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

Tambyah, Paul A.; Oon, Jolene; Asli, Rosmonaliza; Kristanto, William; Hwa, Shi-Hsia; Vang, Fue; Karwal, Lovkesh; Fuchs, Jeremy F.; Santangelo, Joseph D.; Gordon, Gary G.; Thomson, Cynthia A.; Rao, Raman; Dean, Hansi; Das, Subash C.; Stinchcomb, Dan T.

doi:10.1016/j.vaccine.2019.06.023

Cited by 15 publications

(12 citation statements)

References 49 publications

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“…Clinical trials with vaccines and drugs that target enteroviruses and demonstrate their efficacy in preventing or curing T1DM would be definitive proof of the causal role of these viruses in T1DM pathogenesis. Effective and safe vaccines against enteroviruses such as poliovirus and enterovirus 71 have been developed 194 – 197 . Effective antivirals against chronic viral infections such as hepatitis B virus and hepatitis C virus have also been developed 198 , 199 .…”

Section: Prevention and Treatment Of T1dmmentioning

confidence: 99%

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

2022

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Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing β-cells and type 1 diabetes mellitus (T1DM). Although enteroviruses are primarily involved in acute and lytic infections in vitro and in vivo, they can also establish a persistent infection. Prospective epidemiological studies have strongly associated the persistence of enteroviruses, especially coxsackievirus B (CVB), with the appearance of islet autoantibodies and an increased risk of T1DM. CVB can persist in pancreatic ductal and β-cells, which leads to structural or functional alterations of these cells, and to a chronic inflammatory response that promotes recruitment and activation of pre-existing autoreactive T cells and β-cell autoimmune destruction. CVB persistence in other sites, such as the intestine, blood cells and thymus, has been described; these sites could serve as a reservoir for infection or reinfection of the pancreas, and this persistence could have a role in the disturbance of tolerance to β-cells. This Review addresses the involvement of persistent enterovirus infection in triggering islet autoimmunity and T1DM, as well as current strategies to control enterovirus infections for preventing or reducing the risk of T1DM onset.

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Section: Prevention and Treatment Of T1dmmentioning

confidence: 99%

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

2022

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“…companies (Sinovac Biotech, Ltd.; Beijing Vigoo Biological Co., Ltd.; and the Institute of Medical Chinese Academy of Medical Sciences); all have been approved for marketing in China (2)(3)(4). Similar formalin-inactivated vaccines are being developed by the National Health Research Institutes, Taiwan, (5) and by Takeda Pharmaceuticals (6,7). In addition, different types of vaccines are under development; these types include EV71 virus-like particles (VLPs) (8)(9)(10)(11)(12), recombinant VLPs based on other viruses displaying EV71-neutralizing epitopes (13)(14)(15), recombinant VP1 proteins (16)(17)(18)(19), DNA vaccines (20), and live attenuated vaccines (21).…”

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confidence: 99%

Development of an Enterovirus 71 Vaccine Efficacy Test Using Human Scavenger Receptor B2 Transgenic Mice

Imura

Sudaka

Takashino

et al. 2020

J Virol

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Enterovirus 71 (EV71) is a causative agent of hand-foot-mouth disease, and it sometimes causes severe neurological disease. Development of effective vaccines and animal models to evaluate vaccine candidates are needed. However, the animal models currently used for vaccine efficacy testing, monkeys and neonatal mice, have economic, ethical, and practical drawbacks. In addition, EV71 strains prepared for lethal challenge often develop decreased virulence during propagation in cell culture. To overcome these problems, we used a mouse model expressing human scavenger receptor B2 (hSCARB2) that showed lifelong susceptibility to EV71. We selected virulent EV71 strains belonging to the subgenogroups B4, B5, C1, C2, and C4 and propagated them using a culture method for EV71 without an apparent reduction in virulence. Here, we describe a novel EV71 vaccine efficacy test based on these hSCARB2 transgenic (Tg) mice and these virulent viruses. Adult Tg mice were immunized subcutaneously with formalin-inactivated EV71. The vaccine elicited sufficient levels of neutralizing antibodies in the immunized mice. The mice were subjected to lethal challenge with virulent viruses via intravenous injection. Survival, clinical signs, and body weight changes were observed for 2 weeks. Most immunized mice survived without clinical signs or histopathological lesions. The viral replication in immunized mice was much lower than that in nonimmunized mice. Mice immunized with the EV71 vaccine were only partially protected against lethal challenge with coxsackievirus A16. These results indicate that this new model is useful for in vivo EV71 vaccine efficacy testing. IMPORTANCE The development of new vaccines for EV71 relies on the availability of small animal models suitable for in vivo efficacy testing. Monkeys and neonatal mice have been used, but the use of these animals has several drawbacks, including high costs, limited susceptibility, and poor experimental reproducibility. In addition, the related ethical issues are considerable. The new efficacy test based on hSCARB2 Tg mice and virulent EV71 strains propagated in genetically modified cell lines presented here can overcome these disadvantages and is expected to accelerate the development of new EV71 vaccines.

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“…Notably, it was also reported that formaldehyde as an inactivating agent has a limited ability to maintain the structural integrity of antigens from these viruses [27,28], which may result in the failure to induce antibodies covering all the major structural proteins of some viruses [28]. Vaccination can lead to the induction of different types of monoclonal antibodies in vivo by a variety of viral antigens [29,30], and the specific Nab titer is the main reference for assessing the preventive efficacy of the vaccine in most virus-based vaccines [31][32][33]. However, the Nab titer alone does not completely reflect the effect of various antibodies in the body [30,34].…”

Section: Discussionmentioning

confidence: 99%

Single B cells reveal the antibody responses of rhesus macaques immunized with an inactivated enterovirus D68 vaccine

Zheng

Yang

et al. 2020

Arch Virol

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Enterovirus D68 (EV-D68) infection may cause severe respiratory system manifestations in pediatric populations. Because of the lack of an effective preventive vaccine or specific therapeutic drug for this infection, the development of EV-D68-specific vaccines and antibodies has become increasingly important. In this study, we prepared an experimental EV-D68 vaccine inactivated by formaldehyde and found that the serum of rhesus macaques immunized with the inactivated EV-D68 vaccine exhibited potent neutralizing activity against EV-D68 virus in vitro. Subsequently, the antibody-mediated immune response of B cells elicited by the inactivated vaccine was evaluated in a rhesus monkey model. The binding activity, in vitro neutralization activity, and sequence properties of 28 paired antibodies from the rhesus macaques' EV-D68-specific single memory B cells were analyzed, and the EV-D68 VP1-specific antibody group was found to be the main constituent in vivo. Intriguingly, we also found a synergistic effect among the E15, E18 and E20 monoclonal antibodies from the rhesus macaques. Furthermore, we demonstrated the protective efficacy of maternal antibodies in suckling C57BL/6 mice. This study provides valuable information for the future development of EV-D68 vaccines.

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

Cited by 15 publications

References 49 publications

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

Development of an Enterovirus 71 Vaccine Efficacy Test Using Human Scavenger Receptor B2 Transgenic Mice

Single B cells reveal the antibody responses of rhesus macaques immunized with an inactivated enterovirus D68 vaccine

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