Enterovirus 71-Associated Infection in South Vietnam: Vaccination Is a Real Solution.

Hand-foot-and-mouth disease (HFMD) is the most common enteroviral infection in South-East Asia. When evaluating the role of enterovirus 71 (EVA71) as an etiological agent of infectious disease in South Vietnam, we revealed a high proportion of EVA71 among identified species A enteroviruses found in 3542 samples from HFMD cases; 125 samples from cases of enteroviral meningitis; and 130 samples from acute flaccid paralysis (AFP) cases. These represent 50%, 54.8%, and 51.5%, respectively. According to molecular analysis, 90% of EVA71 were attributed to genotype C4 and 10% were attributed to genotype B5. The predominance of EVA71 circulation among the population proves the need to strengthen surveillance (with monitoring of enterovirus circulation for facilitation of HFMD outbreak prediction) and to increase the effectiveness of preventative measures by the implementation of vaccination against EVA71-associated infections. A phase III trial of a Taiwanese vaccine (EV71vac) in Taiwan and South Vietnam showed its safety, tolerability, and efficacy in children aged 2-71 months. This B4 genotype-based vaccine, which features cross-protection against B5 and C4 genotypes, and other existing EV71 vaccines can serve as a good approach to solving the HFMD problem, which is so important for Vietnam.

Safety and Immunogenicity of Enterovirus 71 Vaccine (Vero Cell) Administered Simultaneously with Trivalent Split-Virion Influenza Vaccine in Infants Aged 6-7 Months: A Phase 4, Randomized, Controlled Trial.

Objective: To assess the immunogenicity and safety of the enterovirus 71 vaccine (Vero cell) (EV71 vaccine) and trivalent split-virion influenza vaccine (IIV3). Methods: Healthy infants aged 6-7 months were recruited from Zhejiang Province, Henan Province, and Guizhou Province and randomly assigned to the simultaneous vaccination group, EV71 group, and IIV3 group at a ratio of 1:1:1. Then, 3 mL blood samples were collected before vaccination and 28 days after the second dose of vaccine. Cytopathic effect inhibition assay was used to detect EV71 neutralization antibody, and cytopathic effect inhibition assay was used to detect influenza virus antibody. Results: A total of 378 infants were enrolled and received the first dose of vaccine and were included in the safety analysis, and 350 infants were involved in the immunogenicity analysis. The adverse events rates were 31.75%, 28.57%, and 34.13% in the simultaneous vaccination group, EV71 group, and IIV3 group (p > 0.05), respectively. No vaccine-related serious adverse events were reported. After two doses of EV71 vaccine, the seroconversion rates of EV71 neutralizing antibody were 98.26% and 97.37% in the simultaneous vaccination group and the EV71 group, respectively. After two doses of IIV3, the simultaneous vaccination group and the IIV3 group, respectively, had seroconversion rates of 80.00% and 86.78% for H1N1 antibody, 99.13% and 98.35% for H3N2 antibody, and 76.52% and 80.99% for B antibody. There was no statistically significant difference in the seroconversion rates of influenza virus antibodies between groups (p > 0.05). Conclusions: The coadministration of EV71 vaccine and IIV3 has good safety and immunogenicity in infants aged 6-7 months.

Immunogenicity and safety of an inactivated enterovirus 71 vaccine coadministered with trivalent split-virion inactivated influenza vaccine: A phase 4, multicenter, randomized, controlled trial in China.

Background: Few data exist on the immunogenicity and safety of an inactivated enterovirus 71 vaccine (EV71 vaccine) coadministered with trivalent split-virion inactivated influenza vaccine (IIV3) in infants. Methods: This trial was a phase 4, randomized, controlled trial. Infants aged 6-11 months were eligible, with no history of hand, foot and mouth disease (HFMD) and no history of EV71 vaccine or any influenza vaccine. Eligible infants were randomly assigned to EV71+IIV3 group, EV71 group or IIV3 group. Blood samples were collected on day 0 and 56. Results: Between September 2019 and June 2020, 1151 infants met eligibility criteria and 1134 infants were enrolled. 1045 infants were included in the per-protocol population, including 347 in the EV71+IIV3 group, 343 in the EV71 group, and 355 in the IIV3 group. The seroconversion rate (98.56% vs 98.54%; seroconversion rates difference of 0.02% [95% CI: 0.70-0.98]) and GMT (419.05 vs 503.72; GMT ratio of 0.83 [95% CI 0.70 - 0.98]) of EV71 neutralizing antibodies in the EV71+IIV3 group was not inferior to those in the EV71 group. The non-inferiority results for influenza virus antibodies (A/H1N1, A/H3N2 and B) showed that the seroconversion rates and GMTs of the EV71+IIV3 group were non-inferiority to those of the IIV3 group. Systemic and local adverse event rates were similar between groups. None of serious adverse events (SAEs) were related to vaccination. Conclusions: Coadministration of the EV71 vaccine with IIV3 was safe and did not interfere with immunogenicity. These findings support a viable immunization strategy for infants with the EV71 vaccine coadministered with IIV3 in China. This trial is registered with ClinicalTrials.gov, number NCT04091880.

Vaccine Uptake to Prevent Meningitis and Encephalitis in Shanghai, China.

Multiple vaccines may prevent meningitis and encephalitis (M/E). In China, the meningococcal vaccine and Japanese encephalitis vaccine (JEV) have been included in the expanded program of immunization (EPI). The pneumococcal vaccine, Haemophilus influenzae type b (Hib) vaccine, rotavirus vaccine, and enterovirus 71 (EV-71) vaccine are non-EPI vaccines and are self-paid. We aim to investigate the uptake of these M/E vaccines in children and the related knowledge and health beliefs among family caregivers. A total of 1011 family caregivers with children aged 1-6 years in Shanghai, China were included in the study. The uptake of the pneumococcal vaccine, Hib-containing vaccine, rotavirus vaccine, and EV-71 vaccine remained at 44.0-48.1% in children, compared with the higher uptake of the meningococcal vaccine (88.8%) and JEV (87.1%). Moreover, family caregivers had limited knowledge on the M/E pathogens and possible vaccines. Their health beliefs were moderate to high. Then, a health belief model (HBM) and a structural equation model were established. The uptake of four non-EPI vaccines was significantly influenced by family income (ß = 0.159), knowledge (ß = 0.354), self-efficacy (ß = 0.584), and perceived susceptibility (ß = 0.212) within an HBM. Therefore, it warrants further improving the uptake rate for these non-EPI vaccines to prevent potential M/E in children. A specific health promotion may empower the caregivers' decision-making on childhood vaccination.

Immunogenicity and safety of an enterovirus 71 vaccine in children aged 36-71 months: A double-blind, randomised, similar vaccine-controlled, non-inferiority phase III trial.

Background: The enterovirus 71 (EV71) vaccine produced by Wuhan Institute of Biological Products Co., Ltd. (WIBP) (B-EV71) has been given to children aged 6-35 months, and it has shown good safety, immunogenicity and efficacy. However, the administration of EV71 vaccine in children aged 36-71 months, which is another target population, needs further exploration. Methods: We conducted a double-blind, randomised, controlled, non-inferiority phase III clinical trial in children aged 36-71 months, with a further comparison group of children aged 6-35 months in China. Children aged 6-71 months with no history of hand, foot and mouth disease or prior-vaccination of EV71 vaccine were eligible and recruited. Eligible participants aged 36-71 months were randomly assigned (1:1) to receive two doses of the B-EV71 vaccine (Older-B group) or the control EV71 vaccine (C-EV71 vaccine, produced by Institute of Medical Biology, Chinese Academy of Medical Sciences) (Older-C group), administered at a 30-day interval. Eligible participants aged 6-35 months were enrolled consecutively to receive two doses of the B-EV71 vaccine (Younger-B group) at a 30-day interval. Participants, investigators and those assessing outcomes were masked to the vaccine received. Non-inferiority analyses were conducted to compare the immunogenicity of EV71 vaccine in the Older-B group with that in the Older-C and Younger-B groups. Non-inferiority margins were 10% for seroconversion rate differences and 0.5 for geometric mean titre (GMT) ratios. The primary endpoints were the GMT level and seroconversion rate of anti-EV71 neutralising antibody 30 days after the second dose of vaccination. The primary analysis was performed in the per-protocol population. Safety analyses were conducted amongst participants receiving at least one dose of vaccine. This trial was registered at Chinadrugtrials.org.cn (#CTR20192345). Findings: Between June 3 and June 30, 2020, 1600 participants were enrolled and assigned, including 625 participants in the Older-B group, 625 participants in the Older-C group and 350 participants in the Younger-B group. The seroconversion rate of anti-EV71 neutralising antibody in the Older-B group (99.66%; 95% CI: 99.18%-100.00%) was non-inferior to that of the Older-C (99.32%; 95% CI: 98.65%-99.98%) and Younger-B groups (100.00%; 95% CI: 100.00%-100.00%). The differences in seroconversion rates in the Older-B group to those in the Older-C and Younger-B groups were 0.34% (95%CI: -2.17%-2.86%) and -0.34% (95%CI: -2.78%-2.09%). The GMT of the anti-EV71 neutralising antibody in the Older-B group (693.87) was also non-inferior to that in the Older-C (289.37) and Younger-B groups (634.80). The ratios of GMTs in the Older-B group to those in the Older-C and Younger-B groups were 2.67 (95%CI: 2.00-3.00) and 1.00 (95%CI: 0.75-1.00), respectively. The incidence of any adverse event (AE) related to vaccination was similar amongst the three groups (34/625 [5.44%] in the Older-B group, 32/623 [5.14%] in the Older-C group, and 26/349 [7.45%] in the Younger-B group), with only 2 (0.57%) participants having grade 3 AEs in the Younger-B group. Fifteen (0.94%) participants from these three groups had reported serious AEs (SAEs), all of which were unrelated to vaccines. Interpretation: EV71 vaccine produced by WIBP could extend to be administered to children aged 36-71 months against EV71 infection. However, the persistence of vaccine-induced immunities needs to be further investigated. Funding: Hubei Province's young medical talent program (20191229), Hubei Province's young talent program (2021), Hubei Province's young public health talent program (2021); and the Wuhan Institute of Biological Products Co., Ltd.

Clinical evaluation of the lot-to-lot consistency of an enterovirus 71 vaccine in a commercial-scale phase IV clinical trial.

OBJECTIVE: To evaluate the immunogenicity, safety and lot-to-lot consistency of an inactivated enterovirus 71 (EV71) vaccine cultured in bioreactors with different specifications after full immunization. METHODS: A randomized, double-blind trial was performed in 3,000 children aged 6 ~ 35 months with six vaccine batches, which were prepared in 40 L and 150 L bioreactors for three consecutive batches respectively. Children were immunized on day 0 and 28, serum samples were collected on day 0 and 56, and neutralizing antibody titers were determined by the microcytopathic method. Immediate reactions were recorded within 30 min, local and systemic symptoms were recorded within 0 ~ 28 days, and serious adverse events were recorded within 6 months. RESULTS: After immunization with two doses of the inactivated EV71 vaccine, the neutralizing antibody GMT was 825.52 ± 4.09, and the positive conversion rate was 96.18%, with no significant difference. The 95% CI of the serum neutralizing antibody GMT ratio between the two groups after immunization with the three vaccine batches produced in the 150 L and 40 L bioreactors ranged from .67 ~ 1.5. The overall incidence of adverse reactions, mainly grade 1 reactions, for all 6 batches from 0 to 28 days after vaccination was 49.62%, with no significant difference (p = .8736). The incidence of systemic adverse reactions, primarily fever and diarrhea, was 45.14%; the incidence of local adverse reactions, primarily erythema and tenderness, was 9.43%. CONCLUSION: The EV71 vaccine was highly immunogenic and safe in children aged 6-35 months, and 6 consecutive batches produced by the two bioreactors with different specifications were consistent.

Immunogenicity and Safety of an Inactivated Enterovirus 71 Vaccine Administered Simultaneously with Hepatitis B Virus Vaccine, Group A Meningococcal Polysaccharide Vaccine, Measles-Rubella Combined Vaccine and Japanese Encephalitis Vaccine: A Multi-Center, Randomized, Controlled Clinical Trial in China.

BACKGROUND: The aim of this study was to investigate the immunogenicity and safety of the enterovirus 71 vaccine (EV71 vaccine) administered alone or simultaneously. METHODS: A multi-center, open-label, randomized controlled trial was performed involving 1080 healthy infants aged 6 months or 8 months from Shandong, Shanxi, Shaanxi, and Hunan provinces. These infants were divided into four simultaneous administration groups and EV71 vaccine separate administration group. Blood samples were collected from the infants before the first vaccination and after the completion of the vaccination. This trial was registered in the Clinical Trials Registry (NCT03519568). RESULTS: A total of 895 were included in the per-protocol analysis. The seroconversion rates of antibodies against EV71 in four simultaneous administration groups (98.44% (189/192), 94.57% (122/129), 99.47% (187/188) and 98.45% (190/193)) were non-inferior to EV71 vaccine separate administration group (97.93% [189/193]) respectively. Fever was the most common adverse event, the pairwise comparison tests showed no difference in the incidence rate of solicited, systemic or local adverse events. Three serious adverse events related to the vaccination were reported. CONCLUSIONS: The evidence of immunogenicity and safety supports that the EV71 vaccine administered simultaneously with vaccines need to be administered during the same period of time recommended in China.

Changing epidemiology of hand, foot, and mouth disease in China, 2013-2019: a population-based study.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is an important public health problem. A monovalent EV-A71 vaccine was launched in China in 2016. Previous studies showed that inactivated monovalent EV-A71 vaccines were highly efficient against HFMD associated with EV-A71 but not against HFMD with other etiologies, leading to a hypothesis that the introduction of EV-A71 vaccines might change the pathogen spectrum and epidemiological trend of HFMD. In this study, we described for the first time the changing epidemiological characteristics of HFMD after the launch of the EV-A71 vaccine. METHODS: We extracted individual-based epidemiological data on HFMD cases reported to the Chinese Center for Disease Control and Prevention between January 2013 and December 2019. We described the changing epidemiological characteristics of HFMD before and after vaccine launch according to the distribution of diseases characteristics (demographic, temporal, and geographical) and evaluated the potential changes in risk factors of severe patients. All analyses were stratified by the phase before and after vaccine launch, and by enterovirus serotype. FINDINGS: During 2013-2019, 15,316,710 probable cases of HFMD were reported. Of these, 787,197 (5·1%) were laboratory confirmed and 76,982 (0·5%) were severe. After the launch of the EV-A71 vaccine, the median age of HFMD patients infected with EV-A71 increased from 2·24 years (IQR:1·43, 3·56) to 2·81 years (IQR:1·58, 4·01). The proportion of patients less than 3 years of age decreased while the proportion of patients 3-5 years of age increased. There was a large decrease (60·7%) in the proportion of severe cases as well as a decline (28·3%) in HFMD patients infected with EV-A71. After the launch of the EV-A71 vaccine, the severe illness rate and mortality rate of HFMD patients in all age groups has decreased sharply, 62·20% and 83·78% respectively. The timing of the HFMD epidemic peak was delayed (1-2 months) . After the launch of EV-A71 vaccine, the risk of becoming a severe case for EV-A71 serotype was decreased, whereas that risk was instead increased for CV-A16 (from 0·17 (95% CI:0·16, 0·18) to 0·23 (95% CI:0·21, 0·25)) and other enterovirus compared to EV-A71 (from 0·38 (95% CI:0·37, 0·39) to 0·58 (95% CI:0·56, 0·61)). The longer the time from onset to diagnosis, the higher was the risk of being a severe case, but the effect size was decreased. INTERPRETATION: The introduction of the EV-A71 vaccine has effectively reduced the proportion of severe HFMD cases and mortality, but changes to the dominant serotypes should be closely monitored. Development of multivalent vaccines to avoid an increased case burden due to other enteroviruses is greatly needed. FUNDING: This research was supported by the National Natural Science Foundation of China (81973102, 81773487), Public Health Talents Training Program of Shanghai Municipality (GWV-10.2-XD21), the 5th Three-year Action Program of Shanghai Municipality for Strengthening the Construction of Public Health System (GWV-10.1-XK05), the Major Project of Scientific and Technical Winter Olympics from National Key Research and Development Program of China (2021YFF0306000), 13th Five-Year National Science and Technology Major Project for Infectious Diseases (2018ZX10725-509) and Key projects of the PLA logistics Scientific research Program (BHJ17J013).

Epidemiological characteristics of hand, foot, and mouth disease in Yunnan Province, China, 2008-2019.

BACKGROUND: Since 2016, enterovirus 71 (EV71) vaccines have been approved for market entry, and little is known about how the epidemiology of hand, foot, and mouth disease (HFMD) has been affected by the introduction of the vaccines in Yunnan Province. The study describes the epidemiological characteristics of HFMD before and after the introduction of EV71 vaccination in Yunnan Province. METHODS: Surveillance data collected between 2008 and 2019 were analyzed to produce epidemiological distribution on cases, etiologic composition, and EV71 vaccination coverage, as well as to compare these characteristics before and after EV71 vaccination. RESULTS: A total of 1,653,533 children received EV71 vaccines from 2016 through 2019 in Yunnan. The annual EV71 vaccination coverage rate ranged from 5.53 to 15.01% among children ≤5 years old. After the introduction of EV71 vaccines, the overall incidence of HFMD increased and reached over 200 cases per 100,000 population-years in 2018 and 2019. However, the case severity and case fatality rate decreased and remained lower than 1 and 0.005% after 2016, respectively. EV71-associated mild, severe and fatal cases sharply decreased. The predominant viral serotype changed to non-EV71/non-CV-A16 enteroviruses which were detected across the whole province. CONCLUSIONS: Non-EV71/non-CV-A16 enteroviruses became the predominant strain and led to a higher incidence in Yunnan. Expanding EV71 vaccination and strengthening laboratory-based surveillance could further decrease the burden of severe HFMD and detect and monitor emerging enteroviruses.

Vaccination coverage estimates and utilization patterns of inactivated enterovirus 71 vaccine post vaccine introduction in Ningbo, China.

BACKGROUND: In China, enterovirus 71 (EV71) is the major etiological agents of hand foot mouth disease that poses severe risks to children's health. Since 2015, three inactivated EV71 vaccines have been approved for use. Previous studies indicated the high willingness of EV71 vaccination in eastern China. However, few studies have assessed coverage and utilization patterns of EV71 vaccine in China. METHODS: Children born during 2012-2018 were sampled and their records were abstracted from Ningbo childhood immunization information management system. Descriptive statistics characterized the study population and assessed coverage and timeliness for EV71 vaccination. Simultaneous administration patterns as well as type of EV71 vaccine used were also evaluated. Bivariate and multivariable analysis was used to examine the relationship of socio-demographic characteristics with vaccination coverage and timeliness. RESULTS: Of 716,178 children living in Ningbo. One hundred seventy-two thousand two hundred thirty-six received EV71 vaccine with a coverage rate of 24.05% and only 8.61% received vaccination timely. 21.97% of children received the complete two dose EV71 series but only 6.49% completed timely. Vaccination coverage and timeliness increased significantly from 2012 birth cohort to 2018 birth cohort. Relatively higher coverage and timeliness were observed in resident children, Inner districts, high socioeconomic areas and large-scaled immunization clinics. Of 329,569 doses of EV71 vaccine, only 5853(1.78%) doses were administered at the same day as other vaccines. CONCLUSIONS: There is a need for increasing EV71 vaccination coverage and timeliness as well as eliminating disparities among different populations. Our study highlights the importance of simultaneous administration to increasing coverage and timeliness of EV71 vaccination.

Post-marketing safety surveillance for inactivated Enterovirus 71 vaccines in Jiangsu, China from 2017 to 2019.

INTRODUCTION: Two types of enterovirus 71 (EV71) vaccines, manufactured using human diploid (H2) and Vero cells, have been administered in Jiangsu Province, China since 2017. In this study, we evaluated their safety profiles using records collected from the Chinese National Adverse Events Following Immunization (AEFIs) Information System (CNAEFIS) and Electronic Immunization Registries System (EIRS) between 2017 and 2019. METHODS: Demographic characteristics of the patients, AEFI incidence rates(IRs), symptoms, and time intervals were summarized from the reported AEFI data in the CNAEFIS. Also, the administered doses of the two vaccines were exported from the EIRS to calculate the IRs of AEFIs and thus compare the AEFIs between the two types of EV71 vaccines. RESULTS: In total, 209, 407, and 344 AEFIs cases following EV71 vaccine administration were reported during 2017, 2018, and 2019, respectively, yielding IRs of 59.2, 48.2, and 54.2 per 100,000 doses, respectively. Fever, irritability, allergic eruptions, fatigue, loss of appetite, redness and induration at the injection site were the most commonly reported AEFIs. No significant differences in rare reactions were found between the two types of EV71 vaccinations. The majority of AEFIs were developed within 30 min to 3 days after administration. CONCLUSION: EV71 vaccines showed satisfactory safety profiles since their first use 3 years ago in the Jiangsu Province. The AEFI profiles were identical to those in pre-marketing studies; most AEFIs after vaccination were mild and common. More active surveillance studies should be performed to provide more comprehensive post-marketing safety data.

Assessing the vaccine effectiveness for hand, foot, and mouth disease in Guangzhou, China: a time-series analysis.

Objective: Hand, foot, and mouth disease (HFMD) is an important public health issue in China. Although efficacy has been demonstrated by randomized controlled trials, the evidence for effectiveness of the monovalent Enterovirus 71 (EV71) vaccine against HFMD remains unknown. This study aimed to assess the vaccine effectiveness for HFMD in Guangzhou, China. Methods: Routinely collected vaccination and HFMD surveillance data were captured from the China Information System for Disease Control and Prevention. We estimated the EV71 vaccine effectiveness using spatial ecologic and time-series analysis approaches. Results: A total of 174,002 HFMD cases under 5 years of age were reported to the Guangzhou, China surveillance system from January 2016 to December 2018. A total of 408,664 children completed a two-dose EV71 vaccination series. In an ecologic analysis, a two-dose EV71 vaccination rate above the median conferred lower HFMD risk relative to a vaccination rate below the median (ratio ratio = 0.955, 95% confidence interval (CI): 0.949, 0.962; P < .001). In the time-series approach, 0.9% fewer HFMD cases were associated with a 1% increase in the two-dose EV71 vaccination rate, but without statistical significance (P = .094). However, we detected statistically significant protective associations for HFMD among children 3 years of age (0.9% fewer HFMD cases with a 1% increased vaccination rate; P = .046), and for EV71 (1.4%; P = .012) and "other viruses" (1.3%; P = .002), although not for Coxsackievirus A16 (CVA16). Conclusion: Our findings, based on real-world data, provide evidence of EV71 vaccine effectiveness for preventing EV71 and "other" viruses associated with HFMD. An expanded program of EV71 vaccination is urgently needed.

Immunogenicity and Safety of Inactivated Enterovirus 71 Vaccine in Children Aged 36-71 Months: A Double-Blind, Randomized, Controlled, Non-inferiority Phase III Trial.

BACKGROUND: The Sinovac enterovirus 71 (EV71) vaccine has been given to children aged 6-35 months with good safety, immunogenicity, and efficacy. Further exploration is needed for the application of Sinovac EV71 vaccine in older children. METHODS: A phase III, double-blind, single-center, randomized, controlled, non-inferiority, and bridging-designed trial enrolled 300 participants aged 6-35 months and 600 participants aged 36-71 months. Non-inferiority and superiority analyses were made to determine the immunogenicity of Sinovac EV71 vaccine in older children (Older-S group), comparing with that of control EV71 vaccine in the same age group (Older-C group), or comparing with that of Sinovac EV71 vaccine in younger children (Younger-S group). RESULTS: The seroconversion rate of anti-EV71 in Older-S group (95.5%) was superior to that of Older-C group (86.0%), and non-inferior to that of Younger-S group (98.5%). For baseline seronegative participants, the geometric mean titer of Older-S group (370.0) was non-inferior to that of Older-C group (296.2) and superior to that of Younger-S group (176.5). Incidence of adverse reactions in Older-S group (47.0%) was similar to that of Older-C group (44.8%), or Younger-S group (49.8%). CONCLUSIONS: This study showed good safety and immunogenicity of Sinovac EV71 vaccine in children aged 36-71 months. CLINICAL TRIALS REGISTRATION: NCT03909074. URL: https://clinicaltrials.gov/ct2/show/NCT03909074?term=NCT03909074&draw=2&rank=1.

Willingness of parents to vaccinate their 6-60-month-old children with EV71 vaccines: a cross-sectional study in rural areas of northern Jiangsu Province.

Enterovirus 71 (EV71) is the dominant pathogen in severe and fatal hand-foot-mouth disease (HFMD) cases. Since 2015, three inactivated EV71 vaccines have been approved in China. The vaccination coverage of the EV71 vaccine has been relatively low, especially in rural areas. A cross-sectional survey from July 19 to August 22, 2018, was conducted in three rural counties of northern Jiangsu Province among parents of children aged 6-60 months. We adopted a pretested validated questionnaire to assess knowledge, awareness, and attitude of HFMD and EV71 vaccines among respondents and used univariate and multivariate binary logistic analyses to explore potential factors associated with the acceptance of EV71 vaccines. Of the 1,112 parents who participated, 87.8% were willing to vaccinate their children with EV71 vaccines. Parents over 40 y old were less likely to have their children vaccinated [adjusted odds ratio (aOR) = 2.12, 95% confidence interval (CI): 1.13-3.97]. Parents who lived in Ganyu (aOR = 0.50, 95% CI: 0.31-0.79) or Xinyi county (aOR = 0.33, 95% CI: 0.20-0.53), had a university or higher degree (aOR = 0.26, 95% CI: 0.11-0.64), had good knowledge of EV71 vaccines (aOR = 0.81, 95% CI: 0.67-0.98), perceived their children's disease susceptibility, and worried about the severity of HFMD had a higher willingness to vaccinate their children. Most parents were willing to vaccinate their children against EV71-related HFMD. Parental age, location, education level, knowledge of EV71 vaccines, concern about susceptibility, and severity of HFMD were all factors that influenced willingness to vaccinate.

An inactivated enterovirus 71 vaccine is safe and immunogenic in healthy adults: A phase I, double blind, randomized, placebo-controlled, study of two dosages.

BACKGROUND: Hand, foot and mouth disease (HFMD), especially that caused by enterovirus 71 (EV71) infection, is a public health concern in the Asia-Pacific region. We report a phase I clinical trial of an EV71 candidate vaccine (INV21) based on a binary ethylenimine inactivated B2 sub-genotype formulated with aluminum hydroxide. METHODS: In this double-blind, placebo-controlled, randomized, dose escalation study adult volunteers received two vaccinations 28 days apart of low or high dose formulations of the candidate vaccine and were then monitored for safety and reactogenicity for four weeks after each dose, and for their immune responses up to 28 weeks. RESULTS: Of 36 adults enrolled, 35 completed the study as planned. Either no or mild adverse events were observed, mainly injection site pain and tiredness. Seroconversion was 100% after two vaccinations. High geometric mean neutralizing antibody titers (GMT) were observed 14 days post first dose, peaking 14 days post second dose (at Day 42) in both high and low dose groups; GMTs on days 14, 28, 42, and 56 were 128, 81, 323, 203 and 144, 100, 451, 351 in low- and high-dose groups, respectively. Titers for both doses declined gradually to Day 196 but remained higher than baseline and the placebo groups, which had low GMTs throughout the duration of the study. Cross-neutralizing antibody activity against heterologous sub-genotypes was demonstrated. CONCLUSION: These data show that the EV71 candidate vaccine is safe and immunogenic in adults and supports further clinical development as a potential pediatric vaccine by initiating a dose-escalation study for determining the dose-dependent safety and immunogenicity of the vaccine in young naïve children.

[Post-marketing multi-center safety surveillance of inactivated enterovirus A71 vaccine (Vero cell)].

Objective: To evaluate the post-marketing safety profiles of the inactivated enterovirus type 71 (EV-A71) vaccine (Vero cell) after routine inoculation. Methods: Eleven cities of Zhejiang Province, Fengtai district of Beijing, Qinnan district, two counties as Pingle and Pingguo of Guangxi Zhuang Autonomous Region, and Dongtai city of Jiangsu Province were selected as the field sites. A total of 45 239 subjects were enrolled in this study from children who seeked the vaccination of EV-A71 vaccine during the period from July, 2016 to June, 2018. Different sampling method were adopted in different sites. All vaccinated children were invited to participate in the study in Fengtai and Dongtai, however, systematic sampling method were adopted in other sites. Active surveillance was conducted and information about adverse reactions (ARs) occurred in 30 min, 3 d and 30 d following each dose of EV-A71 immunization was collected by field observation, phone-call or face-to-face interview. The incidence of ARs in different types, symptoms and grades were described. Results: In total, there were 45 239 children who received 71 243 doses EV-A71 vaccine. The overall incidence of ARs was 1.079% (769 doses), with the highest incidence of 1.182% (177/14 973) in 5-11 month group and the lowest incidence of 0.849% (18/2 119) in ≥ 36 month group among different age groups. There was a higher incidence in solicited ARs, which was 1.047% (746 doses). The incidences of grade 1 and grade 2 ARs were also higher, which were 0.404% (288 doses) and 0.554% (395 doses), respectively. No grade 4 ARs occurred. The doses of the first and the second vaccination was 40 736 and 30 507, respectively, and the incidences of ARs were 1.281% (522 doses) and 0.810% (247 doses). Also, the incidences of ARs were 0.091% (37 doses) and 0.043% (13 doses) in local, and 1.168% (476 doses) and 0.760% (232 doses) in system. The symptoms of ARs after the two doses of vaccination were basically the same. Redness at the injection site was the most common local ARs after each dose vaccination, with doses of 24 and 11, while fever was the most common systemic ARs, with doses of 362 and 190. Moreover, ARs mainly occurred in 30 min to 3 d after each dose vaccination, with incidence of 1.016% (414 doses) and 0.698% (213 doses) in the first and second dose, respectively. Conclusion: The ARs had a low incidence after vaccination in children and most were mild or moderate. EV-A71 vaccine with good safety is suitable for inoculation in a large scale.

Willingness and influential factors of parents to vaccinate their children with novel inactivated enterovirus 71 vaccines in Guangzhou, China.

Hand, foot and mouth disease (HFMD) primarily affects children younger than 5 years of age. Recently, HFMD has ranked as the top notifiable infectious disease in China. In December 2015, China approved two novel inactivated enterovirus 71 vaccines (EV71 vaccines) for HFMD. Parents' acceptance is often essential for vaccination program success. The goal of this study was to identify willingness and influential factors to vaccinate among parents of kindergarteners in Guangzhou, China. A cross-sectional survey of face-to-face interviews was conducted from March to July 2016. Fifty-five kindergartens were randomly selected from 11 districts of Guangzhou. An anonymous self-designed questionnaire was used to investigate awareness, knowledge and attitude towards HFMD and EV71 vaccines. A total of 868 parents participated in the survey. Mean(±standard deviation) knowledge score of HFMD was 6.32(±1.70). Approximately 32.03% of parents had heard of the EV71 vaccines with 22.58% receiving information before this study. Nearly 44.24% of parents showed willingness to vaccinate their children. Previously receiving EV71 vaccine-related information [adjusted odds ratio (aOR) = 1.48, 95% confidence interval (CI): 1.04-2.11], no fear of adverse effects (aOR = 4.25, 95%CI: 2.77-6.53), perceived susceptibility of children to HFMD (aOR = 2.15, 95%CI: 1.42-3.25) and children not previously diagnosed with HFMD (aOR = 1.56, 95%CI: 1.07-2.27) were positively associated with EV71 vaccination acceptability. However, parental education background (aOR = 0.54, 95%CI: 0.37-0.80) was negatively correlated with vaccination acceptability. Our study provides baseline information for future vaccination campaigns to help improve the EV71 vaccine uptake rate. Special efforts are urgently needed to improve the awareness and knowledge of EV71 vaccines in China.

A comparative analysis of immunogenicity and safety of an enterovirus 71 vaccine between children aged 3-5 years and infants aged 6-35 months.

BACKGROUND: The Sinovac enterovirus 71 (EV71) vaccine has shown good safety, immunogenicity, and efficacy in infants aged 6-35 months, whom are considered as the priority of the target population. However, 3-5 years old children accounted for approximately 30% of HFMD cases and are also worth our attention. METHODS: A randomized, double-blind, placebo-controlled, batch-to-batch consistency clinical trial enrolling 1400 participants aged 6-59 months was performed. We pooled the participants receiving three batches of EV71 vaccine together and then stratified them into the 6-35 months and 3-5 years. The non-inferiority analysis of the geometric mean titer (GMT) of EV71 neutralizing antibody post-vaccination was the primary endpoint. RESULTS: In the vaccine group, the GMT of 242 children aged 3-5 years was 132.72 (95% CI, 110.3-159.6), which was non-inferior to that generated in 717 infants aged 6-35 months. Following the vaccination, the incidence of adverse reactions was less frequent in children aged 3-5 years (47.0%) than that found in infants aged 6-35 months (60.1%) (p = 0.0026). CONCLUSIONS: Our study indicated that the EV71 vaccine was also safe in children aged 3-5 years, with non-inferior immunogenicity to that in infants aged 6-35 months.

Correlates of protection for inactivated enterovirus 71 vaccine: the analysis of immunological surrogate endpoints.

BACKGROUND: Inactivated Enterovirus 71 (EV71) vaccines showed significant efficacy against the diseases associated with EV71 and a neutralizing antibody (NTAb) titer of 1:16-1:32 was suggested as the correlates of the vaccine protection. This paper aims to further estimate the immunological surrogate endpoints for the protection of inactivated EV71 vaccines and the effect factors. METHODS: Pre-vaccination NTAb against EV71 at baseline (day 0), post-vaccination NTAb against EV71 at day 56, and the occurrence of laboratory-confirmed EV71-associated diseases during a 24-months follow-up period were collected from a phase 3 efficacy trial of an inactivated EV71 vaccine. We used the mixed-scaled logit model and the absolute sigmoid function by some extensions in continuous models to estimate the immunological surrogate endpoint for the EV71 vaccine protection, respectively. RESULTS: For children with a negative baseline of EV71 NTAb titers, an antibody level of 26.6 U/ml (1:30) was estimated to provide at least a 50% protection for 12 months, and an antibody level of 36.2 U/ml (1:42) may be needed to achieve a 50% protective level of the population for 24 months. CONCLUSION: Both the pre-vaccination NTAb level and the vaccine protective period could affect the estimation of the immunological surrogate for EV71 vaccine. A post-vaccination NTAb titer of 1:42 or more may be needed for long-term protection. CLINICAL TRIAL REGISTRATION: NCT01508247.

2-Year Efficacy, Immunogenicity, and Safety of Vigoo Enterovirus 71 Vaccine in Healthy Chinese Children: A Randomized Open-Label Study.

BACKGROUND: This study evaluated the 2-year efficacy, immunogenicity, and safety of the Vigoo enterovirus 71 (EV71) vaccine. METHOD: In an initial phase 3 study, we randomly assigned healthy infants and children aged 6-35 months (ratio, 1:1) to receive 2 doses of either EV71 vaccine (5120 participants) or placebo (5125 participants) at days 0 and 28, and followed them for 12 months after vaccination. In this extended follow-up study, we continued to evaluate the efficacy, immunogenicity, and safety of the EV71 vaccine for up to 2 years. RESULTS: Overall efficacy was 94.84% (95% confidence interval [CI], 83.53%-98.38%) during the 2-year follow-up period (P < .0001), and the vaccine efficacy during the second year was 100.00% (95% CI, 84.15%-100.00%) against EV71-associated hand-foot-and-mouth disease (HFMD; P < .0001). Geometric mean titers of neutralizing antibody in participants remained high during the 2-year follow-up period, and no vaccine-related serious adverse events were recorded. CONCLUSIONS: Two doses of Vigoo EV71 vaccine could provide sustained protection against EV71-associated HFMD in healthy Chinese children. CLINICAL TRIALS REGISTRATION: NCT01508247.