Immunogenicity, Safety, and Lot Consistency of a Novel Inactivated Enterovirus 71 Vaccine in Chinese Children Aged 6 to 59 Months

Hu, Yue; Xu, Wenju; Wang, Jun Zhi; Wang, Ling; Zhang, Yong Jie; Chang, L. W. S.; Liang, Zheng; Xia, Jie; Dai, Qi Gang; Hu, Ya Ling; Mao, Qun; Zhu, Feng; Song, Yu; Gao, Fan; Chen, Jiang Ting

doi:10.1128/cvi.00491-13

Cited by 29 publications

(19 citation statements)

References 16 publications

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“…In our study, EV71 seroprevalence in China and in larger epidemic years was higher than estimates from other Asian areas (ranging from 27.8% to 60.9%) [61, 63, 67, 70]. Our analysis revealed an increasing trend in seroprevalence with a more recent year of sampling except for the year of 2009, which is consistent with the causative pathogens in China HFMD epidemics.…”

Section: Discussionsupporting

confidence: 84%

“…Our meta-analysis showed that, on average, 78% of neonates in China investigated were seropositive (Figure 3, Appendix Figure 1), somewhat higher than reported in studies conducted in Viet Nam, Thailand and Singapore (ranging from 44–67%) [61–63], suggesting a high level of maternal antibody against EV71 infection in China, perhaps due to higher historical incidence of infections among adults [17, 29, 41, 64]. In general, the titer and duration of maternal immunity of infants are associated with the level of mother’s immunity [32].…”

Section: Discussionmentioning

confidence: 65%

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Seroprevalence of Enterovirus 71 Antibody Among Children in China

Yang

et al. 2015

Pediatric Infectious Disease Journal

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Background Hand, foot and mouth disease mostly affects children and carries a substantial disease burden in the Western Pacific region. Enterovirus 71 (EV71) is the most virulent causative agent, and a monovalent vaccine against EV71 will soon become commercially available in China. An improved understanding of EV71 epidemiology could aid policy decisions regarding childhood immunization in China. Objective We aimed to assess and summarize information to date from individual seroepidemiologic studies of EV71 in mainland China in order to determine patterns of the age-specific risk of infection. Methods A systematic review and meta-analysis of studies of children aged 0–15 years, published in English or Chinese, was conducted. Estimates of seroprevalence were summarized by age group. A mixed-effects regression model was used to explore factors co-varying with EV71 seroprevalence. Results We identified 42 published studies, including 15 in English. We found that an average of 78% of neonates were seropositive to EV71 infection but such maternally conferred immunity almost completely waned by 5 months. The seroprevalence of EV71 antibody increased directly with age among pre-school children, from 26% (95% CI, 18–33%) at 1 year to 70% (95% CI, 62–78%) at 5 years. Age of subjects, sample size, sampling year, sampling method, geographic latitude and publication language were associated with variations of individual seroprevalence estimates. Conclusions Seroprevalence of EV71 antibody gradually declined during the first five months in infants. Infection with EV71 was most likely to occur between 2 and 4 years. Our findings may be useful in informing population-based EV71 vaccination strategies.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 65%

Seroprevalence of Enterovirus 71 Antibody Among Children in China

Yang

et al. 2015

Pediatric Infectious Disease Journal

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“…39 However, in both arms the rate of adverse events was dramatically lower following booster injections, 40,41 as has been previously reported for other vaccines. 39,42 The Cochrane-Armitage analysis showed that in the vaccine group age was associated with the occurrence of adverse effects.…”

Section: Discussionsupporting

confidence: 70%

“…These results are supported by previous studies. [39][40][41][42] Factors for adverse reaction severity were assessed by multiple stepwise cumulative odds logistic regression. Gender did not affect the severity of any reaction.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive safety assessment of a human inactivated diploid enterovirus 71 vaccine based on a phase III clinical trial

Zhang

Jiang

et al. 2016

Human Vaccines & Immunotherapeutics

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Human enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease (HFMD). In a previous phase III trial in children, a human diploid cell-based inactivated EV71 vaccine elicited EV71 specific immune responses and protection against EV71 associated HFMD. This study aimed to assess the factors influencing the severity of adverse events observed in this previous trial. This was a randomized, doubleblinded, placebo-controlled, phase III clinical trial of a human diploid vaccine carried out in 12,000 children in Guangxi Zhuang Autonomous Region, China (ClinicalTrials.gov: NCT01569581). Solicited events were recorded for 7 days and unsolicited events were reported for 28 days after each injection. Age trend analysis of adverse reaction was conducted in each treatment group. Multiple logistic regression models were built to identify factors influencing the severity of adverse reactions. Fewer solicited adverse reactions were observed in older participants within the first 7 days after vaccination (P < 0.0001), except local pain and pruritus. More severe adverse reactions were observed after the initial injection than after the booster injection. Serious cold or respiratory tract infections (RTI) were observed more often in children aged 6-36 months than in older children. Only the severity of local swelling was associated with body mass index. Children with throat discomfort before injection had a higher risk of serious cold or RTI. These results indicated that the human diploid cell-based vaccine achieved a satisfactory safety profile.

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“…Various candidates against EV71 or CA16 virus, including inactivated vaccines (3,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), live attenuated vaccines (23, 24), subunit vaccines based on the VP1 protein (25), virus-like particle (VLP) vaccines (26-34), and epitopebased vaccines (35-39), were shown to possess various levels of efficacy in animal studies or human clinical trials. In particular, inactivated EV71 vaccines showed promising results against EV71-associated diseases in recent phase 3 clinical studies conducted in mainland China (20)(21)(22).…”

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confidence: 99%

Cryo-Electron Microscopy Study of Insect Cell-Expressed Enterovirus 71 and Coxsackievirus A16 Virus-Like Particles Provides a Structural Basis for Vaccine Development

Gong

Zhu

Zhou

et al. 2014

J Virol

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Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the two most common etiological agents responsible for the epidemics of hand, foot, and mouth disease (HFMD), a childhood illness with occasional severe neurological complications. A number of vaccine candidates against EV71 or CA16 have been reported; however, no vaccine is currently available for clinical use. Here, we generated a secreted version of EV71 and CA16 virus-like particles (VLPs) using a baculovirus-insect cell expression system and reconstructed the three-dimensional (3D) structures of both VLPs by cryo-electron microscopy (cryo-EM) single-particle analysis at 5.2-Å and 5.5-Å resolutions, respectively. The reconstruction results showed that the cryo-EM structures of EV71 and CA16 VLPs highly resemble the recently published crystal structures for EV71 natural empty particles and CA16 135S-like expanded particles, respectively. Our cryo-EM analysis also revealed that the majority of previously identified linear neutralizing epitopes are well preserved on the surface of EV71 and CA16 VLPs. In addition, both VLPs were able to induce efficiently neutralizing antibodies against various strains of EV71 and CA16 viruses in mouse immunization. These studies provide a structural basis for the development of insect cell-expressed VLP vaccines and for a potential bivalent VLP vaccine against both EV71-and CA16-associated HFMD. IMPORTANCEThe recent outbreaks of hand, foot, and mouth disease (HFMD) in the Asia Pacific region spurred the search for effective vaccines against EV71 and CA16 viruses, the two most common etiological agents responsible for HFMD. In this paper, we show that secreted versions of EV71 and CA16 VLPs generated in the baculovirus-insect cell expression system highly resemble the crystal structures of their viral conterparts and that the majority of previously identified linear neutralizing epitopes are well preserved on the VLP surfaces. In addition, the generated VLPs can efficiently induce neutralizing antibodies against various strains of EV71 and CA16 viruses in mouse immunization. These studies provide a structural basis for the development of insect cell-expressed VLP vaccines and for a potential bivalent VLP vaccine against both EV71-and CA16-associated HFMD. Hand, foot, and mouth disease (HFMD) most frequently occurs in infants or children under 5 years old. Although most cases are mild and self-limited, HFMD can in some cases cause severe symptoms, such as myocarditis, pulmonary edema, and central nervous system complications ranging from flaccid paralysis to fatal encephalitis (1, 2). The recent epidemics of HFMD led to serious public health threats in the Asia Pacific region. In China, 1.16 million and 1.77 million cases of HFMD, including 353 and 905 deaths, were reported for 2009 and 2010, respectively (3). Etiologic studies revealed that enteroviruses, especially enterovirus 71 (EV71) and coxsackievirus A16 (CA16), are the most common causative agents responsible for HFMD epidemics (4-6). A clinical survey of the...

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Immunogenicity, Safety, and Lot Consistency of a Novel Inactivated Enterovirus 71 Vaccine in Chinese Children Aged 6 to 59 Months

Cited by 29 publications

References 16 publications

Seroprevalence of Enterovirus 71 Antibody Among Children in China

Seroprevalence of Enterovirus 71 Antibody Among Children in China

Comprehensive safety assessment of a human inactivated diploid enterovirus 71 vaccine based on a phase III clinical trial

Cryo-Electron Microscopy Study of Insect Cell-Expressed Enterovirus 71 and Coxsackievirus A16 Virus-Like Particles Provides a Structural Basis for Vaccine Development

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