| Objective(s):The safety and immunogenicity of this vaccine in a two-dose immunization program for children aged 3-8 years was investigated by administering two doses of quadrivalent influenza virus cleavage vaccine to this age group.Methods:This clinical trial is divided into two phases.The first phase was a small trial(sample size of 40 cases)to observe only the clinical tolerability and safety of the test vaccine.20 subjects aged 9-59 years and 20 subjects aged 3-8 years were enrolled in a 1:1 ratio.(1)Subjects in the 9-59 years age group were enrolled first according to the trial being conducted first in the older age group subjects.Subjects were enrolled according to the entry row criteria and then vaccinated with the tetravalent lysis test vaccine(15μg/0.5m L/dose of each hemagglutinin type).The incidence of 30 minutes,0-7 days,0-28 days post-exemption,6-month adverse events,serious adverse events and pregnancy events were collected using original record books,diary cards and contact cards,and the incidence was calculated and graded.(2)In the age group of 3-8 years,safety numbers were collected in the same way as in the age group of 9-59 years.The second dose of vaccine was administered 28 days after the first dose,and safety data were collected at 30 minutes,0-7 days,0-30 days,and 6 months.The second phase of the trial focused on demonstrating the immunogenicity and safety of the test vaccine in the target population.A single-center,open-ended,self-controlled,eugenic vaccine clinical trial design was adopted with a sample size of240 subjects in the age group 3-8 years.After enrollment,blood specimens were collected before immunization,and then the first dose of the test vaccine was administered.Blood specimens were collected on the 28 th day after immunization and the 2nd dose of vaccine was administered,and safety data were collected at 30 minutes,0-7 days,0-30 days,and 6 months.Blood specimens were collected on day30 post-exemption.The hemagglutination inhibition(HI)antibodies to H1N1,H3N2,and B/Yamagata and B/Victoria lineages were measured in serum specimens before and on day 28 after the first dose and day 30 after the second dose,respectively,using the hemagglutination inhibition test,and the HI positive conversion rate,protection rate,CMT and GMI were calculated,and the antibody positive conversion rate of the second dose was compared with the positive conversion rate of the first dose.The lower limit of the 95% confidence interval(CI)of the difference between the positive conversion rate after vaccination with dose 2 minus the positive conversion rate after vaccination with dose 1 was >0.The 95% CI of the difference between the positive conversion rate of dose 2 and dose 1 was estimated using the Tango score approximation.e CRFs were created using an electronic data capture system(EDC),raw numbers were entered and data sets were partitioned..The measurement data were described by means,standard deviations,maximum and minimum values and95% confidence intervals(CI),and t-tests were used for normally distributed variables;the count data were described by frequency distribution tables.Comparisons between groups of variables with unordered classification were performed using chi-square test/Fisher’s exact test.All statistical tests were performed using a two-sided test,and P values <0.05 were considered statistically significant differences.Results:1.Subjects enrollment and follow-up: A total of 280 subjects were enrolled in this clinical study,of which 40 were enrolled in the first phase of the clinical study(20 subjects aged 9-59 years and 20 subjects aged 3-8 years),and one subject in the3-8 years group was dislodged during the study(the investigator determined that the second dose was not suitable for vaccination).A total of 240 subjects were enrolled in the second phase of the clinical study,of whom 240 received the first dose and 233 completed the full course of immunization(7 subjects were shed because their parents refused the second dose).2.Safety :(1)A total of 24 adverse events(40.68%)occurred in the Phase I clinical study.A total of 19 adverse events(32.20%)were associated with the vaccine.9 adverse reactions occurred in subjects aged 9-59 years,including 3 systemic and 6 local adverse reactions.10 adverse reactions occurred in subjects aged 3-8 years,9systemic and 1 local adverse reaction.All adverse reactions were grade 1 or 2.The highest incidence was fever(5 cases,8.47%),followed by redness(2 cases,3.39%)and pain(2 cases,3.39%).No adverse reactions of grade 3 and above occurred.(2)A total of 177 adverse events(37.42%)occurred in the phase II clinical study.A total of 95 cases(20.08%)of adverse events related to the trial vaccine occurred.Adverse reactions occurred in 46 cases(19.17%)after the first dose of vaccine,including 35 cases(14.58%)of systemic adverse reactions,mainly fever(11 cases,5.07%)and cough(10 cases,5.71%).Acute allergic reactions occurred in 1 case(0.42%),most of which were grade 1 or 2,and grade 3 in 2 cases;local adverse reactions occurred in 11 cases(4.58%),all of which were grade 1 or 2,mainly redness(5 cases,2.08%)and pain(2 cases,0.83%).Adverse reactions occurred 49 cases(21.03%)after the second dose of vaccination.Systemic adverse reactions occurred in46 cases(19.74%),all of them were grade 1 or 2,mainly cough(17 cases,7.30%)and fever(13 cases,5.58%).Acute allergic reactions occurred in 1 case(0.43%)and were grade 2;local adverse reactions occurred in 3 cases,mainly tenderness(2 cases,0.86%)and redness(1 case,0.43%).A total of 17 cases(3.59%)of SAEs occurred,none of which were related to the experimental vaccine.4.Immunogenicity :(1)The positive conversion rates of HI antibodies to the four antigens after the first dose of vaccination were 72.29% for H1N1,63.64% for H3N2,61.47% for BY and 63.20% for BV,and The positive conversion rates of HI antibodies for the four antigens after the second dose of inoculation were 74.89% for H1N1,73.16% for H3N2,77.49% for BY and 65.37% for BV.The positive conversion rates of HI antibodies to all four antigens were higher after 2 doses of inoculation than after 1dose,with the difference in positive conversion rates and 95% CI of 2.60%(95% CI:-5.55%-10.63%)and 2.17%(95% CI:-6.57%-10.90%)for the H1N1 subtype and BV line after 2 doses of inoculation versus 1 dose,respectively,with the lower limit of95% CI of the positive conversion rate difference < 0.The A/H1N1 type and B/BV line did not meet the primary endpoint of immunogenicity.(2)The protection rates of HI antibody titers for the four antigens after 2 doses of vaccination were 92.21% for H1N1,94.81% for H3N2,83.12% for BY,and 73.59%for BV.The protection rates of HI antibody titers for the four antigens were above70%,but only the protection rates for the H3N2 type and BY lines after 2 doses were statistically different from those after 1 dose(P <0.05).(3)The GMT and standard deviation of antibody titers for the 4 antigens HI after vaccination with the 1st dose were H1N1 229.35±557.22,H3N2 409.27±1264.46,BY 61.43 ± 201.84,and BV 80.97 ± 294.20;the GMT and standard deviation of antibody titers for the 4 antigens HI after vaccination with the 2nd dose were H1N1204.02±326.95,H3N2 454.59±907.40,BY 75.79±138.88,and BV 70.53±275.08;the GMT of H1N1 type and BV type after 2 doses of inoculation was smaller than that after 1 dose,and the difference was statistically significant(P<0.05).(4)In H3N2 type and BY type,the difference in GMI after the 2nd dose of vaccination was not statistically significant compared with that after the 1st dose of vaccination(P>0.05).Conclusion(s):In the 3-8 years old population,administering two doses of the quadrivalent influenza virus split vaccine demonstrates good safety and tolerability.However,no significant immunogenicity advantage has been observed with 2 doses of vaccination compared to 1 dose of vaccination. |
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