Objective: To evaluate the safety of enterovirus 71（EV71）inactivated vaccines produced by Wuhan Institute of Bio Products through learning the incidence of adverse events following immunization（AEFI）in children aged 6 months to 3 years old after vaccination. Methods: According to the national requirement for vaccine safety monitoring program，data of AEFI cases after inoculated EV71 vaccines from September 2017 to October 2018 in Zhejiang Province was collected by combining active and passive monitoring. Demographic characteristics，space distribution，dose and incidence of AEFI were analyzed. Results: A total of 107 503 children were included in this study，of which 27 173 were actively monitored and 80 330 were passively monitored. The monitoring results showed that 288 cases of AEFI occurred after inoculated EV71 vaccines，the reported incidence rate was 267.90/100 000. Of 288 cases，266 cases had common reactions（247.43/100 000），14 cases had abnormal reactions（13.02/100 000）and 8 cases had complications（7.44/100 000）；145 cases were passively monitored（180.51/100 000）and 143 cases were actively monitored（526.26/100 000）；150 cases were males and 138 cases were females，with the males to females ratio of 1.09∶1. The AEFI of EV71 vaccines were reported in all the cities of Zhejiang Province，with Jinhua，Taizhou and Hangzhou ranking the top three and accounting for 50.69% of all the reported cases. About 202 cases of AEFI（70.14%）occurred after the first dose of EV71 vaccines，and 163 cases（56.60%）occurred on the day of inoculation.Most of common reactions were fever，swelling and sclerosis. The harm of the reported abnormal reactions was mild，with 8 cases of anaphylactic rash and no other serious abnormal reactions were found. Conclusion The reported incidence rate of AEFI of the domestic EV71 vaccine in children aged from 6 months to 3 years is 267.90/100 000，without serious abnormal reactions，suggesting that the EV71 vaccine is safe.

Objective:To investigate the predominant serotypes and diversification of Echovirus (ECHOV) from viral encephalitis children in Quzhou area of Zhejiang province and the molecular characteristics of the ECHOV VP1 genes.Methods:Cerebrospinal fluid samples from 53 children with viral encephalitis were collected for viral isolation/culture. Fluorescent RT-PCR or PCR was used to detect human enteroviruses (HEV) including ECHOV, coxsackievirus(CoV) and new enterovirus (EV), and japanese encephalitis virus(JEV), mumps virus(MuV), west Nile virus(WNV) and chikungunya virus(CHLKV) or herpes simplex virus(HSV) and cytomegalovirus(CMV) in the cerebrospinal fluid samples. The complete VP1 gene sequence of HEV-B group in the HEV-positive cerebrospinal fluid samples was amplified by RT-PCR and sequenced, and then the typing of Echovirus isolates was performed. The VP1 genotypes of Echovirus isolates, gene recombination, inheritance and evolution characteristics were analyzed using multiple bioinformatic software.Results:Six viral strains were isolated by cell culture using rhabdomyosarcoma (RD) cells but not human epithelial-2 (Hep-2) cells. Eleven cerebrospinal fluid samples were positive for HEV by RT-PCR but the detection result of all the other viruses were negative. In the 11 HEV-positive samples, 6 samples were positive for ECHOV (4 for ECHO6, 1 for ECHO7 and 1 for ECHO30 serotype), which was coincident with the isolation result , but CoV and EV were undetectable. The 4 ECHO6 isolates belonged to ECHO6-C2 subgenotype but can be divided into two epidemic clones (ECHO6-41/46 and ECHO6-45/48). The ECHO7 and ECHO30 isolates belonged to ECHO7-C and ECHO30-C genotypes. The VP1 gene recombination between the ECHO6 and ECHO30 isolates were found during their evolutionary process.Conclusions:ECHOV is the major pathogen of viral encephalitis children in the area, and there is a possibility of local outbreak or epidemic. Because of the possibility of recombination of the VP1 gene of ECHO6 and ECHO30 virus, ECHO6 may become the dominant ECHOV serotype.

Objective The objective of this study was to analyze the disease burden of influenza in schools and child care settings in rural areas of Hangzhou. Methods Hospital visit influenza cases aged 3-17 years in hospitals that reported based on influenza surveillance system from 2016 to 2018 in Chun′an county, Hangzhou city were selected as study subjects and a total of 294 confirmed cases of influenza were selected using system sampling method. Questionnaires were designed to investigate the basic information and data on inpatients and outpatients among, health care and life quality, etc.. Direct and indirect economic burden and disability adjusted life year (DALY) were analyzed and compared among different age groups. Results The mean age of investigated subjects was (8.88±3.92) years. A total of 143 (48.64%) investigated cases were male. In total of 283 (96.26%) cases were outpatients. The total economic burden was 124 743.95 CNY. The mean economic burden was 424.30 CNY per person. The mean direct and indirect economic burden was 361.33 and 62.97 CNY per person respectively. The difference of the mean direct, indirect and total economic burden per person between different age group was statistically significant (P<0.001). The 3-5 years age group showed the highest economic burden with the median value of direct, indirect and total economic burden per person being 276.24, 50.98 and 321.26 CNY, respectively, while the 12-17 years age group showed the lowest values with 175.30, 26.54, 201.79 CNY, respectively. The DALY of 294 influenza cases was 1.18, and the median of burden strength was 3.21 DALY/thousand. The difference of the burden of strength between different age group influenza case was statistically significant (P<0.001), of which the 12-17 years age group showed the highest value with 4.25 DALYs/thousand while the 3-5 years age group showed the lowest value with 2.60 DALY/thousand. Conclusion The disease burden of influenza was heavy in schools and kindergartens in rural areas of Hangzhou city, with the cases aged from 3 to 5 years showing higher economic burden and cases aged from 12 to 17 years showing greater burden strength.

Objective The objective of this study was to analyze the disease burden of influenza in schools and child care settings in rural areas of Hangzhou. Methods Hospital visit influenza cases aged 3-17 years in hospitals that reported based on influenza surveillance system from 2016 to 2018 in Chun′an county, Hangzhou city were selected as study subjects and a total of 294 confirmed cases of influenza were selected using system sampling method. Questionnaires were designed to investigate the basic information and data on inpatients and outpatients among, health care and life quality, etc.. Direct and indirect economic burden and disability adjusted life year (DALY) were analyzed and compared among different age groups. Results The mean age of investigated subjects was (8.88±3.92) years. A total of 143 (48.64%) investigated cases were male. In total of 283 (96.26%) cases were outpatients. The total economic burden was 124 743.95 CNY. The mean economic burden was 424.30 CNY per person. The mean direct and indirect economic burden was 361.33 and 62.97 CNY per person respectively. The difference of the mean direct, indirect and total economic burden per person between different age group was statistically significant (P<0.001). The 3-5 years age group showed the highest economic burden with the median value of direct, indirect and total economic burden per person being 276.24, 50.98 and 321.26 CNY, respectively, while the 12-17 years age group showed the lowest values with 175.30, 26.54, 201.79 CNY, respectively. The DALY of 294 influenza cases was 1.18, and the median of burden strength was 3.21 DALY/thousand. The difference of the burden of strength between different age group influenza case was statistically significant (P<0.001), of which the 12-17 years age group showed the highest value with 4.25 DALYs/thousand while the 3-5 years age group showed the lowest value with 2.60 DALY/thousand. Conclusion The disease burden of influenza was heavy in schools and kindergartens in rural areas of Hangzhou city, with the cases aged from 3 to 5 years showing higher economic burden and cases aged from 12 to 17 years showing greater burden strength.

Objective:To evaluate the immunogenicity, safety, and immune persistence of the sequential booster with the recombinant protein-based COVID-19 vaccine (CHO cell) in healthy people aged 18-84 years.Methods:An open-label, multi-center trial was conducted in October 2021. The eligible healthy individuals, aged 18-84 years who had completed primary immunization with the inactivated COVID-19 vaccine 3 to 9 months before, were recruited from Shangyu district of Shaoxing and Kaihua county of Quzhou, Zhejiang province. All participants were divided into three groups based on the differences in prime-boost intervals: Group A (3-4 months), Group B (5-6 months) and Group C (7-9 months), with 320 persons per group. All participants received the recombinant COVID-19 vaccine (CHO cell). Blood samples were collected before the vaccination and after receiving the booster at 14 days, 30 days, and 180 days for analysis of GMTs, antibody positivity rates, and seroconversion rates. All adverse events were collected within one month and serious adverse events were collected within six months. The incidences of adverse reactions were analyzed after the booster.Results:The age of 960 participants was (52.3±11.5) years old, and 47.4% were males (455). The GMTs of Groups B and C were 65.26 (54.51-78.12) and 60.97 (50.61-73.45) at 14 days after the booster, both higher than Group A′s 44.79 (36.94-54.30) ( P value<0.05). The GMTs of Groups B and C were 23.95 (20.18-28.42) and 27.98 (23.45-33.39) at 30 days after the booster, both higher than Group A′s 15.71 (13.24-18.63) ( P value <0.05). At 14 days after the booster, the antibody positivity rates in Groups A, B, and C were 91.69% (276/301), 94.38% (302/320), and 93.95% (295/314), respectively. The seroconversion rates in the three groups were 90.37% (272/301), 93.75% (300/320), and 93.31% (293/314), respectively. There was no significant difference among these rates in the three groups (all P values >0.05). At 30 days after the booster, antibody positivity rates in Groups A, B, and C were 79.60% (238/299), 87.74% (279/318), and 90.48% (285/315), respectively. The seroconversion rates in the three groups were 76.92% (230/299), 85.85% (273/318), and 88.25% (278/315), respectively. There was a significant difference among these rates in the three groups (all P values <0.001). During the sequential booster immunization, the incidence of adverse events in 960 participants was 15.31% (147/960), with rates of about 14.38% (46/320), 17.50% (56/320), and 14.06% (45/320) in Groups A, B, and C, respectively. The incidence of adverse reactions was 8.02% (77/960), with rates of about 7.50% (24/320), 6.88% (22/320), and 9.69% (31/320) in Groups A, B, and C, respectively. No serious adverse events related to the booster were reported. Conclusion:Healthy individuals aged 18-84 years, who had completed primary immunization with the inactivated COVID-19 vaccine 3 to 9 months before, have good immunogenicity and safety profiles following the sequential booster with the recombinant COVID-19 vaccine (CHO cell).

Objective:To evaluate the safety and immune effect of recombinant hepatitis B vaccine （CpG ODN adjuvant).Methods:On Oct. 26, 2016, we launched volunteer recruitment in Kaihua county, Quzhou city, Zhejiang Province. In the randomized, double-blind, controlled trial, a total of 48 subjects with negative HBV screening tests and normal hepatorenal function among 18 and 60 years old were selected and divided into two groups randomly, 24 cases each. The experimental group was given 250 μg of CpG ODN recombinant （Hansenula polymorpha) Hepatitis B vaccine and the control group was given 10 μg of commercial Hepatitis B vaccine with timed at 0, 1and 6 months. The inoculation reactions were compared the difference between the two groups after observed and recorded in time periods. We also collected serum before and after immunization to compare the two groups of anti-HBs positive rate, geometric mean concentration（GMC).Results:During the study period, the incidence of adverse events was 66.67%（16/24) in the experimental group and 54.17%（13/24) in the control group, with no significant difference（ P=0.556). The severities of adverse events were level 1 or level 2, and no level 3 or above adverse reactions occurred. After full-course immunization, in the FAS data set, the anti-HBs GMC in the experimental group [2 598.56（1 127.90-5 986.90) mIU/ml] was higher than that in the control group[371.97（164.54-840.91) mIU/ml] In the PPS set, the GMC of test group was 7 808.21（3 377.00-18 052.00) mIU/ml, which was higher than that of the control group [843.22（213.80-3 325.90) mIU/ml]. The anti-HBs positive rate of FAS（PPS) was 95.83%（100.00%) in the experimental group and the control group; The anti-HBs strongly positive rate of FAS（PPS) was 79.17%（90.00%) in the experimental group and 33.33%（50.00%) in the control group, with statistically significant differences among the FAS set（ P=0.003) and no statistically significance differences among the PPS set（ P=0.074). Conclusion:CpG Hepatitis B Vaccine is safe and shows better immunogenicity than the control vaccine.

Objectives:To investigate the prevalence of cough and its influencing factors in community children under 5 years old.Methods:From October to December 2019, we selected 3 102 community children under the age of 5 from 50 natural villages/residential communities in 14 towns/streets of Yiwu, Zhejiang Province, using multi-stage random sampling method. A face-to-face and on-site questionnaire survey was conducted among child caregivers to collect demographic data and information about children′s cough in the last 1 month. Multiple logistic regression model was used to analyze children′s cough and the influencing factors of different cough states.Results:Multivariate logistic regression model analysis results showed that compared with 0-1 year old, dispersed, caregivers with education level below high school, families with 1 child under 5 years old, Cough risk was higher in 1-2, 2-3, 3-4 years old, nurseries, caregivers with education level of high school or above, and families with more than 2 children under 5 years old. OR (95% CI) values were 1.52(1.19-1.92), 1.65(1.29-2.10), 1.86(1.36-2.54), 2.59(1.99-3.38), 1.48(1.26-1.74) and 1.35(1.13-1.62), respectively. Further analysis of the influencing factors of different states of cough, multivariate logistic regression model analysis results showed that preschool status, the number of children under 5 years old in the family and the education level of caregivers were the influencing factors of acute, prolonged and chronic cough. Age was only an influencing factor of acute and persistent cough. Conclusions:The disease burden of cough in children under 5 years old community was heavy, and the cough was related to children′s age, education level of caregivers, number of children under 5 years old in the family and childcare status.

Objective:To evaluate the safety and immune effect of recombinant hepatitis B vaccine （CpG ODN adjuvant).Methods:On Oct. 26, 2016, we launched volunteer recruitment in Kaihua county, Quzhou city, Zhejiang Province. In the randomized, double-blind, controlled trial, a total of 48 subjects with negative HBV screening tests and normal hepatorenal function among 18 and 60 years old were selected and divided into two groups randomly, 24 cases each. The experimental group was given 250 μg of CpG ODN recombinant （Hansenula polymorpha) Hepatitis B vaccine and the control group was given 10 μg of commercial Hepatitis B vaccine with timed at 0, 1and 6 months. The inoculation reactions were compared the difference between the two groups after observed and recorded in time periods. We also collected serum before and after immunization to compare the two groups of anti-HBs positive rate, geometric mean concentration（GMC).Results:During the study period, the incidence of adverse events was 66.67%（16/24) in the experimental group and 54.17%（13/24) in the control group, with no significant difference（ P=0.556). The severities of adverse events were level 1 or level 2, and no level 3 or above adverse reactions occurred. After full-course immunization, in the FAS data set, the anti-HBs GMC in the experimental group [2 598.56（1 127.90-5 986.90) mIU/ml] was higher than that in the control group[371.97（164.54-840.91) mIU/ml] In the PPS set, the GMC of test group was 7 808.21（3 377.00-18 052.00) mIU/ml, which was higher than that of the control group [843.22（213.80-3 325.90) mIU/ml]. The anti-HBs positive rate of FAS（PPS) was 95.83%（100.00%) in the experimental group and the control group; The anti-HBs strongly positive rate of FAS（PPS) was 79.17%（90.00%) in the experimental group and 33.33%（50.00%) in the control group, with statistically significant differences among the FAS set（ P=0.003) and no statistically significance differences among the PPS set（ P=0.074). Conclusion:CpG Hepatitis B Vaccine is safe and shows better immunogenicity than the control vaccine.

Objectives:To investigate the prevalence of cough and its influencing factors in community children under 5 years old.Methods:From October to December 2019, we selected 3 102 community children under the age of 5 from 50 natural villages/residential communities in 14 towns/streets of Yiwu, Zhejiang Province, using multi-stage random sampling method. A face-to-face and on-site questionnaire survey was conducted among child caregivers to collect demographic data and information about children′s cough in the last 1 month. Multiple logistic regression model was used to analyze children′s cough and the influencing factors of different cough states.Results:Multivariate logistic regression model analysis results showed that compared with 0-1 year old, dispersed, caregivers with education level below high school, families with 1 child under 5 years old, Cough risk was higher in 1-2, 2-3, 3-4 years old, nurseries, caregivers with education level of high school or above, and families with more than 2 children under 5 years old. OR (95% CI) values were 1.52(1.19-1.92), 1.65(1.29-2.10), 1.86(1.36-2.54), 2.59(1.99-3.38), 1.48(1.26-1.74) and 1.35(1.13-1.62), respectively. Further analysis of the influencing factors of different states of cough, multivariate logistic regression model analysis results showed that preschool status, the number of children under 5 years old in the family and the education level of caregivers were the influencing factors of acute, prolonged and chronic cough. Age was only an influencing factor of acute and persistent cough. Conclusions:The disease burden of cough in children under 5 years old community was heavy, and the cough was related to children′s age, education level of caregivers, number of children under 5 years old in the family and childcare status.

The elderly are prone to develop severe disease or die after infection with SARS-CoV-2, and inoculation of COVID-19 vaccine is of great significance to reduce the serious case and death. Several COVID-19 vaccines have been administered and demonstrated their safety and effectiveness in the real world. This review summarizes the safety and effectiveness of COVID-19 vaccines in the real-world studies, especially the rare adverse reactions associated with vaccine and protection against severe disease, hospitalization and death in different epidemiological contexts.