email: [email protected]