scholarly journals Incomplete protection against dengue virus type 2 re-infection in Peru

2015 ◽  
Author(s):  
Brett M. Forshey ◽  
Robert C. Reiner ◽  
Sandra Olkowski ◽  
Amy C. Morrison ◽  
Angelica Espinoza ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Age Distribution ◽  
Neutralizing Antibody ◽  
Denv Infection ◽  
Contact Tracing ◽  
Individual Level ◽  
The Individual

Background. Nearly half of the world’s population is at risk for dengue, yet no licensed vaccine or anti-viral drug is currently available. Dengue is caused by any of four dengue virus serotypes (DENV-1 through DENV-4), and infection by a DENV serotype is assumed to provide life-long protection against re-infection by that serotype. We investigated the validity of this fundamental assumption during a large dengue epidemic caused by DENV-2 in Iquitos, Peru, in 2010-2011, 15 years after the first outbreak of DENV-2 in the region.Methodology/Principal Findings. We estimated the age-dependent prevalence of serotype-specific DENV antibodies from longitudinal cohort studies conducted between 1993 and 2010. During the 2010-2011 epidemic, active dengue cases were identified through active community- and clinic-based febrile surveillance studies, and acute inapparent DENV infections were identified through contact tracing studies. Based on the age-specific prevalence of DENV-2 neutralizing antibodies, the age distribution of DENV-2 cases was markedly older than expected. Homologous protection was estimated at 35.1% (95% confidence interval: 0% -- 65.2%). At the individual level, pre-existing DENV-2 antibodies were associated with an incomplete reduction in the frequency of symptoms. Among dengue cases, 43% (26/66) exhibited elevated DENV-2 neutralizing antibody titers for years prior to infection, compared with 76% (13/17) of inapparent infections (age-adjusted odds ratio: 4.2; 95% confidence interval: 1.1 – 17.7).Conclusions/Significance. Our data indicate that protection from homologous DENV re-infection may be incomplete in some circumstances, which provides context for the limited vaccine efficacy against DENV-2 in recent trials. Further studies are warranted to confirm this phenomenon and to evaluate the potential role of incomplete homologous protection in DENV transmission dynamics.Author SummaryHomotypic immunity against DENV infection has been assumed to be complete and lifelong, and to our knowledge, instances of homologous DENV re-infection have not been rigorously documented. However, few long-term studies have been conducted in such a way that homologous re-infection could be observed, if it did in fact occur. Our study provides evidence that homologous re-infection may occur in certain circumstances. We draw from data collected during a 2010-2011 DENV-2 epidemic in northeastern Peru, 15 years after the initial DENV-2 outbreak in the region. This finding has significant implications for our understanding of dengue epidemiology and for dengue vaccine formulation, which may need to consider multiple genotypes of each serotype. Data from other long-term dengue epidemiology studies should be analyzed to determine of homologous re-infection is a more widespread phenomenon.

scholarly journals Neutralizing antibody titers against dengue virus correlate with protection from symptomatic infection in a longitudinal cohort

2016 ◽  
Vol 113 (3) ◽  
pp. 728-733 ◽  
Author(s):  
Leah C. Katzelnick ◽  
Magelda Montoya ◽  
Lionel Gresh ◽  
Angel Balmaseda ◽  
Eva Harris
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Secondary Infection ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Denv Infection ◽  
Severe Dengue ◽  
Symptomatic Infection ◽  
Denv Serotypes ◽  
Antibody Titers

The four dengue virus serotypes (DENV1–4) are mosquito-borne flaviviruses that infect ∼390 million people annually; up to 100 million infections are symptomatic, and 500,000 cases progress to severe disease. Exposure to a heterologous DENV serotype, the specific infecting DENV strains, and the interval of time between infections, as well as age, ethnicity, genetic polymorphisms, and comorbidities of the host, are all risk factors for severe dengue. In contrast, neutralizing antibodies (NAbs) are thought to provide long-lived protection against symptomatic infection and severe dengue. The objective of dengue vaccines is to provide balanced protection against all DENV serotypes simultaneously. However, the association between homotypic and heterotypic NAb titers and protection against symptomatic infection remains poorly understood. Here, we demonstrate that the titer of preinfection cross-reactive NAbs correlates with reduced likelihood of symptomatic secondary infection in a longitudinal pediatric dengue cohort in Nicaragua. The protective effect of NAb titers on infection outcome remained significant when controlled for age, number of years between infections, and epidemic force, as well as with relaxed or more stringent criteria for defining inapparent DENV infections. Further, individuals with higher NAb titers immediately after primary infection had delayed symptomatic infections compared with those with lower titers. However, overall NAb titers increased modestly in magnitude and remained serotype cross-reactive in the years between infections, possibly due to reexposure. These findings establish that anti-DENV NAb titers correlate with reduced probability of symptomatic DENV infection and provide insights into longitudinal characteristics of antibody-mediated immunity to DENV in an endemic setting.

scholarly journals Does workplace social capital protect against long-term sickness absence? Linking workplace aggregated social capital to sickness absence registry data

2017 ◽  
Vol 46 (3) ◽  
pp. 290-296 ◽  
Author(s):  
Anne-Sophie K. Hansen ◽  
Ida E. H. Madsen ◽  
Sannie Vester Thorsen ◽  
Ole Melkevik ◽  
Jakob Bue Bjørner ◽  
...  
Keyword(s):  
Social Capital ◽  
Private Sector ◽  
Sickness Absence ◽  
Collective Good ◽  
Standard Deviation Increase ◽  
Individual Level ◽  
The Individual ◽  
Adjusted Model ◽  
Workplace Social Capital

Aims: Most previous prospective studies have examined workplace social capital as a resource of the individual. However, literature suggests that social capital is a collective good. In the present study we examined whether a high level of workplace aggregated social capital (WASC) predicts a decreased risk of individual-level long-term sickness absence (LTSA) in Danish private sector employees. Methods: A sample of 2043 employees (aged 18–64 years, 38.5% women) from 260 Danish private-sector companies filled in a questionnaire on workplace social capital and covariates. WASC was calculated by assigning the company-averaged social capital score to all employees of each company. We derived LTSA, defined as sickness absence of more than three weeks, from a national register. We examined if WASC predicted employee LTSA using multilevel survival analyses, while excluding participants with LTSA in the three months preceding baseline. Results: We found no statistically significant association in any of the analyses. The hazard ratio for LTSA in the fully adjusted model was 0.93 (95% CI 0.77–1.13) per one standard deviation increase in WASC. When using WASC as a categorical exposure we found a statistically non-significant tendency towards a decreased risk of LTSA in employees with medium WASC (fully adjusted model: HR 0.78 (95% CI 0.48–1.27)). Post hoc analyses with workplace social capital as a resource of the individual showed similar results. Conclusions: WASC did not predict LTSA in this sample of Danish private-sector employees.

scholarly journals A renewal equation model to assess roles and limitations of contact tracing for disease outbreak control

2021 ◽  
Vol 8 (4) ◽  
Author(s):  
Francesca Scarabel ◽  
Lorenzo Pellis ◽  
Nicholas H. Ogden ◽  
Jianhong Wu
Keyword(s):  
Deterministic Model ◽  
Infected Individual ◽  
Equation Model ◽  
Renewal Equation ◽  
Contact Tracing ◽  
Calendar Time ◽  
Individual Level ◽  
Total Incidence ◽  
Community Transmission ◽  
The Individual

We propose a deterministic model capturing essential features of contact tracing as part of public health non-pharmaceutical interventions to mitigate an outbreak of an infectious disease. By incorporating a mechanistic formulation of the processes at the individual level, we obtain an integral equation (delayed in calendar time and advanced in time since infection) for the probability that an infected individual is detected and isolated at any point in time. This is then coupled with a renewal equation for the total incidence to form a closed system describing the transmission dynamics involving contact tracing. We define and calculate basic and effective reproduction numbers in terms of pathogen characteristics and contact tracing implementation constraints. When applied to the case of SARS-CoV-2, our results show that only combinations of diagnosis of symptomatic infections and contact tracing that are almost perfect in terms of speed and coverage can attain control, unless additional measures to reduce overall community transmission are in place. Under constraints on the testing or tracing capacity, a temporary interruption of contact tracing may, depending on the overall growth rate and prevalence of the infection, lead to an irreversible loss of control even when the epidemic was previously contained.

scholarly journals Assessment of Prolonged Dengue Virus Infection in Dermal Fibroblasts and Hair-Follicle Dermal Papilla Cells

Viruses ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 267
Author(s):  
Kai-Che Wei ◽  
Wan-Ju Wei ◽  
Yi-Shan Liu ◽  
Li-Chen Yen ◽  
Tsung-Hsien Chang
Keyword(s):  
Dengue Virus ◽  
Hair Follicle ◽  
Hair Loss ◽  
Human Hair ◽  
Dermal Papilla ◽  
Denv Infection ◽  
Dermal Fibroblasts ◽  
Type I ◽  
Dermal Papilla Cells

Dengue virus (DENV)-mediated hair loss is one of the post-dengue fatigue syndromes and its pathophysiology remains unknown. Whether long-term or persistent infection with DENV in the scalp results in hair loss is unclear. In this study, we cultured human dermal fibroblasts (WS1 cells) and primary human hair-follicle dermal papilla cells (HFDPCs) in the long term with DENV-2 infection. The production of virion, the expression of inflammatory and anti-virus genes, and their signaling transduction activity in the infected cells were analyzed. DENV-2 NS3 protein and DENV-2 5′ UTR RNA were detected in fibroblasts and HFDPCs that were subjected to long-term infection with DENV-2 for 33 days. A significant amount of DENV-2 virion was produced by both WS1 cells and HFDPCs in the first two days of acute infection. The virion was also detected in WS1 cells that were infected in the long term, but HFDPCs failed to produce DENV-2 after long-term culture. Type I and type III interferons, and inflammatory cytokines were highly expressed in the acute phase of DENV infection in HFPDC and WS1 cells. However, in the long-term cultured cells, modest levels of anti-viral protein genes were expressed and we observed reduced signaling activity, which was correlated with the level of virus production changes. Long-term infection of DENV-2 downregulated the expression of hair growth regulatory factors, such as Rip1, Wnt1, and Wnt4. This in vitro study shows that the long-term infection with DENV-2 in dermal fibroblasts and dermal papilla cells may be involved with the prolonged-DENV-infection-mediated hair loss of post-dengue fatigue syndrome. However, direct evidence for viral replication in the human hair of a dengue victim or animal infection model is required.

scholarly journals Tracking the polyclonal neutralizing antibody response to a dengue virus serotype 1 type-specific epitope across two populations in Asia and the Americas

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Daniela V. Andrade ◽  
Colin Warnes ◽  
Ellen Young ◽  
Leah C. Katzelnick ◽  
Angel Balmaseda ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Sri Lankan ◽  
Human Monoclonal Antibodies ◽  
Virus Serotype ◽  
Serotype 1 ◽  
Dengue Virus Serotypes ◽  
Kinetics Of ◽  
Two Populations

Abstract The four dengue virus serotypes (DENV1-4) cause major public health problems worldwide. Highly neutralizing type-specific human monoclonal antibodies (hmAbs) target conformation-dependent epitopes on the DENV envelope protein, including 1F4, a DENV1 type-specific hmAb. Using a recombinant DENV2 virus displaying the DENV1 1F4 epitope (rDENV2/1), we measured the proportion and kinetics of DENV1 neutralizing antibodies targeting the 1F4 epitope in individuals living in Asia and the Americas where different DENV1 genotypes were circulating. Samples from 20 individuals were analyzed 3 and 18 months post-primary DENV1 infection, alongside samples from 4 individuals collected annually for four years post-primary DENV1 infection, from two studies in Nicaragua. We also analyzed convalescent post-primary DENV1 plasma samples from Sri Lankan individuals. We found that neutralizing antibodies recognizing the 1F4 epitope vary in prevalence across both populations and were detected from 20 days to four years post-infection. Additionally, both populations displayed substantial variability, with a range of high to low proportions of DENV1 type-specific neutralizing antibodies recognizing the 1F4 epitope seen across individuals. Thus, the 1F4 epitope is a major but not exclusive target of type-specific neutralizing antibodies post-primary infection with different DENV1 genotypes in Asia and Latin America, and additional epitopes likely contribute to type-specific neutralization of DENV1.

scholarly journals 2764. Generation of a Balanced, Tetravalent Dengue Vaccine Based on Contemporary Strains Using a Computational, Synthetic Biology-Based Platform

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S975-S975
Author(s):  
Ying Wang ◽  
Charles B Stauft ◽  
Kanakatte Raviprakash ◽  
J Robert Coleman ◽  
Steffen Mueller
Keyword(s):  
Human Cell ◽  
Neutralizing Antibodies ◽  
Vaccine Dose ◽  
Neutralizing Antibody ◽  
Denv Infection ◽  
The United States ◽  
Wild Type ◽  
Lethal Challenge ◽  
Denv Serotypes ◽  
Tetravalent Vaccine

Abstract Background The WHO estimates that there may be 50 million cases of dengue virus (DENV) infection worldwide every year. There is no safe vaccine against DENV licensed in the United States. The development of a balanced and effective anti-DENV vaccine is vital to preventing morbidity and mortality. Codagenix used its proprietary SAVE (Synthetic Attenuated Virus Engineering) platform to generate and test a live attenuated, tetravalent vaccine against DENV. Methods Codagenix used SAVE to substitute under-represented human codons and codon-pairs into the E protein sequences of contemporary strains of DENV1-4, producing either a fully human-cell-deoptimized prM-E (E-Min), or a partially deoptimized prM-E (E-W/Min) to allow for balancing of the vaccine’s immunogenicity. Full genomes containing deoptimized E-Min and E-W/Min in the DENV2 backbone were transfected into cells to recover live-attenuated, human-cell-deoptimized vaccine strains. Mice were vaccinated with 106 FFU of each DENV vaccine (alone or together), boosted on day 21 and assessed for neutralizing antibodies by PRNT50 and survival after lethal challenge with mouse-adapted wild-type (WT) DENV. Cynomolgus macaques were immunized with a mixture of 106 FFU of each DENV vaccine strain. Two doses were administered on study day 1 and 57 and serum neutralizing antibodies were determined on day 57 and 85 by a microneutralization assay. Results SAVE deoptimized DENV viruses grew to wild-type (between 107 and 108 FFU/ml) levels at permissive temperatures (<37C). All vaccine strains generated neutralizing antibody levels comparable to WT. A tetravalent formulation containing all four E-Min strains protected mice from lethal challenge with DENV3. A tetravalent formulation of Codagenix DENV-E-W/Min vaccine elicited a robust and balanced neutralizing antibody response in non-human primates (NHPs) against all four DENV serotypes after a single dose. A second vaccine dose did not boost antibody titers significantly. Conclusion The ability to rationally balance the attenuation of multiple vaccine strains, thereby avoiding antibody-dependent enhancement, is a unique advantage of the Codagenix SAVE platform. Codagenix DENV vaccine viruses generated balanced, sterilizing immunity in NHPs after one dose. Disclosures All authors: No reported disclosures.

scholarly journals Epitope Determinants of a Chimpanzee Dengue Virus Type 4 (DENV-4)-Neutralizing Antibody and Protection against DENV-4 Challenge in Mice and Rhesus Monkeys by Passively Transferred Humanized Antibody

2007 ◽  
Vol 81 (23) ◽  
pp. 12766-12774 ◽  
Author(s):  
Ching-Juh Lai ◽  
Ana P. Goncalvez ◽  
Ruhe Men ◽  
Claire Wernly ◽  
Olivia Donau ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Virus Type ◽  
High Titer ◽  
Neutralizing Antibody ◽  
Denv Infection ◽  
Passive Transfer ◽  
Escape Mutant ◽  
Protective Capacity

ABSTRACT The chimpanzee monoclonal antibody (MAb) 5H2 is specific for dengue virus type 4 (DENV-4) and neutralizes the virus at a high titer in vitro. The epitope detected by the antibody was mapped by sequencing neutralization escape variants of the virus. One variant contained a Lys174-Glu substitution and another contained a Pro176-Leu substitution in domain I of the DENV-4 envelope protein (E). These mutations reduced binding affinity for the antibody 18- to >100-fold. Humanized immunoglobulin G (IgG) 5H2, originally produced from an expression vector, has been shown to be a variant containing a nine-amino-acid deletion in the Fc region which completely ablates antibody-dependent enhancement of DENV replication in vitro. The variant MAb, termed IgG 5H2 ΔD, is particularly attractive for exploring its protective capacity in vivo. Passive transfer of IgG 5H2 ΔD at 20 μg/mouse afforded 50% protection of suckling mice against challenge with 25 50% lethal doses of mouse neurovirulent DENV-4 strain H241. Passive transfer of antibody to monkeys was conducted to demonstrate proof of concept for protection against DENV challenge. Monkeys that received 2 mg/kg of body weight of IgG 5H2 ΔD were completely protected against 100 50% monkey infectious doses (MID50) of DENV-4, as indicated by the absence of viremia and seroconversion. A DENV-4 escape mutant that contained a Lys174-Glu substitution identical to that found in vitro was isolated from monkeys challenged with 106 MID50 of DENV-4. This substitution was also present in all naturally occurring isolates belonging to DENV-4 genotype III. These studies have important implications for possible antibody-mediated prevention of DENV infection.

Suitability of a young deciduous-dominated forest for American marten and the effects of forest removal

2004 ◽  
Vol 82 (3) ◽  
pp. 423-435 ◽  
Author(s):  
Kim G Poole ◽  
Aswea D Porter ◽  
Andrew de Vries ◽  
Chris Maundrell ◽  
Scott D Grindal ◽  
...  
Keyword(s):  
Populus Tremuloides ◽  
Forest Cover ◽  
Agricultural Land ◽  
Prey Availability ◽  
Population Level ◽  
Home Ranges ◽  
American Marten ◽  
Individual Level ◽  
The Individual

American marten (Martes americana (Turton, 1806)) are generally considered to be reliant upon and most successful in continuous late-successional coniferous forests. By contrast, young seral forests and deciduous-dominated forests are assumed to provide low-quality marten habitat, primarily as a result of insufficient structure, overhead cover, and prey. This study examined a moderate-density population of marten in northeastern British Columbia in what appeared to be comparatively low-quality, deciduous-dominated habitat, overgrown agricultural land primarily consisting of 30- to 40-year-old stands of regenerating trembling aspen (Populus tremuloides Michx.). Over 4 years, we monitored 52 radio-collared marten. The population appeared to be stable, as indicated by large numbers of adults, relatively constant densities, long-term residency of many individuals, low mortality rates, and older age structure. Relatively small home ranges (males, 3.3 km2; females, 2.0 km2) implied good habitat quality and prey availability. Shearing (removal of immature forest cover) of 17% of the study area resulted in home range shifts at the individual level but no detectable impact at the population level. Categorically, marten avoided nonforested cover types and preferred mature coniferous (>25% conifer) stands (7% of the study area) but otherwise appeared to use all forested stands relative to their availability, including extensive use of deciduous-dominated stands and deciduous stands <40 years of age. Thus, these young deciduous forests appeared to have sufficient structure, overhead cover, and prey to maintain moderate densities of resident marten on a long-term basis.

scholarly journals Complexity of Neutralizing Antibodies against Multiple Dengue Virus Serotypes after Heterotypic Immunization and Secondary Infection Revealed by In-Depth Analysis of Cross-Reactive Antibodies

2015 ◽  
Vol 89 (14) ◽  
pp. 7348-7362 ◽  
Author(s):  
Wen-Yang Tsai ◽  
Anna Durbin ◽  
Jih-Jin Tsai ◽  
Szu-Chia Hsieh ◽  
Stephen Whitehead ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Secondary Infection ◽  
Denv Infection ◽  
Primary Immunization ◽  
Dengue Vaccine ◽  
Alternative Strategies ◽  
Live Attenuated Vaccines ◽  
Human Sera ◽  
Arboviral Diseases

ABSTRACTThe four serotypes of dengue virus (DENV) cause the most important and rapidly emerging arboviral diseases in humans. The recent phase 2b and 3 studies of a tetravalent dengue vaccine reported a moderate efficacy despite the presence of neutralizing antibodies, highlighting the need for a better understanding of neutralizing antibodies in polyclonal human sera. Certain type-specific (TS) antibodies were recently discovered to account for the monotypic neutralizing activity and protection after primary DENV infection. The nature of neutralizing antibodies after secondary DENV infection remains largely unknown. In this study, we examined sera from 10 vaccinees with well-documented exposure to first and second DENV serotypes through heterotypic immunization with live-attenuated vaccines. Higher serum IgG avidities to both exposed and nonexposed serotypes were found after secondary immunization than after primary immunization. Using a two-step depletion protocol to remove different anti-envelope antibodies, including group-reactive (GR) and complex-reactive (CR) antibodies separately, we found GR and CR antibodies together contributed to more than 50% of neutralizing activities against multiple serotypes after secondary immunization. Similar findings were demonstrated in patients after secondary infection. Anti-envelope antibodies recognizing previously exposed serotypes consisted of a large proportion of GR antibodies, CR antibodies, and a small proportion of TS antibodies, whereas those recognizing nonexposed serotypes consisted of GR and CR antibodies. These findings have implications for sequential heterotypic immunization or primary immunization of DENV-primed individuals as alternative strategies for DENV vaccination. The complexity of neutralizing antibodies after secondary infection provides new insights into the difficulty of their application as surrogates of protection.IMPORTANCEThe four serotypes of dengue virus (DENV) are the leading cause of arboviral diseases in humans. Despite the presence of neutralizing antibodies, a moderate efficacy was recently reported in phase 2b and 3 trials of a dengue vaccine; a better understanding of neutralizing antibodies in polyclonal human sera is urgently needed. We studied vaccinees who received heterotypic immunization of live-attenuated vaccines, as they were known to have received the first and second DENV serotype exposures. We found anti-envelope antibodies consist of group-reactive (GR), complex-reactive (CR), and type-specific (TS) antibodies, and that both GR and CR antibodies contribute significantly to multitypic neutralizing activities after secondary DENV immunization. These findings have implications for alternative strategies for DENV vaccination. Certain TS antibodies were recently discovered to contribute to the monotypic neutralizing activity and protection after primary DENV infection; our findings of the complexity of neutralizing activities after secondary immunization/infection provide new insights for neutralizing antibodies as surrogates of protection.

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