Insights from direct studies on human dengue infections

Halstead, Scott B.

doi:10.1073/pnas.1819607116

Cited by 10 publications

(8 citation statements)

References 24 publications

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“…While in animal models, endothelial cells are rapidly damaged by DENV NS1, in humans, severe vascular permeability is a rare event. 52 Furthermore, vascular leakage is temporally linked to defervescence, a time when circulating levels of NS1 are low. Defervescence in viral diseases usually signals the termination of intracellular infection by cell-mediated immunity.…”

Section: Background (1) Dengue Viruses and Its Vectorsmentioning

confidence: 99%

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Severe dengue in travellers: pathogenesis, risk and clinical management

Halstead

Wilder‐Smith

2019

Journal of Travel Medicine

102

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Rationale for review Dengue is a frequent cause of febrile illness among travellers and has overtaken malaria as the leading cause of febrile illness for those traveling to Southeast Asia. The purpose is to review the risk of dengue and severe dengue in travellers with a particular focus on the pathogenesis and clinical management of severe dengue. Risk, pathogenesis and clinical management The risk of travel-acquired dengue depends on destination, season and duration of travel and activities during travel. Seroconversion rates reported in travellers, therefore, vary between <1% and >20%. The most common life-threatening clinical response to dengue infection is the dengue vascular permeability syndrome, epidemiologically linked to secondary infection, but can also occur in primary infection. Tertiary and quaternary infections are usually associated with mild or no disease. Antibody-dependent enhancement, viral factors, age, host factors and clinical experience of the managing physician modulate the risk of progressing to severe dengue. The relative risk of severe dengue in secondary versus primary infection ranges from 2 to 7. The absolute risk of severe dengue in children in highly endemic areas is ~0.1% per year for primary infections and 0.4% for secondary infections. About 2–4% of secondary infections lead to severe dengue. Severe dengue and death are both relatively rare in general travellers but more frequently in those visiting friends and relatives. Clinical management of severe dengue depends on judicious use of fluid rehydration. Conclusions Although dengue is a frequent cause of travel illness, severe dengue and deaths are rare. Nevertheless, dengue infections can interrupt travel and lead to evacuation and major out-of-pocket costs. Dengue is more frequent than many other travel-related vaccine preventable diseases, such as hepatitis A, hepatitis B, rabies, Japanese encephalitis and yellow fever, indicating a need for a dengue vaccine for travellers.

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Section: Background (1) Dengue Viruses and Its Vectorsmentioning

confidence: 99%

“…Following recovery from a second infection a broadened immune response appears to be induced that prevents severe disease accompanying a third or fourth infection with different serotypes, as observed from natural cohort studies 120 , possibly explained by multitypic immunity. 52…”

Section: What Is the Risk Of Severe Dengue Following A Secondary Infementioning

confidence: 99%

Severe dengue in travellers: pathogenesis, risk and clinical management

Halstead

Wilder‐Smith

2019

Journal of Travel Medicine

102

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“…Maturation of flaviviruses occurs by the cleavage of the prM protein to M [11], but this is generally incomplete, with virus maturity (whether live virus or RVP) being influenced by the producing cell type [30,53]. In addition, patient-derived DENV has been reported to show higher levels of maturity compared with the same virus following passage in cells [54,55]. The maturation state of flaviviruses is thought to be important for infectivity and for neutralization by sera in clinical studies.…”

Section: Generation Of Zikv Rvps With Distinct Maturation Statesmentioning

confidence: 99%

Antigenicity, stability, and reproducibility of Zika reporter virus particles for long-term applications

et al. 2020

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The development of vaccines against flaviviruses, including Zika virus (ZIKV) and dengue virus (DENV), continues to be a major challenge, hindered by the lack of efficient and reliable methods for screening neutralizing activity of sera or antibodies. To address this need, we previously developed a plasmid-based, replication-incompetent DENV reporter virus particle (RVP) production system as an efficient and safe alternative to the Plaque Reduction Neutralization Test (PRNT). As part of the response to the 2015–2016 ZIKV outbreak, we developed pseudo-infectious ZIKV RVPs by modifying our DENV RVP system. The use of ZIKV RVPs as critical reagents in human clinical trials requires their further validation using stability and reproducibility metrics for large-scale applications. In the current study, we validated ZIKV RVPs using infectivity, neutralization, and enhancement assays with monoclonal antibodies (MAbs) and human ZIKV-positive patient serum. ZIKV RVPs are antigenically equivalent to live virus based on binding ELISA and neutralization results and are nonreplicating based on the results of live virus replication assays. We demonstrate reproducible neutralization titer data (NT50 values) across different RVP production lots, volumes, time frames, and laboratories. We also show RVP stability across experimentally relevant time intervals and temperatures. Our results demonstrate that ZIKV RVPs provide a safe, high-throughput, and reproducible reagent for large-scale, long-term studies of neutralizing antibodies and sera, which can facilitate large-scale screening and epidemiological studies to help expedite ZIKV vaccine development.

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“…Maturation of flaviviruses occurs by the cleavage of the prM protein to M (9), but this is generally incomplete, with virus maturity (whether live virus or RVP) (Cherrier 2009; ref for ZIKV) being influenced by the producing cell type (Dejninarattisai et al, 2015). In addition, patient-derived DENV showed higher levels of maturity compared with the same virus following passage in cells (47,48). The maturation state of flaviviruses is thought to be important for infectivity and for neutralization by sera in clinical studies.…”

Section: Generation Of Zikv Rvps With Distinct Maturation Statesmentioning

confidence: 99%

Antigenicity, stability, and reproducibility of Zika reporter virus particles for long-term applications

Whitbeck

Thomas

Kadash-Edmondson

et al. 2020

Preprint

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The development of vaccines against flaviviruses, including Zika virus (ZIKV) and dengue virus (DENV), continues to be a major challenge, hindered by the lack of efficient and reliable methods for screening neutralizing activity of sera or antibodies. To address this need, we previously developed a plasmid-based, replication-incompetent DENV reporter virus particle (RVP) production system as an efficient and safe alternative to the Plaque Reduction Neutralization Test (PRNT). As part of the response to the 2015-2016 ZIKV outbreak, we recently developed pseudoinfectious ZIKV RVPs by modifying our DENV RVP system. The use of ZIKV RVPs as critical reagents in human clinical trials requires their further validation using stability and reproducibility metrics for large-scale applications. In the current study, we validated ZIKV RVPs using infectivity, neutralization, and enhancement assays with monoclonal antibodies (MAbs) and human ZIKV-positive patient serum. ZIKV RVPs are antigenically identical to live virus based on binding ELISA and neutralization results and are nonreplicating based on the results of plaque formation assays. We demonstrate reproducible neutralization titer data (NT50 values) across different RVP production lots, volumes, time frames, and laboratories. We also show RVP stability across experimentally relevant time intervals and temperatures. Our results demonstrate that ZIKV RVPs provide a safe, rapid, and reproducible reagent for large-scale, long-term studies of neutralizing antibodies and sera, which can facilitate large-scale screening and epidemiological studies to help expedite ZIKV vaccine development.

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Insights from direct studies on human dengue infections

Cited by 10 publications

References 24 publications

Severe dengue in travellers: pathogenesis, risk and clinical management

Severe dengue in travellers: pathogenesis, risk and clinical management

Antigenicity, stability, and reproducibility of Zika reporter virus particles for long-term applications

Antigenicity, stability, and reproducibility of Zika reporter virus particles for long-term applications

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