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Table 2 contains some incorrect values regarding the number of schools and children examined in previous surveys. Reference 1 Okoyo C, Campbell SJ, Williams K, Simiyu E, Owaga C, Mwandawiro C (2020) Prevalence, intensity and associated risk factors of soil-transmitted helminth and schistosome infections in Kenya: Impact assessment after five rounds of mass drug administration in Kenya. Graph Table 2 Overall prevalence % (95%CI), mean intensity epg (95%CI) of infections and relative reductions (RR) % (p-value) among school children in Kenya after five rounds of MDA. [Extracted from the article]

Background: Sustainability within neglected tropical disease (NTD) programs is a complex and challenging issue. The need for a shared understanding about what sustainability means for NTD programs is more important than ever as stakeholders are currently realigning for the next decade of NTD programming with the launch of WHO's new NTD roadmap for 2012–2030. The aim of this paper is to assess different perspectives to generate a working definition of sustainability for NTD programs. Methodology/Principal findings: This study surveyed affiliates of the NTD NGO Network (NNN) about their definitions of sustainability and then analyzed the data using an inductive and deductive process. The research team drafted a sustainability statement based on the survey findings and then solicited and incorporated feedback on the statement from a diverse group of expert reviewers. The final statement includes a working definition of sustainability for NTD programs that highlights three key essential components to sustainability: domestic commitment, responsive resource mobilization, and accountability. Conclusions/Significance: This research resulted in a sustainability statement, based on a survey and extensive consultation with stakeholders, that represents a starting point for shared understanding around the concept of sustainability for NTD programs. Future collaborative work should build off this definition and seek to incorporate indicators for sustainability into programmatic decision-making. Author summary: The question of whether a global public health program can be sustainable is as important as whether that program is effective. While neglected tropical disease (NTD) programs have achieved tangible success in reducing the burden of NTDs over the past decade through a massive collaboration between global and local stakeholders, the achievement of global NTD control and elimination goals will depend in large part on whether these efforts are sustained. This study seeks to encourage more and better dialogue around NTD program sustainability by incorporating a wide variety of expert perspectives to create and propose a shared definition of sustainability upon which future NTD programming decisions can be made. The sustainability statement based on the findings from this study suggests that three essential components to NTD program sustainability are commitment from decision-makers within NTD-endemic countries, resource mobilization that is responsive to local needs, and enhanced mechanisms for accountability. [ABSTRACT FROM AUTHOR]

Background: In Kenya, over five million school age children (SAC) are estimated to be at risk of parasitic worms causing soil-transmitted helminthiasis (STH) and schistosomiasis. As such, the Government of Kenya launched a National School Based Deworming (NSBD) program in 2012 targeting the at-risk SAC living in endemic regions, with the aim of reducing infections prevalence to a level where they no longer constitute a public health problem. The impact of the program has been consistently monitored from 2012 to 2017 through a robust and extensive monitoring and evaluation (M&E) program. The aim of the current study was to evaluate the parasitological outcomes and additionally investigate water, sanitation and hygiene (WASH) related factors associated with infection prevalence after five rounds of mass drug administration (MDA), to inform the program's next steps. Materials and methods: We utilized a cross-sectional design in a representative, stratified, two-stage sample of school children across six regions in Kenya. A sample size of 100 schools with approximately 108 children per school was purposively selected based on the Year 5 STH infection endemicity prior to the survey. Stool samples were examined for the presence of STH and Schistosoma mansoni eggs using double-slide Kato-Katz technique, urine samples were processed using urine filtration technique for the presence of S. haematobium eggs. Survey questionnaires were administered to all the participating children to collect information on their demographic and individual, household and school level WASH characteristics. Principal findings: Overall, STH prevalence was 12.9% (95%CI: 10.4–16.1) with species prevalence of 9.7% (95%CI: 7.5–12.6) for Ascaris lumbricoides, 3.6% (95%CI: 2.2–5.8) for Trichuris trichiura and 1.0% (95%CI: 0.6–1.5) for hookworm. S. mansoni prevalence was 2.2% (95%CI: 1.2–4.3) and S. haematobium prevalence was 0.3% (95%CI: 0.1–1.0). All the infections showed significant prevalence reductions when compared with the baseline prevalence, except S. mansoni. From multivariable analysis, increased odds of any STH infections were associated with not wearing shoes, adjusted odds ratio (aOR) = 1.36 (95%CI: 1.09–1.69); p = 0.007; high number of household members, aOR = 1.21 (95%CI: 1.04–1.41); p = 0.015; and school absenteeism of more than two days, aOR = 1.33 (95%CI: 1.01–1.80); p = 0.045. Further, children below five years had up to four times higher odds of getting STH infections, aOR = 4.68 (95%CI: 1.49–14.73); p = 0.008. However, no significant factors were identified for schistosomiasis, probably due to low prevalence levels affecting performance of statistical analysis. Conclusions: After five rounds of MDA, the program shows low prevalence of STH and schistosomiasis, however, not to a level where the infections are not a public health problem. With considerable inter-county infection prevalence heterogeneity, the program should adopt future MDA frequencies based on the county's infection prevalence status. Further, the program should encourage interventions aimed at improving coverage among preschool age children and improving WASH practices as long-term infection control strategies. Author summary: This paper presents the findings of an evaluation survey conducted in Year 6 of the Kenya National School-Based Deworming (NSBD) Program, following five years (2012–2017) of prior baseline and subsequent impact monitoring. The survey was conducted in 20 counties, covering six regions in Kenya. The survey showed continued and considerable reductions in prevalence over time, with most marked decline for hookworm, followed by Ascaris lumbricoides. Overall, the mass drug administration (MDA) program has driven both STH and schistosomiasis prevalence to relatively low levels, however not to a point where they no longer constitute a public health problem in Kenya. For these neglected tropical diseases (NTDs), and STH in particular, there are relatively few published examples of programmatic impact assessments enabling refined decisions regarding helminth control strategies. Kenya's experiences in implementing, monitoring, and evaluating a high-coverage NSBD program are a continuing and increasingly important success story for the country, which provides learnings of importance for the international community. [ABSTRACT FROM AUTHOR]

FSHD is characterized by the misexpression of DUX4 in skeletal muscle. Although DUX4 upregulation is thought to be the pathogenic cause of FSHD, DUX4 is lowly expressed in patient samples, and analysis of the consequences of DUX4 expression has largely relied on artificial overexpression. To better understand the native expression profile of DUX4 and its targets, we performed bulk RNA-seq on a 6-day differentiation time-course in primary FSHD2 patient myoblasts. We identify a set of 54 genes upregulated in FSHD2 cells, termed FSHD-induced genes. Using single-cell and single-nucleus RNA-seq on myoblasts and differentiated myotubes, respectively, we captured, for the first time, DUX4 expressed at the single-nucleus level in a native state. We identified two populations of FSHD myotube nuclei based on low or high enrichment of DUX4 and FSHD-induced genes ("FSHD-Lo" and "FSHD Hi", respectively). FSHD-Hi myotube nuclei coexpress multiple DUX4 target genes including DUXA, LEUTX and ZSCAN4, and also upregulate cell cycle-related genes with significant enrichment of E2F target genes and p53 signaling activation. We found more FSHD-Hi nuclei than DUX4-positive nuclei, and confirmed with in situ RNA/protein detection that DUX4 transcribed in only one or two nuclei is sufficient for DUX4 protein to activate target genes across multiple nuclei within the same myotube. DUXA (the DUX4 paralog) is more widely expressed than DUX4, and depletion of DUXA suppressed the expression of LEUTX and ZSCAN4 in late, but not early, differentiation. The results suggest that the DUXA can take over the role of DUX4 to maintain target gene expression. These results provide a possible explanation as to why it is easier to detect DUX4 target genes than DUX4 itself in patient cells and raise the possibility of a self-sustaining network of gene dysregulation triggered by the limited DUX4 expression. Author summary: Although misexpression of DUX4 has been known as the major cause in FSHD, it is lowly expressed in patient samples and analysis of the consequences of DUX4 expression has largely relied on artificial overexpression. Here, we took advantage of recent methodological advances to observe native DUX4 expression at the single-nucleus level in FSHD2 patient-derived myotubes. Using single-nucleus RNA-seq (snRNA-seq), we were able to detect endogenous DUX4-expressing nuclei and the extent of spreading of DUX4-target gene expression across many nuclei. Our highly sensitive snRNA-seq method further allowed us to identify two populations of FSHD myotube nuclei with distinct transcriptional profiles. One is highly enriched with DUX4 and target genes (FSHD-Hi) while the other has sparser DUX4 and FSHD-induced genes expressed (FSHD-Lo), reflecting two potentially different pathological states of patient myotubes. We observed a set of transcription factors specifically upregulated in FSHD-Hi myotube nuclei associated with the cell cycle, and significant upregulation of DUX4 paralog DUXA that contributes to further upregulation of DUX4 target genes. We propose that transcription factors downstream of DUX4 may amplify DUX4 signal and thus act to perpetuate FSHD. [ABSTRACT FROM AUTHOR]

When allocating resources, people often diversify across categories even when those categories are arbitrary, such that allocations differ when identical sets of options are partitioned differently ("partition dependence"). The first goal of the present work (Experiment 1) was to replicate an experiment by Fox and colleagues in which graduate students exhibited partition dependence when asked how university financial aid should be allocated across arbitrarily partitioned income brackets. Our sample consisted of community members at a liberal arts college where financial aid practices have been recent topics of debate. Because stronger intrinsic preferences can reduce partition dependence, these participants might display little partition dependence with financial aid allocations. Alternatively, a demonstration of strong partition dependence in this population would emphasize the robustness of the effect. The second goal was to extend a "high transparency" modification to the present task context (Experiment 2) in which participants were shown both possible income partitions and randomly assigned themselves to one, to determine whether partition dependence in this paradigm would be reduced by revealing the study design (and the arbitrariness of income categories). Participants demonstrated clear partition dependence in both experiments. Results demonstrate the robustness of partition dependence in this context. [ABSTRACT FROM AUTHOR]

Antibodies that mediate killing of HIV-infected cells through antibody-dependent cellular cytotoxicity (ADCC) have been implicated in protection from HIV infection and disease progression. Despite these observations, these types of HIV antibodies are understudied compared to neutralizing antibodies. Here we describe four monoclonal antibodies (mAbs) obtained from one individual that target the HIV transmembrane protein, gp41, and mediate ADCC activity. These four mAbs arose from independent B cell lineages suggesting that in this individual, multiple B cell responses were induced by the gp41 antigen. Competition and phage peptide display mapping experiments suggested that two of the mAbs target epitopes in the cysteine loop that are highly conserved and a common target of HIV gp41-specific antibodies. The amino acid sequences that bind these mAbs are overlapping but distinct. The two other mAbs were competed by mAbs that target the C-terminal heptad repeat (CHR) and the fusion peptide proximal region (FPPR) and appear to both target a similar unique conformational epitope. These gp41-specific mAbs mediated killing of infected cells that express high levels of Env due to either pre-treatment with interferon or deletion of vpu to increase levels of BST-2/Tetherin. They also mediate killing of target cells coated with various forms of the gp41 protein, including full-length gp41, gp41 ectodomain or a mimetic of the gp41 stump. Unlike many ADCC mAbs that target HIV gp120, these gp41-mAbs are not dependent on Env structural changes associated with membrane-bound CD4 interaction. Overall, the characterization of these four new mAbs that target gp41 and mediate ADCC provides evidence for diverse gp41 B cell lineages with overlapping but distinct epitopes within an individual. Such antibodies that can target various forms of envelope protein could represent a common response to a relatively conserved HIV epitope for a vaccine. [ABSTRACT FROM AUTHOR]

While there is substantial evidence that adults who violate gender stereotypes often face backlash (i.e. social and economic penalties), less is known about the nature of gender stereotypes for young children, and the penalties that children may face for violating them. We conducted three experiments, with over 2000 adults from the US, to better understand the content and consequences of adults’ gender stereotypes for young children. In Experiment 1, we tested which characteristics adults (N = 635) believed to be descriptive (i.e. typical), prescriptive (i.e. required), and proscriptive (i.e. forbidden) for preschool-aged boys and girls. Using the characteristics that were rated in Experiment 1, we then constructed vignettes that were either ‘masculine’ or ‘feminine’, and manipulated whether the vignettes were said to describe a boy or a girl. Experiment 2 (N = 697) revealed that adults rated stereotype-violating children as less likeable than their stereotype-conforming peers, and that this difference was more robust for boys than girls. Experiment 3 (N = 731) was a direct replication of Experiment 2, and revealed converging evidence of backlash against stereotype-violating children. In sum, our results suggest that even young children encounter backlash from adults for stereotype violations, and that these effects may be strongest for boys. [ABSTRACT FROM AUTHOR]

Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are severe disease manifestations that can occur following sequential infection with different dengue virus serotypes (DENV1-4). At present, there are no licensed therapies to treat DENV-induced disease. DHF and DSS are thought to be mediated by serotype cross-reactive antibodies that facilitate antibody-dependent enhancement (ADE) by binding to viral antigens and then Fcγ receptors (FcγR) on target myeloid cells. Using genetically engineered DENV-specific antibodies, it has been shown that the interaction between the Fc portion of serotype cross-reactive antibodies and FcγR is required to induce ADE. Additionally, it was demonstrated that these antibodies were as neutralizing as their non-modified variants, were incapable of inducing ADE, and were therapeutic following a lethal, antibody-enhanced infection. Therefore, we hypothesized that avian IgY, which do not interact with mammalian FcγR, would provide a novel therapy for DENV-induced disease. We demonstrate here that goose-derived anti-DENV2 IgY neutralized DENV2 and did not induce ADE in vitro. Anti-DENV2 IgY was also protective in vivo when administered 24 hours following a lethal DENV2 infection. We were also able to demonstrate via epitope mapping that both full-length and alternatively spliced anti-DENV2 IgY recognized different epitopes, including epitopes that have not been previously identified. These observations provide evidence for the potential therapeutic applications of goose-derived anti-DENV2 IgY. [ABSTRACT FROM AUTHOR]

Dengue viruses (DENV) are mosquito-borne flaviviruses of global importance. DENV exist as four serotypes, DENV1-DENV4. Following a primary infection, individuals produce DENV-specific antibodies that bind only to the serotype of infection and other antibodies that cross-react with two or more serotypes. People exposed to a secondary DENV infection with another serotype are at greater risk of developing more severe forms of dengue disease. The increased risk of severe dengue in people experiencing repeat DENV infections appear to be due, at least in part, to the ability of pre-existing serotype cross-reactive antibodies to form virus-antibody complexes that can productively infect Fcγ receptor-bearing target cells. While the theory of antibody-dependent enhancement (ADE) is supported by several human and small animal model studies, the specific viral antigens and epitopes recognized by enhancing human antibodies after natural infections have not been fully defined. We used antibody-depletion techniques to remove DENV-specific antibody sub-populations from primary DENV-immune human sera. The effects of removing specific antibody populations on ADE were tested both in vitro using K562 cells and in vivo using the AG129 mouse model. Removal of serotype cross-reactive antibodies ablated enhancement of heterotypic virus infection in vitro and antibody-enhanced mortality in vivo. Further depletion studies using recombinant viral antigens showed that although the removal of DENV E-specific antibodies using recombinant E (rE) protein resulted in a partial reduction in DENV enhancement, there was a significant residual enhancement remaining. Competition ADE studies using prM-specific Fab fragments in human immune sera showed that both rE-specific and prM-specific antibodies in primary DENV-immune sera significantly contribute to enhancement of heterotypic DENV infection in vitro. Identification of the targets of DENV-enhancing antibodies should contribute to the development of safe, non-enhancing vaccines against dengue. [ABSTRACT FROM AUTHOR]

: The objective of this study was to examine the effects of estrogen-based hormone therapy (HT) on regional cerebral metabolism in postmenopausal women (mean age = 58, SD = 5) at risk for development of dementia. The prospective clinical trial design included pre- and post-intervention neuroimaging of women randomized to continue (HT+) or discontinue (HT−) therapy following an average of 10 years of use. The primary outcome measure was change in brain metabolism during the subsequent two years, as assessed with fluorodeoxyglucose-18 positron emission tomography (FDG-PET). Longitudinal FDG-PET data were available for 45 study completers. Results showed that women randomized to continue HT experienced relative preservation of frontal and parietal cortical metabolism, compared with women randomized to discontinue HT. Women who discontinued 17-β estradiol (17βE)-based HT, as well as women who continued conjugated equine estrogen (CEE)-based HT, exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical (PCC) area. Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins (with either 17βE or CEE). Together, these findings suggest that among postmenopausal subjects at risk for developing dementia, regional cerebral cortical metabolism is relatively preserved for at least two years in women randomized to continue HT, compared with women randomized to discontinue HT. In addition, continuing unopposed 17βE therapy is associated specifically with preservation of metabolism in PCC, known to undergo the most significant decline in the earliest stages of Alzheimer's disease. Trial Registration: ClinicalTrials.gov NCT00097058 [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) is the leading cause of arboviral diseases in humans worldwide. The envelope (E) protein of DENV is the major target of neutralizing antibodies (Abs). Previous studies have shown that a significant proportion of anti-E Abs in human serum after DENV infection recognize the highly conserved fusion loop (FL) of E protein. The role of anti-FL Abs in protection against subsequent DENV infection versus pathogenesis remains unclear. A human anti-E monoclonal Ab was used as a standard in a virion-capture ELISA to measure the concentration of anti-E Abs, [anti-E Abs], in dengue-immune sera from Nicaraguan patients collected 3, 6, 12 and 18 months post-infection. The proportion of anti-FL Abs was determined by capture ELISA using virus-like particles containing mutations in FL, and the concentration of anti-FL Abs, [anti-FL Abs], was calculated. Neutralization titers (NT50) were determined using a previously described flow cytometry-based assay. Analysis of sequential samples from 10 dengue patients revealed [anti-E Abs] and [anti-FL Abs] were higher in secondary than in primary DENV infections. While [anti-FL Abs] did not correlate with NT50 against the current infecting serotype, it correlated with NT50 against the serotypes to which patients had likely not yet been exposed ("non-exposed" serotypes) in 14 secondary DENV3 and 15 secondary DENV2 cases. These findings demonstrate the kinetics of anti-FL Abs and provide evidence that anti-FL Abs play a protective role against "non-exposed" serotypes after secondary DENV infection. Author Summary: The four serotypes of dengue virus (DENV) are the leading cause of mosquito-borne viral diseases in humans. Whereas infection with one DENV serotype is thought to confer protection against re-infection with that serotype, it can be either protective or enhance disease severity upon subsequent ("secondary") infection with a different serotype. The envelope (E) protein of DENV is the major target of neutralizing antibodies. Previously, we and others reported that a significant proportion of anti-E antibodies in human dengue-immune sera recognize the fusion loop (FL) of E protein. The role of anti-FL antibodies in protection against subsequent DENV infections versus pathogenesis remains unclear. In this study, we developed capture ELISAs to measure the concentrations of anti-E and anti-FL antibodies in sera of Nicaraguan dengue patients collected 3, 6, 12 and 18 months post-illness, and investigated the kinetics of these antibodies and their relationship to neutralization activity. While the concentrations of anti-FL antibodies did not correlate with 50% neutralization titers (NT50) against the current infecting serotype, it correlated with NT50 against serotypes to which patients had likely not yet been exposed ("non-exposed" serotypes) in secondary DENV infections. These findings provide evidence that anti-FL antibodies play a protective role against "non-exposed" serotypes after secondary DENV infection. [ABSTRACT FROM AUTHOR]

Four dengue virus serotypes (DENV1-4) circulate globally, causing more human illness than any other arthropod-borne virus. Dengue can present as a range of clinical manifestations from undifferentiated fever to Dengue Fever to severe, life-threatening syndromes. However, most DENV infections are inapparent. Yet, little is known about determinants of inapparent versus symptomatic DENV infection outcome. Here, we analyzed over 2,000 DENV infections from 2004 to 2011 in a prospective pediatric cohort study in Managua, Nicaragua. Symptomatic cases were captured at the study health center, and paired healthy annual samples were examined on a yearly basis using serological methods to identify inapparent DENV infections. Overall, inapparent and symptomatic DENV infections were equally distributed by sex. The mean age of infection was 1.2 years higher for symptomatic DENV infections as compared to inapparent infections. Although inapparent versus symptomatic outcome did not differ by infection number (first, second or third/post-second DENV infections), substantial variation in the proportion of symptomatic DENV infections among all DENV infections was observed across study years. In participants with repeat DENV infections, the time interval between a first inapparent DENV infection and a second inapparent infection was significantly shorter than the interval between a first inapparent and a second symptomatic infection. This difference was not observed in subsequent infections. This result was confirmed using two different serological techniques that measure total anti-DENV antibodies and serotype-specific neutralizing antibodies, respectively. Taken together, these findings show that, in this study, age, study year and time interval between consecutive DENV infections influence inapparent versus symptomatic infection outcome, while sex and infection number had no significant effect. Moreover, these results suggest that the window of cross-protection induced by a first infection with DENV against a second symptomatic infection is approximately 2 years. These findings are important for modeling dengue epidemics and development of vaccines. Author Summary: The four serotypes of the mosquito-borne dengue virus (DENV) infect an estimated 100 million humans annually, resulting in tens of millions of dengue cases and hundreds of thousands of cases of severe disease. However, infection with DENV does not always lead to clinical signs, and a large proportion of DENV infections are inapparent. Here, we studied the factors that influence whether a DENV infection is inapparent or symptomatic. Data from over 2,000 DENV infections (∼1,600 inapparent and ∼400 symptomatic) were collected during 7 years from an ongoing prospective cohort study of children in Managua, Nicaragua. We show that whether a person is infected for the first, the second, or the third time with different DENV serotypes, the proportion of symptomatic infections is similar. However, the proportion of symptomatic infection varied substantially across study years, and symptomatic infections tended to happen in older children when compared to inapparent infections. We also show that if a second DENV infection happens within a period of ∼2 years after the first infection, the second infection is more likely to be inapparent. However, if the time interval between first and second DENV infections is longer, this protection wanes and the infection is likely to be symptomatic. These findings are important for the modeling of dengue epidemics and the development of new vaccines. [ABSTRACT FROM AUTHOR]

Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are life-threatening complications following infection with one of the four serotypes of dengue virus (DENV). At present, no vaccine or antiviral therapies are available against dengue. Here, we characterized a panel of eight human or mouse-human chimeric monoclonal antibodies (MAbs) and their modified variants lacking effector function and dissected the mechanism by which some protect against antibody-enhanced lethal DENV infection. We found that neutralizing modified MAbs that recognize the fusion loop or the A strand epitopes on domains II and III of the envelope protein, respectively, act therapeutically by competing with and/or displacing enhancing antibodies. By analyzing these relationships, we developed a novel in vitro suppression-of-enhancement assay that predicts the ability of modified MAbs to act therapeutically against antibody-enhanced disease in vivo. These studies provide new insight into the biology of DENV pathogenesis and the requirements for antibodies to treat lethal DENV disease. [ABSTRACT FROM AUTHOR]

The lack of reliable, high-throughput tools for characterizing anti-dengue virus (DENV) antibodies in large numbers of serum samples has been an obstacle in understanding the impact of neutralizing antibodies on disease progression and vaccine efficacy. A reporter system using pseudoinfectious DENV reporter virus particles (RVPs) was previously developed by others to facilitate the genetic manipulation and biological characterization of DENV virions. In the current study, we demonstrate the diagnostic utility of DENV RVPs for measuring neutralizing antibodies in human serum samples against all four DENV serotypes, with attention to the suitability of DENV RVPs for large-scale, long-term studies. DENV RVPs used against human sera yielded serotype-specific responses and reproducible neutralization titers that were in statistical agreement with Plaque Reduction Neutralization Test (PRNT) results. DENV RVPs were also used to measure neutralization titers against the four DENV serotypes in a panel of human sera from a clinical study of dengue patients. The high-throughput capability, stability, rapidity, and reproducibility of assays using DENV RVPs offer advantages for detecting immune responses that can be applied to large-scale clinical studies of DENV infection and vaccination. [ABSTRACT FROM AUTHOR]

Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody-dependent enhancement (ADE). However, despite decades of investigation, no in vivo model for antibody enhancement of dengue disease severity has been described. Analogous to human infants who receive anti-DV antibodies by transplacental transfer and develop severe dengue disease during primary infection, we show here that passive administration of anti-DV antibodies is sufficient to enhance DV infection and disease in mice using both mouse-adapted and clinical DV isolates. Antibody-enhanced lethal disease featured many of the hallmarks of severe dengue disease in humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, and increased systemic viral burden in serum and tissue phagocytes. Passive transfer of a high dose of serotype-specific antibodies eliminated viremia, but lower doses of these antibodies or cross-reactive polyclonal or monoclonal antibodies all enhanced disease in vivo even when antibody levels were neutralizing in vitro. In contrast, a genetically engineered antibody variant (E60-N297Q) that cannot bind FcγR exhibited prophylactic and therapeutic efficacy against ADE-induced lethal challenge. These observations provide insight into the pathogenesis of antibody-enhanced dengue disease and identify a novel strategy for the design of therapeutic antibodies against dengue. [ABSTRACT FROM AUTHOR]