Non-polio enteroviruses, including enterovirus 71 (EV71), have caused severe and fatal cases of hand, foot and mouth disease (HFMD) in the Asia-Pacific region. The development of a vaccine or ...antiviral against these pathogens has been hampered by the lack of a reliable small animal model. In this study, a mouse adapted EV71 strain was produced by conducting serial passages through A129 (α/β interferon (IFN) receptor deficient) and AG129 (α/β, γ IFN receptor deficient) mice. A B2 sub genotype of EV71 was inoculated intraperitoneally (i.p.) into neonatal AG129 mice and brain-harvested virus was subsequently passaged through 12 and 15 day-old A129 mice. When tested in 10 week-old AG129 mice, this adapted strain produced 100% lethality with clinical signs including limb paralysis, eye irritation, loss of balance, and death. This virus caused only 17% mortality in same age A129 mice, confirming that in the absence of a functional IFN response, adult AG129 mice are susceptible to infection by adapted EV71 isolates. Subsequent studies in adult AG129 and young A129 mice with the adapted EV71 virus examined the efficacy of an inactivated EV71 candidate vaccine and determined the role of humoral immunity in protection. Passive transfer of rabbit immune sera raised against the EV71 vaccine provided protection in a dose dependent manner in 15 day-old A129 mice. Intramuscular injections (i.m.) in five week-old AG129 mice with the alum adjuvanted vaccine also provided protection against the mouse adapted homologous strain. No clinical signs of disease or mortality were observed in vaccinated animals, which received a prime-and-boost, whereas 71% of control animals were euthanized after exhibiting systemic clinical signs (P<0.05). The development of this animal model will facilitate studies on EV71 pathogenesis, antiviral testing, the evaluation of immunogenicity and efficacy of vaccine candidates, and has the potential to establish correlates of protection studies.
Highlights • A tetravalent dengue vaccine (TDV) was evaluated in a Phase 1b clinical trial. • The different dose schedules and formulations of TDV were well tolerated. • Greater that 80% of subjects ...seroconverted to three or more dengue viruses. • Dosing twice on one day or reducing the dose had little effect on immunogenicity. • These dose ranging studies help inform future Phase 2 and Phase 3 trials of TDV.
Elastic sheets offer a path to encapsulating a droplet of one fluid in another that is different from that of traditional molecular or particulate surfactants. In wrappings of fluids by sheets of ...moderate thickness with petals designed to curl into closed shapes, capillarity balances bending forces. Here, we show that, by using much thinner sheets, the constraints of this balance can be lifted to access a regime of high sheet bendability that brings three major advantages: ultrathin sheets automatically achieve optimally efficient shapes that maximize the enclosed volume of liquid for a fixed area of sheet; interfacial energies and mechanical properties of the sheet are irrelevant within this regime, thus allowing for further functionality; and complete coverage of the fluid can be achieved without special sheet designs. We propose and validate a general geometric model that captures the entire range of this new class of wrapped and partially wrapped shapes.
Human enterovirus 71 (EV71) is a significant cause of morbidity and mortality from Hand, Foot and Mouth Disease (HFMD) and neurological complications, particularly in young children in the ...Asia-Pacific region. There are no vaccines or antiviral therapies currently available for prevention or treatment of HFMD caused by EV71. Therefore, the development of therapeutic and preventive strategies against HFMD is of growing importance. We report the immunogenic and safety profile of inactivated, purified EV71 preparations formulated with aluminum hydroxide adjuvant in preclinical studies in mice and rabbits. In mice, the candidate vaccine formulations elicited high neutralizing antibody responses. A toxicology study of the vaccine formulations planned for human use performed in rabbits showed no vaccine-related pathological changes and all animals remained healthy. Based on these preclinical studies, Phase 1 clinical testing of the EV71 inactivated vaccine was initiated.
•Enteroviruses increasingly noted as causing severe disease, especially in children.•Phase I clinical trial of inactivated B2 sub-genotype EV71 vaccine candidate.•Vaccine was safe, tolerable and ...induced 100% seroconversion after 2 doses in adults.•Measurable cross-neutralizing activity against heterologous sub-genotypes.•Results support further clinical development as a potential pediatric vaccine.
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.
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.
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.
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.
Enterovirus 71 (EV71)-associated hand, foot and mouth disease has emerged as a serious public health problem in South East Asia over the last decade. To better understand the prevalence of EV71 ...infection, we determined EV71 seroprevalence and seroincidence amongst healthy infants and children in Ho Chi Minh City, Viet Nam. In a cohort of 200 newborns, 55% of cord blood samples contained EV71 neutralizing antibodies and these decayed to undetectable levels by 6 months of age in 98% of infants. The EV71 neutralizing antibody seroconversion rate was 5.6% in the first year and 14% in the second year of life. In children 5-15 yrs of age, seroprevalence of EV71 neutralizing antibodies was 84% and in cord blood it was 55%. Taken together, these data suggest EV71 force of infection is high and highlights the need for more research into its epidemiology and pathogenesis in high disease burden countries.
In this meta-analysis, we examined whether children identified with reading difficulties (RD) evidence writing difficulties. We included studies comparing children with RD with (a) typically ...developing peers matched on age (k = 87 studies) and (b) typically developing younger peers with similar reading capabilities (k = 24 studies). Children identified with RD scored lower on measures of writing than their same age peers (g = −1.25) when all writing scores in a study were included in the analysis. This same pattern occurred for specific measures of writing: quality (g = −0.95), output (g = −0.66), organization (g = −0.72), sentence skills (g = −0.78), vocabulary (g = −1.17), syntax (g = −1.07), handwriting (g = −0.64), and spelling (g = −1.42). Differences in the writing scores of children identified with RD and same age peers were moderated by whether the writing assessment was a norm-referenced or researcher-designed measure when all writing measures or just spelling were included in the analyses. Depth of orthography for studies involving European languages also moderated differences in the spelling scores of children identified with RD and same age peers. Finally, children identified with RD scored lower on writing than younger peers with similar reading capabilities (g = −0.94) and more specifically on spelling (−0.93). We concluded that children with RD experience difficulties with writing, providing support for theoretical propositions of reading and writing connections as well as the importance of writing instruction for these students.
Educational Impact and Implications Statement
This meta-analysis of 95 studies found that children with reading difficulties also experience difficulties with writing when compared with their same-aged peers and younger-peers matched on reading capabilities. These findings demonstrate that reading and writing performance are connected, and students with reading difficulties are likely to have writing difficulties. As a result, literacy instruction needs to focus on both of these critical skills.
Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using ...half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.
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