title: Long-term immunogenicity studies of formalin-inactivated enterovirus 71 whole-virion vaccine in macaques.
abstract: Enterovirus 71 (EV71) has caused epidemics of hand, foot and mouth diseases in Asia during the past decades and no vaccine is available. A formalin-inactivated EV71 candidate vaccine (EV71vac) based on B4 subgenotype has previously been developed and found to elicit strong neutralizing antibody responses in mice and humans. In this study, we evaluated the long-term immunogenicity and safety of this EV71vac in a non-human primate model. Juvenile macaques were immunized at 0, 3 and 6 weeks either with 10 or 5 µg doses of EV71vac formulated with AlPO4 adjuvant, or PBS as control. During the 56 weeks of studies, no fever nor local redness and swelling at sites of injections was observed in the immunized macaques. After single immunization, 100% seroconversion based on 4-fold increased in neutralization titer (Nt) was detected in EV71vac immunized monkeys but not PBS controls. A dose-dependent IgG antibody response was observed in monkeys receiving EV71vac immunization. The Nt of EV71vac immunized macaques had reached the peak after 3 vaccinations, then decreased gradually; however, the GMT of neutralizing antibody in the EV71vac immunized macaques were still above 100 at the end of the study. Correspondingly, both dose- and time-dependent interferon-γ and CD4+ T cell responses were detected in monkeys receiving EV71vac. Interestingly, similar to human responses, the dominant T cell epitopes of macaques were identified mainly in VP2 and VP3 regions. In addition, strong cross-neutralizing antibodies against most EV71 subgenotypes except some C2 and C4b strains, and Coxsackievirus A16 were observed. In summary, our results indicate that EV71vac elicits dose-dependent T-cell and antibody responses in macaques that could be a good animal model for evaluating the long-term immune responses elicited by EV71 vaccines.
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan.
authors.forename: Chia-Chyi
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Animal Health Research Institute, Council of Agriculture, Tamsui, Taipei, Taiwan.
authors.forename: Chyi-Sing
authors.initials: CS
authors.lastname: Hwang
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan.
authors.forename: Wun-Syue
authors.initials: WS
authors.lastname: Yang
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan.
authors.forename: Dan-Chin
authors.initials: DC
authors.lastname: Tsai
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan.
authors.forename: Sze-Hsien
authors.initials: SH
authors.lastname: Wu
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan.
authors.forename: Ai-Hsiang
authors.initials: AH
authors.lastname: Chou
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan.
authors.forename: Yen-Hung
authors.initials: YH
authors.lastname: Chow
authors.affiliation: Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Suh-Chin
authors.initials: SC
authors.lastname: Wu
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan.
authors.forename: Jen-Ren
authors.initials: JR
authors.lastname: Wang
authors.affiliation: Centers for Disease Control, Taipei, Taiwan.
authors.forename: Jen-Ron
authors.initials: JR
authors.lastname: Chiang
authors.affiliation: Animal Health Research Institute, Council of Agriculture, Tamsui, Taipei, Taiwan.
authors.forename: Chin-Cheng
authors.initials: CC
authors.lastname: Huang
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan; Graduate Institute of Immunology, China Medical University, Taichung, Taiwan.
authors.forename: Chien-Hsiung
authors.initials: CH
authors.lastname: Pan
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan; Graduate Institute of Immunology, China Medical University, Taichung, Taiwan.
authors.forename: Pele
authors.initials: P
authors.lastname: Chong
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D029821:Enterovirus A, Human / Q000276:immunology*; D005557:Formaldehyde; D008251:Macaca / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D014765:Viral Vaccines; D005557:Formaldehyde