扫码关注科兴官方微信号“疫苗之益”

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.

 

Link:http://www.sinovacbio.com/news/shownews.php?id=1154&lang=en