Adv Ther (2022) 39:3789–3798

https://doi.org/10.1007/s12325-022-02206-1

ORIGINAL RESEARCH

Immune Persistence and Safety After SARS-CoV-2

BNT162b1 mRNA Vaccination in Chinese Adults:
A Randomized, Placebo-Controlled, Double-Blind
Phase 1 Trial
Jingxin Li . Ai-Min Hui . Xiang Zhang . Lei Ge . Yuanzheng Qiu . Rong Tang . Huayue Ye .
Xiyuan Wang . Mei Lin . Zhongkui Zhu . Jianfei Zheng . Jingjun Qiu . Eleni Lagkadinou . Svetlana Shpyro .
Orkun Ozhelvaci . Özlem Türeci . Zakaria Khondker . Wanrong Yin . Yoana Shishkova . Siyue Jia .
Hongxing Pan . Fuzhong Peng . Zhilong Ma . Zhenggang Wu . Xiling Guo . Yunfeng Shi . Alexander Muik .
Uğur Şahin . Li Zhu . Fengcai Zhu

Received: April 6, 2022 / Accepted: May 20, 2022 / Published online: June 30, 2022
Ó The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature 2022

ABSTRACT 18–55 years) and at month 6 in 70 younger and

69 older participants (aged 65–85 years).
Introduction: BNT162b1 is a lipid nanoparti- Results: In younger participants, neutralizing
cle-formulated, nucleoside-modified mRNA antibody (nAb) geometric mean titers (GMTs)
SARS-CoV-2 vaccine. Here, we report safety and for the 10 and 30 lg dose levels declined from
immune persistence data following a primary 233 and 254 (21 days after dose 2) to 55 and 87
two-dose vaccination schedule administered at month 3, respectively, and to 16 and 27 at
21 days apart. month 6, respectively. In older participants,
Methods: Immune persistence was determined nAb GMTs declined from 80 and 160 (21 days
at month 3 in 72 younger participants (aged after dose 2) to 10 and 21 at month 6. Overall,
higher antibody titers were observed in younger
participants, and the 30 lg dose induced higher
Jingxin Li and Ai-Min Hui contributed equally. levels of nAb, which declined more slowly by

J. Li  R. Tang  S. Jia  H. Pan  X. Guo  Y. Shi  H. Ye

F. Zhu (&) Department of Pharmacy, Army Medical University,
NHC Key Laboratory of Enteric Pathogenic Chongqing, China
Microbiology, Jiangsu Provincial Center for Disease
Control and Prevention, Nanjing, China M. Lin  Z. Wu  L. Zhu (&)
e-mail: [email protected] Taizhou People’s Hospital, Taizhou, China
e-mail: [email protected]
A.-M. Hui (&)
Fosun Pharma, Boston, MA, USA E. Lagkadinou  S. Shpyro  O. Ozhelvaci  Ö. Türeci
e-mail: [email protected]  Y. Shishkova  A. Muik  U. Şahin
BioNTech SE, Mainz, Germany
X. Zhang  Z. Zhu  Z. Ma
Taizhou City Center for Disease Control and Z. Khondker  W. Yin
Prevention, Taizhou, China BioNTech, Cambridge, MA, USA

L. Ge  Y. Qiu  X. Wang  J. Zheng  J. Qiu F. Zhu

Fosun Pharma, Shanghai, China Center for Global Health, Nanjing Medical
University, Nanjing, China
H. Ye  F. Peng
Taizhou Vaccine Clinical Research Center, Taizhou,
China
3790 Adv Ther (2022) 39:3789–3798

month 6. No serious adverse events were design, accelerating the development of poten-
reported in the vaccine group. tial vaccine candidates [2, 3].
Conclusion: This study showed BNT162b1 BioNTech, in collaboration with Pfizer and
maintains a favorable safety profile in younger Fosun Pharma, has launched an extensive vac-
and older participants in the 6 months after cine development program involving multiple
vaccination. This study further extends our clinical trials in Germany (phase 1/2;
understanding of immune persistence and the NCT04380701), the USA (phase 1/2/3;
safety of the BNT162b1 vaccine as a candidate NCT04368728) and China (phase 1;
vaccine in the BioNTech pipeline. ChiCTR2000034825; NCT04523571) [4–7]. Two
Trial Registration Number: NCT04523571, vaccine candidates, BNT162b1 and BNT162b2,
registered August 21, 2020. were selected for further investigation.
BNT162b1 and BNT162b2 are lipid nanoparti-
Keywords: SARS-CoV-2; COVID; mRNA cle-formulated, pharmacologically optimized
vaccine; Immune persistence [5, 6, 8, 9], nucleoside-modified mRNA [10]
vaccine candidates targeting SARS-CoV-2.
BNT162b1 encodes a trimerized, secreted SARS-
Key Summary Points
CoV-2 receptor binding domain (RBD) [11],
whereas BNT162b2 encodes the full-length,
mRNA vaccine platforms are crucial in
membrane-anchored spike protein, stabilized in
reducing SARS-CoV-2 transmission and
the prefusion conformation.
improving disease prognosis.
In a China-based phase 1 study [4], it was
BNT162b1 is a lipid-formulated shown that BNT162b1 had an acceptable safety
nucleoside-modified mRNA SARS-CoV-2 and tolerability profile, and a robust humoral
vaccine formulation, generated by and T-cell response, with SARS-CoV-2 neutral-
BioNTech in collaboration with Pfizer and izing immunoglobulin G (IgG) titers (21 days
Fosun Pharma. after dose 2) up to 2.1-fold higher than in those
who had recovered from a natural infection.
This brief report described immune
The results were similar to those observed in the
persistence data at 3 and 6 months in 144
initial clinical trial in Germany [6], which
Chinese adults who received two doses of
showed that two doses of BNT162b1 elicited
BNT162b1 vaccine 21 days apart.
robust, non-dose–dependent T-cell responses
This study showed BNT162b1 maintained and RBD-binding IgG concentrations that were
a favorable safety profile in younger and up to 3.5-fold higher than in a cohort who had
older participants in the 6 months after recovered from a natural SARS-CoV-2 infection.
vaccination. In parallel, a phase 1/2 clinical trial was con-
ducted in the US [5], which showed that two
doses of 10–30 lg BNT162b1 produced mild-to-
moderate, transient, dose-dependent reactions
and yielded dose-dependent RBD-binding IgG
concentrations and SARS-CoV-2 neutralizing
INTRODUCTION titers, increasing after a second dose.
To determine which of the two vaccine
SARS-CoV-2, the causative agent of COVID-19, candidates, BNT162b1 or BNT162b2, was more
has produced [ 360 million confirmed cases promising, the safety and immunogenicity of
and 5.6 million deaths globally as of January 27, BNT162b1 and BNT162b2 were compared;
2022 [1]. SARS-CoV-2 vaccine development is BNT162b2 was found to have milder systemic
critical for the prevention of infection and dis- reactogenicity than BNT162b1, with a humoral
ease. Vaccine platforms based on messenger and cellular immune response that was broadly
RNA (mRNA) are a new development in vaccine similar to that of BNT162b1 [7, 12]. These more
technology; they enable rapid, targeted antigen favorable safety data have prompted the
Adv Ther (2022) 39:3789–3798 3791

decision to advance BNT162b2 to the phase 2/3 were used to assess antibody persistence. Serious
trial [13], which has subsequently led to its adverse events were collected during the follow-
global roll out. up period and graded according to the guideli-
To gain a better understanding of the long- nes set by the China National Medical Products
term safety and efficacy of BNT162b1, here we Administration [14] and the US Food and Drug
report safety and immune-persistence data at Administration [15] and categorized by investi-
month 3 and month 6 in participants who gators as possibly, probably or definitely vac-
received two doses of the SARS-CoV-2 cine-related.
BNT162b1 vaccine.
Immune Persistence Assessment
METHODS
To assess antibody persistence, sera were col-
Study Design lected 3 (for younger adults only) and 6 (for
younger and older adults) months after the first
vaccination to determine total anti-SARS-CoV-2
We previously reported preliminary safety and
neutralizing antibodies, anti-S1 IgG and anti-
immunogenicity of a SARS-CoV-2 mRNA vac-
RBD IgG antibody titers by ELISA. A cytopathic
cine candidate, BNT162b1, in healthy Chinese
effect-based microneutralization assay was used
adults aged 18–55 years or 65–85 years in a
to determine SARS-CoV-2–specific neutralizing
phase 1, randomized, placebo-controlled,
antibody titers [4]. Seroconversion is defined as
observed-blind study [4]. Here, we report the
an increase by a factor of 4 or more in antibody
immune persistence and safety of BNT162b1
titer over baseline, or the lower limit value if the
vaccine in those participants over a 6-month
baseline titer is below the limit of detection.
follow-up period (NCT04523571,
Antibody titers were compared by calculating
ChiCTR2000034825). Only those participants
the geometric mean fold increase (GMFI). More
who had received two doses of the active treat-
detailed information can be found in the pre-
ment or placebo were included in the immune
vious published phase 1 study [4].
persistence analysis.

Compliance with Ethics Guidelines RESULTS

All procedures performed in studies involving Participant disposition and baseline demo-
human participants were in accordance with graphics have been previously reported [4]. In
the ethical standards of the institutional and/or brief, between July 18 and August 14, 2020, 144
national research committee and with the 1964 eligible participants (72 participants aged 18–55
Helsinki Declaration and its later amendments and 72 aged 65–85 years) were randomized 1:1:1
or comparable ethical standards. The study to receive two doses (10 or 30 lg) of the
protocol was approved by Chinese NMPA and BNT162b1 vaccine or placebo, 21 days apart.
the institutional review board of the Jiangsu Two participants in the older group (one in each
Provincial Center of Disease Control and of the 10 and 30 lg dose groups) withdrew
Prevention. Informed consent was obtained before receiving the second dose because of
from all individual participants included in the adverse events [4]; additionally, one older and
study. two younger participants in the placebo group
were lost to follow-up before the 6-month time
Outcomes point. Sixty-nine patients in the older group
and 70 patients in the younger group were
therefore eligible for full analysis.
Geometric mean titer, seroconversion rate and
Preliminary safety and tolerability data
geometric mean fold increase of virus-neutral-
through day 28 after the second vaccination
izing antibody, anti-S1 IgG and anti-RBD IgG
have been previously reported [4]. No
3792 Adv Ther (2022) 39:3789–3798

additional serious adverse events were reported month 6) participants. Anti-RBD IgG SCRs in
in the vaccine groups by the 6 month follow- younger participants were 100% for 10 and
up. One serious adverse event (a thyrolin- 30 lg doses at months 3 and 6. In older partic-
gual cyst 152 days after the second dose of pla- ipants, anti-RBD IgG SCRs at month 6 remained
cebo, which resulted in hospitalization and 100% for the 10 lg dose but declined from 100
resolved within 12 days) was reported in a to 96% for the 30 lg dose.
42-year-old woman in the placebo group during The significant BNT162b1-induced Sp1-reac-
the follow-up period. tive T-cell responses on day 29 and day 43 have
The highest neutralizing antibody (nAb), been reported previously [4]. Similar to GMTs of
anti-S1 IgG, and anti-RBD IgG antibody geo- nAb and binding IgGs, at month 6, geometric
metric mean titers (GMTs) were recorded on day mean IFN-c? spot counts for the 10 and 30 lg
43 (21 days after the second dose) in both dose doses in younger participants declined from 36
groups (10 and 30 lg), as previously reported (95% CI 21– 60) and 51 (95% CI 30–86) to 15
[4]. Antibody titers at month 3 (day 85) and (95% CI 8–29) and 18 (95% CI 12–28) per 105
month 6 (day 184) after the first dose are shown peripheral blood mononuclear cells (PBMCs),
in Fig. 1 and Table 1. As compared with the peak respectively, compared to 2 (95% CI 1–3) per
titer on day 43, GMTs of nAb for the 10 and 105 PBMCs for the placebo controls.
30 lg doses in younger participants declined
from 233 (95% confidence interval [CI]
151–359) and 254 (95% CI 185–349) to 55 (95% DISCUSSION
CI 38–79) and 87 (95% CI 64–118) at month 3
and to 16 (95% CI 11–24) and 27 (95% CI Initial clinical trials examining the safety, tol-
20–37) at month 6, respectively. In older par- erability, and immunogenicity of both
ticipants, GMTs of nAb at month 6 declined BNT162b1 and BNT162b2 conducted in the US,
from 80 (95% CI 49–130) and 160 (95% CI Germany and China [4–7, 12] showed that both
97–265) to 10 (95% CI 7–14) and 21 (95% CI candidate vaccines demonstrated an accept-
13–32), respectively. Similar declining trends able level of immunogenicity.
were also found in GMTs and the geometric Twenty-one to 28 days after administration
mean fold increase (GMFI) of binding anti-S1 of a second vaccine dose, systemic events after
IgG and anti-RBD IgG for the 10 and 30 lg doses administration of BNT162b1 were more severe
in both the younger and older adult groups. than those following vaccination with
The BNT162b1 vaccine elicited antibody BNT162b2; the incidence of fever in partici-
responses in a dose-dependent manner, with pants in the younger and older groups after the
higher antibody titers observed in those receiv- second dose of 30 lg of BNT162b1 was 75% and
ing the 30 lg dose (vs. the 10 lg dose). After 33%, respectively, compared to 17% and 8% in
mounting a peak response, the titers of all three the BNT162b2 group [7]. BNT162b2 has been
types of antibody gradually declined in both age shown to maintain a favorable safety profile up
groups through month 6 (Fig. 1). However, to 6 months post full vaccination [16].
those induced by the 30 lg dose declined more SARS-CoV-2 antibodies were induced by
slowly over this period. BNT162b1 in a dose-dependent manner in the
Seroconversion rates (SCRs) are shown in 18–55 years and 65–85 years age groups and
Table 1. In younger participants, SCRs of nAb only marginal differences were observed in nAb
declined from 100 to 88% for the 10 lg dose GMT across both doses, peaking at 21 days after
level and remained 100% for the 30 lg dose the primary two-dose vaccination schedule,
level at month 3. SCRs declined further to 58% which is in line with reporting from trials con-
(10 lg) and 83% (30 lg) at month 6. In older ducted in the US and Germany [5–7, 12].
adults, SCRs of nAb at month 6 were 30% Moreover, the two doses showed different
(10 lg) and 61% (30 lg) at month 6. The anti-S1 extents of waning immunity, with the 30 lg
IgG SCR remained 100% for both dose levels in vaccine eliciting higher antibody titers, which
both younger (at months 3 and 6) and older (at declined more slowly than the 10 lg dose. The
Adv Ther (2022) 39:3789–3798 3793
 3794 Adv Ther (2022) 39:3789–3798

b Fig. 1 Longitudinal geometric mean titer of virus-neu- BTN162b2 [24, 25], and boosters would likely be
tralizing antibody, anti-S1 IgG and anti-RBD IgG in needed for BNT126b1 if it were being further
healthy participants over 6 months. A GMT of neutral- developed.
izing SARS-CoV-2 antibodies. B GMT of anti-S1
antibodies. C GMT of anti-RBD antibodies. Participants
received two doses of BNT162b1 (10 or 30 lg) or placebo LIMITATIONS
(saline) on days 1 and 22. Blood samples were not collected
from older participants (aged 65–85 years) at day 8 and This study is limited by its small sample size of
3 months after dose 1. The error bar was standard error. adult Chinese participants only, which limits
anti-RBD IgG antibody to receptor binding domain, anti- generalizability to other populations. Addi-
S1 IgG antibody to S1 protein, GMT geometric mean titer, tionally, we did not measure cross-neutralizing
SARS-CoV-2 severe acute respiratory syndrome coron- antibody levels against recently emerged vari-
avirus 2 ants of concern during the follow-up period,
and persistence of cellular response was not
determined in the older participants. A key
GMTs of nAb, anti-S1 IgG and anti-RBD IgG limitation of the findings in this report is that,
remained higher in younger participants than of the two BNT162 vaccines in this pipeline,
in older participants at month 6. though the immunogenicity was comparable
As with other disease vaccines, antibody with BNT162b2, the BNT162b1 vaccine is less
waning following vaccination against SARS- promising in terms of systemic reactogenicity
CoV-2 is expected [17, 18]. In this trial, there and therefore has not been further developed.
was a gradual decline in GMTs of neutralizing,
anti-S1 IgG and anti-RBD antibodies, though
humoral immune responses were observed CONCLUSION
through 6 months of follow-up. These results
are comparable to other SARS-CoV-2 vaccines The current data confirm a favorable safety
(including BNT162b2), which have also profile of the mRNA-based SARS-CoV-2
demonstrated waning antibody titers over the BNT162b1 vaccine candidate in younger and
6 months post-vaccination [19–22]. As T-cell older participants over a 6-month period. The
response is thought to play a role in preventing study also extends our understanding of
reinfection, particularly in the context of wan- immune persistence and the safety of the
ing antibody titers, these reduced titers may not BNT162b1 vaccine in the context of other vac-
correspond to a less efficacious vaccine [23]. cines in the BioNTech pipeline.
Waning antibody titers of other mRNA SARS-
CoV-2 vaccines have prompted the administra-
tion of booster doses after 6 months, including
 Adv Ther (2022) 39:3789–3798

Table 1 Antibody persistence 3 and 6 months after the first dose of BNT162b1 vaccination
Three months after the first dose Six months after the first dose
Younger participants (aged 18–55 years) Younger participants (aged 18–55 years) Older participants (65–85 years)
10 lg (N = 24) 30 lg (N = 24) Placebo (N = 24) 10 lg (N = 24) 30 lg (N = 24) Placebo (N = 22) 10 lg (N = 23) 30 lg (N = 23) Placebo (N = 23)

Virus neutralizing antibody

GMT 55 (38–79) 87 (64–118) 5 (5–5) 16 (11–24) 27 (20–37) 5 (5–5) 10 (7–14) 21 (13–32) 5 (5–5)
GMFI 11.0 (7.6–15.8) 17.4 (12.9–23.6) 1.0 (1.0–1.0) 3.3 (2.3–4.7) 5.5 (4.1–7.4) 1.0 (1.0–1.0) 2.0 (1.4–2.8) 4.1 (2.7–6.4) 1.0 (1.0–1.0)
SCR 21 (88; 68–97) 24 (100; 86–100) 0 (0; 0–14) 14 (58; 37–78) 20 (83; 63–95) 0 (0; 0–15) 7 (30; 13–53) 14 (61; 39–80) 0 (0; 0–15)
Anti-S1 IgG
GMT 27,143 (21,023–35,044) 31,584 (26,379–37,817) 50 (50–50) 4,169 (2,979–5,836) 5,693 (4,412–7,346) 55 (48–63) 2,224 (1,566–3,158) 4,970 (3,626–6814) 61 (46–81)
GMFI 488.9 (359.3–665.2) 532.2 (371.3–762.7) 0.9 (0.8–1.1) 75.1 (50.1–112.6) 95.9 (66.9–137.6) 1.0(0.9–1.1) 42.7 (29.5–61.8) 90.6 (64.5–127.4) 1.0 (0.9–1.1)
SCR 24 (100; 86–100) 24(100; 86–100) 0 (0; 0–14) 24 (100; 86–100) 24 (100; 86–100) 0 (0; 0–15) 23 (100; 85–100) 23 (100; 85–100) 0 (0; 0–15)
Anti-RBD IgG
GMT 40,236 (33,000–49,060) 43,051 (38,768–47,807) 60 (50–73) 8250 (6186–11,001) 9608 (7410–12,459) 62 (50–76) 4114 (2717–6231) 7188 (5139–10,054) 55 (48–62)
GMFI 804.7 (660.0–981.2) 815.0 (706.6–940.0) 1.1 (1.0–1.1) 165.0 (123.7–220.0) 181.9 (145.9–226.8) 1.1 (0.9–1.3) 69.8 (48–102) 104.6 (65.8–166.3) 0.8 (0.6–1.0)
SCR 24 (100; 86–100) 24 (100; 86–100) 0 (0; 0–14) 24 (100; 86–100) 24 (100; 86–100) 0 (0; 0–15) 23 (100; 85–100) 22 (96; 78–100) 0 (0; 0–15)

Data are GMT (95% CI) and number of participants (%, 95% CI) for SCR. The participants received two doses of the BNT162b1 vaccine 21 days apart
anti-RBD IgG antibody to receptor binding domain, anti-S1 IgG antibody to S1 protein, CI confidence interval, GMT geometric mean titer, GMFI geometric mean fold increase, N number of participants included in each treatment
group with determinate immunogenicity results, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, SCR seroconversion rate
3795
3796 Adv Ther (2022) 39:3789–3798

ACKNOWLEDGEMENTS Zhenggang Wu, Xiling Guo, Yunfeng Shi, Li

Zhu and Fengcai Zhu all have nothing to
The authors thank all the participants who disclose.
volunteered for this study and Andrew Fin-
layson of BioNTech SE for his editorial contri- Compliance with Ethics Guidelines. All
bution. We thank Yuhuan Han (previous staff of procedures performed in studies involving
Fosun Pharma) for his study design human participants were in accordance with
contribution. the ethical standards of the institutional and/or
national research committee and with the 1964
Helsinki Declaration and its later amendments
Funding. This study was funded by BioN-
or comparable ethical standards. The study
Tech SE and Shanghai Fosun Pharmaceutical
protocol was approved by Chinese NMPA and
Development. BioNTech was the regulatory
the institutional review board of the Jiangsu
sponsor, and Shanghai Fosun organized and
Provincial Center of Disease Control and
conducted the trial. The journal’s Rapid Service
Prevention. Informed consent was obtained
Fee was funded by Fosun.
from all individual participants included in the
study.
Medical Writing Support. Medical writing
support was provided by Stacey Human and
Data Availability. We support sharing of
Zhigang Ma of Parexel International, which was
individual participant data. The individual par-
funded by Fosun.
ticipant data that underlie the results reported
in this article (text, table, figure, and extended
Author Contributions. All authors con-
data) will be shared after de-identification. The
tributed to study conception, protocol design,
raw data will be available for 1 year after the
data collection, statistical analysis, data inter-
publication of this article. Researchers that
pretation or manuscript draft. All authors had
provide a scientifically sound proposal will be
full access to all trial data and approved the final
allowed access to the individual participant
version of the manuscript for submission for
data. Proposals should be directed to
publication.
[email protected] or aimin.hui@fosun-
Disclosures. Ai-Min Hui, Lei Ge, Xiyuan pharma.com. All code used to produce the
Wang, Jianfei Zheng, Jingjun Qiu are employees results can be accessed by sending a scientifi-
of Fosun Pharma and may hold stock options. cally sound proposal to [email protected] or
Yuanzheng Qiu is the ex-employee of [email protected]. The code will be
Fosun. Uğur Şahin and Özlem Türeci are man- available with the raw data.
agement board members and employees of
BioNTech SE (Mainz, Germany). Eleni Lagkadi-
nou, Svetlana Shpyro, Orkun Ozhelvaci, Yoana
Shiskova and Alexander Muik are employees of
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