Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China.

BACKGROUND Enterovirus 71 (EV71) is one of the major causative agents of outbreaks of hand, foot, and mouth disease or herpangina worldwide. This phase 3 trial was designed to evaluate the efficacy, safety, and immunogenicity of an EV71 vaccine. METHODS We conducted a randomized, double-blind, placebo-controlled, multicenter trial in which 10,007 healthy infants and young children (6 to 35 months of age) were randomly assigned in a 1:1 ratio to receive two intramuscular doses of either EV71 vaccine or placebo, 28 days apart. The surveillance period was 12 months. The primary end point was the occurrence of EV71-associated hand, foot, and mouth disease or herpangina. RESULTS During the 12-month surveillance period, EV71-associated disease was identified in 0.3% of vaccine recipients (13 of 5041 children) and 2.1% of placebo recipients (106 of 5028 children) in the intention-to-treat cohort. The vaccine efficacy against EV71-associated hand, foot, and mouth disease or herpangina was 94.8% (95% confidence interval [CI], 87.2 to 97.9; P<0.001) in this cohort. Vaccine efficacies against EV71-associated hospitalization (0 cases vs. 24 cases) and hand, foot, and mouth disease with neurologic complications (0 cases vs. 8 cases) were both 100% (95% CI, 83.7 to 100 and 42.6 to 100, respectively). Serious adverse events occurred in 111 of 5044 children in the vaccine group (2.2%) and 131 of 5033 children in the placebo group (2.6%). In the immunogenicity subgroup (1291 children), an anti-EV71 immune response was elicited by the two-dose vaccine series in 98.8% of participants at day 56. An anti-EV71 neutralizing antibody titer of 1:16 was associated with protection against EV71-associated hand, foot, and mouth disease or herpangina. CONCLUSIONS The EV71 vaccine provided protection against EV71-associated hand, foot, and mouth disease or herpangina in infants and young children. (Funded by Sinovac Biotech; ClinicalTrials.gov number, NCT01507857.).

[1]  Zhenglun Liang,et al.  Immunogenicity, safety, and immune persistence of a novel inactivated human enterovirus 71 vaccine: a phase II, Randomized, double-blind, placebo-controlled Trial. , 2014, The Journal of infectious diseases.

[2]  Yi-Tsung Lin,et al.  A Phase I, randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine. , 2013, Vaccine.

[3]  Fan Gao,et al.  Progress on the research and development of human enterovirus 71 (EV71) vaccines , 2013, Frontiers of Medicine.

[4]  K. Chu,et al.  Reactogenicity and Immunogenicity of an Enterovirus 71 Vaccine in Chinese Healthy Children and Infants , 2012, The Pediatric infectious disease journal.

[5]  Rong-cheng Li,et al.  Safety and immunogenicity of a novel human Enterovirus 71 (EV71) vaccine: a randomized, placebo-controlled, double-blind, Phase I clinical trial. , 2012, Vaccine.

[6]  Min-Shi Lee,et al.  Pilot Scale Production of Highly Efficacious and Stable Enterovirus 71 Vaccine Candidates , 2012, PloS one.

[7]  Wenbo Xu,et al.  Emergence and Transmission Pathways of Rapidly Evolving Evolutionary Branch C4a Strains of Human Enterovirus 71 in the Central Plain of China , 2011, PloS one.

[8]  H. Kung,et al.  The virology and developments toward control of human enterovirus 71 , 2011, Critical reviews in microbiology.

[9]  Hongling Zhao,et al.  Immunoprotection elicited by an enterovirus type 71 experimental inactivated vaccine in mice and rhesus monkeys. , 2011, Vaccine.

[10]  P. Phuektes,et al.  Formalin-inactivated vaccine provokes cross-protective immunity in a mouse model of human enterovirus 71 infection. , 2011, Vaccine.

[11]  P. Chong,et al.  Purification and Characterization of Enterovirus 71 Viral Particles Produced from Vero Cells Grown in a Serum-Free Microcarrier Bioreactor System , 2011, PloS one.

[12]  Min Kang,et al.  An enterovirus 71 epidemic in Guangdong Province of China, 2008: epidemiological, clinical, and virogenic manifestations. , 2011, Japanese journal of infectious diseases.

[13]  Tom Solomon,et al.  Virology, epidemiology, pathogenesis, and control of enterovirus 71. , 2010, The Lancet. Infectious diseases.

[14]  W. Kim,et al.  Molecular characterization of enteroviruses detected in Gyeong-Ju and Po-Hang provinces of Korea in 2003 , 2010, Archives of Virology.

[15]  Weizhong Yang,et al.  An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of Hand Foot and Mouth Disease in Fuyang city of China , 2010, Virology Journal.

[16]  Wenbo Xu,et al.  An outbreak of hand, foot, and mouth disease associated with subgenotype C4 of human enterovirus 71 in Shandong, China. , 2009, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[17]  N. Tien,et al.  Epidemiologic and Virologic Investigation of Hand, Foot, and Mouth Disease, Southern Vietnam, 2005 , 2007, Emerging infectious diseases.

[18]  P. White,et al.  Norovirus GII.4 Strains and Outbreaks, Australia , 2007, Emerging infectious diseases.

[19]  I. Mihály,et al.  Virological diagnosis of enterovirus type 71 infections: Experiences gained during an epidemic of acute CNS diseases in Hungary in 1978 , 2005, Archives of Virology.

[20]  U. Parashar,et al.  Deaths of children during an outbreak of hand, foot, and mouth disease in sarawak, malaysia: clinical and pathological characteristics of the disease. For the Outbreak Study Group. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[21]  Kow-Tong Chen,et al.  An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. , 1999, The New England journal of medicine.

[22]  G. Gilbert,et al.  Outbreak of enterovirus 71 infection in Victoria, Australia, with a high incidence of neurologic involvement. , 1988, The Pediatric infectious disease journal.

[23]  M. Chumakov,et al.  Epidemiological, clinical, and pathomorphological characteristics of epidemic poliomyelitis-like disease caused by enterovirus 71. , 1979, Journal of hygiene, epidemiology, microbiology, and immunology.

[24]  T. Yoneyama,et al.  Epidemic of hand, foot and mouth disease associated with enterovirus 71 infection. , 1978, Intervirology.

[25]  I. Tagaya,et al.  Epidemic of hand, foot and mouth disease in Japan, 1972-1973: difference in epidemiologic and virologic features from the previous one. , 1975, Japanese journal of medical science & biology.

[26]  J. Blomberg,et al.  NEW ENTEROVIRUS TYPE ASSOCIATED WITH EPIDEMIC OF ASEPTIC MENINGITIS AND/OR HAND, FOOT, AND MOUTH DISEASE , 1974 .

[27]  S. Locarnini,et al.  Enterovirus type 71 infection in Melbourne. , 1974, Bulletin of the World Health Organization.