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Safety and Immunogenicity of Inactivated SARS-CoV-2 Vaccine in High-Risk Occupational Population: a randomized, parallel, controlled clinical trial

09 Aug 2021-medRxiv (Cold Spring Harbor Laboratory Press)-

Abstract: Vaccination is urgently needed to prevent the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we conducted a randomized, parallel, controlled clinical trial for assessment of the immunogenicity and safety of an inactivated SARS-CoV-2 vaccine, aiming to determine an appropriate vaccination interval for high-risk occupational population. Participants were randomly assigned to receive two doses of inactivated SARS-CoV-2 vaccine (4 µg per dose) at an interval of either 14 days, 21 days or 28 days. The primary immunogenicity endpoints were neutralization antibody seroconversion and geometric mean titer (GMT) at 28 days after the second dose. Our results showed that the seroconversion rates (GMT ≥ 16) were all 100% in the three groups and the 0-21 and 0-28 groups elicited significantly higher SARS-CoV-2 neutralizing antibody level. All reported adverse reactions were mild. (Chinese Clinical Trial Registry: ChiCTR2100041705, ChiCTR2100041706)
Topics: Seroconversion (56%), Population (53%), Immunogenicity (52%), Vaccination (52%)

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1
Safety and Immunogenicity of Inactivated SARS-CoV-2
Vaccine in High-Risk Occupational Population: a
randomized, parallel, controlled clinical trial
Yongliang Feng
a,b#
, Jing Chen
c,d#
, Tian Yao
a,b#
,
Yue Chang
a,b
, Xiaoqing Li
c,d
, Rongqin
Xing
e
, Hong Li
c,d
, Ruixue Xie
a,b
, Xiaohong Zhang
c,d
, Zhiyun Wei
c,d
, Shengcai Mu
c,d
,
Ling Liu
c,d
, Lizhong Feng
c,d
* & Suping Wang
a,b
*
a
School of Public Health, Shanxi Medical University, Taiyuan, China
b
Center of Clinical Epidemiology and Evidence Based Medicine, Shanxi Medical
University, Taiyuan, China
c
Shanxi Provincial Center for Disease Control and Prevention, Taiyuan, China
d
Shanxi Provincial Key Laboratory for major infectious disease response
e
Outpatient Department of Shanxi Aviation Industry Group Co. LTD
#
Co-first authors
*Author for correspondence:
Suping Wang, professor, Email: supingwang@sxmu.edu.cn; Address: Department of
Epidemiology, School of Public Health, Shanxi Medical University, 56 Xinjian South
Road Taiyuan, 030001, Shanxi Province, China
Lizhong Feng, chief physician, Email: 1508717672@qq.com; Address: Shanxi
Provincial Center for Disease Control and Prevention, 8 Xiaonanguan Street Taiyuan,
030012, Shanxi Province, China
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted August 9, 2021. ; https://doi.org/10.1101/2021.08.06.21261696doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

2
Abstract
Vaccination is urgently needed to prevent the global spread of severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we conducted a
randomized, parallel, controlled clinical trial for assessment of the immunogenicity
and safety of an inactivated SARS-CoV-2 vaccine, aiming to determine an appropriate
vaccination interval for high-risk occupational population. Participants were randomly
assigned to receive two doses of inactivated SARS-CoV-2 vaccine (4 µg per dose) at
an interval of either 14 days, 21 days or 28 days. The primary immunogenicity
endpoints were neutralization antibody seroconversion and geometric mean titer
(GMT) at 28 days after the second dose. Our results showed that the seroconversion
rates (GMT
16) were all 100% in the three groups and the 0-21 and 0-28 groups
elicited significantly higher SARS-CoV-2 neutralizing antibody level. All reported
adverse reactions were mild. (Chinese Clinical Trial Registry: ChiCTR2100041705,
ChiCTR2100041706)
Introduction
The ongoing pandemic of coronavirus disease 2019 (COVID-19) induced by
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an
unprecedented global public health crisis. Globally, as of August 4, 2021, more than
199 million cases of SARS-CoV-2 infection and more than 4.2 million deaths have
been reported
1
. SARS-CoV-2 belongs to the Betacoronavirus of the family
Coronaviridae, and commonly induces a spectrum of clinical manifestations ranging
from asymptomatic, minor flu-like symptoms to acute respiratory distress syndrome
(ARDS), pneumonia and even death
2
. Compared with other coronaviruses,
SARS-CoV-2 appears to undergo more rapid transmission and variation
3, 4
. Although
it is proved to be effective that the COVID-19 pandemic can be controlled using strict
social hygiene measures such as physical distancing and masks, the absence of herd
immunity leaving people susceptible to further waves of SARS-CoV-2 infection,
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted August 9, 2021. ; https://doi.org/10.1101/2021.08.06.21261696doi: medRxiv preprint

3
especially for the high-risk occupational population. Meantime, the measures taken to
contain SARS-CoV-2 have placed a substantial burden on health-care systems around
the world, with far-reaching social and economic consequences. Hence, a safe and
effective vaccine against COVID-19 is urgently needed to prevent the resurgence of
the epidemic.
Many countries have accelerated the process of clinical trials to determine an
effective and safe vaccine to prevent COVID-19 pandemic. Currently, more than 292
candidate vaccines are in development worldwide, 37 of which are already in phase 3
trials using different platforms
5
, including nucleic acid (DNA and RNA) vaccines,
viral vector (replicating and non-replicating) vaccines, virus-like particles vaccines,
peptide-based vaccines, recombinant protein vaccines and inactivated vaccines
6-8
.
Inactivated vaccines have been widely used against various infectious diseases for
decades. Their long history of use confers some advantages, such as well-developed
and mature manufacturing processes, ease of scaling up production and storage, and
the ability to present multiple viral proteins for immune recognition. In addition,
inactivated vaccines induce high levels of neutralizing antibody titers in mice, rats,
guinea pigs, rabbits, and nonhuman primates to provide protection against
SARS-CoV-2
9-11
. Moreover, the results of previous clinical trials on the inactivated
vaccines conducted in several countries showed good neutralizing antibody responses
and/or efficacy against disease caused by COVID-19
12-21
. To date, two inactivated
SARS-CoV-2 vaccines manufactured by the Beijing Institute of Biological
Products/Sinopharm (China) and Sinovac Life Sciences/CoronaVac (China) have been
placed on WHO's Emergency Use Listing. Here, we report the analysis of
immunogenicity and safety of an inactivated SARS-CoV-2 vaccine manufactured by
Beijing Institute of Biological Products Co., Ltd (China).
Previous studies
15-17, 22-24
have shown that the three immunization programs (0,
14 procedure, 0, 21 procedure or 0, 28 procedure) induce varying degrees of immune
effect, but the optimal interval of injections remains unclear. Furthermore, the safety
and immunogenicity of inactivated SARS-CoV-2 vaccine in occupational high-risk
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted August 9, 2021. ; https://doi.org/10.1101/2021.08.06.21261696doi: medRxiv preprint

4
population have not been reported. Therefore, based on the preliminary clinical trials,
we explored the immunogenicity and safety of the three different SARS-CoV-2
inactivated vaccination schemes at an interval of either 14 days, 21 days or 28 days in
high-risk occupational population to optimize the inactivated vaccination regimen. We
would continue to follow up until months 3, 6, and 12 in the further study.
Methods
Study design and participants
We conducted a randomized, controlled clinical trial of the SARS-CoV-2
inactivated vaccine manufactured by Beijing Biological Products Institute Co., Ltd. in
Taiyuan City, Shanxi Province, China. Written informed consents were obtained from
all participants before enrollment. Eligible participants were people aged 18-59 years,
signed the informed consent form and participated voluntarily with good compliance.
Exclusion criteria were participants with history or family history of allergy,
convulsion, epilepsy, encephalopathy or psychosis; any intolerance or allergy to any
component of the vaccine; known or suspected diseases including severe respiratory
disease, severe cardiovascular disease, severe liver or kidney disease, medically
uncontrollable hypertension (systolic blood pressure
140 mmHg and diastolic blood
pressure
90 mmHg), complications of diabetes mellitus, malignancy, various acute
diseases or acute episodes of chronic disease; various infectious, suppurative and
allergic skin diseases; congenital or acquired immunodeficiency, other vaccination
history within 14 days before vaccination, a history of coagulation dysfunction, a
history of non-specific immunoglobulin injection within 1 month prior to enrollment,
acute illness with fever (body temperature > 37.0°C); and being pregnant or
breastfeeding.
The protocol was approved by the Ethics Committee of Shanxi Provincial Center
for Disease Control and Prevention and was conducted in accordance with the
Declaration of Helsinki and Good Clinical Practice. All participants signed a consent
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted August 9, 2021. ; https://doi.org/10.1101/2021.08.06.21261696doi: medRxiv preprint

5
form after being informed about the study. The trial was registered with
ChiCTR.org.cn (ChiCTR2100041705, ChiCTR2100041706).
Procedures
A computerized random number generator performed block randomization with
a randomly selected block size of 6, and eligible participants were randomly assigned
into three groups to receive two doses inactivated COVID-19 vaccine at the schedule
of day 0-14, day 0-21, or day 0-28. Each dose of vaccine containing 4 µg of
inactivated SARS-CoV-2 virus antigen was intramuscularly injected into the lateral
deltoid muscle of the upper arm. The vaccines used in this study were inactivated
vaccine (Vero Cell) produced by Beijing Biological Products Institute Co., Ltd.
Demographic information (age, gender, body mass index (BMI), marital status, and
education level), influenza vaccination history, smoking, drinking, and chronic
diseases were collected via questionnaire investigation.
Safety assessment
After each dose was vaccinated, the participants were observed for any
immediate reaction for 30 min, and local and systemic adverse reactions were
collected. Participants were required to record the local adverse events and systemic
adverse events on diary cards within 7 days of each injection. Any other unsolicited
symptoms were also recorded during a 28-day follow-up period after each injection
by spontaneous report from the participants combined with the regular visit. The
solicited adverse reactions included local reactions (pain, induration, swelling, rash,
flush, and pruritus) and systematic reactions (fever, diarrhea, dysphagia, anorexia,
vomiting, nausea, muscle pain (non-vaccination sites), arthralgia, headache, cough,
dyspnea, skin and mucosal abnormalities, acute allergic reactions, and fatigue).
Laboratory methods
Oropharyngeal/nasal swabs were collected for detecting SARS-CoV-2 nucleic
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted August 9, 2021. ; https://doi.org/10.1101/2021.08.06.21261696doi: medRxiv preprint

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Nanshan Chen1, Min Zhou2, Xuan Dong1, Jie-Ming Qu2  +10 moreInstitutions (3)
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Abstract: In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020.

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Jasper Fuk-Woo Chan1, Shuofeng Yuan1, Kin-Hang Kok1, Kelvin K. W. To2  +19 moreInstitutions (2)
15 Feb 2020-The Lancet
TL;DR: The findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions.
Abstract: Summary Background An ongoing outbreak of pneumonia associated with a novel coronavirus was reported in Wuhan city, Hubei province, China. Affected patients were geographically linked with a local wet market as a potential source. No data on person-to-person or nosocomial transmission have been published to date. Methods In this study, we report the epidemiological, clinical, laboratory, radiological, and microbiological findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an additional family member who did not travel to Wuhan. Phylogenetic analysis of genetic sequences from these patients were done. Findings From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020. Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus. Additionally, one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members. None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital. Five family members (aged 36–66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhoea, or a combination of these 3–6 days after exposure. They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6–10 days after symptom onset. They and one asymptomatic child (aged 10 years) had radiological ground-glass lung opacities. Older patients (aged >60 years) had more systemic symptoms, extensive radiological ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels. The nasopharyngeal or throat swabs of these six patients were negative for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR positive for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing. Phylogenetic analysis of these five patients' RT-PCR amplicons and two full genomes by next-generation sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiatory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats. Interpretation Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions. Funding The Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, Sanming Project of Medicine (Shenzhen), and High Level-Hospital Program (Guangdong Health Commission).

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09 Jan 2021-The Lancet
TL;DR: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials.
Abstract: Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials.

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