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Infection with any of the four dengue virus serotypes (DENV1-4) can protect against or enhance subsequent dengue depending on preexisting antibodies and infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) is associated with increased risk of DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by DENV1-4 in a pediatric Nicaraguan cohort. Of 3412 participants in 2022, 10.6% experienced dengue cases caused by DENV1 (n = 139), DENV4 (n = 133), DENV3 (n = 54), DENV2 (n = 9), or an undetermined serotype (n = 39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since last infection, and year, and repeat measurements were used to predict disease risk. Compared with flavivirus-naïve participants, primary ZIKV infection was associated with increased risk of disease caused by DENV4 (relative risk = 2.62, 95% confidence interval: 1.48 to 4.63) and DENV3 (2.90, 1.34 to 6.27), but not DENV1 infection. Primary DENV infection or DENV followed by ZIKV infection was also associated with increased risk of DENV4 disease. We reanalyzed 19 years of cohort data and demonstrated that prior flavivirus immunity and antibody titer had distinct associations with disease risk depending on incoming serotype. We thus find that prior ZIKV infection, like prior DENV infection, is associated with increased risk of disease with certain DENV serotypes. Cross-reactivity among flaviviruses should be considered when assessing vaccine safety and efficacy.
Assuntos
Vírus da Dengue , Dengue , Sorogrupo , Infecção por Zika virus , Zika virus , Humanos , Zika virus/imunologia , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/imunologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Criança , Feminino , Masculino , Nicarágua/epidemiologia , Pré-Escolar , Fatores de Risco , Adolescente , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Estudos de CoortesRESUMO
Antigenic assessments of SARS-CoV-2 variants inform decisions to update COVID-19 vaccines. Primary infection sera are often used for assessments, but such sera are rare due to population immunity from SARS-CoV-2 infections and COVID-19 vaccinations. Here, we show that neutralization titers and breadth of matched human and hamster pre-Omicron variant primary infection sera correlate well and generate similar antigenic maps. The hamster antigenic map shows modest antigenic drift among XBB sub-lineage variants, with JN.1 and BA.4/BA.5 variants within the XBB cluster, but with five to six-fold antigenic differences between these variants and XBB.1.5. Compared to sera following only ancestral or bivalent COVID-19 vaccinations, or with post-vaccination infections, XBB.1.5 booster sera had the broadest neutralization against XBB sub-lineage variants, although a five-fold titer difference was still observed between JN.1 and XBB.1.5 variants. These findings suggest that antibody coverage of antigenically divergent JN.1 could be improved with a matched vaccine antigen.
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The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires ongoing monitoring to judge the ability of newly arising variants to escape the immune response. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal serum samples. We compared 18 datasets generated using human, hamster, and mouse serum and six different neutralization assays. Datasets using animal model serum samples showed higher titer magnitudes than datasets using human serum samples in this comparison. Fold change in neutralization of variants compared to ancestral SARS-CoV-2, immunodominance patterns, and antigenic maps were similar among serum samples and assays. Most assays yielded consistent results, except for differences in fold change in cytopathic effect assays. Hamster serum samples were a consistent surrogate for human first-infection serum samples. These results inform the transition of surveillance of SARS-CoV-2 antigenic variation from dependence on human first-infection serum samples to the utilization of serum samples from animal models.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19 , Testes de Neutralização , SARS-CoV-2 , Animais , Humanos , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/sangue , COVID-19/virologia , Camundongos , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Cricetinae , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Modelos Animais de DoençasRESUMO
Cross-reactive antibodies (Abs) to epitopes that span envelope proteins on the virion surface are hypothesized to protect against dengue. Here, we measured Abs targeting the quaternary envelope dimer epitope (EDE) as well as neutralizing and binding Abs and evaluate their association with dengue virus (DENV) infection, vaccine response, and disease outcome in dengue vaccinated and unvaccinated children (n=252) within a longitudinal cohort in Cebu, Philippines (n=2,996). Abs targeting EDE were prevalent and strongly associated with broad neutralization of DENV1-4 in those with baseline multitypic immunity. Subsequent natural infection and vaccination boosted EDE-like, neutralizing, and binding Abs. EDE-like Abs were associated with reduced dengue risk and mediated the protective effect of binding and neutralizing Abs on symptomatic and severe dengue. Thus, Abs targeting quaternary epitopes help explain broad cross protection in those with multiple prior DENV exposures, making them useful for evaluation and development of future vaccines and therapeutics.
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Many pathogens continuously change their protein structure in response to immune-driven selection, resulting in weakened protection even in previously exposed individuals. In addition, for some pathogens, such as dengue virus, poorly targeted immunity is associated with increased risk of severe disease through a mechanism known as antibody-dependent enhancement. However, it remains unclear whether the antigenic distances between an individual's first infection and subsequent exposures dictate disease risk, explaining the observed large-scale differences in dengue hospitalizations across years. Here, we develop a framework that combines detailed antigenic and genetic characterization of viruses with details on hospitalized cases from 21 years of dengue surveillance in Bangkok, Thailand, to identify the role of the antigenic profile of circulating viruses in determining disease risk. We found that the risk of hospitalization depended on both the specific order of infecting serotypes and the antigenic distance between an individual's primary and secondary infections, with risk maximized at intermediate antigenic distances. These findings suggest that immune imprinting helps determine dengue disease risk and provide a pathway to monitor the changing risk profile of populations and to quantifying risk profiles of candidate vaccines.
Assuntos
Antígenos Virais , Vírus da Dengue , Dengue , Humanos , Dengue/imunologia , Dengue/epidemiologia , Dengue/virologia , Vírus da Dengue/imunologia , Antígenos Virais/imunologia , Tailândia/epidemiologia , Fatores de Risco , HospitalizaçãoRESUMO
BACKGROUND: A three-dose dengue vaccine (CYD-TDV) was licensed for use in children aged 9 years and older starting in 2015 in several dengue-endemic countries. In 2016, the Philippine Department of Health implemented a dengue vaccination programme, which was discontinued because of safety concerns. We assessed the relative risk of developing virologically confirmed dengue among children who did or did not receive a single dose of CYD-TDV by previous dengue virus (DENV) infections at baseline classified as none, one, and two or more infections. METHODS: In this longitudinal, prospective, population-based cohort study, we enrolled healthy children (aged 9-14 years) residing in Bogo or Balamban, Cebu, Philippines, between May 2, and June 2, 2017, before a mass dengue vaccination campaign, via the Rural Health Unit in Bogo and three Rural Health Units in Balamban. We collected demographic information and sera for baseline DENV serostatus and conducted active surveillance for acute febrile illness. Children who developed acute febrile illness were identified, clinical data were collected, and blood was drawn for confirmation of dengue by RT-PCR. The primary outcome was the relative risk of developing virologically confirmed dengue among children who received or did not receive a single dose of CYD-TDV by DENV serostatus at baseline. FINDINGS: A single dose of CYD-TDV did not confer protection against virologically confirmed dengue in children who had none or one previous DENV infection at baseline. One dose conferred significant protection against hospital admission for virologically confirmed dengue among participants who had two or more previous DENV infections at baseline during the first 3 years (70%, 95% CI 20-88; p=0·017) and the entire follow-up period (67%, 19-87; p=0·016). INTERPRETATION: The risk of developing virologically confirmed dengue after a single dose of CYD-TDV varied by baseline DENV serostatus. Since the study assessed the effect of only a single dose, the findings cannot inform decisions on vaccination by public health officers. However, the findings have implications for children who receive an incomplete vaccination regimen and these results should prompt more detailed analyses in future trials on dengue vaccines. FUNDING: The Philippine Department of Health, Hanako Foundation, WHO, Swedish International Development Cooperation Agency, International Vaccine Institute, University of North Carolina, and US National Institute of Allergy and Infectious Diseases.
Assuntos
Vacinas contra Dengue , Dengue , Vacinas Atenuadas , Humanos , Filipinas/epidemiologia , Criança , Dengue/prevenção & controle , Dengue/epidemiologia , Vacinas contra Dengue/administração & dosagem , Vacinas contra Dengue/imunologia , Estudos Prospectivos , Feminino , Masculino , Adolescente , Estudos Longitudinais , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Vírus da Dengue/imunologia , VacinaçãoRESUMO
Dengue, caused by four closely related viruses, is a growing global public health concern, with outbreaks capable of overwhelming health-care systems and disrupting economies. Dengue is endemic in more than 100 countries across tropical and subtropical regions worldwide, and the expanding range of the mosquito vector, affected in part by climate change, increases risk in new areas such as Spain, Portugal, and the southern USA, while emerging evidence points to silent epidemics in Africa. Substantial advances in our understanding of the virus, immune responses, and disease progression have been made within the past decade. Novel interventions have emerged, including partially effective vaccines and innovative mosquito control strategies, although a reliable immune correlate of protection remains a challenge for the assessment of vaccines. These developments mark the beginning of a new era in dengue prevention and control, offering promise in addressing this pressing global health issue.
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Aedes , Vírus da Dengue , Dengue , Vacinas , Animais , Humanos , Dengue/epidemiologia , Dengue/prevenção & controle , Surtos de Doenças/prevenção & controle , Saúde PúblicaRESUMO
Dengue viruses (DENV1-4) are the most prevalent arboviruses in humans and a major public health concern. Understanding immune mechanisms that modulate DENV infection outcome is critical for vaccine development. Neutralizing antibodies (nAbs) are an essential component of the protective immune response, yet their measurement often relies on a single cellular substrate and partially mature virions, which does not capture the full breadth of neutralizing activity and may lead to biased estimations of nAb potency. Here, we analyze 125 samples collected after one or more DENV infections but prior to subsequent symptomatic or inapparent DENV1, DENV2, or DENV3 infections from a long-standing pediatric cohort study in Nicaragua. By assessing nAb responses using Vero cells with or without DC-SIGN and with mature or partially mature virions, we find that nAb potency and the protective NT50 cutoff are greatly influenced by cell substrate and virion maturation state. Additionally, the correlation between nAb titer and protection from disease depends on prior infection history and infecting serotype. Finally, we uncover variations in nAb composition that contribute to protection from symptomatic infection differently after primary and secondary prior infection. These findings have important implications for identifying antibody correlates of protection for vaccines and natural infections.
Assuntos
Coinfecção , Dengue , Chlorocebus aethiops , Animais , Humanos , Criança , Anticorpos Neutralizantes , Estudos de Coortes , Sorogrupo , Células Vero , Dengue/prevenção & controleRESUMO
The distribution and intensity of viral diseases transmitted by Aedes aegypti mosquitoes, including dengue, have rapidly increased over the last century. Here, we study dengue virus (DENV) transmission across the ecologically and demographically distinct regions or Ecuador. We analyzed province-level age-stratified dengue incidence data from 2000-2019 using catalytic models to estimate the force of infection of DENV over eight decades. We found that provinces established endemic DENV transmission at different time periods. Coastal provinces with the largest and most connected cities had the earliest and highest increase in DENV transmission, starting around 1980 and continuing to the present. In contrast, remote and rural areas with reduced access, like the northern coast and the Amazon regions, experienced a rise in DENV transmission and endemicity only in the last 10 to 20 years. The newly introduced chikungunya and Zika viruses have age-specific distributions of hospital-seeking cases consistent with recent emergence across all provinces. To evaluate factors associated with geographic differences in DENV transmission potential, we modeled DENV vector risk using 11,693 Aedes aegypti presence points to the resolution of 1 hectare. In total, 56% of the population of Ecuador, including in provinces identified as having increasing DENV transmission in our models, live in areas with high risk of Aedes aegypti, with population size, trash collection, elevation, and access to water as important determinants. Our investigation serves as a case study of the changes driving the expansion of DENV and other arboviruses globally and suggest that control efforts should be expanded to semi-urban and rural areas and to historically isolated regions to counteract increasing dengue outbreaks.
Assuntos
Aedes , Vírus da Dengue , Dengue , Infecção por Zika virus , Zika virus , Animais , Humanos , Equador/epidemiologia , Mosquitos Vetores , Fatores de RiscoRESUMO
Seroprevalence studies are the gold standard for disease surveillance, and serology was used to determine eligibility for the first licensed dengue vaccine. However, expanding flavivirus endemicity, co-circulation, and vaccination complicate serology results. Among 713 healthy Cambodian children, a commonly used indirect dengue virus IgG ELISA (PanBio) had a lower specificity than previously reported (94% vs. 100%). Of those with false positive PanBio results, 46% had detectable neutralizing antibodies against other flaviviruses, with the highest frequency against West Nile virus (WNV). Immunity to non-dengue flaviviruses can impact dengue surveillance and potentially pre-vaccine screening efforts.
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Sequential infection with multiple dengue virus (DENV) serotypes is thought to induce enduring protection against dengue disease. However, long-term antibody waning has been observed after repeated DENV infection. Here, we provide evidence that highly immune Nicaraguan children and adults (n = 4478) experience boosting and waning of antibodies during and after major Zika and dengue epidemics. We develop a susceptible-infected-recovered-susceptible (SIRS-type) model that tracks immunity by titer rather than number of infections to show that boosts in highly immune individuals can contribute to herd immunity, delaying their susceptibility to transmissible infection. In contrast, our model of lifelong immunity in highly immune individuals, as previously assumed, results in complete disease eradication after introduction. Periodic epidemics under this scenario can only be sustained with a constant influx of infected individuals into the population or a high basic reproductive number. We also find that Zika virus infection can boost DENV immunity and produce delays and then surges in dengue epidemics, as observed with real epidemiological data. This work provides insight into factors shaping periodicity in dengue incidence and may inform vaccine efforts to maintain population immunity.
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Vírus da Dengue , Dengue , Infecção por Zika virus , Zika virus , Adulto , Criança , Humanos , Dengue/epidemiologia , Anticorpos Antivirais , Reações CruzadasAssuntos
Vírus da Dengue , Dengue , Dengue Grave , Humanos , Anticorpos Facilitadores , Anticorpos AntiviraisRESUMO
The antigenic evolution of SARS-CoV-2 requires ongoing monitoring to judge the immune escape of newly arising variants. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal sera. We compared 18 datasets generated using human, hamster, and mouse sera, and six different neutralization assays. Titer magnitude was lowest in human, intermediate in hamster, and highest in mouse sera. Fold change, immunodominance patterns and antigenic maps were similar among sera. Most assays yielded similar results, except for differences in fold change in cytopathic effect assays. Not enough data was available for conclusively judging mouse sera, but hamster sera were a consistent surrogate for human first-infection sera.
RESUMO
Many pathogens continuously change their protein structure in response to immune-driven selection, resulting in weakened protection. In addition, for some pathogens such as dengue virus, poorly targeted immunity is associated with increased risk of severe disease, through a mechanism known as antibody-dependent enhancement. However, it remains a mystery whether the antigenic distance between an individual's first infection and subsequent exposures dictate disease risk, explaining the observed large-scale differences in dengue hospitalisations across years. Here we develop an inferential framework that combines detailed antigenic and genetic characterisation of viruses, and hospitalised cases from 21 years of surveillance in Bangkok, Thailand to identify the role of the antigenic profile of circulating viruses in determining disease risk. We find that the risk of hospitalisation depends on both the specific order of infecting serotypes and the antigenic distance between an individual's primary and secondary infections, with risk maximised at intermediate antigenic distances. These findings suggest immune imprinting helps determine dengue disease risk, and provides a pathway to monitor the changing risk profile of populations and to quantifying risk profiles of candidate vaccines.
RESUMO
The distribution and intensity of viral diseases transmitted by Aedes aegypti mosquitoes, including dengue, have rapidly increased over the last century. Ecuador is an interesting country to study drivers of dengue virus (DENV) transmission given it has multiple ecologically and demographically distinct regions. Here, we analyze province-level age-stratified dengue prevalence data from 2000-2019 using catalytic models to estimate the force of infection of DENV over eight decades and across provinces in Ecuador. We found that provinces established endemic DENV transmission at different time periods. Coastal provinces with the largest and most connected cities had the earliest and highest increase in DENV transmission, starting around 1980 and continuing to the present. In contrast, remote and rural areas with reduced access, like the northern coast and the Amazon regions, experienced a rise in DENV transmission and endemicity only in the last 10 to 20 years. The newly introduced chikungunya and Zika viruses have distinct age-specific prevalence distributions consistent with recent emergence across all provinces. We evaluated factors to the resolution of 1 hectare associated with geographic differences in vector suitability and arbovirus disease in the last 10 years by modeling 11,693 A aegypti presence points and 73,550 arbovirus cases. In total, 56% of the population of Ecuador lives in areas with high risk of Aedes aegypti. Most suitable provinces had hotspots for arbovirus disease risk, with population size, elevation, sewage connection, trash collection, and access to water as important determinants. Our investigation serves as a case study of the changes driving the expansion of DENV and other arboviruses globally and suggest that control efforts should be expanded to semi-urban and rural areas and to historically isolated regions to counteract increasing dengue outbreaks.
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The four dengue virus serotypes (DENV1-4) are the most prevalent arboviruses in humans and a major public health concern worldwide. Understanding immune mechanisms that modulate DENV infection outcome is critical for epidemic preparedness and development of a safe and effective vaccine. Neutralizing antibodies (nAbs) are an essential component of the protective response, yet their measurement often relies on a single cellular substrate and partially mature virions, which do not capture the full breadth of neutralizing activity and may lead to biased estimations of nAb potency. Here, we investigated the characteristics of nAbs associated with protection against dengue cases using samples collected after one or more DENV infections but prior to subsequent symptomatic or inapparent DENV1, DENV2, or DENV3 infections from a long- standing pediatric cohort study in Nicaragua. By assessing nAb responses using Vero cells with or without the attachment factor DC-SIGN and with mature or partially mature virions, we found that nAb potency and the protective NT 50 cutoff were greatly influenced by cell substrate and virion maturation state. Additionally, the correlation between nAb titer and protection from disease depended on an individual's prior infection history and the subsequent infecting DENV serotype. Finally, we uncovered variations in nAbs composition that contributed to protection from symptomatic DENV infection differently after primary and secondary prior infection. These findings have important implications for identifying antibody correlates of protection in the context of vaccines and natural infections.
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BACKGROUND: The four co-circulating and immunologically interactive dengue virus serotypes (DENV1-4) pose a unique challenge to vaccine design because sub-protective immunity can increase the risk of severe dengue disease. Existing dengue vaccines have lower efficacy in DENV seronegative individuals but higher efficacy in DENV exposed individuals. There is an urgent need to identify immunological measures that are strongly associated with protection against viral replication and disease following sequential exposure to distinct serotypes. METHODS/DESIGN: This is a phase 1 trial wherein healthy adults with neutralizing antibodies to zero (seronegative), one non-DENV3 (heterotypic), or more than one (polytypic) DENV serotype will be vaccinated with the live attenuated DENV3 monovalent vaccine rDEN3Δ30/31-7164. We will examine how pre-vaccine host immunity influences the safety and immunogenicity of DENV3 vaccination in a non-endemic population. We hypothesize that the vaccine will be safe and well tolerated, and all groups will have a significant increase in the DENV1-4 neutralizing antibody geometric mean titer between days 0 and 28. Compared to the seronegative group, the polytypic group will have lower mean peak vaccine viremia, due to protection conferred by prior DENV exposure, while the heterotypic group will have higher mean peak viremia, due to mild enhancement. Secondary and exploratory endpoints include characterizing serological, innate, and adaptive cell responses; evaluating proviral or antiviral contributions of DENV-infected cells; and immunologically profiling the transcriptome, surface proteins, and B and T cell receptor sequences and affinities of single cells in both peripheral blood and draining lymph nodes sampled via serial image-guided fine needle aspiration. DISCUSSION: This trial will compare the immune responses after primary, secondary, and tertiary DENV exposure in naturally infected humans living in non-endemic areas. By evaluating dengue vaccines in a new population and modeling the induction of cross-serotypic immunity, this work may inform vaccine evaluation and broaden potential target populations. TRIAL REGISTRATION: NCT05691530 registered on January 20, 2023.
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Vacinas contra Dengue , Dengue Grave , Adulto , Humanos , Viremia , Vacinas Atenuadas , Vacinação , Anticorpos NeutralizantesRESUMO
The rapid emergence of SARS-CoV-2 variants challenges vaccination strategies. Here, we collected 201 serum samples from persons with a single infection or multiple vaccine exposures, or both. We measured their neutralization titers against 15 natural variants and 7 variants with engineered spike mutations and analyzed antigenic diversity. Antigenic maps of primary infection sera showed that Omicron sublineages BA.2, BA.4/BA.5, and BA.2.12.1 are distinct from BA.1 and more similar to Beta/Gamma/Mu variants. Three mRNA COVID-19 vaccinations increased neutralization of BA.1 more than BA.4/BA.5 or BA.2.12.1. BA.1 post-vaccination infection elicited higher neutralization titers to all variants than three vaccinations alone, although with less neutralization to BA.2.12.1 and BA.4/BA.5. Those with BA.1 infection after two or three vaccinations had similar neutralization titer magnitude and antigenic recognition. Accounting for antigenic differences among variants when interpreting neutralization titers can aid the understanding of complex patterns in humoral immunity that informs the selection of future COVID-19 vaccine strains.
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Vacinas contra COVID-19 , COVID-19 , Humanos , SARS-CoV-2/genética , COVID-19/prevenção & controle , Vacinação , Anticorpos Antivirais , Anticorpos NeutralizantesRESUMO
The severity of the COVID-19 pandemic and the development of multiple SARS-CoV-2 vaccines expedited vaccine 'mix and match' trials in humans and demonstrated the benefits of mixing vaccines that vary in formulation, strength, and immunogenicity. Heterologous sequential vaccination may be an effective approach for protecting against dengue, as this strategy would mimic the natural route to broad dengue protection and may overcome the imbalances in efficacy of the individual leading live attenuated dengue vaccines. Here we review 'mix and match' vaccination trials against SARS-CoV-2, HIV, and dengue virus and discuss the possible advantages and concerns of future heterologous immunization with the leading dengue vaccines. COVID-19 trials suggest that priming with a vaccine that induces strong cellular responses, such as an adenoviral vectored product, followed by heterologous boost may optimize T cell immunity. Moreover, heterologous vaccination may induce superior humoral immunity compared to homologous vaccination when the priming vaccine induces a narrower response than the boost. The HIV trials reported that heterologous vaccination was associated with broadened antigen responses and that the sequence of the vaccines significantly impacts the regimen's immunogenicity and efficacy. In heterologous dengue immunization trials, where at least one dose was with a live attenuated vaccine, all reported equivalent or increased immunogenicity compared to homologous boost, although one study reported increased reactogenicity. The three leading dengue vaccines have been evaluated for safety and efficacy in thousands of study participants but not in combination in heterologous dengue vaccine trials. Various heterologous regimens including different combinations and sequences should be trialed to optimize cellular and humoral immunity and the breadth of the response while limiting reactogenicity. A blossoming field dedicated to more accurate correlates of protection and enhancement will help confirm the safety and efficacy of these strategies.
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COVID-19 , Vacinas contra Dengue , Dengue , Infecções por HIV , Humanos , Vacinas Atenuadas , Vacinas contra COVID-19 , Pandemias , SARS-CoV-2 , COVID-19/prevenção & controle , Vacinação , Infecções por HIV/prevenção & controle , Anticorpos Antivirais , Imunogenicidade da VacinaRESUMO
Preexisting cross-reactive antibodies have been implicated in both protection and pathogenesis during subsequent infections with different dengue virus (DENV) serotypes (DENV1-4). Nonetheless, humoral immune correlates and mechanisms of protection have remained elusive. Using a systems serology approach to evaluate humoral responses, we profiled plasma collected before inapparent or symptomatic secondary DENV3 infection from our pediatric cohort in Nicaragua. Children protected from symptomatic infections had more anti-envelope (E) and anti-nonstructural protein 1 (NS1) total immunoglobulin G (IgG), IgG4, and greater Fc effector functions than those with symptoms. Fc effector functions were also associated with protection from hemorrhagic manifestations in the pre-symptomatic group. Furthermore, in vitro virological assays using these plasma samples revealed that protection mediated by antibody-dependent complement deposition was associated with both lysis of virions and DENV-infected cells. These data suggest that E- and NS1-specific Fc functions may serve as correlates of protection, which can be potentially applied toward the design and evaluation of dengue vaccines.