The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Intramuscular AZD7442 (Tixagevimab–

Cilgavimab) for Prevention of Covid-19
M.J. Levin, A. Ustianowski, S. De Wit, O. Launay, M. Avila, A. Templeton, Y. Yuan,
S. Seegobin, A. Ellery, D.J. Levinson, P. Ambery, R.H. Arends, R. Beavon, K. Dey,
P. Garbes, E.J. Kelly, G.C.K.W. Koh, K.A. Near, K.W. Padilla, K. Psachoulia,
A. Sharbaugh, K. Streicher, M.N. Pangalos, and M.T. Esser,
for the PROVENT Study Group*​​

A BS T R AC T

BACKGROUND
The monoclonal-antibody combination AZD7442 is composed of tixagevimab and The authors’ full names, academic de-
cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome grees, and affiliations are listed in the Ap-
pendix. Dr. Esser can be contacted at
coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to ­mark​.­esser@​­astrazeneca​.­com or at Vac-
have prophylactic and therapeutic effects in animal models. Pharmacokinetic data cines and Immune Therapies, BioPhar-
in humans indicate that AZD7442 has an extended half-life of approximately 90 days. maceuticals Research and Development,
AstraZeneca, 1 MedImmune Way, Gaith-
ersburg, MD 20878-2204.
METHODS
In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an in- *A list of the PROVENT Study Group
members is provided in the Supplemen-
creased risk of an inadequate response to vaccination against coronavirus disease tary Appendix, available at NEJM.org.
2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants
This article was published on April 20,
were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intra- 2022, at NEJM.org.
muscular injections, one containing tixagevimab and the other containing cilgavimab)
DOI: 10.1056/NEJMoa2116620
of either 300 mg of AZD7442 or saline placebo, and they were followed for up to Copyright © 2022 Massachusetts Medical Society.
183 days in the primary analysis. The primary safety end point was the incidence
of adverse events after a single dose of AZD7442. The primary efficacy end point
was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-
transcriptase–polymerase-chain-reaction assay) occurring after administration of
AZD7442 or placebo and on or before day 183.
RESULTS
A total of 5197 participants underwent randomization and received one dose of
AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group).
The primary analysis was conducted after 30% of the participants had become
aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%)
in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group
reported having at least one adverse event, most of which were mild or moderate
in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the
AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative
risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended
follow-up at a median of 6 months showed a relative risk reduction of 82.8%
(95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19–
related deaths occurred, all in the placebo group.
CONCLUSIONS
A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evi-
dent safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT
ClinicalTrials.gov number, NCT04625725.)

n engl j med  nejm.org 1

The New England Journal of Medicine
Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

V
accination against severe acute re- dose of AZD7442 (two consecutive intramuscular
spiratory syndrome coronavirus 2 (SARS- injections; one each of tixagevimab and cilgavimab)
CoV-2) has reduced the burden of corona- for preexposure prophylaxis against Covid-19 in
virus disease 2019 (Covid-19).1-4 However, some adults who had an increased risk of an inade-
persons, including immunocompromised persons quate response to Covid-19 vaccination, an in-
and those who cannot be vaccinated, remain at creased risk of exposure to SARS-CoV-2, or both.
risk for severe Covid-19.5-13 Participants who were at increased risk for an
Monoclonal antibodies, which protect against inadequate response to Covid-19 vaccination were
disease irrespective of immune system status and those who were classified as older (≥60 years of
provide rapid protection,14,15 are potential options
age), obese, immunocompromised, or unable to
for Covid-19 immunoprophylaxis. Some combi- receive vaccines without adverse effects or as hav-
nations of monoclonal antibodies are already in ing congestive heart failure, chronic obstructive
use through emergency or temporary authoriza- pulmonary disease, chronic kidney disease, or
tion for preexposure16 or postexposure17 prophy- chronic liver disease. Participants at increased risk
laxis against Covid-19 or treatment of mild-to- for exposure to SARS-CoV-2 included, but were
moderate disease.18,19 not limited to, health care workers (including
AZD7442 is a combination of two fully human, staff working in long-term care facilities), workers
SARS-CoV-2–neutralizing monoclonal antibodies in industrial settings such as meatpacking plants
(tixagevimab and cilgavimab) that are derived from (who have been shown to be at high risk for
antibodies isolated from B cells obtained from SARS-CoV-2 transmission), military personnel, stu-
persons infected with SARS-CoV-2. These anti- dents living in dormitories, and others living
bodies contain the half-life–extending M252Y/ together in close or high-density proximity. The
S254T/T256E (YTE) modification20 and the L234F/ trial is being conducted at 87 sites in Belgium,
L235E/P331S (TM) modification that decreases France, Spain, the United Kingdom, and the
binding of the Fc receptor and complement com- United States.
ponent C1q.21,22 Tixagevimab and cilgavimab si- The primary analysis was planned after ap-
multaneously bind to distinct, nonoverlapping proximately 24 primary end-point events had
epitopes of the SARS-CoV-2 spike-protein receptor- been confirmed or 30% of the trial participants
binding domain to potently neutralize the vi- had become aware of their randomized assign-
rus.22-25 AZD7442 has been shown to neutralize ment. The data cutoff for the primary analysis
SARS-CoV-2 and its variants of concern in vitro occurred on May 5, 2021. An additional extended
and has prophylactic and therapeutic effects in follow-up data cutoff for the primary end point,
nonhuman primates.22 key supportive analyses, and key secondary end
In a phase 1 study, intramuscular administra- points occurred on August 29, 2021. The estimated
tion of 300 mg of AZD7442 provided higher SARS- trial completion date is June 29, 2022.
CoV-2 serum neutralizing titers than those as- The trial consisted of a screening period of up
sociated with convalescent serum. SARS-CoV-2 to 7 days, a 366-day safety and efficacy assessment
serum neutralizing antibody titers remained three period, and an optional additional safety assess-
times as high as those associated with convales- ment 91 days after the end of the 366-day safety
cent plasma after 9 months, and AZD7442 was and efficacy assessment period. Participants were
also detected in the nasal mucosa.22 Here, we re- randomly assigned in a 2:1 ratio to receive a
port results from the ongoing, phase 3 PROVENT single 300-mg dose of AZD7442 (one 1.5-ml in-
trial, which evaluated AZD7442 for the preven- tramuscular injection of each antibody adminis-
tion of symptomatic and severe Covid-19 in adults tered consecutively) or saline placebo (two 1.5-ml
(≥18 years of age). intramuscular injections administered consecu-
tively) on day 1. The participants were monitored
Me thods for adverse events for 1 to 4 hours after the injec-
tions, and they were contacted weekly to monitor
Trial Design and Oversight for Covid-19 symptoms. Full details of the trial
In this ongoing, multicenter, double-blind, par- conduct are provided in the protocol (which in-
allel-group, randomized, placebo-controlled trial, cludes the statistical analysis plan), available with
we assessed the safety and efficacy of a single the full text of this article at NEJM.org.

2 n engl j med  nejm.org

The New England Journal of Medicine

Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 Monoclonal Antibodies for Prevention of Covid-19

The trial was conducted in accordance with SARS-CoV-2 result at screening, previous receipt
the ethical principles derived from international of a vaccine or biologic agent indicated for the
guidelines, including the Declaration of Helsinki prevention of SARS-CoV-2 infection or Covid-19,
(7th revision, 2013), the international ethical or an allergy to any component of AZD7442 or the
guidelines of the Council for International Or- placebo.
ganizations of Medical Sciences, applicable Good
Clinical Practice guidelines of the International End Points
Council for Harmonisation, and all applicable laws The primary safety end point was the incidence
and regulations. The trial protocol and all other of adverse events after intramuscular adminis-
relevant documentation were reviewed and ap- tration of a single dose of AZD7442, as compared
proved by a local or central institutional review with placebo. Adverse events, serious adverse
board or ethics committee for each site. All the events, medically attended adverse events, and ad-
participants provided written informed consent verse events of special interest were assessed. The
(with assistance from a legally authorized repre- primary efficacy end point was the first episode
sentative if required) before enrollment. An in- of symptomatic Covid-19, confirmed by positive
dependent, external adjudication committee, results on reverse-transcriptase–polymerase-chain-
whose members were unaware of the randomized reaction (RT-PCR) testing, with an onset after
assignments, provided a systematic assessment the administration of AZD7442 or placebo and on
of whether any deaths that occurred during the or before day 183. Participants were considered to
trial were associated with Covid-19. Details re- have had a primary end-point event if they pre-
garding the committee are provided in the Sup- sented with qualifying symptoms that were
plementary Appendix, available at NEJM.org. prespecified in the protocol (Table S1) and had
Representatives of AstraZeneca designed the a positive RT-PCR result between 5 days before
trial. Data were collected by the trial site inves- and up to 10 days after the onset of symptoms.
tigators in collaboration with a contract research Data for participants who had become aware of
organization (IQVIA) and AstraZeneca and were their randomized assignment for any reason and
analyzed by another contract research organiza- data for participants who had received a Covid-19
tion (ClinChoice) and AstraZeneca. All the authors vaccine were censored at the date of unblinding
vouch for the accuracy and completeness of the or vaccine administration, whichever was earlier.
data and for the fidelity of the trial to the protocol.
All the authors contributed to the writing and Statistical Analysis
editing of the manuscript and reviewed and ap- The safety analysis set consisted of all the partici-
proved the manuscript for submission, with legal pants who had undergone randomization and
approval from AstraZeneca. Agreements requir- received at least one injection of AZD7442 or
ing authors to maintain data confidentiality were placebo. The primary and secondary efficacy anal-
in place between AstraZeneca and the authors. yses involved the full preexposure analysis set,
AstraZeneca paid for medical writing and edito- which consisted of all the participants who had
rial support with an earlier version of the manu- undergone randomization, received at least one
script, which was developed in accordance with injection of AZD7442 or placebo, and did not have
Good Publication Practice guidelines. Additional RT-PCR–confirmed SARS-CoV-2 infection at base-
details regarding the trial design and methods line. The full analysis set consisted of all the par-
are provided in the Supplementary Appendix. ticipants who had undergone randomization and
received at least one injection. For the primary
Participants efficacy end-point analysis, we calculated that a
Eligible participants were adults (≥18 years of trial population of approximately 5150 participants
age) who had an increased risk of an inadequate who were randomly assigned in a 2:1 ratio, with a
response to Covid-19 vaccination or exposure to minimum of 18 observed events, would provide
SARS-CoV-2 owing to location or circumstance. the trial with approximately 90% power to detect
All the participants were required to have a nega- AZD7442 efficacy (a lower boundary of >0 for the
tive point-of-care SARS-CoV-2 serologic test result two-sided 95% confidence interval). This calcu-
at screening. Participants were excluded if they lation assumed 80% true efficacy and an annual-
had a history of SARS-CoV-2 infection, a positive ized attack rate of 3% in the placebo group.

n engl j med  nejm.org 3

The New England Journal of Medicine
Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

A Poisson regression with robust variance AZD7442 or placebo and were excluded from the
was used as the primary efficacy analysis model primary efficacy analysis. In the AZD7442 group,
to estimate the relative risk of the incidence of 1413 participants had become aware of their
symptomatic infection in the AZD7442 group as randomized assignment; 1406 participants (99.5%)
compared with the placebo group.26 The model had elected to become aware of their random-
included the trial group (AZD7442 or placebo) ized assignment because they wanted to consider
and age at informed consent (≥60 years or <60 receiving a Covid-19 vaccine. In the AZD7442
years) as covariates, with the log of follow-up group, 1161 received a Covid-19 vaccine (Fig. S1).
time used as an offset. AZD7442 efficacy was cal- In the placebo group, 749 participants had be-
culated as the relative risk reduction in the inci- come aware of their randomized assignment;
dence of infection in the AZD7442 group as 742 participants (99.1%) had elected to become
compared with that in the placebo group, or aware of their randomized assignment because
100% × (1 – the relative risk), with the result ex- they wanted to consider receiving a Covid-19 vac-
pressed as a percentage. cine. In the placebo group, 853 received a Covid-19
Missing events were not imputed for either vaccine. The percentages of participants with data
trial group. A hierarchical approach was used to that were censored because of loss to follow-up or
control for multiplicity of the primary, key sup- discontinuation, unblinding, or vaccination were
portive, and key secondary analyses on the basis balanced between the AZD7442 and placebo
of a two-sided alpha level of 0.05. A P value of less groups (Tables S2 and S3).
than 0.05 was considered to indicate statistical The demographic and clinical characteristics
significance. No statistical testing was performed at baseline were similar in the two groups (Ta-
for the safety end points. ble 1) and were consistent with those of the
broader population of persons with SARS-CoV-2
infection (Table S4). The mean age was 53.5 years,
R e sult s
43.4% of the participants were 60 years of age or
Participants older, 46.1% were female, 14.5% identified as
Between November 21, 2020, and March 22, 2021, Hispanic or Latinx, 73.0% were White, and 17.3%
a total of 5973 participants underwent screen- were Black. At baseline, a large proportion of the
ing; in the full analysis set, 3460 were randomly participants were considered by the investigators
assigned to receive AZD7442 and 1737 were ran- to have an increased risk of an inadequate re-
domly assigned to receive placebo. The last par- sponse to Covid-19 vaccination (73.3%) or exposure
ticipant received an injection on March 29, 2021. to SARS-CoV-2 (52.5%), and 77.5% had coexisting
In both groups, the median follow-up time from conditions that placed them at high risk for pro-
receipt of AZD7442 or placebo to the primary gression to severe Covid-19 disease.
analysis was 83 days, and the median 6-month
follow-up was 196 days. The primary analysis was Safety
conducted after 30% of the participants had elect- At the data-cutoff date for the primary analysis,
ed to become aware of their randomized as- at least one adverse event was reported in 1221
signment (e.g., in order to consider Covid-19 of 3461 participants (35.3%) in the AZD7442 group
vaccination). and 593 of 1736 participants (34.2%) in the pla-
The primary safety analysis included 3461 par- cebo group (Table 2). Most adverse events were
ticipants who had received AZD7442 and 1736 mild or moderate in intensity. The most common
participants who had received placebo; 1 partici- adverse event of special interest was an injection-
pant was assigned to receive placebo but incor- site reaction, which occurred in 2.4% of the par-
rectly received AZD7442. The primary efficacy ticipants in the AZD7442 group and in 2.1% of
analysis included 3441 participants who had re- those in the placebo group. The incidence of seri-
ceived AZD7442 and 1731 participants who had ous adverse events was similar in the two groups
received placebo. (Table S5).
All the participants underwent SARS-CoV-2 Eight deaths occurred; two deaths (both in the
RT-PCR testing at baseline; 25 of 5197 participants placebo group) were assessed by the adjudication
(0.5%; 19 in the AZD7442 group and 6 in the committee and were confirmed by testing as be-
placebo group) tested positive after receiving ing related to Covid-19 (Table 2). The other deaths

4 n engl j med  nejm.org

The New England Journal of Medicine

Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 Monoclonal Antibodies for Prevention of Covid-19

were the result of illicit-drug overdose (in 4 par- hospitalizations are provided in the Supplementary
ticipants [0.1%], 2 each in the AZD7442 and pla- Results section in the Supplementary Appendix.
cebo groups), myocardial infarction (in 1 partici- As compared with the primary analysis of the
pant [<0.1%] in the AZD7442 group), and renal primary end point, the median 6-month follow-up
failure (in 1 participant [<0.1%] in the AZD7442 data analyses showed an even lower incidence of
group). All the deaths were assessed by the site symptomatic Covid-19 (Table 3) in the AZD7442
investigators as being unrelated to AZD7442 or group than in the placebo group, with a relative
placebo. risk reduction of 82.8% (95% CI, 65.8 to 91.4).
The safety analysis at the median 6-month This increase in the efficacy estimate since the
data-cutoff date revealed no additional adverse time of the primary analysis was driven by a
events of special interest (Table S6) or unexpected greater percentage of events in the placebo group
longer-term safety signals (Table S7). Nine deaths (1.2%, in 12 of 960 participants) than in the
occurred in the AZD7442 group, and seven deaths AZD7442 group (0.1%, in 3 of 2003 participants)
occurred in the placebo group; none were con- during months 3 through 6, as compared with
sidered by the investigator to be related to AZD7442 months 0 through 3 (Table S10).
or placebo. No additional Covid-19–related deaths The efficacy of AZD7442 was consistent
occurred. across subgroups of participants with data that
could be evaluated; all point estimates of the
Efficacy relative risk reduction in the incidence of symp-
At the data-cutoff date for the primary analysis, tomatic illness with AZD7442 as compared with
symptomatic SARS-CoV-2 RT-PCR–positive illness placebo were greater than 44% (Fig. 1). Among
had occurred in 8 of 3441 participants (0.2%) in participants who were at increased risk for either
the AZD7442 group and in 17 of 1731 partici- an inadequate response to Covid-19 vaccination
pants (1.0%) in the placebo group. The primary or exposure to SARS-CoV-2, the relative risk re-
efficacy analysis met the statistical criterion for ductions (80.7% and 82.6%, respectively) were
trial success; that is, it showed a significantly similar to the relative risk reduction in the over-
lower incidence of symptomatic SARS-CoV-2 all population in the primary efficacy analysis
RT-PCR–positive illness in the AZD7442 group (76.7%). The time until symptomatic illness was
than in the placebo group (relative risk reduction, longer with AZD7442 than with placebo (hazard
76.7%; 95% confidence interval [CI], 46.0 to 90.0; ratio, 0.17; 95% CI, 0.08 to 0.33) (Fig. 2).
P<0.001) (Table 3). The unadjusted relative risk
reduction was the same as the relative risk re- Pharmacokinetics
duction after adjustment for age. The between- Serum levels of AZD7442 remained elevated for
group differences in the key supportive analyses 6 months after administration (Fig. S2A). The
and the key secondary end point (Table S8) were geometric mean (±SD) serum level of AZD7442
statistically significant within the testing strategy. was 18.9±2.1 μg per milliliter at day 8 and
At the data-cutoff date for the primary analy- 24.0±1.8 μg per milliliter at day 29, which trans-
sis, SARS-CoV-2 RT-PCR–positive severe or criti- lated to a SARS-CoV-2 geometric mean neutral-
cal illness (defined in Table S9) had occurred in izing antibody titer of 493.1 (95% CI, 469.3 to
none of the 3441 participants in the AZD7442 518.1) at day 8 and 677.3 (95% CI, 647.1 to 709.0)
group and in 1 of the 1731 participants (0.1%) in at day 29 in an 80% plaque-reduction neutraliza-
the placebo group. In the median 6-month follow- tion test that used wild-type virus (Fig. S2B). These
up data analyses, an additional four cases of se- titers were 16 times and 22 times as high, respec-
vere or critical Covid-19 were reported, for a total tively, as those from samples of convalescent plas-
of five cases, all of which occurred in the placebo ma obtained from patients with Covid-19.22
group. Six participants (0.2%) in the AZD7442
group and none of the participants in the pla- SARS-CoV-2 Variants
cebo group had emergency department visits for Viral genotypic data collected at illness visits were
symptoms that were consistent with Covid-19; available for 7 of 11 symptomatic participants in
the 6 participants were not hospitalized, and 3 of the AZD7442 group and 13 of 31 symptomatic
them subsequently tested positive for Covid-19. participants in the placebo group. Eleven of these
Results of the post hoc analysis of Covid-19–related participants were infected with a SARS-CoV-2 vari-

n engl j med  nejm.org 5

The New England Journal of Medicine
Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

ant of concern,27 including 1 participant with safety concerns. Pharmacokinetic data showed
B.1.351 (beta) in the AZD7442 group and 10 par- AZD7442 persistence in serum for 6 months af-
ticipants in the placebo group (5 participants ter administration, which resulted in SARS-
with B.1.1.7_1 [an alpha subvariant] and 5 par- CoV-2–neutralizing antibody titers that remained
ticipants with B.1.617.2 [delta]) (Table S11). higher at days 8 and 29 than those reported in
convalescent serum.22
Although Covid-19 vaccines are highly effec-
Discussion
tive, a need remains to protect persons who have
The data reported here provide support for the an insufficient response to Covid-19 vaccination.
use of AZD7442 as immunoprophylaxis to pre- Other monoclonal-antibody combinations that
vent Covid-19. The primary efficacy analysis and do not have extended half-lives can effectively
the key supportive analyses met the statistical prevent Covid-19,28,29 although those with half-
criterion for trial success. The incidences of lives of 18 to 32 days18,29 are administered month-
symptomatic RT-PCR–positive SARS-CoV-2 in- ly,16 and some are administered intravenously.28
fection and severe disease among infected par- Pharmacokinetic modeling data suggest that a
ticipants were lower in the AZD7442 group than single dose of AZD7442 could provide protection
in the placebo group, and there were no evident against Covid-19 for at least 6 months22; these

Table 1. Baseline Demographic and Clinical Characteristics of the Participants in the Full Analysis Set.*

AZD7442 Placebo Total

Characteristic (N = 3460) (N = 1737) (N = 5197)
Age — yr 53.6±15.0 53.3±14.9 53.5±15.0
Age group — no. (%)
≥60 yr 1500 (43.4) 757 (43.6) 2257 (43.4)
≥65 yr 817 (23.6) 409 (23.5) 1226 (23.6)
≥75 yr 148 (4.3) 70 (4.0) 218 (4.2)
Female sex — no. (%) 1595 (46.1) 802 (46.2) 2397 (46.1)
Race or ethnic group — no. (%)†
White race 2545 (73.6) 1249 (71.9) 3794 (73.0)
Black race 597 (17.3) 302 (17.4) 899 (17.3)
Asian race 110 (3.2) 60 (3.5) 170 (3.3)
American Indian or Alaska Native ethnic group 19 (0.5) 10 (0.6) 29 (0.6)
Native Hawaiian or other Pacific Islander ethnic group 4 (0.1) 4 (0.2) 8 (0.2)
Other‡ 185 (5.3) 112 (6.4) 297 (5.7)
Hispanic or Latinx ethnic group
No 2731 (78.9) 1412 (81.3) 4143 (79.7)
Yes 539 (15.6) 215 (12.4) 754 (14.5)
Unknown or not reported 190 (5.5) 110 (6.3) 300 (5.8)
BMI§ 29.6±6.9 29.6±7.0 29.6±6.9
Resident in long-term care facility — no. (%) 14 (0.4) 12 (0.7) 26 (0.5)
SARS-CoV-2 RT-PCR status — no. (%)¶
Negative 3334 (96.4) 1672 (96.3) 5006 (96.3)
Positive 19 (0.5) 6 (0.3) 25 (0.5)
Missing data 107 (3.1) 59 (3.4) 166 (3.2)
Increased risk of inadequate response to Covid-19 vaccination — no. (%)‖ 2546 (73.6) 1264 (72.8) 3810 (73.3)
Increased risk of exposure to SARS-CoV-2 — no. (%)** 1820 (52.6) 909 (52.3) 2729 (52.5)

6 n engl j med  nejm.org

The New England Journal of Medicine

Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 Monoclonal Antibodies for Prevention of Covid-19

Table 1. (Continued.)

AZD7442 Placebo Total

Characteristic (N = 3460) (N = 1737) (N = 5197)
High-risk factors for severe Covid-19 — no. (%)
Any high-risk factor 2666 (77.1) 1362 (78.4) 4028 (77.5)
Obesity: BMI ≥30 1456 (42.1) 712 (41.0) 2168 (41.7)
Hypertension 1229 (35.5) 637 (36.7) 1866 (35.9)
Smoking 720 (20.8) 370 (21.3) 1090 (21.0)
Diabetes 492 (14.2) 242 (13.9) 734 (14.1)
Asthma 378 (10.9) 198 (11.4) 576 (11.1)
Cardiovascular disease 272 (7.9) 151 (8.7) 423 (8.1)
Cancer 250 (7.2) 133 (7.7) 383 (7.4)
COPD 179 (5.2) 95 (5.5) 274 (5.3)
Chronic kidney disease 184 (5.3) 86 (5.0) 270 (5.2)
Chronic liver disease 149 (4.3) 91 (5.2) 240 (4.6)
Receipt of immunosuppressive therapy 109 (3.2) 63 (3.6) 172 (3.3)
Immunosuppressive disease 15 (0.4) 9 (0.5) 24 (0.5)
Sickle cell disease 1 (<0.1) 1 (0.1) 2 (<0.1)

* Plus–minus values are means ±SD. The full analysis set consisted of all the participants who had undergone randomization and received
at least one injection. COPD denotes chronic obstructive pulmonary disease, Covid-19 coronavirus disease 2019, and RT-PCR reverse-
transcriptase–polymerase chain reaction.
† Race and ethnic group were reported by the participants.
‡ This category may include unknown, not reported, or multiple races or ethnic groups, or missing data.
§ The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters.
¶ The 25 participants with a positive SARS-CoV-2 RT-PCR test at baseline were excluded from the full preexposure efficacy analyses but were
included in the safety analyses.
‖ Participants who were at increased risk for an inadequate response to Covid-19 vaccination were those who were classified as older (≥60
years of age), obese (BMI ≥30), immunocompromised, unable to receive vaccines without adverse effects, or as having congestive heart
failure, COPD, chronic kidney disease, or chronic liver disease (based on historical information from the Centers for Disease Control and
Prevention before Covid-19 vaccines became available).
** Participants who were at increased risk for exposure to SARS-CoV-2 included, but were not limited to, health care workers (including
staff working in long-term care facilities), workers in industrial settings such as meatpacking plants (who have been shown to be at high
risk for SARS-CoV-2 transmission), military personnel, students living in dormitories, and others living together in close or high-density
proximity.

data are supported by the pharmacokinetic data fore, AZD7442 is likely to be clinically active
presented here. Data from a phase 1 study have against the BA.1 subvariant. Emerging evidence
shown that AZD7442 has an extended half-life of suggests that the neutralizing activity of AZD7442
approximately 90 days, with levels detectable in against the BA.2 subvariant is only minimally
serum for 9 months.22 lower than that against the wild-type virus (lower
The complementary binding of tixagevimab by a factor of five in live-virus assays and by a
and cilgavimab to distinct regions of the viral factor of three in pseudovirus assays).30,35 Addi-
spike protein receptor-binding domain presents tional clinical studies are warranted to evaluate
a barrier to virus escape. In vitro studies have this issue further.
shown that AZD7442 and its parental antibodies The current trial was designed early in the
(CoV-2130 plus CoV-2196) retain some neutral- SARS-CoV-2 pandemic, when the effectiveness of
izing activity against the BA.1 subvariant of the Covid-19 vaccines in populations known to have
B.1.1.259 (omicron) variant, with neutralizing an insufficient response to vaccines (e.g., adults
activity reduced by a factor of 12 to 30 in live- ≥60 years of age) was uncertain. Although
virus assays30-32 and by a factor of 132 to 183 in Covid-19 vaccination has since been shown to be
pseudovirus30,33 assays. The potency of AZD7442 effective in such populations, some immuno-
(half-maximal inhibitory concentration geomet- compromised persons still have a poor response
ric mean titer of 51 to 277 ng per milliliter33,34) to vaccination.36 As such, AZD7442 was autho-
is higher than that of convalescent serum; there- rized by the Food and Drug Administration

n engl j med  nejm.org 7

The New England Journal of Medicine
Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Adverse Events in the Safety Analysis Set.*

AZD7442 Placebo Total

Adverse Event (N = 3461)† (N = 1736)† (N = 5197)

number of participants (percent)

Adverse events
Any adverse event 1221 (35.3) 593 (34.2) 1814 (34.9)
Mild 761 (22.0) 369 (21.3) 1130 (21.7)
Moderate 387 (11.2) 191 (11.0) 578 (11.1)
Severe 64 (1.8) 27 (1.6) 91 (1.8)
Serious adverse events
Any serious adverse event 50 (1.4) 23 (1.3) 73 (1.4)
Related to AZD7442 or placebo‡ 1 (<0.1)§ 0 1 (<0.1)
Adverse events leading to trial discontinuation 1 (<0.1)¶ 0 1 (<0.1)
Medically attended adverse events 360 (10.4) 157 (9.0) 517 (9.9)
Adverse events of special interest
Any adverse event of special interest 93 (2.7) 37 (2.1) 130 (2.5)
Injection-site reaction 82 (2.4) 36 (2.1) 118 (2.3)
Anaphylaxis‖ 1 (<0.1) 0 1 (<0.1)
Immune complex disease** 1 (<0.1) 0 1 (<0.1)
Other 9 (0.3) 2 (0.1) 11 (0.2)
Related to AZD7442 or placebo‡ 87 (2.5) 36 (2.1) 123 (2.4)
Adverse events leading to outcome of death††
All adverse events 4 (0.1) 4 (0.2) 8 (0.2)
Illicit-drug overdose 2 (0.1) 2 (0.1) 4 (0.1)
Myocardial infarction 1 (<0.1) 0 1 (<0.1)
Renal failure 1 (<0.1) 0 1 (<0.1)
Covid-19‡‡ 0 1 (0.1) 1 (<0.1)
Covid-19–related ARDS‡‡ 0 1 (0.1) 1 (<0.1)

* The safety analysis set consisted of all the participants who had undergone randomization and received at least one
injection of AZD7442 or placebo. Listed are data from participants with at least one event. Participants may have had
more than one event. Adverse events were coded with the use of the Medical Dictionary for Regulatory Activities, ver-
sion 24.0. ARDS denotes acute respiratory distress syndrome.
† One participant was assigned to receive placebo and incorrectly received AZD7442; in accordance with the trial proto-
col, this participant was included in the AZD7442 group for the safety analysis.
‡ Events were determined to be related to AZD7442 or placebo according to the judgment of the investigators.
§ The participant was hospitalized for severe (grade 3) inferior mesenteric-artery thrombosis. The investigator consid-
ered the event to be related to receipt of the trial agent. The sponsor did not find evidence to suggest a causal rela-
tionship between the event and the trial agent because of insufficient information about the circumstances surround-
ing the event, including possible risk factors, the clinical course, the trial agent received, and a detailed etiologic and
diagnostic workup. The participant remained in the trial.
¶ The participant, who had a medical history of type 2 diabetes mellitus and chronic kidney disease, died from kidney
failure. The investigator did not consider the event to be related to the trial agent and determined that the most likely
cause of death was renal failure.
‖ The participant had severe chest pain shortly after receiving an injection, and because of the participant’s labored
breathing, the investigator determined that the participant had had an anaphylactic reaction. The participant was
hospitalized on the same day for a severe (grade 3) elevated troponin level. The investigator considered the event
(anaphylaxis) to be an adverse event of special interest because of the timing of administration and the onset of
shortness of breath. The sponsor’s medical team assessed the causality of the adverse event of special interest and
did not agree that the event was anaphylaxis because the event did not meet the protocol definition of anaphylaxis.
The participant remained in the trial.
** The participant had hypothyroidism that was initially categorized as immune complex disease, an adverse event of
special interest, but this event was later removed as an adverse event of special interest because it did not meet the
protocol definition of immune complex disease.
†† All deaths were determined by the investigator to be unrelated to AZD7442 or placebo.
‡‡ The independent and external adjudication committee determined that this death was related to Covid-19.

8 n engl j med  nejm.org

The New England Journal of Medicine

Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 Monoclonal Antibodies for Prevention of Covid-19

(FDA) for the prevention of Covid-19 in persons

adjusted relative risk reductions for both the primary analysis and the median 6-month follow-up. An estimated relative risk reduction greater than 0 favored AZD7442, with a P value of
* The full preexposure analysis set consisted of all the participants who had undergone randomization, received at least one injection of AZD7442 or placebo, and did not have RT-PCR–

informed consent (≥60 years or <60 years), with the log of the follow-up time as an offset. Unadjusted relative risk reductions (95% CI) for the primary end point were the same as the
Relative Risk Reduction
with moderate-to-severe immune compromise

confirmed SARS-CoV-2 infection at baseline. Estimates were based on a Poisson regression with robust variance. The model included trial group (AZD7442 or placebo) and age at
or those in whom Covid-19 vaccination is not

82.8 (65.8–91.4)

77.4 (61.7–86.7)

75.8 (57.3–86.2)
% (95% CI)
recommended.30 In February 2022, the FDA rec-
ommended an increase in the dose of AZD7442
to 600 mg because of the emergence of the BA.1

Median 6-Mo Follow-up†

subvariant; recommendations for repeat dosing
intervals have yet to be confirmed, pending fur-
ther data. Other countries have continued to use
the 300-mg dose that was studied in the current

(N = 1731)

31 (1.8)

44 (2.5)

36 (2.1)
Placebo

no. of participants (%)

trial.37,38 Additional studies, including real-world
evidence studies, are under way to assess the ef-
fectiveness of AZD7442 in immunocompromised
populations, given the limited subgroup analy-

(N = 3441)
AZD7442
ses afforded by this trial.

11 (0.3)

20 (0.6)

18 (0.5)
The limitations of our trial include the low
number of events in smaller but important sub-
groups, including immunocompromised persons,
so that efficacy in these groups could not be

P Value

<0.001

<0.001

0.002
estimated. The allowance of participants to be-
come aware of their randomized assignment in
order to consider Covid-19 vaccination decreased
the number of participants who were available Relative Risk Reduction

76.7 (46.0–90.0)

77.3 (52.0–89.3)

68.8 (35.6–84.9)
for longer-term, double-blind follow-up. Chang-
Table 3. Primary End Point and Key Supportive Efficacy Analyses in the Full Preexposure Analysis Set.*

% (95% CI)
es in the clinical landscape that were driven by
the availability of vaccines resulted in a higher-
Primary Analysis

than-anticipated proportion of participants who

elected to become aware of their randomized as-

† This analysis was not prespecified in the trial protocol, so P values were not calculated.
signment in order to consider Covid-19 vaccina-
tion. Guidance from the data and safety monitor-
(N = 1731)

17 (1.0)

22 (1.3)

19 (1.1)
ing board and regulatory feedback from the FDA
Placebo

no. of participants (%)

regarding the need for participants to become

aware of their randomized assignment so that
they could consider vaccination increased the
incidence of unblinding in the latter part of the
(N = 3441)
AZD7442

8 (0.2)

10 (0.3)

12 (0.3)

trial. Also, the introduction of vaccines in par-

ticipating countries may have affected the inci-
dence of SARS-CoV-2 infection during the trial.
The strengths of our trial include the diverse
less than 0.05 indicating statistical significance.
First case of illness, regardless of unblind-
data censored at unblinding or receipt

trial population that encompassed a high pro-

First case of illness, including all deaths,
Primary end point: first case of illness, with
First Case of SARS-CoV-2 RT-PCR–Positive

with data censored at unblinding or

portion of adults older than 60 years of age and

ing or receipt of Covid-19 vaccine

persons with coexisting conditions who had an

increased risk of severe Covid-19, although there
receipt of Covid-19 vaccine

were too few events to statistically assess the

benefit of AZD7442 in preventing severe disease
of Covid-19 vaccine
Key supportive analyses

in these groups. Populations that are dispropor-

Symptomatic Illness

tionately affected by Covid-19 (e.g., Black and

Hispanic or Latinx populations39,40) were well
represented.
Clinical and pharmacokinetic assessments from
this trial are expected to continue for at least
12 months, with studies under way to evaluate

n engl j med  nejm.org 9

The New England Journal of Medicine
Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

A
Subgroup According to Baseline Characteristics AZD7442 Placebo Relative Risk Reduction (95% CI)
no. of participants with event (%)
Overall 11/3441 (0.3) 31/1731 (1.8) 82.8 (65.8 to 91.4)
Age
<60 yr 8/1945 (0.4) 19/976 (1.9) 79.6 (53.5 to 91.1)
≥60 yr 3/1496 (0.2) 12/755 (1.6) 87.8 (56.9 to 96.6)
Sex
Male 2/1856 (0.1) 16/934 (1.7) 93.9 (73.7 to 98.6)
Female 9/1585 (0.6) 15/797 (1.9) 70.3 (32.4 to 87.0)
Race or ethnic group
Asian 1/109 (0.9) 1/60 (2) 48.0 (−743.4 to 96.8)
Black 0/593 4/302 (1.3) 100
White 10/2533 (0.4) 24/1243 (1.9) 80.8 (59.9 to 90.8)
American Indian or Alaska Native 0/18 0/10
Native Hawaiian or other Pacific Islander 0/4 1/4 (25) 100
Hispanic or Latinx ethnic group
Yes 2/531 (0.4) 5/215 (2.3) 84.1 (18.1 to 96.9)
No 9/2721 (0.3) 25/1406 (1.8) 82.1 (61.7 to 91.6)
Resident in long-term care facility
Yes 0/13 1/12 (8) 100
No 11/3428 (0.3) 30/1719 (1.7) 82.3 (64.7 to 91.1)
Increased risk of inadequate response to Covid-19 vaccination
Yes 9/2536 (0.4) 22/1260 (1.7) 80.7 (58.0 to 91.1)
No 2/905 (0.2) 9/471 (1.9) 88.6 (47.4 to 97.5)
Increased risk of exposure to SARS-CoV-2
Yes 5/1806 (0.3) 14/905 (1.5) 82.6 (51.8 to 93.7)
No 6/1635 (0.4) 17/826 (2.1) 83.1 (57.2 to 93.3)
Geographic region
North America 9/2470 (0.4) 22/1228 (1.8) 80.3 (57.2 to 90.9)
United Kingdom 1/611 (0.2) 5/311 (1.6) 89.6 (11.1 to 98.8)
European Union 1/360 (0.3) 4/192 (2.1) 88.1 (–6.3 to 98.7)
–50 0 50 100
Placebo Better AZD7442 Better

B
Subgroup According to Coexisting Conditions AZD7442 Placebo Relative Risk Reduction (95% CI)
no. of participants with event (%)
Coexisting conditions
None 0/1126 12/541 (2.2) 100
≥1 11/2315 (0.5) 19/1190 (1.6) 71.3 (39.8 to 86.4)
High risk of severe Covid-19
Yes 11/2656 (0.4) 21/1359 (1.5) 74.1 (46.3 to 87.5)
No 0/785 10/372 (2.7) 100
Obesity (BMI ≥30)
Yes 7/1450 (0.5) 14/708 (2.0) 76.3 (41.3 to 90.4)
No 4/1982 (0.2) 16/1014 (1.6) 87.8 (63.4 to 95.9)
Hypertension
Yes 4/1227 (0.3) 10/634 (1.6) 79.5 (34.4 to 93.6)
No 7/2214 (0.3) 21/1097 (1.9) 84.4 (63.2 to 93.4)
Smoking
Yes 2/716 (0.3) 5/370 (1.4) 80.8 (–2.3 to 96.4)
No 9/2725 (0.3) 26/1361 (1.9) 83.5 (64.8 to 92.3)
Diabetes
Yes 1/486 (0.2) 3/242 (1.2) 82.9 (–62.6 to 98.2)
No 10/2955 (0.3) 28/1489 (1.9) 82.9 (64.7 to 91.7)
Asthma
Yes 2/377 (0.5) 3/198 (1.5) 66.6 (–97.8 to 94.4)
No 9/3064 (0.3) 28/1533 (1.8) 84.5 (67.2 to 92.7)
Cardiovascular disease
Yes 1/270 (0.4) 2/151 (1.3) 76.7 (–152.5 to 97.9)
No 10/3171 (0.3) 29/1580 (1.8) 83.2 (65.6 to 91.8)
Cancer
Yes 0/252 6/135 (4.4) 100
No 11/3189 (0.3) 25/1596 (1.6) 78.7 (56.8 to 89.5)
COPD
Yes 0/179 4/95 (4) 100
No 11/3262 (0.3) 27/1636 (1.7) 80.3 (60.4 to 90.2)
Chronic kidney disease
Yes 0/185 1/86 (1) 100
No 11/3256 (0.3) 30/1645 (1.8) 82.1 (64.4 to 91.1)
Chronic liver disease
Yes 1/149 (0.7) 1/91 (1) 44.5 (–1494.4 to 98.1)
No 10/3292 (0.3) 30/1640 (1.8) 84.0 (67.3 to 92.2)
Immunosuppressive treatment
Yes 1/109 (0.9) 2/64 (3) 71.7 (–301.0 to 98.0)
No 10/3332 (0.3) 29/1667 (1.7) 83.4 (65.9 to 91.9)
Immunosuppressive disease
Yes 0/16 0/9
No 11/3425 (0.3) 31/1722 (1.8) 82.8 (65.8 to 91.4)
Sickle cell disease
Yes 0/1 0/1
No 11/3440 (0.3) 31/1730 (1.8) 82.8 (65.8 to 91.4)
–50 0 50 100
Placebo Better AZD7442 Better

10 n engl j med  nejm.org

The New England Journal of Medicine

Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 Monoclonal Antibodies for Prevention of Covid-19

Figure 1 (facing page). Relative Risk Reduction in the In- the effectiveness of AZD7442 in immunocompro-
cidence of the First SARS-CoV-2 RT-PCR–Positive Symp- mised persons who receive this agent as immuno-
tomatic Illness with AZD7442 as Compared with Place- prophylaxis under emergency use authorization.
bo, at a Median 6-Month Follow-up. The results of this trial support the use of a single
Estimates are based on Poisson regression with robust dose of AZD7442 (two consecutive intramuscular
variance with the use of a full model or reduced model.
injections) for the prevention of symptomatic and
An estimated relative risk reduction greater than 0 fa-
vored AZD7442. Panel A shows the relative risk reduc- severe Covid-19.
tion according to the baseline demographic and clinical Supported by AstraZeneca and the U.S. government. AZD7442
characteristics of the participants. The relative risk re- is being developed under a contract (W911QY-21-9-0001) with
duction with AZD7442 could not be estimated for par- the Department of Health and Human Services, Office of the
ticipants of American Indian or Alaskan Native heritage Assistant Secretary for Preparedness and Response, Biomedical
or those with immunosuppressive disease or sickle cell Advanced Research and Development Authority, in partnership
disease, because there were no instances of SARS- with the Department of Defense, and with the Joint Program
CoV-2 RT-PCR–positive symptomatic illness in partici- Executive Office for Chemical, Biological, Radiological and
Nuclear Defense.
pants in those subgroups. Panel B shows the relative
Disclosure forms provided by the authors are available with
risk reduction according to the participants’ coexisting the full text of this article at NEJM.org.
conditions. The body-mass index (BMI) is the weight in A data sharing statement provided by the authors is available
kilograms divided by the square of the height in me- with the full text of this article at NEJM.org.
ters. Immunosuppressive treatment is medication that We thank the trial participants, their families, and all
suppresses the immune response, and immunosup- investigators involved in this trial; the members of the ad-
pressive disease is a medical condition that could sup- judication committee, who assessed deaths that occurred
press the immune response, regardless of treatment. during the trial: Mark A. Tidswell, M.D., of Tufts University
CI denotes confidence interval, COPD chronic obstruc- School of Medicine, Toby M. Maher, M.D., of the University
of Southern California, and Ashley Whittington, M.D., of the
tive pulmonary disease, Covid-19 coronavirus disease
London North West University Healthcare NHS Trust; Yousef
2019, NE not estimable, RT-PCR reverse-transcriptase– Fawadleh, B.Sc., and Elaine Harrop, M.Sc., of AstraZeneca, for
polymerase chain reaction, and SARS-CoV-2 severe leading the operational management of the trial; Yee-Man Ch-
acute respiratory syndrome coronavirus 2. ing, Ph.D., of AstraZeneca, for facilitating author discussions,
coordinating manuscript development, and critically reviewing

100 4
Hazard ratio, 0.17 (95% CI, 0.08–0.33)
90 Placebo, N=31 (1.8%)
3
Percentage of Participants with

80
Symptomatic Covid-19

70
2
60
50 1
AZD7442, N=11 (0.3%)
40
0
30
0 11 30 60 90 120 150 180
20
10
0
0 11 30 60 90 120 150 180
Days since Injection
No. at Risk
Placebo 1731 1680 1483 1177 991 856 774 472
AZD7442 3441 3323 2957 2393 2054 1815 1667 1044

Figure 2. Time to First SARS-CoV-2 RT-PCR–Positive Symptomatic Illness.

Shown are Kaplan–Meier curves from a time-to-event analysis of the proportion of participants in the full preexpo-
sure analysis set who had a first SARS-CoV-2 RT-PCR–positive symptomatic illness, with a median follow-up of 6
months. The hazard ratio and corresponding 95% confidence interval were obtained from a Cox proportional-haz-
ards model with the group as a covariate and with the stratification factor of age at informed consent (≥60 years or
<60 years). Tick marks indicate censored data. The inset shows the same data on an enlarged y axis.

n engl j med  nejm.org 11

The New England Journal of Medicine
Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

the manuscript; Lorna Forse, Ph.D., for medical writing sup- Stone, M.Res., and India Wright, M.Sc., all of Core Medica,
port and preparing the first draft of the manuscript, and Joe Knutsford, United Kingdom, for editorial support with an ear-
Alling, B.Sc., Linda Brown, B.Sc., Cellan Ellis, B.Sc., Matthew lier version of the manuscript.

Appendix
The authors’ full names and academic degrees are as follows: Myron J. Levin, M.D., Andrew Ustianowski, M.D., Ph.D., Stéphane
De Wit, M.D., Odile Launay, M.D., Ph.D., Miles Avila, M.P.H., Alison Templeton, Ph.D., Yuan Yuan, Ph.D., Seth Seegobin, Ph.D., Adam
Ellery, M.D., Dennis J. Levinson, M.D., Philip Ambery, M.B., Ch.B., Rosalinda H. Arends, Ph.D., Rohini Beavon, Ph.D., Kanika Dey,
M.Sc., Pedro Garbes, M.D., Elizabeth J. Kelly, Ph.D., Gavin C.K.W. Koh, Ph.D., F.R.C.P., Karen A. Near, M.D., Kelly W. Padilla,
Pharm.D., Konstantina Psachoulia, Ph.D., Audrey Sharbaugh, R.N., Ph.D., Katie Streicher, Ph.D., Menelas N. Pangalos, D.Sc., Ph.D.,
and Mark T. Esser, Ph.D.
The authors’ affiliations are as follows: the University of Colorado School of Medicine, Aurora (M.J.L.); North Manchester General
Hospital, Manchester (A.U.), Biometrics (A.T., S.S.) and Clinical Development (R.B., G.C.K.W.K.), Vaccines and Immune Therapies,
Biopharmaceuticals Research and Development (M.N.P.), AstraZeneca, Cambridge, and Mounts Bay Medical, Penzance (A.E.) — all in
the United Kingdom; the Division of Infectious Diseases, Saint-Pierre University Hospital, Université Libre de Bruxelles, Brussels
(S.D.W.); Université de Paris, INSERM French Clinical Research Infrastructure Network, Innovative Clinical Research Network in Vac-
cinology, Assistance Publique–Hôpitaux de Paris, Paris (O.L.); Chicago Clinical Research Institute, Chicago (D.J.L.); Clinical Develop-
ment, Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals Research and Development, AstraZeneca,
Gothenburg, Sweden (P.A.); Clinical Pharmacology and Quantitative Pharmacology (R.H.A.), Clinical Development (K.D., P.G., K.A.N.,
K.P.), Biometrics (M.A., Y.Y.), Translational Medicine (E.J.K., K.S.), and Vaccines and Immune Therapies (M.T.E.), Biopharmaceuticals
Research and Development, AstraZeneca, Gaithersburg, MD; and Clinical Development, Vaccines and Immune Therapies, Biopharma-
ceuticals Research and Development, AstraZeneca, Durham, NC (K.W.P., A.S.).

References
1. Haas EJ, Angulo FJ, McLaughlin JM, disease. Ann Rheum Dis 2021;​ 80:​1339- mL solution for injection or infusion.
et al. Impact and effectiveness of mRNA 44. Summary of product characteristics. 2021
BNT162b2 vaccine against SARS-CoV-2 8. Kamar N, Abravanel F, Marion O, (https://assets​.­publishing​.­service​.­gov​.­uk/​
infections and COVID-19 cases, hospitali- Couat C, Izopet J, Del Bello A. Three dos- ­government/​­uploads/​­system/​­uploads/​
sations, and deaths following a nation- es of an mRNA Covid-19 vaccine in solid- ­attachment_data/​­f ile/​­1012415/​­revised​-­gb​
wide vaccination campaign in Israel: an organ transplant recipients. N Engl J Med -­spc​-­ronapreve​-­clean​-­120mg​
observational study using national sur- 2021;​385:​661-2. -­ml12aug2021docx​.­pdf).
veillance data. Lancet 2021;​397:​1819-29. 9. Kennedy NA, Lin S, Goodhand JR, et 17. Food and Drug Administration. Fact
2. Lopez Bernal J, Andrews N, Gower C, al. Infliximab is associated with attenu- sheet for health care providers: emergency
et al. Effectiveness of the Pfizer-BioNTech ated immunogenicity to BNT162b2 and use authorization (EUA) of REGEN-COV
and Oxford-AstraZeneca vaccines on cov- ChAdOx1 nCoV-19 SARS-CoV-2 vaccines (casirivimab and imdevimab). 2021
id-19 related symptoms, hospital admis- in patients with IBD. Gut 2021;​70:​1884-93. (https://www​.­fda​.­gov/​­media/​­145611/​
sions, and mortality in older adults in 10. Narasimhan M, Mahimainathan L, ­download).
England: test negative case-control study. Clark AE, et al. Serological response in 18. Food and Drug Administration. Fact
BMJ 2021;​373:​n1088. lung transplant recipients after two doses sheet for health care providers: emergen-
3. Nasreen S, Chung H, He S, et al. Ef- of SARS-CoV-2 mRNA vaccines. Vaccines cy use authorization (EUA) of bamla-
fectiveness of COVID-19 vaccines against (Basel) 2021;​9:​708. nivimab and etesevimab. January 2022
symptomatic SARS-CoV-2 infection and 11. Bergwerk M, Gonen T, Lustig Y, et al. (https://www​.­fda​.­gov/​­media/​­145802/​
severe outcomes with variants of concern Covid-19 breakthrough infections in vac- ­download).
in Ontario. Nat Microbiol 2022;​7(3):​379- cinated health care workers. N Engl J Med 19. Food and Drug Administration. Fact
85. 2021;​385:​1474-84. sheet for healthcare providers: emergency
4. Pritchard E, Matthews PC, Stoesser N, 12. Dyal JW, Grant MP, Broadwater K, et use authorization (EUA) of sotrovimab.
et al. Impact of vaccination on new SARS- al. Covid-19 among workers in meat and February 2022 (https://www​.­fda​.­gov/​
CoV-2 infections in the United Kingdom. poultry processing facilities — 19 states, ­media/​­149534/​­download).
Nat Med 2021;​27:​1370-8. April 2020. MMWR Morb Mortal Wkly 20. Robbie GJ, Criste R, Dall’acqua WF, et
5. Agha ME, Blake M, Chilleo C, Wells Rep 2020;​69:​557-61. al. A novel investigational Fc-modified
A, Haidar G. Suboptimal response to 13. Taylor H, Wall W, Ross D, et al. Cross humanized monoclonal antibody, mota-
coronavirus disease 2019 messenger RNA sectional investigation of a COVID-19 vizumab-YTE, has an extended half-life in
vaccines in patients with hematologic outbreak at a London army barracks: neu- healthy adults. Antimicrob Agents Che-
malignancies: a need for vigilance in the tralising antibodies and virus isolation. mother 2013;​57:​6147-53.
postmasking era. Open Forum Infect Dis Lancet Reg Health Eur 2021;​2:​100015. 21. Oganesyan V, Gao C, Shirinian L, Wu
2021;​8(7):​ofab353. 14. Taylor PC, Adams AC, Hufford MM, H, Dall’Acqua WF. Structural character-
6. Medeiros-Ribeiro AC, Aikawa NE, de la Torre I, Winthrop K, Gottlieb RL. ization of a human Fc fragment engi-
Saad CGS, et al. Immunogenicity and Neutralizing monoclonal antibodies for neered for lack of effector functions. Acta
safety of the CoronaVac inactivated vac- treatment of COVID-19. Nat Rev Immunol Crystallogr D Biol Crystallogr 2008;​ 64:​
cine in patients with autoimmune rheu- 2021;​21:​382-93. 700-4.
matic diseases: a phase 4 trial. Nat Med 15. Pelfrene E, Mura M, Cavaleiro Sanch- 22. Loo Y-M, McTamney PM, Arends RH,
2021;​27:​1744-51. es A, Cavaleri M. Monoclonal antibodies as et al. The SARS-CoV-2 monoclonal anti-
7. Haberman RH, Herati R, Simon D, et anti-infective products: a promising fu- body combination, AZD7442, is protective
al. Methotrexate hampers immunogenic- ture? Clin Microbiol Infect 2019;​25:​60-4. in nonhuman primates and has an ex-
ity to BNT162b2 mRNA COVID-19 vac- 16. Medicines and Healthcare Products tended half-life in humans. Sci Transl
cine in immune-mediated inflammatory Regulatory Agency. Ronapreve 120 mg/ Med 2022;​14(635):​eabl8124.

12 n engl j med  nejm.org

The New England Journal of Medicine

Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 Monoclonal Antibodies for Prevention of Covid-19

23. Zost SJ, Gilchuk P, Case JB, et al. Po- 30. Food and Drug Administration. Fact 36. Kearns P, Siebert S, Willicombe M, et
tently neutralizing and protective human sheet for healthcare providers: emergency al. Examining the immunological effects
antibodies against SARS-CoV-2. Nature use authorization for Evusheld (tixa- of COVID-19 vaccination in patients with
2020;​584:​443-9. gevimab co-packaged with cilgavimab). conditions potentially leading to dimin-
24. Zost SJ, Gilchuk P, Chen RE, et al. 2021 (https://www​.­fda​.­gov/​­media/​­154701/​ ished immune response capacity — the
Rapid isolation and profiling of a diverse ­download). OCTAVE trial. August 23, 2021 (http://dx​
panel of human monoclonal antibodies 31. Dejnirattisai W, Huo J, Zhou D, et al. .­doi​.­org/​­10​.­2139/​­ssrn​.­3910058). preprint.
targeting the SARS-CoV-2 spike protein. SARS-CoV-2 Omicron-B.1.1.529 leads to 37. Therapeutic Goods Administration.
Nat Med 2020;​26:​1422-7. widespread escape from neutralizing an- Australian product information EVUSH-
25. Dong J, Zost SJ, Greaney AJ, et al. Ge- tibody responses. Cell 2022;​ 185(3):​ 467. ELD tixagevimab and cilgavimab. 2022
netic and structural basis for SARS-CoV-2 e15-484.e15. (https://www​.­ebs​.­tga​.­gov​.­au/​­ebs/​­picmi/​
variant neutralization by a two-antibody 32. VanBlargan LA, Errico JM, Halfmann ­picmirepository​.­nsf/​­pdf?OpenAgent&id
cocktail. Nat Microbiol 2021;​6:​1233-44. PJ, et al. An infectious SARS-CoV-2 =​­CP​-­2022​-­PI​-­01156​-­1&d=​
26. Zou G. A modified Poisson regression B.1.1.529 Omicron virus escapes neutral- ­20220314172310101&d=​
approach to prospective studies with bi- ization by therapeutic monoclonal anti- ­20220314172310101).
nary data. Am J Epidemiol 2004;​159:​702-6. bodies. Nat Med 2022;​28:​490-5. 38. Haute Autorité de Santé. Evusheld
27. World Health Organization. Tracking 33. National Center for Advancing Trans- (tixagévimab/cilgavimab) décision d’accès
SARS-CoV-2 variants. November 2021 lational Sciences. SARS-CoV-2 variants & précoce. 2021 (https://www​.­has​-­sante​.­fr/​
(https://www​.­who​.­int/​­en/​­activities/​ therapeutics: dataset browser. OpenData ­jcms/​­p_3304034/​­fr/​­evusheld​-­t ixagevimab/​
­t racking​-­SARS​-­CoV​-­2​-­variants/​­). portal. January 5, 2022 (https://opendata​ ­cilgavimab).
28. Cohen MS, Nirula A, Mulligan MJ, et .­ncats​.­nih​.­gov/​­variant/​­datasets?id=​­160). 39. Kirby T. Evidence mounts on the dis-
al. Effect of bamlanivimab vs placebo on 34. Zhou T, Wang L, Misasi J, et al. Struc- proportionate effect of COVID-19 on eth-
incidence of COVID-19 among residents tural basis for potent antibody neutraliza- nic minorities. Lancet Respir Med 2020;​8:​
and staff of skilled nursing and assisted tion of SARS-CoV-2 variants including 547-8.
living facilities: a randomized clinical B.1.1.529. Science 2022. Epub ahead of 40. Tai DBG, Shah A, Doubeni CA, Sia IG,
trial. JAMA 2021;​326:​46-55. print. Wieland ML. The disproportionate impact
29. O’Brien MP, Forleo-Neto E, Musser BJ, 35. Iketani S, Liu L, Guo Y, et al. Antibody of COVID-19 on racial and ethnic minori-
et al. Subcutaneous REGEN-COV anti- evasion properties of SARS-CoV-2 Omi- ties in the United States. Clin Infect Dis
body combination to prevent Covid-19. cron sublineages. Nature 2022. Epub 2021;​72:​703-6.
N Engl J Med 2021;​385:​1184-95. ahead of print. Copyright © 2022 Massachusetts Medical Society.

n engl j med  nejm.org 13

The New England Journal of Medicine
Downloaded from nejm.org at AZ LIBRARY on May 31, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.