INSIGHTS | PRIZE ESSAY
830 25 FEBRUARY 2022 • VOL 375 ISSUE 6583 science.org SCIENCE
Autoantibodies (auto-Abs) have been de-
scribed for IFN-g, interleukin-6 (IL-6), IL-
17A, and IL-17F and associated with suscep-
tibility to infection ( 9 ). We first tested for the
presence of auto-Abs in a cohort of 987 in-
dividuals with critical COVID-19 compared
with more than 663 asymptomatic patients
( 10 ). In patients with critical COVID-19, 10%
had immunoglobulin G (IgG) auto-Abs that
neutralized high amounts of IFN-v and/or
the 13 individual types of IFN-a. Further,
these auto-Abs prevented IFN-a2 from
blocking SARS-CoV-2 in vitro.
In autoimmune polyglandular syndrome
type-1 (APS-1), affected individuals produce
auto-Abs against type I IFNs from early
childhood onward. Among a group of APS-1
patients, aged 8 to 48 years, infected with
SARS-CoV-2, we found that most were hospi-
talized for COVID-19 pneumonia, with a fatal
outcome for 18% ( 11 ). In a separate study of
over 4000 patients with severe and/or criti-
cal COVID-19, we detected auto-Abs that
neutralized more physiological concentra-
tions of IFN-a2 and/or IFN-v in over 15% of
patients with critical COVID-19 pneumonia,
including more than 20% of patients over
80 years, and ~20% of those who died ( 12 ).
Notably, another 1% of the patients only had
auto-Abs against IFN-b. When we looked at
a group of 34,000 uninfected individuals, we
found that the prevalence of auto-Abs that
neutralized high concentrations of type I
IFNs increased markedly with age. Auto-
Abs were present in 0.18% of those 18 to 69
years, 1.1% of those 70 to 80 years, and 3.4%
of those over 80 years. The proportion of pa-
tients that produced auto-Abs neutralizing
physiological concentrations (i.e., 100-fold
lower) was even greater, with 1% of those
under 70 years, 2.3% of those 70 to 80 years,
and 6.4% of those over 80 years.
The findings outlined here provide
clues to the reasons why COVID-19 is fa-
tal for some individuals 70 years and older
( 8 ). The presence of preexisting auto-Abs
against type I IFNs can account for severe
disease in some older individuals, as it
does in many younger patients present-
ing with life-threatening COVID-19. Since
discovering the role of auto-Abs to type I
IFNs in COVID-19 in 2020, I have focused
on leading the studies of these auto-Abs
in our laboratory and performing studies
on COVID-19 as part of the effort led by
Qian Zhang and Jean-Laurent Casanova
within the CHGE ( 4 ). Our observations
have several important medical implica-
tions: Patients infected with SARS-CoV-2
could be tested for auto-Abs against type
I IFNs (e.g., IFN-a2, IFN-v, IFN-b), and in
individuals in at-risk groups (e.g., people
70 years and older, or patients with au-
toimmune conditions), these tests could
be performed at any time (5, 9, 10, 12).
Auto-Ab–positive patients should be vac-
cinated against SARS-CoV-2 as a matter
of priority, but not with a live attenuated
vaccine (13, 14). In cases of infection, these
patients should be hospitalized and would
benefit from early treatment with antivi-
ral compounds, monoclonal antibodies
(15 –17), and/or IFN-b, provided they have
neither pneumonia nor auto-Abs against
IFN-b ( 18 ). Early administration of type I
IFNs in patients infected with SARS-CoV-2
could prevent viral growth and uncon-
trolled infection, which can lead to a cyto-
kine storm and life-threatening COVID-19.
Other treatments designed to enhance the
type I IFN pathway, or to replicate its an-
tiviral effects, are of potential interest for
the treatment of SARS-CoV-2 infection.
Beyond COVID-19, many other viral
diseases increase in severity with age,
suggesting a possible role of auto-Abs
against type I IFNs in their severity. We
have shown previously that auto-Abs that
neutralize type I IFNs underlie one-third
of adverse reactions to the live-attenuated
yellow fever virus vaccine ( 11 ). It therefore
appears likely that these auto-Abs also
underlie other viral infections, especially
those for which severity increases with age.
Influenza affects millions of people world-
wide every year, causing between 200,000and 650,000 deaths ( 19 ). It remains un-
clear why deaths from influenza dispro-
portionately affect the elderly ( 20 ), but
some of these deaths could be due to auto-
Abs that neutralize type I IFNs. Why does the
prevalence of auto-Abs against IFNs increase
with age? The answer might provide hints to
targeted treatments for preventing auto-Abs
from being produced in the first place, or for
their targeted removal prior to infection. It
might also help to explain other issues, from
the redundancy of type I IFNs to the causes
of various autoimmune diseases. jREFERENCES AND NOTES- A. T. Levin et al., Eur. J. Epidemiol. 35 , 1123 (2020).
- M. O’Driscoll et al., Nature 590 , 140 (2021).
- E. J. Williamson et al., Nature 584 , 430 (2020).
- J. L. Casanova, H. C. Su, Cell 181 , 1194 (2020).
- Q. Zhang et al., Science 370 , abd4570 (2020).
- M. J. Ciancanelli et al., Science 348 , 448 (2015).
- T. Asano et al., Sci. Immunol. 6 , abl4348 (2021).
- J. L. Casanova, L. Abel, Science 374 , 1080 (2021).
- C.-L. Ku, C.-Y. Chi, H. von Bernuth, R. Doffinger,
Hum. Genet. 139 , 783 (2020). - P. Bastard et al., Science 370 , abd4585 (2020).
- P. Bastard et al., J. Exp. Med. 218 , e20210554 (2021).
- P. Bastard et al., Sci. Immunol. 6 , abl4340 (2021).
- L. Sanchez-Felipe et al., Nature 590 , 320 (2021).
- P. Bastard et al., J. Exp. Med. 218 , e20202486 (2021).
- P. Chen et al., N. Engl. J. Med. 384 , 229 (2021).
- D. M. Weinreich et al., N. Engl. J. Med. 384 , 238 (2021).
- E. M. N. Ferré et al., Front. Immunol. 12 , 720205 (2021).
- P. Bastard et al., J. Clin. Immunol. 41 , 931 (2021).
- J. Paget et al., J. Glob. Health 9 , 020421 (2019).
- F. Krammer et al., Nat. Rev. Dis. Primers 4 , 3 (2018).
10.1126/science.abn9649
PHOTOS: (TOP TO BOTTOM COURTESY OF QUENTIN LEMAIRE/INSTITUT IMAGINE; COURTESY OF SCOTT BIERING; ANDREW SORNGRAND PRIZE WINNER
Paul Bastard
Paul Bastard, MD, PhD, is currently working as a chief resident in the
Department of Pediatrics at the Necker Hospital for Sick Children (AP-HP,
Paris, France) while also doing research in the Necker branch of the labora-
tory of Jean-Laurent Casanova, located at the Imagine Institute (University
of Paris and INSERM) and the Rockefeller University (New York, USA). His
research focuses on the genetic and immunological determinants of severe viral diseases,
including the causes and consequences of autoantibodies against type I interferons.FINALIST
Scott Biering
Scott Biering received undergraduate degrees from the University of
California, Los Angeles, and a PhD in microbiology from the University
of Chicago. He is currently a postdoctoral scholar at the University of
California, Berkeley, in the laboratory of Eva Harris. His present research
investigates the role of viral proteins like flavivirus nonstructural protein
1 (NS1) and SARS-CoV-2 spike (S) in inducing viral pathogenesis and promoting viral
dissemination. http://www.science.org/doi/10.1126/science.abn9651FINALIST
Lisa Wagar
Lisa Wagar received a BSc from the University of Ontario Institute of
Technology and a PhD from the University of Toronto. After complet-
ing her postdoctoral fellowship at Stanford University, she started her
laboratory in 2020 in the Department of Physiology and Biophysics at
the University of California, Irvine, where she is currently an assistant
professor. Her research focuses on translational human immunology and the use of or-
ganoids to understand the complex interactions that occur between immune cells upon
vaccination and infection in humans. http://www.science.org/doi/10.1126/science.abn9652