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A Blurry Picture
* Case Records of the MGH
Case 20-2023: A 52-Year-Old Man with a Solitary Fibrous Tumor and
Hypoglycemia
* IMAGE CHALLENGE
What is the diagnosis?
* Editorial
Anticoagulation Conundrum in Acute Ischemic Stroke with Atrial Fibrillation
* Original Article
Familial Clonal Hematopoiesis in a Long Telomere Syndrome
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Oz...
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Editor’s Note: This article was published on February 9, 2022, at NEJM.org.
Original Article
FINAL ANALYSIS OF EFFICACY AND SAFETY OF SINGLE-DOSE AD26.COV2.S
List of authors.
* Jerald Sadoff, M.D.,
* Glenda Gray, M.B., B.Ch.,
* An Vandebosch, Ph.D.,
* Vicky Cárdenas, Ph.D.,
* Georgi Shukarev, M.D.,
* Beatriz Grinsztejn, M.D.,
* Paul A. Goepfert, M.D.,
* Carla Truyers, Ph.D.,
* Ilse Van Dromme, Ph.D.,
* Bart Spiessens, Ph.D.,
* Johan Vingerhoets, Ph.D.,
* Jerome Custers, Ph.D.,
* Gert Scheper, Ph.D.,
* Merlin L. Robb, M.D.,
* John Treanor, M.D.,
* Martin F. Ryser, M.D.,
* Dan H. Barouch, M.D.,
* Edith Swann, Ph.D.,
* Mary A. Marovich, M.D.,
* Kathleen M. Neuzil, M.D.,
* Lawrence Corey, M.D.,
* Jeffrey Stoddard, M.D.,
* Karin Hardt, Ph.D.,
* Javier Ruiz-Guiñazú, M.D.,
* Mathieu Le Gars, Ph.D.,
* Hanneke Schuitemaker, Ph.D.,
* Johan Van Hoof, M.D.,
* Frank Struyf, M.D.,
* and Macaya Douoguih, M.D.
* et al.,
* for the ENSEMBLE Study Group*
The members of the ENSEMBLE Study Group are listed in the Supplementary
Appendix, available at NEJM.org.
March 3, 2022
N Engl J Med 2022; 386:847-860
DOI: 10.1056/NEJMoa2117608
* Article
* Figures/Media
Metrics
* 26 References
* 23 Citing Articles
ABSTRACT
BACKGROUND
The Ad26.COV2.S vaccine was highly effective against severe–critical coronavirus
disease 2019 (Covid-19), hospitalization, and death in the primary phase 3
efficacy analysis.
METHODS
We conducted the final analysis in the double-blind phase of our multinational,
randomized, placebo-controlled trial, in which adults were assigned in a 1:1
ratio to receive single-dose Ad26.COV2.S (5×1010 viral particles) or placebo.
The primary end points were vaccine efficacy against moderate to severe–critical
Covid-19 with onset at least 14 days after administration and at least 28 days
after administration in the per-protocol population. Safety and key secondary
and exploratory end points were also assessed.
RESULTS
Median follow-up in this analysis was 4 months; 8940 participants had at least 6
months of follow-up. In the per-protocol population (39,185 participants),
vaccine efficacy against moderate to severe–critical Covid-19 at least 14 days
after administration was 56.3% (95% confidence interval [CI], 51.3 to 60.8; 484
cases in the vaccine group vs. 1067 in the placebo group); at least 28 days
after administration, vaccine efficacy was 52.9% (95% CI, 47.1 to 58.1; 433
cases in the vaccine group vs. 883 in the placebo group). Efficacy in the United
States, primarily against the reference strain (B.1.D614G) and the B.1.1.7
(alpha) variant, was 69.7% (95% CI, 60.7 to 76.9); efficacy was reduced
elsewhere against the P.1 (gamma), C.37 (lambda), and B.1.621 (mu) variants.
Efficacy was 74.6% (95% CI, 64.7 to 82.1) against severe–critical Covid-19 (with
only 4 severe–critical cases caused by the B.1.617.2 [delta] variant), 75.6%
(95% CI, 54.3 to 88.0) against Covid-19 leading to medical intervention
(including hospitalization), and 82.8% (95% CI, 40.5 to 96.8) against
Covid-19–related death, with protection lasting 6 months or longer. Efficacy
against any severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection was 41.7% (95% CI, 36.3 to 46.7). Ad26.COV2.S was associated with
mainly mild-to-moderate adverse events, and no new safety concerns were
identified.
CONCLUSIONS
A single dose of Ad26.COV2.S provided 52.9% protection against moderate to
severe–critical Covid-19. Protection varied according to variant; higher
protection was observed against severe Covid-19, medical intervention, and death
than against other end points and lasted for 6 months or longer. (Funded by
Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number,
NCT04505722. opens in new tab.)
INTRODUCTION
The Ad26.COV2.S vaccine (Johnson & Johnson–Janssen) is a recombinant,
replication-incompetent human adenovirus type 26 (Ad26) vector encoding a
full-length, membrane-bound severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) spike protein in a prefusion stabilized conformation.1,2 Primary
analysis of the phase 3 ENSEMBLE trial, performed when preset criteria had been
met and conducted during the early emergence of variants and for a median
follow-up of 58 days, showed 66.9% efficacy against moderate to severe–critical
(i.e., severe or critical) coronavirus disease 2019 (Covid-19) and greater than
85% efficacy against severe–critical disease.3 Here, we report the final
analysis of the double-blind phase of ENSEMBLE, which was conducted in
accordance with the protocol when data for more than 90% of the participants had
been unblinded.
METHODS
TRIAL DESIGN AND OVERSIGHT
We have reached the stage in this ongoing multinational, randomized,
double-blind, placebo-controlled, phase 3 trial at which crossover vaccination
of the participants in the control group has occurred. The trial was designed
and conducted and the data were analyzed and interpreted by the sponsor (Janssen
Research and Development) and collaborators (see the Supplementary Methods
section in the Supplementary Appendix, available with the full text of this
article at NEJM.org). The trial-site investigators collected and contributed to
the interpretation of the data. All the data were available to the authors, who
vouch for the accuracy and completeness of the data and for the fidelity of the
trial to the protocol, available at NEJM.org. Medical writers funded by the
sponsor assisted in drafting the manuscript.
TRIAL PARTICIPANTS
Participants were adults who were 18 years of age or older and were in good or
stable health, without coexisting conditions or with stable and well-controlled
coexisting conditions. Key exclusion criteria were previous receipt of a
Covid-19 vaccine or abnormal immune system function (see the Supplementary
Methods section). After emergency use authorization, participants who received
placebo during the double-blind phase became eligible for vaccination with
Ad26.COV2.S (crossover vaccination), provided they had not received another
Covid-19 vaccine outside the trial. This crossover shortened the follow-up time
in the projected double-blind phase of the trial.
PROCEDURES
Trial procedures are described in the Supplementary Methods section.
Participants were randomly assigned in a 1:1 ratio with the use of randomly
permuted blocks in an interactive Web-response system to receive Ad26.COV2.S
(5×1010 viral particles) or saline placebo as an intramuscular injection (0.5
ml). The investigators at the trial sites and the participants remained unaware
of the group assignments until the unblinding or crossover visit.
Primary and key secondary efficacy evaluations were based on centrally confirmed
Covid-19 cases (confirmed molecularly with the use of m-2000 SARS-CoV-2
real-time reverse-transcriptase polymerase chain reaction [RT-PCR], Abbott);
cases were clinically assessed independently by a clinical severity adjudication
committee. Participants responded to a twice-weekly questionnaire assessing
whether they had Covid-19 symptoms, which were reported with the use of the
electronic Symptoms of Infection with Coronavirus-19 questionnaire. Additional
details are provided in the Supplementary Methods section.
EFFICACY ASSESSMENTS
The two primary end points were vaccine efficacy against the first occurrence of
centrally RT-PCR–confirmed moderate to severe–critical Covid-19 with onset at
least 14 days after administration and at least 28 days after administration in
the per-protocol population (Table S1 in the Supplementary Appendix). Covid-19
case definitions and protocol-defined secondary and exploratory end points
(e.g., efficacy according to SARS-CoV-2 lineage) are provided in the
Supplementary Methods.
SAFETY ASSESSMENTS
Serious adverse events and suspected adverse events of special interest are
recorded throughout the trial. During the double-blind phase of the trial, a
safety subpopulation that included approximately 6000 participants recorded
solicited local and systemic adverse events in an electronic diary for 7 days
after administration and unsolicited adverse events for 28 days after
administration.
STATISTICAL ANALYSIS
The full analysis population included all the participants who underwent
randomization and received a dose of trial vaccine or placebo. The at-risk
population excluded participants who had a Covid-19 case with an onset before
day 15 or before day 29 for the vaccine efficacy evaluations at least 14 days
after administration or at least 28 days after administration, respectively.
Efficacy analyses were conducted in the per-protocol population, which included
participants who received vaccine or placebo in the double-blind phase;
participants who were seropositive or RT-PCR–positive at baseline were excluded
from the per-protocol population. Safety analyses were conducted with the full
analysis population. Participant data were censored on unblinding or receipt of
a Covid-19 vaccine outside the trial.
Statistical hypothesis testing was conducted in accordance with the prespecified
scheme for the control of familywise type I error as indicated with adjusted 95%
confidence intervals. End points that had already been inferentially evaluated
in the primary analysis were summarized descriptively with 95% confidence
intervals. Other prespecified end points not included in the prespecified scheme
for familywise type I error control (such as exploratory end points) are
summarized with descriptive 95% confidence intervals. Nonprespecified end points
are designated as post hoc. Exact Poisson regression was used for analyses of
efficacy and associated calculations of confidence intervals.4 Cumulative
incidence was estimated with Kaplan–Meier methods to evaluate time to the first
occurrence of Covid-19 and vaccine efficacy over time.
The frequency of serious adverse events was tabulated for the full analysis
population; the frequency and severity of solicited and unsolicited adverse
events were tabulated in the safety subpopulation.
RESULTS
PARTICIPANTS
Figure 1. Figure 1. Cases of Covid-19 According to SARS-CoV-2 Lineage (Full
Analysis Population).
The distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
lineages among cases of coronavirus disease 2019 (Covid-19) is shown for each
country in the trial over time during the double-blind phase of the trial. The
reference sequence is defined as the SARS-CoV-2 Wuhan-Hu-1 sequence but with the
D614G amino acid variation. At the time of the trial, sequences categorized as
“other” were those with substitutions not resulting in another SARS-CoV-2
lineage or variant. “Other+E484K” refers to sequences with E484K but no other
substitutions resulting in another SARS-CoV-2 lineage or variant.
Next-generation sequencing was performed with the use of the Swift Biosciences
SNAP Assay, version 2. Amino acid variants are defined as changes from the
reference sequence. The last available visit date across countries was July 1
through 9, 2021, and the last available date of onset for a primary end-point
case was June 26 (Argentina), March 24 (Brazil), April 22 (Chile), June 23
(Colombia), May 27 (Mexico), July 1 (Peru), July 5 (South Africa), and April 16
(United States). None of the cases were caused by the eta, kappa, theta, or
C.36.3 variant. The alpha, beta, gamma, and delta variants were variants of
concern according to World Health Organization definitions at the time of the
analysis.
Trial enrollment began on September 21, 2020, and the data cutoff for the final
analysis was July 9, 2021, with the end of the double-blind period varying among
countries. Table S2 shows case numbers in each country according to viral
lineage, and Figure 1 shows the detection of viral lineages over time according
to country. Emergency use authorization for Ad26.COV2.S occurred on February 27,
2021; crossover began after approval of protocol amendment 4, with the first
participant in the placebo group vaccinated on March 10, 2021. The
characteristics of the participants at baseline were balanced between trial
groups (Table S3) and were generally representative of the population at risk
for Covid-19 in the United States (Table S4). Worldwide, 19.5% of the
participants in the trial were 65 years of age or older, and 42.0% had
coexisting conditions.
In total, 43,788 participants underwent randomization and received vaccine or
placebo, and 39,185 participants who were seronegative for SARS-CoV-2 at
baseline were included in the per-protocol analysis population for the
double-blind phase (Fig. S1). At the time of the final analysis, 97% of the
participants had completed the double-blind phase or had withdrawn prematurely.
Median follow-up was 121 days (range, 1 to 284), and 35,788 (91.3%) and 8940
(22.8%) of the participants in the per-protocol population had follow-up of at
least 2 months and at least 6 months, respectively, in the double-blind phase.
Follow-up was nearly identical in the full analysis population (median, 123 days
[range, 0 to 284]; 40,260 [91.9%] and 11,290 [25.8%] of the participants had
follow-up of ≥2 months and ≥6 months, respectively).
EFFICACY AGAINST MODERATE TO SEVERE–CRITICAL COVID-19
Table 1. Table 1. Vaccine Efficacy against Covid-19 with Onset at Least 14 Days
and at Least 28 Days after the Administration of Vaccine or Placebo
(Per-Protocol at-Risk Population).
In the per-protocol at-risk population, 484 moderate to severe–critical Covid-19
cases with onset at least 14 days after administration were noted in the vaccine
group, as compared with 1067 in the placebo group (vaccine efficacy, 56.3%; 95%
confidence interval [CI], 51.3 to 60.8) (Table 1). Vaccine efficacy against
moderate to severe–critical Covid-19 with onset at least 28 days after
administration was 52.9% (95% CI, 47.1 to 58.1). The primary end point captured
most symptomatic disease with onset at least 28 days after administration, with
only 10 cases of mild Covid-19 occurring in the vaccine group and 12 in the
placebo group, resulting in efficacy of 52.4% (95% CI, 46.6 to 57.6) against any
symptomatic infection.
Figure 2. Figure 2. Cumulative Incidence of Moderate to Severe–Critical Covid-19
and Vaccine Efficacy over Time (Per-Protocol Population).
Panel A shows the Kaplan–Meier cumulative incidence of molecularly confirmed
moderate to severe–critical Covid-19 with onset at least 1 day after
administration of vaccine or placebo. Shading indicates the 95% confidence
interval. Panel B shows vaccine efficacy against moderate to severe–critical
Covid-19 over time; dark gray shading indicates the 95% pointwise confidence
interval, and light gray shading the 95% simultaneous confidence interval. The
graph includes 95% of the events that occurred before day 189, with the hazard
smoothed over 21 days. Participants were seronegative at baseline, as determined
by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) and serologic tests.
The Kaplan–Meier cumulative incidence curves for moderate to severe–critical
Covid-19 separated after 14 days (Figure 2A); vaccine efficacy persisted through
approximately 6 to 7 months after administration with a modest decline, after
which wide confidence intervals and low numbers of at-risk participants preclude
interpretation (Figure 2B). This apparent reduction in efficacy may be related
to the emergence of more neutralization-resistant variants toward the end of the
trial (Figure 1), as evidenced by the absence of a decline in efficacy against
minor, “other” viral sequences (i.e., SARS-CoV-2 with substitutions not
considered to result in another lineage or variant) (Fig. S2). Because efficacy
results for the primary end point were similar at 14 or more days and at 28 or
more days after administration, only the latter results are shown for secondary
and exploratory end points.
EFFICACY ACCORDING TO VIRAL LINEAGE
Figure 3. Figure 3. Vaccine Efficacy against Moderate to Severe–Critical
Covid-19 According to SARS-CoV-2 Lineage (Per-Protocol Population).
Shown is vaccine efficacy against moderate to severe–critical Covid-19 with
onset at least 14 days after administration (Panel A) and at least 28 days after
administration (Panel B). SARS-CoV-2 in the category of “Lineages other than the
reference strain” were all variants of concern or interest, with “other”
sequences excluded. At the time of the trial, sequences categorized as “other”
were those with substitutions not resulting in another SARS-CoV-2 lineage or
variant. “Other+E484K” refers to sequences with E484K but no other substitutions
resulting in another SARS-CoV-2 lineage or variant. Vaccine efficacy was not
calculated if fewer than 6 cases were observed for an end point. Confidence
intervals have not been adjusted for multiplicity and should not be used to
infer statistical significance.
New viral lineages emerged and became dominant in most countries in the trial
during the analysis period, with some variants occurring predominately in one
country (e.g., B.1.351 [beta] in South Africa, C.37 [lambda] in Peru, and
B.1.621 [mu] in Colombia) (Figure 1). Vaccine efficacy was 70.2% (95% CI, 35.3
to 87.6) against moderate to severe–critical Covid-19 caused by the B.1.1.7
(alpha) variant; 69.0% (95% CI, 59.1 to 76.8) against moderate to
severe–critical Covid-19 caused by SARS-CoV-2 classified as “other,” with
efficacy remaining stable through 195 days of follow-up; and 58.2% (95% CI, 35.0
to 73.7) against moderate to severe–critical Covid-19 caused by the reference
strain (B.1.D614G). Overall efficacy was 44.4% (95% CI, 34.6 to 52.8) against
SARS-CoV-2 lineages other than the reference strain (Figure 3), including 51.9%
(95% CI, 19.1 to 72.2) against the beta variant and 36.5% (95% CI, 14.1 to 53.3)
against the P.1 (gamma) variant; at the end of the double-blind period, there
was no observed difference between vaccine and placebo with respect to the 21
cases caused by the B.1.617.2 (delta) variant in South Africa (vaccine efficacy,
−5.7%; 95% CI, −177.7 to 59.2). The Kaplan–Meier curves suggest that efficacy
against the circulating reference strain and beta variant began 14 days and 25
days after immunization, respectively, and began immediately on exposure to the
alpha variant, which emerged at least 2 months after vaccination of the
participants in the vaccine group was completed (Figure 1). Kaplan–Meier curves
were plotted to the end of the double-blind phase, independent of whether cases
were occurring in both groups. An additional variant analysis was conducted for
cases that occurred during the double-blind period but were sequenced after
database lock; results were consistent with those of the initial analysis (Fig.
S3).
EFFICACY AGAINST SEVERE–CRITICAL COVID-19
Figure 4. Figure 4. Cumulative Incidence of Severe–Critical Covid-19 and Vaccine
Efficacy over Time (Per-Protocol Population).
Panel A shows the Kaplan–Meier cumulative incidence of molecularly confirmed
severe–critical Covid-19 with onset at least 1 day after administration of
vaccine or placebo. Shading indicates the 95% confidence interval. Panel B shows
vaccine efficacy against severe–critical Covid-19 over time; dark gray shading
indicates the 95% pointwise confidence interval, and light gray shading the 95%
simultaneous confidence interval. The graph includes 95% of the events that
occurred before day 189, with the hazard smoothed over 21 days. Participants
were seronegative at baseline, as determined by RT-PCR and serologic tests.
For severe–critical Covid-19, overall vaccine efficacy was 74.6% (95% CI, 64.7
to 82.1) (Table 1). The cumulative incidence curves, which began to separate
approximately 7 days after administration (Figure 4), with no evidence of waning
for approximately 6 to 7 months after administration.
Vaccine efficacy against severe–critical Covid-19 was 93.1% (95% CI, 54.4 to
99.8) for the reference strain; 71.8% (95% CI, 56.3 to 82.3) for non–reference
strain SARS-CoV-2 lineages, including “other” sequences with the E484K mutation;
78.4% (95% CI, 34.5 to 94.7) for the beta variant; 63.6% (95% CI, 18.8 to 85.1)
for the gamma variant; 67.6% (95% CI, −29.8 to 94.4) for the lambda variant; and
79.5% (95% CI, 38.5 to 94.9) for the mu variant. Only six cases of
severe–critical Covid-19 caused by the alpha variant and four caused by the
delta variant were reported (Fig. S4).
ADDITIONAL SECONDARY AND EXPLORATORY EFFICACY END POINTS
Vaccine efficacy against moderate to severe–critical Covid-19 with onset at
least 28 days after administration in all participants regardless of serostatus
at baseline, excluding participants in whom Covid-19 developed before day 29
(at-risk population), was 53.2% (95% CI, 47.5 to 58.4). Vaccine efficacy against
moderate to severe–critical Covid-19 with onset 1 day after administration was
52.6% (95% CI, 47.6 to 57.2).
Vaccine efficacy against Covid-19 with onset at least 28 days after
administration that led to medical intervention (including hospitalization) was
75.6% (adjusted 95% CI, 54.3 to 88.0) (Table 1) and lasted 6 to 7 months (Fig.
S5). Efficacy against severe–critical Covid-19 leading to medical intervention
(including hospitalization) was approximately 90% initially and tapered to 70%
by approximately 6 weeks, remaining at that level for 5 to 6 months. On the
basis of available sequences, 3 such cases were caused by the reference strain
(all in the placebo group) and 44 were caused by variants (11 in the vaccine
group and 33 in the placebo group; vaccine efficacy, 67.5%; 95% CI, 34.1 to
85.2) (Fig. S6). The severity and duration of symptoms, the effect on Covid-19
lasting longer than 28 days, and vaccine efficacy against any infection,
including asymptomatic infection, are described in the Supplementary Results
(Figs. S7 through S10).
Among the 2131 participants in the vaccine group who were seropositive for
SARS-CoV-2 nucleocapsid (N) protein at baseline as compared with the 18,924
participants in the placebo group who were seronegative at baseline, observed
vaccine efficacy against moderate to severe–critical Covid-19 was 97.7% (post
hoc 95% CI, 93.3 to 99.5) (Table S5); the small number of cases (3) in the
vaccine group precludes analysis of this end point according to viral lineage.
Previous infection alone, in an analysis involving seropositive and seronegative
placebo recipients, was found to provide 90.4% (95% CI, 83.2 to 95.1) protection
against moderate to severe–critical Covid-19.
Vaccine efficacy against Covid-19–related death was 82.8% (95% CI, 40.5 to 96.8)
(Table 1), with protection sustained through at least 6 months after
administration. At least 28 days after administration, 3 Covid-19–related deaths
occurred in the vaccine group (all in participants who were ≥60 years of age),
as compared with 17 in the placebo group.
EFFICACY IN SUBGROUPS
In subgroup analyses, vaccine efficacy against moderate to severe–critical
Covid-19 in participants with human immunodeficiency virus (HIV) infection was
found to be 23.5% (95% CI, −78.3 to 68.2). Vaccine efficacy against moderate to
severe–critical disease varied according to country: 33.1 (95% CI, 6.3 to 52.5)
in Peru, 45.3 (95% CI, 29.1 to 58.0) in Brazil, 49.3 (95% CI, 26.9 to 65.3) in
South Africa, and 69.7 (95% CI, 60.7 to 76.9) in the United States. Data on
additional subgroup analyses are provided in the Supplementary Results (Figs.
S11 and S12 and Table S6).
SAFETY
The safety subpopulation included 3356 participants in the vaccine group and
3380 in the placebo group. Overall, more solicited adverse events occurred in
the vaccine group than in the placebo group during the 7-day period after
administration. Grade 3 local and systemic solicited adverse events during the
7-day period were similar to those reported in the primary analysis (Fig. S13).
In general, lower reactogenicity was observed among older adults than among
younger adults. Among the 155 participants in the vaccine group who were
seropositive for SARS-CoV-2 at baseline (safety subpopulation), 60.0% and 52.9%
reported a solicited local or systemic adverse event, respectively, similar to
the percentages among the 3201 baseline-seronegative participants (54.5% and
60.6%, respectively). Grade 3 or higher solicited local adverse events were rare
among vaccine recipients, regardless of their serostatus at baseline (occurring
among 1.3% of those who were seropositive and 0.6% of those who were
seronegative). Grade 3 or higher systemic adverse events occurred in 1.3% of
seropositive vaccine recipients and 2.3% of seronegative vaccine recipients.
Unsolicited events of grade 3 or higher severity (safety subpopulation) and
unsolicited events of grade 3 or higher that were considered by the
investigators to be related to vaccine or placebo (full analysis population and
safety subpopulation) are summarized in Tables S7 and S8. Serious adverse events
that were not related to Covid-19 (full analysis population) occurred in 223
participants (1.0%) in the vaccine group and in 265 participants (1.2%) in the
placebo group. Additional information on serious adverse events is provided in
Table S9.
Imbalances in adverse events that occurred during a 28-day risk window after
administration are described in the Supplementary Results (Table S10). At the
time of the final analysis with prolonged follow-up, imbalances were seen for
tinnitus (15 cases in the vaccine group vs. 4 in the placebo group), urticaria
(13 vs. 6), convulsion (9 vs. 4), pulmonary embolism (10 vs. 5), and deep-vein
thrombosis (11 vs. 3); no imbalances were observed for the Guillain–Barré
syndrome (1 case per group) or Bell’s palsy (2 cases in the vaccine group and 1
in the placebo group) (Table S10). No cases of capillary leak syndrome,
myocarditis, or encephalitis were reported. Thrombosis with thrombocytopenia was
defined as an adverse event of special interest (Supplementary Methods). One
event, which occurred in a 25-year-old man within 28 days after administration
of Ad26.COV2.S, occurred in association with positivity for anti-PF4 antibodies
and met the Centers for Disease Control and Prevention (CDC) tier 1–2 and
Brighton Collaboration level 1 criteria for vaccine-induced immune thrombotic
thrombocytopenia (VITT, also known as thrombosis with thrombocytopenia
syndrome).
At the time of the final analysis, 83 deaths had been reported in the
double-blind phase (28 in the vaccine group and 55 in the placebo group, with 5
and 22, respectively, related to Covid-19 in the full analysis population). All
deaths were considered by the investigators to be unrelated to the vaccine or
placebo.
DISCUSSION
In the final analysis of the double-blind portion of our phase 3 trial, median
follow-up was 4 months, with 8940 participants having at least 6 months of
follow-up. A single dose of the Ad26.COV2.S vaccine remained effective (52.9%)
in preventing moderate to severe–critical Covid-19 and all symptomatic Covid-19
(52.4%), despite the emergence of variants during the trial. Efficacy against
severe–critical disease remained higher (74.6%) than efficacy against moderate
to severe–critical disease, with a lower point estimate for variants (93.1%
efficacy against the reference strain and 71.8% efficacy against non–reference
strain lineages, including “other” sequences with the E484K mutation),
indicating that Ad26.COV2.S induces higher levels of protection in proportion to
the severity of the disease and the nature of the viral mutation.
During the placebo-controlled period, which differed between countries on the
basis of when the participants became aware of the trial-group assignments, the
incidence of SARS-CoV-2 infection was highly variable geographically and over
time as new viral variants emerged. The reduction in overall efficacy in the
final analysis as compared with the primary analysis3 (vaccine efficacy for the
primary end point at least 28 days after administration, 66.1% in the primary
analysis and 52.9% in the final analysis) was most likely due to lower vaccine
efficacy against variants that appeared outside the United States (Latin
America) in this multinational trial after the primary analysis — for example,
10.1% against the lambda variant and 36.5% against the gamma variant. Regional
emergence of variants such as lambda and gamma contributed to the lower vaccine
efficacy that was observed for some subgroups (e.g., Asian, Hispanic, and
American Indian or Alaskan Native populations). In the United States, where the
alpha variant emerged after the reference strain, vaccine efficacy against
moderate to severe–critical Covid-19 was 69.7%.
The efficacy findings in this trial are consistent with durable immune responses
being elicited by Ad26.COV2.S5 and with immediate efficacy against the alpha
variant occurring at least 60 days after vaccination. Furthermore, the onset of
protection differed between the original strain (14 days) and the more
neutralization-resistant beta variant (25 days). The higher vaccine efficacy
observed against the more resistant beta variant6 as compared with the lower
efficacy against the less resistant lambda variant suggests that other factors
also played a role in protection.
Conclusions about vaccine efficacy against symptomatic Covid-19 caused by the
delta variant, including severe–critical Covid-19 (with only 4 cases among the
participants), were not possible in this trial because of the wide confidence
intervals. Real-world data from several studies7-10 — some of which analyzed
more severe symptomatic disease, against which this vaccine has higher efficacy
— have shown varying degrees of efficacy of Ad26.COV2.S against symptomatic
delta-variant infection. Effectiveness ranged from 60% to 94% against
hospitalization,7,8,10-12 13% to 78% against SARS-CoV-2 infection,8,9,12-14 and
52% to 82% against death after SARS-CoV-2 infection9,10 during periods and in
regions in which the delta variant was prominent.
Vaccine efficacy against symptomatic Covid-19 in participants with HIV infection
in our trial was low, at 23.5%, with wide confidence intervals. However, in a
large phase 3B study involving 477,234 participants, vaccine effectiveness was
73% against hospitalization and 65% against death among the approximately 37,000
participants living with HIV infection.10
We observed that participants with previous asymptomatic infection (defined by
serologic positivity for SARS-CoV-2 N protein and an absence of history of
symptomatic Covid-19) can benefit from immunization with a Covid-19 vaccine. In
a post hoc analysis, previous infection alone provided 90.4% protection against
symptomatic infection, and after administration of Ad26.COV2.S in seropositive
participants, 97.7% protection was observed in a comparison with seronegative
placebo recipients; these findings extended observations from previous
immunologic studies.15-17
When Covid-19 developed in participants who had received Ad26.COV2.S, they had
lower severity of illness, shorter duration of illness, and lower viral loads
than placebo recipients. In addition, vaccination with Ad26.COV2.S led to fewer
medical interventions (including hospitalization) than placebo (vaccine efficacy
against medical intervention ≥28 days after administration, 75.6%). Vaccine
efficacy against Covid-19–related death was 82.8% with onset at least 28 days
after administration, and the three Covid-19–related deaths among vaccine
recipients occurred in participants 60 years of age or older who were
seronegative at baseline and had coexisting conditions associated with an
increased risk of severe Covid-19.
Serious adverse events were rare: serious adverse events not associated with
Covid-19 occurred in approximately 1% of the participants in each group during
the double-blind period. Tinnitus was observed in postauthorization surveillance
and is classified as “very rare” in the fact sheet associated with the label.18
Of the very rare events occurring after vaccination that were identified after
marketing began,18,19 no cases of anaphylaxis or capillary leak syndrome
occurred, and one case of VITT20-22 meeting the CDC and Brighton Collaboration
criteria occurred in this trial. With 3 to 4 cases per million vaccinations
being reported in the postmarketing period, we would not expect to see more than
1 case of VITT in a clinical trial involving more than 43,000 participants
(21,898 of whom received Ad26.COV2.S).
Strengths of the current analysis included a longer follow-up period than in our
primary analysis that extends our primary findings, as well as the analysis of
vaccine efficacy across geographic regions, across diverse populations, and
against infection with variants. A limitation of the trial was the premature
discontinuation of follow-up in the placebo-controlled phase and variable
follow-up times among countries, depending on when approval of the
post–emergency use authorization amendment occurred (which permitted group
assignments to be revealed to participants and those in the placebo group to be
vaccinated). Therefore, for the delta and omicron variants, limited or no data
were obtained in the double-blind phase of the study. Going forward, vaccine
effectiveness for new variants will need to come from studies involving
real-world evidence.
On the basis of the reported results at the end of the double-blind phase, the
efficacy of Ad26.COV2.S against moderate to severe–critical disease and against
severe–critical disease was lower than that observed in clinical trials
assessing messenger RNA vaccines.23,24 The recently noted incidence of
breakthrough infections with the omicron variant in vaccine-primed persons,25
regardless of the primary vaccine regimen, suggests that a booster may be
required for all primary vaccine regimens. Recent data from a study involving
South African health care workers conducted during the omicron wave indicate 85%
efficacy of Ad26.COV2.S against hospitalization when given as a single priming
dose followed by a booster 6 to 9 months later.26
Overall, our findings indicate that a single dose of Ad26.COV2.S provided
protection against severe disease and hospitalization, which could be important
in regions requiring mass vaccination or in populations with poor adherence to
two-dose prime regimens, and support the use of Ad26.COV2.S in the ongoing
effort against the global Covid-19 pandemic.
FUNDING AND DISCLOSURES
Supported by Janssen Research and Development, an affiliate of Janssen Vaccines
and Prevention and part of the Janssen pharmaceutical companies of Johnson &
Johnson, and in whole or in part by federal funds from the Biomedical Advanced
Research and Development Authority, part of the Office of the Assistant
Secretary for Preparedness and Response at the Department of Health and Human
Services, under Other Transaction Agreement HHSO100201700018C, and from the
National Institute of Allergy and Infectious Diseases (NIAID), National
Institutes of Health. The NIAID provides grant funding to the HIV Vaccine Trials
Network (HVTN) Leadership and Operations Center(UM1 AI68614), the HVTN
Statistics and Data Management Center (UM1 AI68635), the HVTN Laboratory Center
(UM1 AI68618), the HIV Prevention Trials Network (HPTN) Leadership and
Operations Center(UM1 AI68619), the AIDS Clinical Trials Group (ACTG) Leadership
and Operations Center(UM1 AI68636), the Infectious Diseases Clinical Research
Consortium Leadership Group (UM1 AI148684) and Vaccine and Therapeutic
Evaluation Units (UM1 AI148576, UM1 AI148373, UM1 AI148685, UM1 AI148452).
Disclosure forms provided by the authors are available with the full text of
this article at NEJM.org.
This article was published on February 9, 2022, at NEJM.org.
A data sharing statement provided by the authors is available with the full text
of this article at NEJM.org.
We thank all the participants in this trial, the staff members at the trial
locations, the members of the data and safety monitoring board, all the
investigators at the clinical sites, the members of the clinical severity
adjudication committee (Janet S. Lee, Brian T. Garibaldi, Charles Shey Wiysonge,
Anoma Nellore, Timothy E. Albertson, Christian Sandrock, and Victor F. Tapson),
the COV3001 study team (Richard Gorman, Carmen A. Paez, James Kublin, Simbarashe
G. Takuva, Alex Greninger, Pavitra Roychoudhury, Robert W. Coombs, Keith R.
Jerome, Kimberly L. Taylor, Flora Castellino, Xiaomi Tong, Corrina Pavetto,
Teletha Gipson, Tina Tong, Marina Lee, James Zhou, Michael Fay, Daniel Wolfe,
Peter B. Gilbert, Ollivier Hyrien, Alex Luedtke, Hein Fennema, Kim Offergeld,
Nancy Cauwenberghs, Tamzin Tanner, Kelly McQuarrie, Chimeremma Nnadi, Obiageli
Sogbetun, Nina Ahmad, Ian De Proost, Cyrus Hoseyni, Paul Coplan, Najat Khan,
Peter Ronco, Sanne Roels, Daniel Backenroth, Jennifer Bogert, Fei Chen, Pei-Ling
Chu, Kimberly Cooper, Hilde Delanghe, John T. Jones, Monika Peeters, Willem
Talloen, Jose Pinheiro, Ilse Scheys, Pallavi Shetti, Nathalie Vaissiere, Jose
Salas, Molli Imola Sandor, Jiajun Xu, Dawn Furey, Jodi Meck, Boerries
Brandenburg, Jenny Hendriks, Jarek Juraszek, Marit de Groot, Griet Van Roey, and
Dirk Heerwegh), and Catherine DeBrosse and Jill E. Kolesar (Cello Health
Communications–MedErgy) for writing and editorial assistance, funded by Janssen
Global Services, with an earlier version of the manuscript.
AUTHOR AFFILIATIONS
From Janssen Vaccines and Prevention, Leiden, the Netherlands (J. Sadoff, G.
Shukarev, J.C., G. Scheper, M.L.G., H.S., J.V.H., M.D.); the South African
Research Council, Cape Town, South Africa (G.G.); Janssen Research and
Development, Beerse, Belgium (A.V., C.T., I.V.D., B.S., J.V., M.F.R., K.H.,
J.R.-G., F.S.); Janssen Research and Development, Spring House, PA (V.C.);
Evandro Chagas National Institute of Infectious Diseases–Fiocruz, Rio de Janeiro
(B.G.); the University of Alabama at Birmingham, Birmingham (P.A.G.); Walter
Reed Army Institute of Research, Silver Spring (M.L.R.), the National Institute
of Allergy and Infectious Diseases, Rockville (E.S., M.A.M.), and the Center for
Vaccine Development and Global Health, University of Maryland School of
Medicine, Baltimore (K.M.N.) — all in Maryland; the Biomedical Advanced Research
and Development Authority, Washington, DC (J.T.); the Center for Virology and
Vaccine Research, Beth Israel Deaconess Medical Center, Boston (D.H.B.); the
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center,
Seattle (L.C.); and Janssen Research and Development, Raritan, NJ (J. Stoddard).
Dr. Douoguih can be contacted at mdouogui@its.jnj.com or at Janssen Vaccines and
Prevention, Newtonweg 1, CP 2333 Leiden, the Netherlands.
The members of the ENSEMBLE Study Group are listed in the Supplementary
Appendix, available at NEJM.org.
SUPPLEMENTARY MATERIAL
ProtocolPDF8506KBSupplementary AppendixPDF4313KBDisclosure FormsPDF934KBData
Sharing StatementPDF72KB
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CITING ARTICLES (23)
Close Citing Articles
10.1056/NEJMoa2117608-t1
Table 1. Vaccine Efficacy against Covid-19 with Onset at Least 14 Days and at
Least 28 Days after the Administration of Vaccine or Placebo (Per-Protocol
at-Risk Population).*
End Point≥14 Days after Administration†≥28 Days after Administration‡Ad26.COV2.S
(N=19,400)Placebo
(N=19,398)Vaccine Efficacy (95% CI)Ad26.COV2.S
(N=19,113)Placebo
(N=18,924)Vaccine Efficacy (95% CI)no. of casesperson-yrno. of
casesperson-yr%no. of casesperson-yrno. of casesperson-yr%Moderate to
severe–critical Covid-19§4846685.610676440.256.3 (51.3 to
60.8)4336658.48836400.452.9 (47.1 to 58.1)18–59 yr3814682.18474514.256.6 (51.0
to 61.7)3404663.87164486.754.3 (48.0 to 60.0)≥60 yr1032003.52201926.055.0 (42.9
to 64.7)931994.61671913.746.6 (30.7 to 59.0)Symptomatic Covid-19 of any
severity¶4956683.810826437.455.9 (51.0 to 60.5)4436656.88956398.352.4 (46.6 to
57.6)Mild‖116683.8156437.429.4 (−64.6 to 70.7)106656.8126398.319.9 (−102.3 to
69.0)Moderate‖4296685.68626440.252.1 (46.1 to 57.4)3886658.47076400.447.2 (40.2
to 53.5)Severe–critical¶566774.62056625.273.3 (63.9 to
80.5)466733.81766542.174.6 (64.7 to 82.1)Any SARS-CoV-2
infection¶**††—————10386560.816996257.541.7 (36.3 to 46.7)‡‡Asymptomatic
SARS-CoV-2 infection¶††—————4986581.06696289.328.9 (20.0 to 36.8)‡‡Covid-19
leading to medical intervention¶§§186783.9746656.776.1 (56.9 to
87.7)¶166739.8646567.175.6 (54.3 to 88.0)‡‡Death from any
cause¶¶196787.0456669.358.5 (27.6 to 77.1)196742.4376577.349.9 (10.6 to
72.8)Covid-19–related death¶¶36786.9196668.484.5 (47.3 to
97.1)36742.2176576.482.8 (40.5 to 96.8)Covid-19 according to FDA harmonized
definition‖‖‖4926684.710676440.555.6 (50.5 to 60.2)4416657.38846399.652.0 (46.2
to 57.3)
* All coronavirus disease 2019 (Covid-19) cases were centrally confirmed unless
stated otherwise and occurred in participants who had been seronegative at
baseline, had negative results on
reverse-transcriptase–polymerase-chain-reaction (RT-PCR) testing before 14 or 28
days after administration of vaccine or placebo, and were considered to be at
risk for Covid-19. The follow-up time for each participant was defined as the
time from administration until onset of a Covid-19 episode or the end of the
double-blind period (July 9, 2021). Mild Covid-19 cases were defined by a
positive RT-PCR test result and at least one of the following signs or symptoms:
fever (body temperature, ≥38.0°C), sore throat, malaise, headache, myalgia,
gastrointestinal symptoms, cough, chest congestion, runny nose, wheezing, skin
rash, eye irritation or discharge, chills, loss of taste or smell, red or
bruised-looking feet or toes, and shaking chills or rigors. Moderate Covid-19
cases were defined by a positive RT-PCR test result and two or more of the
following symptoms: fever (body temperature, ≥38.0°C), heart rate of at least 90
beats per minute, shaking chills or rigors, sore throat, cough, malaise,
headache, myalgia, gastrointestinal symptoms, loss of taste or smell, and red or
bruised-looking feet or toes; or one or more of the following symptoms:
respiratory rate of at least 20 breaths per minute, abnormal oxygen saturation
(but >93% while breathing room air at sea level), clinical or radiologic
evidence of pneumonia, radiologic evidence of deep-vein thrombosis, and
shortness of breath or difficulty breathing. Severe–critical Covid-19 cases were
defined by a positive RT-PCR test result and one or more of the following
features: signs of severe systemic illness (respiratory rate, ≥30 breaths per
minute; heart rate, ≥125 beats per minute; oxygen saturation, ≤93% while
breathing room air at sea level; or ratio of partial pressure of oxygen [in mm
Hg] to fraction of inspired oxygen, <300); respiratory failure (leading to
receipt of high-flow oxygen, noninvasive ventilation, mechanical ventilation, or
extracorporeal membrane oxygenation [ECMO]); shock; significant acute renal,
hepatic, or neurologic dysfunction; admission to an intensive care unit; or
death.
† The at-risk population excluded participants who were RT-PCR–positive between
day 1 and day 14.
‡ The at-risk population excluded participants who were RT-PCR–positive between
day 1 and day 28.
§ The primary end points were the first occurrence of centrally RT-PCR–confirmed
moderate to severe–critical Covid-19 with onset at least 14 days after
administration and at least 28 days after administration. One participant had a
moderate case of Covid-19 and later had a severe case; the adjudication
committee considered these to be two separate infections.
¶ This end point was a confirmatory secondary end point.
‖ This end point was a supportive secondary end point.
** This category includes undetected cases that were subsequently detected
through a positive serologic result (according to the clinical severity
adjudication committee), which did not count as either symptomatic cases
(because they were RT-PCR–negative) or asymptomatic cases.
†† Data on this end point were not obtained for cases in which onset occurred
after 14 days after administration.
‡‡ The 95% confidence intervals for vaccine efficacy against any severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, asymptomatic
infections, and Covid-19 leading to medical intervention were adjusted for
multiplicity on the basis of prespecified procedures for familywise type I error
control. All other confidence intervals have not been adjusted for multiplicity
and should not be used to infer statistical significance.
§§ Medical intervention included hospitalization as adjudicated by the clinical
severity adjudication committee, admission to an intensive care unit, mechanical
ventilation, and ECMO, linked to objective measures such as decreased
oxygenation and findings on radiography or computed tomography.
¶¶ This end point was an exploratory end point.
‖‖ At the time the protocol was written, the Food and Drug Administration (FDA)
harmonized Covid-19 definition was a positive RT-PCR test result plus any of the
following symptoms: fever or chills, cough, shortness of breath or difficulty
breathing, fatigue, muscle or body aches, headache, new loss of taste or smell,
sore throat, congestion or runny nose, nausea or vomiting, and diarrhea.
* Permissions
* Slide Set
FIGURES/MEDIA
1. Figure 1. Cases of Covid-19 According to SARS-CoV-2 Lineage (Full Analysis
Population).
Figure 1. Cases of Covid-19 According to SARS-CoV-2 Lineage (Full Analysis
Population).
The distribution of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) lineages among cases of coronavirus disease 2019 (Covid-19) is
shown for each country in the trial over time during the double-blind phase
of the trial. The reference sequence is defined as the SARS-CoV-2 Wuhan-Hu-1
sequence but with the D614G amino acid variation. At the time of the trial,
sequences categorized as “other” were those with substitutions not resulting
in another SARS-CoV-2 lineage or variant. “Other+E484K” refers to sequences
with E484K but no other substitutions resulting in another SARS-CoV-2
lineage or variant. Next-generation sequencing was performed with the use of
the Swift Biosciences SNAP Assay, version 2. Amino acid variants are defined
as changes from the reference sequence. The last available visit date across
countries was July 1 through 9, 2021, and the last available date of onset
for a primary end-point case was June 26 (Argentina), March 24 (Brazil),
April 22 (Chile), June 23 (Colombia), May 27 (Mexico), July 1 (Peru), July 5
(South Africa), and April 16 (United States). None of the cases were caused
by the eta, kappa, theta, or C.36.3 variant. The alpha, beta, gamma, and
delta variants were variants of concern according to World Health
Organization definitions at the time of the analysis.
2. Table 1. Vaccine Efficacy against Covid-19 with Onset at Least 14 Days and
at Least 28 Days after the Administration of Vaccine or Placebo
(Per-Protocol at-Risk Population).*
Table 1. Vaccine Efficacy against Covid-19 with Onset at Least 14 Days and
at Least 28 Days after the Administration of Vaccine or Placebo
(Per-Protocol at-Risk Population).
3. Figure 2. Cumulative Incidence of Moderate to Severe–Critical Covid-19 and
Vaccine Efficacy over Time (Per-Protocol Population).
Figure 2. Cumulative Incidence of Moderate to Severe–Critical Covid-19 and
Vaccine Efficacy over Time (Per-Protocol Population).
Panel A shows the Kaplan–Meier cumulative incidence of molecularly confirmed
moderate to severe–critical Covid-19 with onset at least 1 day after
administration of vaccine or placebo. Shading indicates the 95% confidence
interval. Panel B shows vaccine efficacy against moderate to severe–critical
Covid-19 over time; dark gray shading indicates the 95% pointwise confidence
interval, and light gray shading the 95% simultaneous confidence interval.
The graph includes 95% of the events that occurred before day 189, with the
hazard smoothed over 21 days. Participants were seronegative at baseline, as
determined by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) and
serologic tests.
4. Figure 3. Vaccine Efficacy against Moderate to Severe–Critical Covid-19
According to SARS-CoV-2 Lineage (Per-Protocol Population).
Figure 3. Vaccine Efficacy against Moderate to Severe–Critical Covid-19
According to SARS-CoV-2 Lineage (Per-Protocol Population).
Shown is vaccine efficacy against moderate to severe–critical Covid-19 with
onset at least 14 days after administration (Panel A) and at least 28 days
after administration (Panel B). SARS-CoV-2 in the category of “Lineages
other than the reference strain” were all variants of concern or interest,
with “other” sequences excluded. At the time of the trial, sequences
categorized as “other” were those with substitutions not resulting in
another SARS-CoV-2 lineage or variant. “Other+E484K” refers to sequences
with E484K but no other substitutions resulting in another SARS-CoV-2
lineage or variant. Vaccine efficacy was not calculated if fewer than 6
cases were observed for an end point. Confidence intervals have not been
adjusted for multiplicity and should not be used to infer statistical
significance.
5. Figure 4. Cumulative Incidence of Severe–Critical Covid-19 and Vaccine
Efficacy over Time (Per-Protocol Population).
Figure 4. Cumulative Incidence of Severe–Critical Covid-19 and Vaccine
Efficacy over Time (Per-Protocol Population).
Panel A shows the Kaplan–Meier cumulative incidence of molecularly confirmed
severe–critical Covid-19 with onset at least 1 day after administration of
vaccine or placebo. Shading indicates the 95% confidence interval. Panel B
shows vaccine efficacy against severe–critical Covid-19 over time; dark gray
shading indicates the 95% pointwise confidence interval, and light gray
shading the 95% simultaneous confidence interval. The graph includes 95% of
the events that occurred before day 189, with the hazard smoothed over 21
days. Participants were seronegative at baseline, as determined by RT-PCR
and serologic tests.
* Contents
* Abstract
* Introduction
* Methods
* Results
* Discussion
* Funding and Disclosures
* Author Affiliations
* Supplementary Material
* References
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March 3, 2022
N Engl J Med 2022; 386:847-860
DOI: 10.1056/NEJMoa2117608
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{* #forgotPasswordForm *}
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Enter the email address associated with your account then click Continue. We
will email you a link to a page where you can easily create a new password.
{* signInEmailAddress *}
{* /resetPasswordForm *}
If the address matches an existing account, you will receive an email with
instructions to reset your password.
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