Articles
https://doi.org/10.1038/s41591-021-01330-9
1
NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.
2
Fosun Pharma,
Boston, MA, USA.
3
Taizhou City Center for Disease Control and Prevention, Taizhou, China.
4
Fosun Pharma, Beijing, China.
5
Taizhou Vaccine Clinical
Research Center, Taizhou, China.
6
Department of Pharmacy, Army Medical University, Chongqing, China.
7
Taizhou People’s Hospital, Taizhou, China.
8
BioNTech SE, Mainz, Germany.
9
Center for Global Health, Nanjing Medical University, Nanjing, China.
10
These authors contributed equally: Jingxin Li,
Aimin Hui.
✉
e-mail: aimin.hui@fosunpharma.com; tzheart@126.com; jszfc@vip.sina.com
S
ince the identification of the first cases of coronavirus disease
2019 (COVID-19) caused by severe acute respiratory syn
-
drome coronavirus 2 (SARS-CoV-2) in December 2019, the
resulting pandemic has led to more than 130 million confirmed
COVID-19 cases, and more than 2.8 million deaths worldwide as of
6 April 2021 (refs.
1–3
). The development of an efficacious COVID-19
vaccine is currently the world’s leading research priority
4
. According
to a survey conducted by the World Health Organization, 87 vac
-
cine candidates are being assessed in clinical trials, of which 23 are
ongoing phase 3 trials, and an additional 186 vaccine candidates are
in preclinical trials
5
.
Compared with other traditional approaches such as those
involving inactivated or live virus vaccines or recombinant pro
-
teins, the messenger RNA-based prophylactic vaccine platform
is a recently developed vaccine technology
6–8
. The RNA-based
platform has enabled rapid vaccine development in response
to the COVID-19 pandemic and provides flexibility in antigen
design
9,10
. The candidate vaccine BNT162b1 is one of two lipid
nanoparticle (LNP) formulated, pharmacologically optimized
11,12
,
1-methylpseudouridine nucleoside-modified mRNA (modRNA)
13
vaccines against SARS-CoV-2, developed in Project Lightspeed,
which was launched by BioNTech in collaboration with Pfizer and
Fosun Pharma. BNT162b1 encodes a trimerized, secreted version
of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain
(RBD)
14
, in which the RBD is a key target of virus-neutralizing anti-
bodies
15,16
. The BioNTech–Pfizer–Fosun RNA vaccine development
program involves a series of clinical trials that are currently being
conducted in Germany, the United States and China
17–19
, among
other countries. At the time of writing, BNT162b2, a second vac
-
cine candidate from the same platform, which encodes a prefusion
stabilized, full-length SARS-CoV-2 S protein, has been selected as a
pivotal candidate based on the totality of data obtained in the US and
German phase 1 and 2 trials and in non-human primate challenge
studies
14,17,19,20
. BNT162b2 has been authorized or approved for emer-
gency or temporary use or granted conditional marketing authoriza-
tion in more than 50 countries worldwide, including the European
Union countries, the United States and the United Kingdom
21,22
.
The safety, tolerability and immunogenicity of the BNT162b1
vaccine have been reported recently from the ongoing phase 1, 2
and 3 NCT04368728 trials in the United States
17,18
, and from the
phase 1 and 2 NCT04380701 and EudraCT 2020-001038-36 vaccine
trials in Germany
19
.
Here, we present a clinical report on an mRNA-based vaccine in
a Chinese population from the China-based ChiCTR2000034825–
Safety and immunogenicity of the SARS-CoV-2
BNT162b1 mRNA vaccine in younger and older
Chinese adults: a randomized, placebo-controlled,
double-blind phase 1 study
Jingxin Li
1,10
, Aimin Hui
2,10
✉
, Xiang Zhang
3
, Yumei Yang
4
, Rong Tang
1
, Huayue Ye
5,6
, Ruiru Ji
2
,
Mei Lin
7
, Zhongkui Zhu
3
, Özlem Türeci
8
, Eleni Lagkadinou
8
, Siyue Jia
1
, Hongxing Pan
1
, Fuzhong Peng
5,7
,
Zhilong Ma
3
, Zhenggang Wu
7
, Xiling Guo
1
, Yunfeng Shi
1
, Alexander Muik
8
, Uğur Şahin
8
, Li Zhu
7
✉
and Fengcai Zhu
1,9
✉
An effective vaccine is needed to end the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Here, we
assess the preliminary safety, tolerability and immunogenicity data from an ongoing single-center (in Jiangsu province, China),
parallel-group, double-blind phase 1 trial of the vaccine candidate BNT162b1 in 144 healthy SARS-CoV-2-naive Chinese partici-
pants. These participants are randomized 1:1:1 to receive prime and boost vaccinations of 10 µg or 30 µg BNT162b1 or placebo,
given 21 d apart, with equal allocation of younger (aged 18–55 years) and older adults (aged 65–85 years) to each treatment
group (ChiCTR2000034825). BNT162b1 encodes the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) and is
one of several messenger RNA-based vaccine candidates under clinical investigation. Local reactions and systemic events were
generally dose dependent, transient and mild to moderate. Fever was the only grade 3 adverse event. BNT162b1 induced robust
interferon-γ T cell responses to a peptide pool including the RBD in both younger and older Chinese adults, and geometric mean
neutralizing titers reached 2.1-fold (for younger participants) and 1.3-fold (for the older participants) that of a panel of COVID-
19 convalescent human sera obtained at least 14 d after positive SARS-CoV-2 polymerase chain reaction test. In summary,
BNT162b1 has an acceptable safety profile and produces high levels of humoral and T cell responses in an Asian population.
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NCT04523571 study investigating the preliminary safety and
immunogenicity data of the BNT162b1 vaccine in healthy, young
and older Chinese participants.
Results
Study design and analysis set. Between 18 July 2020 and 14 August
2020, a total of 296 adults aged between 18 and 55 years or between
65 and 85 years were screened at Taizhou Vaccine Clinical Research
Center in Jiangsu Province, China. A total of 144 eligible partici
-
pants consented to participate in the trial and were randomized
1:1:1 to receive prime and boost doses of BNT162b1 at 10 µg or
30 µg, or two placebo (saline) doses, 21 d apart (Fig. 1). Participants
in each age group were allocated equally to each treatment group
(48 participants per dose or placebo group, consisting of 24 par
-
ticipants aged 18–55 years and 24 participants aged 65–85 years).
Following the priming dose, two participants in the 65–85 years age
group (one in the 10 µg group and one in the 30 µg group) with
-
drew before receiving the boost dose (Supplementary Table 1). The
demographic characteristics of the participants are listed in Table 1.
In the three treatment groups the mean age of the younger par-
ticipants ranged from 37.9 to 42.0 years, and the mean age of the
older participants ranged from 68.5 to 70.7 years, with equal gender
distribution across treatment groups. People with a known allergy,
hypersensitivity or intolerance to vaccines or to any excipients
in the tested BNT162b1 mRNA vaccine were excluded from the
study. The medical history or other existing underlying disorders
of the participants were similar across treatment groups, except for
hypertension, which was noted at a higher prevalence in all of the
older participant groups (i.e., including the placebo group) in the
BNT162b1 older participant groups at baseline.
Preliminary safety and tolerability data. Adverse events were
graded according to the guidelines for vaccine clinical trials issued
by the US Food and Drug Administration (FDA)
23
(Table 2) and
the National Medical Products Administration (NMPA), China
24
(Table 3). In the 7 d after the prime or boost vaccination, 21 (88%)
of the younger participants in the 10 µg BNT162b1 dose group and
24 (100%) of the younger participants in the 30 µg BNT162b1 dose
group reported at least one solicited adverse reaction, versus four
(17%) of the younger participants in the placebo group. A similar
trend was seen for older participants, in that 83% of participants
(20 of 24) in the 10 µg BNT162b1 dose group and 92% of partici
-
pants (22 of 24) in the 30 µg BNT162b1 dose group reported at least
one solicited adverse reaction, versus 8% of participants (2 of 24) in
the placebo group (Table 2). Reactogenicity was dose-level depen
-
dent and was most evident in the group receiving 30 µg BNT162b1.
The most common solicited adverse reactions reported were injec
-
tion site pain, fever, headache, fatigue, malaise, joint pain, muscle
pain and chills (Tables 2 and 3). The adverse events were transient
and were either managed with simple standard of care or resolved
spontaneously. Most of the reported adverse reactions were mild
or moderate in severity, and resolved in the first 7 d after each
BNT162b1 dose for the prime and boost vaccinations. None of
the injection site reactions was graded as severe (grade 3). Grade 3
fever was the only severe systemic adverse reaction associated with
BNT162b1 vaccination, and it was predominantly observed in par
-
ticipants who received 30 µg BNT162b1. Grade 3 fever was reported
in 17% of younger participants (4 of 24) and in 8% of older partici
-
pants (2 of 24) who received 30 µg BNT162b1, and in 4% of younger
participants (1 of 24) who received 10 µg BNT162b1 (Table 2
and Supplementary Table 2). One male participant in the older age
group experienced an episodic grade 3 fever accompanied by pain
and pruritus at the injection site after the prime BNT162b1 dose at
30 µg, and electively withdrew before receiving the boost vaccina
-
tion. Mild or moderate headache was predominantly observed in
the younger participants who received 30 µg BNT162b1 (79%, 19
127 participants aged 18−55 years and
169 participants aged 65−85 years
screened for eligibility
72 aged 18−55 years and 72 aged
65−85 years underwent randomization
152 participants excluded:
2 with BMI > 30 kg m
−2
31 with other diseases
27 who did not consent
58 who had at least one clinically significant result in laboratory tests or
ECG
26 who had abnormal chest CT
1 who was eligible but was not enrolled because the number of
participants was met
7 who withdrew for other reasons
144 participants randomized 1:1:1 to receive
BNT162b1 at 10 µg or 30 µg, or placebo
48 received the first dose of 10 µg
BNT162b1
24 aged 18−55 years
24 aged 65−85 years
48 received the first dose of
placebo
24 aged 18−55 years
24 aged 65−85 years
47 received the second dose of
10 µg BNT162b1
24 aged 18−55 years
23 aged 65−85 years
48 received the first dose of 30 µg
BNT162b1
24 aged 18−55 years
24 aged 65−85 years
47 received the second dose of
30 µg BNT162b1
24 aged 18−55 years
23 aged 65−85 years
48 received the second dose of
placebo
24 aged 18−55 years
24 aged 65−85 years
1 aged 65−85 years withdrew
due to adverse events
1 aged 65−85 years withdrew
due to adverse events
Fig. 1 | Study flow diagram. BMI, body mass index; CT, computed tomography; ECG, electrocardiograph.
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of 24 participants); far fewer younger participants who received
placebo (13%, 3 of 24) and older participants who received
30 µg BNT162b1 (8%, 2 of 24) had mild or moderate headache
(Tables 2 and 3).
No pre-specified trial-halting criteria were met during
the study. Only one serious adverse event was reported by an
older participant, which was considered as not related to the
vaccine or study procedure (they were involved in an accident
that prevented them from receiving the boost dose). The overall
frequencies of the post-vaccination local adverse reactions were
similar after the BNT162b1 prime and boost doses. Some sys
-
temic adverse reactions such as fever (oral temperature >38 °C),
headache, fatigue and malaise occurred more commonly after the
BNT162b1 boost dose than after the prime dose in younger adults
(Extended Data Fig. 1). Fever generally resolved in the 48 h after
onset. In contrast to the younger participants, older participants did
not have increased reactogenicity after the BNT162b1 boost dose
(Extended Data Fig. 2).
There were no changes reported in participant blood pres
-
sure or respiratory rate across the different treatment groups after
BNT162b1 administration. Transient increases in temperature and
pulse rate in the 24 h after the prime and the boost vaccinations
were noted in both younger and older participants, especially in
the 30 µg BNT162b1 dose group (Extended Data Fig. 3). The most
common abnormalities in laboratory values from baseline were
transient decreases in lymphocyte and platelet counts and increases
in C-reactive protein (CRP) level. All of the laboratory abnormali
-
ties were self-limited and resolved in a short period of time without
clinical symptoms (Extended Data Fig. 4). These data are in line
with the results seen in the EudraCT 2020-001038-36 study and in
other mRNA vaccine trials that have found CRP level
25,26
and lym-
phocyte count
27
to act as pharmacodynamic markers for the mode
of action of these vaccines.
Results of a long-term follow up of safety and tolerability up to
12 months following vaccination for participants in the BNT162b1
vaccination dose cohorts will be published separately.
Vaccine-induced antibody responses. SARS-CoV-2-neutralization
titers as well as RBD-binding and S1-binding antibody titers
were assessed at baseline (on d 1, immediately before the prim
-
ing dose on that day), 7 and 21 d after the priming dose (d 8 and
22, respectively), and 7 and 21 d after the boost dose (d 29 and 43,
respectively). The SARS-CoV-2-neutralizing titer is defined as the
reciprocal of the highest sample dilution that protects at least 50%
of the cells from cytopathic effects (CPEs). The BNT162b1-induced
neutralizing antibody responses in vaccinated participants were
simultaneously tested against a panel of human COVID-19 conva
-
lescent sera obtained at least 14 d after polymerase chain reaction
(PCR)-confirmed diagnosis from 24 Asian patients hospitalized
with COVID-19, 21 (87.5%) of whom had symptomatic disease.
All of the participants were seronegative at baseline (on d 1, imme
-
diately before the priming dose on that day) and had a modest
vaccine-induced antibody response 21 d after the priming dose
(d 22), which further increased on d 29 (Fig. 2 and Supplementary
Table 3). The highest neutralizing titers were observed on d 43 (that is,
21 d after the BNT162b1 boost dose) for both the younger and older
adults in the BNT162b1 group, indicating a continuous increase in
neutralizing titers in this group of Asian participants after d 29. On
d 43 the 50% neutralizing geometric mean titer (GMT) in the 10 μg
and the 30 μg dose groups was 232.9 (95% confidence interval (CI),
151.3 to 358.5) and 254.0 (95% CI, 184.6 to 349.4) in the younger
participants, and 80.0 (95% CI, 49.2 to 130.2) and 160.0 (95% CI,
96.7 to 264.6) in the older participants, respectively, which was sig
-
nificantly higher than that on d 29 for both the dose groups and
the age groups (all P < 0.0001). The peak SARS-CoV-2-neutralizing
antibody GMT for the younger participants in the 10 μg and 30 μg
Table 1 | Baseline characteristics of the participants by age group
Characteristic Younger participants (18–55years) Older participants (65–85years)
10μg BNT162b1 30μg BNT162b1 Placebo 10μg BNT162b1 30μg BNT162b1 Placebo
No. of participants 24 24 24 24 24 24
Age (years), mean (s.d.) 37.9 (9.6) 39.7 (9.0) 42.0 (8.7) 70.5 (5.0) 68.5 (3.0) 70.7 (4.4)
Sex, n (%)
Male 12 (50) 12 (50) 12 (50) 12 (50) 12 (50) 12 (50)
Female 12 (50) 12 (50) 12 (50) 12 (50) 12 (50) 12 (50)
BMI (kg m
−2
), mean (s.d.) 24.7 (3.2) 23.0 (2.7) 24.3 (3.4) 24.0 (3.0) 24.8 (2.9) 23.5 (2.5)
Race, n (%)
Chinese (Asian) 24 (100) 24 (100) 24 (100) 24 (100) 24 (100) 24 (100)
Other 0 0 0 0 0 0
Medical history or existing disorder, n (%)
Cardiac ischemia 2 (8) 2 (8) 2 (8) 0 0 0
Sinus bradycardia 0 2 (8) 1 (4) 0 0 0
Hyperuricemia 3 (13) 1 (4) 1 (4) 3 (13) 2 (8) 2 (8)
Nasopharyngitis 2 (8) 0 0 0 0 0
Blood uric acid increased 2 (8) 1 (4) 1 (4) 0 0 0
Hypertension 3 (13) 0 1 (4) 12 (50) 9 (38) 7 (29)
Diabetes 0 0 0 1 (4) 2 (8) 1 (4)
Gastric inflammation 0 0 0 0 0 2 (8)
Others
a
3 (13) 5 (21) 1 (4) 3 (13) 3 (13) 4 (17)
a
Tonsillitis, Helicobacter infection, human papilloma virus infection, periodontitis, electrocardiogram high voltage, lymphadenopathy, anemia, hepatic cyst, oropharyngeal discomfort, hyperthyroidism,
non-infective gingivitis, hyperlipidemia, benign prostatic hyperplasia, prostatitis, unilateral blindness, cerebral infarct, limb injury, deformity of spine, urinary calculus and lymphadenopathy.
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dose groups was 1.9-fold and 2.1-fold the GMT of the entire conva-
lescent serum panel (n = 24, GMT = 119.9, 95% CI, 70.4 to 203.9)
(Supplementary Table 4). The d 43 GMT of younger participants
vaccinated with 30 μg BNT162b1 was significantly higher than the
GMT of the entire convalescent serum panel (P = 0.042). In the
older participants, the peak neutralizing antibody GMTs on d 43
in the 10 μg and 30 μg dose groups were 0.7-fold and 1.3-fold the
GMT of the entire convalescent serum panel, respectively (P = 0.532
for the 30 µg dose group). Participants who received the 30 μg dose
appeared to have a relatively higher virus-neutralizing antibody
response than those who received the 10 μg dose. The older par
-
ticipants generally had a lower peak neutralizing antibody response
than the younger participants.
For all of the younger participants, seroconversion (a fourfold
or greater increase in neutralizing antibody GMT above baseline)
had occurred by d 43, while the rate of seroconversion in the older
recipients was 91% at the 10 μg dose and 96% at the 30 μg dose
(Extended Data Fig. 5). A post-hoc multivariate repeated measure
-
ments analysis of neutralizing antibody GMT on d 1, 22, 29 and 43
across the treatment and age groups showed that GMT significantly
Table 2 | Solicited adverse reactions in the 7d after prime or boost vaccinations, and unsolicited adverse reactions until d50, graded
by FDA criteria, by age group
Younger participants (18–55years) Older participants (65–85years)
BNT162b1 BNT162b1
Adverse reactions
10μg
(n=24)
30μg
(n=24)
Placebo
(n=24)
P value 10μg
(n=24)
30μg
(n=24)
Placebo
(n=24)
P value
Solicited adverse reactions within 7 d, n (%)
Any 21 (88) 24 (100) 4 (17) <0.0001 20 (83) 22 (92) 2 (8) <0.0001
Grade 3 1 (4) 4 (17) 0 0.0015 0 2 (8) 0 0.3239
Injection site adverse reactions, n (%)
Any 21 (88) 24 (100) 2 (8) <0.0001 18 (75) 21 (88) 0 <0.0001
Grade 3 0 0 0 — 0 0 0 —
Pain 21 (88) 23 (96) 2 (8) <0.0001 16 (67) 21 (88) 0 <0.0001
Redness 6 (25) 8 (33) 0 0.0059 3 (13) 4 (17) 0 0.1492
Swelling 5 (21) 7 (29) 0 0.0137 0 5 (21) 0 0.0091
Induration 0 3 (13) 0 0.1018 0 1 (4) 0 1.0000
Systemic adverse reactions, n (%)
Any 17 (71) 21 (88) 3 (13) <0.0001 4 (17) 18 (75) 2 (8) <0.0001
Grade 3 1 (4) 4(17) 0 0.0015 0 2 (8) 0 0.3239
Fever
a
9 (38) 18 (75) 0 <0.0001 1 (4) 16 (67) 0 <0.0001
Grade 3
b
1 (4) 4 (17) 0 0.1185 0 2 (8) 0 0.3239
Headache 11 (46) 19 (79) 3 (13) <0.0001 1 (4) 2 (8) 0 0.7682
Fatigue 12 (50) 16 (67) 0 <0.0001 3 (13) 8 (33) 0 0.0045
Malaise 8 (33) 9 (38) 0 0.0013 2 (8) 4 (17) 1 (4) 0.4858
Joint pain 4 (17) 10 (42) 1 (4) 0.0067 0 1 (4) 0 1.0000
Muscle pain 2 (8) 10 (42) 0 <0.0001 0 1 (4) 0 1.0000
Chills 4 (17) 7 (29) 0 0.0118 1 (4) 4 (17) 0 0.1185
Nausea 3 (13) 3 (13) 0 0.2330 0 0 0 —
Anorexia 1 (4) 4 (17) 0 0.1185 0 3 (13) 1 (4) 0.3143
Diarrhea 2 (8) 1 (4) 1 (4) 1.0000 0 0 0 —
Vomiting 0 2 (8) 0 0.3239 0 0 0 —
Unsolicited adverse reactions until d 50 related to investigational vaccine, n (%)
Any 9 (38) 10 (42) 1 (4%) 0.0046 4 (17) 9 (38) 2 (8) 0.0590
Fever
c
0 0 0 — 0 1 (4) 0 1.0000
Temperature intolerance 2 (8) 6 (25) 0 0.0230 0 4(17) 0 0.0310
Injection site discomfort 3 (13) 4 (17) 0 0.1492 2 (8) 3 (13) 0 0.3580
Injection site pruritus 2 (8) 3 (13) 0 0.3580 0 1 (4) 0 1.0000
Pain not at injection site 1 (4) 1 (4) 0 1.0000 0 0 0 —
Dizziness 3 (13) 1 (4) 0 0.3142 0 3 (13) 0 0.1018
Blood uric acid increased 1 (4) 1 (4) 0 1.0000 2 (8) 1 (4) 2 (8) 1.0000
a
Oral temperature of ≥38.0 °C (ref.
23
).
b
Oral temperature of 39–40 °C (ref.
23
).
c
One participant experienced grade 3 fever accompanied by pain, itching and pruritus at the injection site after the prime dose,
and electively withdrew before the boost vaccination. Grade 3 reactions are defined as vaccination-related events that are severe enough to prevent normal activities. A participant was counted only once in
a specific reaction category, regardless of the number of episodes of the adverse reaction. Only unsolicited adverse reactions reported by two or more participants are listed.
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correlated with treatment (BNT162b1 vaccine versus placebo),
time after treatment (days after immunization), participant age and
combinations thereof (time × treatment interaction, age × treatment
interaction and time × age interaction) (Supplementary Table 5).
In line with the neutralizing antibody titers, BNT162b1 induced
high levels of S1-binding and RBD-binding immunoglobulin-γ
(IgG) GMTs after the prime–boost regimen. Binding IgG GMTs
from the younger participants who received 30 µg BNT162b1
reached the upper limit of quantification in the ELISA test by
d 29 (7 d after the boost dose), indicating that the analysis of the
S1-binding and RBD-binding IgG titers in this participant subset
could be compromised. Putting aside this methodological limita
-
tion, the S1-binding IgG levels were positively correlated with the
neutralizing antibody titers across all of the time points evaluated in
the participants, regardless of age group or dose level, with a corre
-
lation coefficient of 0.66 for younger participants and 0.55 for older
participants (both P < 0.0001) (Extended Data Fig. 6a,b).
Vaccine-induced T cell responses. Vaccine-induced T cell
responses were analyzed on d 29 (7 d after the boost dose) and on
Table 3 | Solicited adverse reactions in the 14d after prime or boost vaccinations, and unsolicited adverse reactions until d50, graded
by NMPA criteria, by age group
Younger participants (18–55years) Older participants (65–85years)
BNT162b1 BNT162b1
Adverse reactions
10μg
(n=24)
30μg
(n=24)
Placebo
(n= 24)
P value 10μg
(n=24)
30μg
(n=24)
Placebo
(n=24)
P value
Solicited adverse reactions within 14 d, n (%)
21 (88) 24 (100) 4 (17) <0.0001 21 (88) 23 (96) 2 (8) <0.0001
Grade 3 3 (13) 9 (38) 0 0.0015 0 2 (8) 0 0.3239
Injection site adverse reactions, n (%)
Any 21 (88) 24 (100) 2 (8) <0.0001 18 (75) 21 (88) 0 <0.0001
Grade 3 0 0 0 — 0 0 0 —
Pain 21 (88) 23 (96) 2 (8) <0.0001 16 (67) 21 (88) 0 <0.0001
Redness 6 (25) 8 (33) 0 0.0059 3 (13) 4 (17) 0 0.1492
Swelling 5 (21) 7 (29) 0 0.0137 0 5 (21) 0 0.0091
Induration 0 3 (13) 0 0.1018 0 1 (4) 0 1.0000
Systemic adverse reactions, n (%)
Any 17 (71) 22 (92) 3 (13) <0.0001 9 (38) 19 (79) 2 (8) <0.0001
Grade 3 3 (13) 9 (38) 0 0.0015 0 2 (8) 0 0.3239
Fever
a
14 (58) 21 (88) 1 (4) <0.0001 7 (29) 19 (79) 1 (4) <0.0001
Grade 3
b
3 (13) 9 (38) 0 0.0015 0 2 (8) 0 0.3239
Headache 11 (46) 19 (79) 3 (13) <0.0001 1 (4) 2 (8) 0 0.7682
Fatigue 12 (50) 16 (67) 0 <0.0001 3 (13) 8 (33) 0 0.0045
Malaise 8 (33) 9 (38) 0 0.0013 2 (8) 4 (17) 1 (4) 0.4858
Joint pain 4 (17) 10 (42) 1 (4) 0.0067 0 1 (4) 0 1.0000
Muscle pain 2 (8) 10 (42) 0 <0.0001 0 1 (4) 0 1.0000
Chills 4 (17) 7 (29) 0 0.0118 1 (4) 4 (17) 0 0.1185
Nausea 3 (13) 3 (13) 0 0.2330 0 0 0 —
Anorexia 1 (4) 4 (17) 0 0.1185 0 3 (13) 1 (4) 0.3143
Diarrhea 2 (8) 0 1 (4) 0.7682 0 0 0 —
Vomiting 0 2 (8) 0 0.3239 0 0 0 —
Unsolicited adverse reactions until d 50 related to investigational vaccine, n (%)
Any 9 (38) 10 (42) 1 (4) 0.0046 4 (17) 9 (38) 2 (8) 0.0590
Fever
c
0 0 0 — 0 1 (4) 0 1.0000
Temperature intolerance 2 (8) 6 (25) 0 0.0230 0 4 (17) 0 —
Injection site discomfort 3 (13) 4 (17) 0 0.1492 2 (8) 3 (13) 0 0.3580
Injection site pruritus 2 (8) 3 (13) 0 0.3580 0 1 (4) 0 1.0000
Pain not at injection site 1 (4) 1 (4) 0 1.0000 0 0 0 —
Dizziness 3 (13) 1 (4) 0 0.3142 0 3 (13) 0 0.1018
Blood uric acid increased 1 (4) 1 (4) 0 1.0000 2 (8) 1 (4) 2 (8) 1.0000
a
Axillary temperature of ≥37.3 °C (ref.
24
).
b
Axillary temperature of 38.5 to <39.5 °C (ref.
24
).
c
One participant experienced grade 3 fever accompanied by pain, itching and pruritus at the injection site after
the prime dose, and electively withdrew before the boost vaccination. Grade 3 reactions are defined as vaccination-related events that are severe enough to prevent normal activities. A participant was
counted only once in a specific reaction category, regardless of the number of episodes of the adverse reaction. Only unsolicited adverse reactions reported by two or more participants are listed.
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