EN
Summary of Clinical Trial Data of Sinovac’s COVID-19 Vaccine (CoronaVac®)
2021-04-03
【ADVERSE REACTIONS】
The safety of CoronaVac® was evaluated in 4 clinical trials conducted domestic and overseas, including randomized, double-blind, placebo-controlled phase I/II clinical trials in people aged 18-59 years and in elderly aged 60 years and above, a phase III clinical efficacy trial in Brazilian health professionals aged 18 years and above, and a phase IIIb bridging trial in different production scales and different populations. Systematic safety observation was carried out within 7 days after each vaccination, and adverse events were collected by voluntary report of subjects and regular follow-up of investigators on 8-14/28 days, long-term of serious adverse events within 12 months after the full vaccination is still ongoing.
1. General description of adverse reactions in clinical trials of CoronaVac®
A total of 14,572 subjects aged 18 and above were enrolled in a series of clinical trials conducted domestic and overseas, of which 7,658 subjects received at least one dose. All subjects have completed at least 28 days follow-up after full immunization, and long-term safety visits are ongoing.
According to the grading standard of adverse reaction incidence from Council for International Organizations of Medical Sciences (CIOMS), i.e. very common (≥10%), common (1%-10%, 1% was inclusive), uncommon (0.1%-1%, 0.1% was inclusive), rare (0.01%-0.11%, 0.01% was inclusive) and very rare (<0.01%), all adverse reactions were summarized and described as follows.
1) Adverse reactions at injection site
Very common: pain
Common: swelling, pruritus, erythema, induration
Uncommon: burn at injection site
2) System adverse reactions
Very common: headache, fatigue
Common: myalgia, nausea, diarrhea, arthralgia, cough, chills, pruritus, loss of appetite, rhinorrhea, sore throat, nasal congestion, abdominal pain
Uncommon: vomit, hypersensitivity, abnormal skin and mucosa, fever, tremor, flushing, edema, dizziness, drowsiness
Rare: muscle spasms, eyelid edema, nasal congestion, abdominal distension, constipation, hyposmia, ocular congestion, hot flashes, hiccup, conjunctival congestion
3) Severity of adverse reactions
The severity of adverse reactions observed in these clinical trials is mainly Grade 1 (mild), the incidence rate of adverse reactions for Grade 3 and the above was 1.31%.
Grade 3 and above adverse reactions includes pain at injection site, fever, headache, fatigue, myalgia, nausea, diarrhea, arthralgia, chills, pruritus, vomiting, hypersensitivity, abnormal skin and mucous membrane, sore throat, abdominal pain, dizziness and drowsiness.
4) Serious adverse event (SAE)
No serious adverse event related to vaccination was identified up to February 3, 2021.
2. Adverse reactions in clinical trials conducted domestic and overseas
1) Domestic clinical trials
A total of 2203 subjects aged 18 years and above were enrolled into phase I/II and phase IIIb bridging clinical trials, of which 1452 subjects received at least one dose of vaccination (medium dosage in phase I/II), including 1067 subjects aged 18-59 years (73.48%) and 385 subjects aged 60 years and above (26.52%). All subjects have completed at least 28 days of follow-up after whole immunization, and long-term safety monitoring is ongoing.
Solicited adverse reactions were mainly reported within 28 days after immunization. The incidence rates of unsolicited adverse reactions in adults and elderly subjects were 1.50% and 1.30%, respectively. Grade 3 adverse reactions occurred in 2 subjects aged 18-59 years. The incidence of Grade 3 adverse reactions was 0.14%, and the symptoms were fever and headache.
The safety results for phase I/II and phase IIIb bridging trials are shown in Table 1.
Table 1 Incidence of Adverse Reactions in domestic Phase I/II and Phase IIIb Bridging Clinical Trials n (%)
|
Age Group
|
18-59 Years
|
≥60 Years
|
|||||
|
Administration Schedule
|
0, 14 days
|
0,28 days
|
0,14 days
|
0,28 days
|
|||
|
Groups
|
Vaccine
(N=923)
n (%)
|
Placebo
(N=84)
n (%)
|
Vaccine
(N=144)
n (%)
|
Placebo
(N=83)
n (%)
|
Vaccine
(N=260)
n (%)
|
Vaccine
(N=125)
n (%)
|
Placebo
(N=73)
n (%)
|
|
Overall adverse reactions
|
159(17.23)
|
15(17.86)
|
26(18.06)
|
14(16.87)
|
15(5.77)
|
25(20.00)
|
15(20.55)
|
|
Solicited adverse reactions
|
152(16.47)
|
15(17.86)
|
26(18.06)
|
13(15.66)
|
13(5.00)
|
24(19.20)
|
12(16.44)
|
|
Systemic adverse reaction
|
93(10.08)
|
10(11.90)
|
16(11.11)
|
7(8.43)
|
8(3.08)
|
12(9.60)
|
9(12.33)
|
|
Fatigue
|
25(2.71)
|
7(8.33)
|
10(6.94)
|
2(2.41)
|
2(0.77)
|
4(3.20)
|
1(1.37)
|
|
Fever
|
28(3.03)
|
1(1.19)
|
4(2.78)
|
2(2.41)
|
3(1.15)
|
4(3.20)
|
1(1.37)
|
|
Myalgia
|
14(1.52)
|
1(1.19)
|
2(1.39)
|
3(3.61)
|
0(0.00)
|
2(1.60)
|
2(2.74)
|
|
Diarrhea
|
19(2.06)
|
1(1.19)
|
2(1.39)
|
1(1.20)
|
4(1.54)
|
1(0.80)
|
1(1.37)
|
|
Headache
|
13(1.41)
|
1(1.19)
|
3(2.08)
|
0(0.00)
|
1(0.38)
|
0(0.00)
|
0(0.00)
|
|
Cough
|
11(1.19)
|
0(0.00)
|
3(2.08)
|
0(0.00)
|
1(0.38)
|
1(0.80)
|
1(1.37)
|
|
Nausea
|
7(0.76)
|
0(0.00)
|
2(1.39)
|
0(0.00)
|
0(0.00)
|
1(0.80)
|
3(4.11)
|
|
Abnormal skin and mucous membrane
|
4(0.43)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
|
Anorexia
|
2(0.22)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
2(0.77)
|
1(0.80)
|
0(0.00)
|
|
Vomiting
|
2(0.22)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
|
Acute allergic reaction
|
0(0.00)
|
0(0.00)
|
1(0.69)
|
0(0.00)
|
0(0.00)
|
1(0.80)
|
0(0.00)
|
|
Local adverse reactions
|
77(8.34)
|
7(8.33)
|
15(10.42)
|
9(10.84)
|
7(2.69)
|
15(12.00)
|
3(4.11)
|
|
Pain
|
71(7.69)
|
7(8.33)
|
15(10.42)
|
9(10.84)
|
6(2.31)
|
15(12.00)
|
3(4.11)
|
|
Pruritus
|
6(0.65)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
1(0.38)
|
0(0.00)
|
0(0.00)
|
|
Swelling
|
6(0.65)
|
0(0.00)
|
0(0.00)
|
1(1.20)
|
0(0.00)
|
1(0.80)
|
0(0.00)
|
|
Redness
|
2(0.22)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
1(1.37)
|
|
Induration
|
1(0.11)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
0(0.00)
|
|
Unsolicited adverse reactions
|
16(1.73)
|
0(0.00)
|
0(0.00)
|
2(2.41)
|
2(0.77)
|
3(2.40)
|
5(6.85)
|
2) Brazil clinical trial
A total of 12,396 subjects aged 18 years and above were enrolled in phase III clinical trials, of which 6202 subjects received at least one dose, including 316 subjects aged 60 years and above (5.10%). All subjects have completed at least 28 days of follow-up after whole immunization, and long-term safety monitoring is ongoing.
The results of solicited adverse reactions in phase III clinical trial are shown in Table 2. The incidence rate of unsolicited adverse reactions was 36.83%, the symptoms were mainly runny nose (7.01%), sore throat (6.93%), nasal congestion (2.74%), abdominal pain (1.34%) and dizziness (0.66%).
The severity of adverse reactions was mainly Grade 1 and Grade 2, the incidence of Grade 3 adverse reactions was 1.58%. Among the unsolicited adverse reactions, the Grade 3 symptoms compared with solicited adverse reactions were sore throat (0.03%), abdominal pain (0.03%), dizziness (0.02%) and drowsiness (0.02%).
Table 2 Incidence of Solicited Adverse Reactions in Phase III Clinical Trials in Brazil n (%)
|
Name of adverse reactions
|
Vaccine (N=6202) n (%)
|
Placebo (N=6194) n (%)
|
|
Solicited adverse reactions
|
4536(73.14)
|
3714(59.96)
|
|
Grade 3
|
66(1.06)
|
69(1.11)
|
|
Local adverse reactions
|
3815(61.51)
|
2143(34.6)
|
|
Grade 3
|
4(0.06)
|
1(0.02)
|
|
Pain
|
3742(60.34)
|
2014(32.52)
|
|
Grade 3
|
4(0.06)
|
1(0.02)
|
|
Swelling
|
359(5.79)
|
130(2.1)
|
|
Grade 3
|
0(0.00)
|
0(0.00)
|
|
Pruritus
|
263(4.24)
|
181(2.92)
|
|
Grade 3
|
0(0.00)
|
0(0.00)
|
|
Redness
|
241(3.89)
|
89(1.44)
|
|
Grade 3
|
0(0.00)
|
0(0.00)
|
|
Induration
|
235(3.79)
|
67(1.08)
|
|
Grade 3
|
0(0.00)
|
0(0.00)
|
|
Systemic adverse reaction
|
2999(48.36)
|
2947(47.58)
|
|
Grade 3
|
64(1.03)
|
69(1.11)
|
|
Headache
|
2128(34.31)
|
2157(34.82)
|
|
Grade 3
|
34(0.55)
|
46(0.74)
|
|
Fatigue
|
989(15.95)
|
922(14.89)
|
|
Grade 3
|
12(0.19)
|
13(0.21)
|
|
Myalgia
|
727(11.72)
|
648(10.46)
|
|
Grade 3
|
5(0.08)
|
10(0.16)
|
|
Nausea
|
490(7.9)
|
522(8.43)
|
|
Grade 3
|
6(0.10)
|
6(0.10)
|
|
Diarrhea
|
492(7.93)
|
501(8.09)
|
|
Grade 3
|
8(0.13)
|
7(0.11)
|
|
Arthralgia
|
353(5.69)
|
321(5.18)
|
|
Grade 3
|
8(0.13)
|
3(0.05)
|
|
Cough
|
343(5.53)
|
322(5.2)
|
|
Grade 3
|
0(0.00)
|
0(0.00)
|
|
Chills
|
309(4.98)
|
313(5.05)
|
|
Grade 3
|
1(0.02)
|
1(0.02)
|
|
Pruritus
|
263(4.24)
|
225(3.63)
|
|
Grade 3
|
1(0.02)
|
0(0.00)
|
|
Appetite impaired
|
217(3.5)
|
243(3.92)
|
|
Grade 3
|
0(0.00)
|
0(0.00)
|
|
Vomiting
|
61(0.98)
|
61(0.98)
|
|
Grade 3
|
3(0.05)
|
3(0.05)
|
|
Hypersensitivity
|
58(0.94)
|
58(0.94)
|
|
Grade 3
|
2(0.03)
|
2(0.03)
|
|
Abnormal skin and mucous membrane
|
49(0.79)
|
42(0.68)
|
|
Grade 3
|
1(0.02)
|
0(0.00)
|
|
Fever
|
9(0.15)
|
4(0.06)
|
|
Grade 3
|
0(0.00)
|
0(0.00)
|
【CLINICAL TRIALS】
1. Efficacy
A multicenter, randomized, double-blind, placebo-controlled design was adopted in the pivotal phase III clinical trial, which was carried out among healthcare professionals aged 18 years and above in Brazil and healthy adults aged 18-59 years in Turkey, to evaluate the efficacy in high-risk populations and regular population. The primary study hypotheses is that the lower limit of 95% confidence interval of vaccine efficacy (VE) is greater than 30% compared with the placebo group after 14 days of the whole vaccination. The primary analysis of the efficacy in Brazilian clinical trial is based on person-year incidence, and the efficacy of the vaccine in Turkish clinical trial is based on incidence rate. All valid COVID-19 cases were confirmed by the Clinical Endpoint Adjudication Committee.
1) Phase III clinical trial in Brazil
The target population in Brazil was healthcare professionals who work in direct contact with COVID-19 cases. A total of 12,396 subjects were enrolled, a total of 253 cases of symptomatic COVID-19 were reported in the case monitoring period in the primary efficacy analysis. The efficacy against hospitalized, severe and dead COVID-19 cases was 100.00% (95% CI: 56.37-100.00). And the efficacy against symptomatic COVID-19 cases who need medical treatment was 83.70% (95% CI: 57.99-93.67). The efficacy against symptomatic COVID-19 cases was 50.65% (95% CI: 35.66-62.15). The average follow-up time was 70.3 ± 25.6 days, and the median follow-up duration was 73.0 days.
Table 3 Efficacy against COVID-19, 14 Days after 2 Doses of Vaccination in Phase III Clinical Trial in Brazil
|
Group
|
The Vaccine (N=4953)
|
Placebo (N=4870)
|
VE(%) (95% CI)
|
||||
|
Number of cases
|
Person-year of exposure
|
Person-year incidence (%)
|
Number of cases
|
Person-year of exposure
|
Person-year incidence (%)
|
||
|
COVID-19 cases
|
85
|
754.6
|
11.03
|
168
|
736.5
|
22.34
|
50.65 (35.66, 62.15)
|
|
WHO-Grade 3 and above*
|
5
|
755.6
|
0.66
|
30
|
737.9
|
4.07
|
83.70 (57.99, 93.67)
|
|
WHO-Grade 4 and above#
|
0
|
755.6
|
0.00
|
10
|
738.2
|
1.35
|
100.00 (56.37, 100.00)
|
*WHO-Grade 3 and above: COVID-19 cases requiring medical treatment;
#WHO-Grade 4 and above: hospitalized, severe and dead COVID-19 cases, including 5 severe cases and 1 death case;
VE: vaccine efficacy.
2) Phase III clinical trial in Turkey
The target population in Turkey contains high-risk healthcare professionals (K-1) and regular population (K-2). As of December 23, 2020, a total of 7,371 subjects were enrolled, including 918 subjects in K-1 and 6,453 subjects in K-2. Among which, 1,322 subjects completed two doses vaccination and entered the monitoring period of 14 days after the second vaccination. Based on the analysis result of 29 cases, the efficacy against symptomatic COVID-19 cases was 91.25% (95% CI: 71.25- 97.34). See more details in Table 4.
Table 4 Efficacy against COVID-19, 14 Days after 2 Doses of Vaccination in Phase III Clinical Trial in Turkey
|
Group Index
|
The Vaccine (N=752)
|
|
Placebo (N=570)
|
VE (%)
(95%CI)
|
||
|
Number of cases
|
Incidence rate
(%)
|
|
Number of cases
|
Incidence rate
(%)
|
||
|
COVID-19
|
3
|
0.40
|
|
26
|
4.56
|
91.25
(71.25,97.34)
|
2. Immunogenicity
The seroconversion rate and geometric mean titer (GMT) of neutralizing antibody were used to evaluate the immunogenicity of CoronaVac. Seroconversion was defined by a titer of less than 1:8 before any injections with a titer of 1:8 or more after any injections, or by an increase in the antibody titer by a factor of four or more. Neutralizing antibody was determined by cytopathogenic effect assay.
Table 5 Seroconversion Rate and GMT of Neutralizing Antibody in Different Immunization Schedules of Subjects Aged 18 and above (95%CI)(PPS)
|
Group
|
Trial Phase
(Immunization Schedule)
|
Index
|
14 Days after Two Doses Vaccination
|
28 Days after Two Doses Vaccination
|
|
Adult aged 18-59 years
|
Phase Ⅱ (0, 14 days)
|
N
|
118
|
118
|
|
No. of positive cases (Seroconversion rate %)
|
109(92.37)
(86.01, 96.45)
|
111(94.07)
(88.16, 97.58)
|
||
|
GMT
|
27.6(22.7, 33.5)
|
23.8(20.5, 27.7)
|
||
|
Phase Ⅱ (0, 28 days)
|
N
|
-
|
117
|
|
|
No. of positive cases (Seroconversion rate %)
|
-
|
114(97.44)
(92.69, 99.47)
|
||
|
GMT
|
-
|
44.1(37.2, 52.2)
|
||
|
Elderly aged 60 years and above
|
Phase Ⅱ (0, 28 days)
|
N
|
-
|
98
|
|
No. of positive cases (Seroconversion rate %)
|
-
|
96(97.96)
(92.82, 99.75)
|
||
|
GMT
|
-
|
42.2(35.2, 50.6)
|
3. Cross-neutralization
The cross-neutralizing immunogenicity with 80 subjects carried out for 12 SARS-CoV-2 strains (CZ02, WZL, WGF, ZJY, SSH, JWL, ZYF, HAC, HJL, ZXZ, QHF and NOOR). Neutralizing antibody was determined by cytopathogenic effect assay. The results showed that the seroconversion rate of neutralizing antibody after vaccination against 12 SARS-CoV-2 strains (including D614G mutant) range in 80.00% to 100%, GMT (1:) range in 9.3 to 46.7.
About SINOVAC
Sinovac Biotech Ltd. (SINOVAC) is a China-based biopharmaceutical company that focuses on the R&D, manufacturing, and commercialization of vaccines that protect against human infectious diseases.
SINOVAC's product portfolio includes vaccines against COVID-19, enterovirus 71 (EV71) infected Hand-Foot-Mouth disease (HFMD), hepatitis A, varicella, influenza, poliomyelitis, pneumococcal disease, and mumps.
The COVID-19 vaccine, CoronaVac®, has been approved for use in more than 60 countries and regions worldwide. The hepatitis A vaccine, Healive®, passed WHO prequalification requirements in 2017. The EV71 vaccine, Inlive®, is an innovative vaccine under "Category 1 Preventative Biological Products" and was commercialized in China in 2016. In 2022, SINOVAC's Sabin-strain inactivated polio vaccine (sIPV) and varicella vaccine were prequalified by the WHO.
SINOVAC was the first company to be granted approval for its H1N1 influenza vaccine Panflu.1®, which has supplied the Chinese government's vaccination campaign and stockpiling program. The Company is also the only supplier of the H5N1 pandemic influenza vaccine, Panflu®, to the Chinese government stockpiling program.
SINOVAC continually dedicates itself to new vaccine R&D, with more combination vaccine products in its pipeline, and constantly explores global market opportunities. SINOVAC plans to conduct more extensive and in-depth trade and cooperation with additional countries, and business and industry organizations.
For more information, please see the Company’s website at www.sinovac.com.
Contact:
Sinovac Biotech Ltd.
PR Team
pr@sinovac.com