Lec 14 Dengue

The Complex Interactions Between Dengue and Zika Immunology and Epidemiology

Overview

  • Speaker: Eva Harris, PhD

  • Affiliations:

    • Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley

    • Sustainable Sciences Institute, San Francisco & Managua, Nicaragua

Baltimore Virus Classification System

  • Classification of viruses:

    • Positive-stranded RNA viruses

    • Retro-transcribing viruses

    • DNA viruses

    • RNA viruses

  • Subcategories based on genetic material:

    • ds DNA

    • ss DNA

    • dsRNA

    • ss RNA (+)

    • ss RNA (-)

    • ss RNA (RT)

    • ds DNA (RT)

  • Visualization details suggest a genetic structure, possibly using a logo representation.

Flavivirus Replication

Mechanism

  • Relies on RNA-dependent RNA polymerase for replication.

  • Occurs primarily in the cytoplasm for genome replication and protein synthesis.

  • + strands are utilized as mRNA for translating into proteins.

Process Details

  • Endocytosis : Viruses enter host cells via clathrin-mediated endocytosis.

  • pH-dependent conformational change occurs during uncoating, where the virus sheds its protective coat to release its genome into the host cell.

  • The virion structure transitions from immature to mature forms involving specific cleavage of proteins such as prM, indicating virus maturation.

  • Related structures include the rough endoplasmic reticulum and the nucleus involved in translation, replication, and assembly processes.

Epidemiology of Dengue

Global Emergence and Spread

  • Increase in reported cases of dengue from 1981 to 2003 and beyond:

    • Approximately 5.8 billion people are at risk for dengue infection.

    • An estimated 50-100 million dengue cases occur annually.

    • Severe cases leading to Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) number between 250,000 - 500,000 yearly.

  • Visualization data shows a marked increase in dengue cases in a timeline format (1955-2008), with annual counts escalating over the decades.

Factors Influencing Spread

  • Increased international trade and travel correlates highly with co-circulation of multiple dengue virus serotypes (DENV1-4).

  • Prior infection with different dengue serotypes is the greatest risk factor for severe dengue disease.

Clinical Manifestations of Dengue

Dengue Fever (DF)

  • Symptoms include:

    • High fever

    • Headache

    • Retro-orbital pain

    • Myalgias/arthralgias

    • Fatigue

    • Nausea and vomiting

    • Rash (cutaneous)

    • Hemorrhagic manifestations

    • Thrombocytopenia

Dengue Hemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS)

  • Characterized by:

    • Increased vascular permeability

    • Hemoconcentration

    • Hypovolemic shock

    • Hemorrhagic manifestations

    • Severe thrombocytopenia (platelet count <100,000/mL)

    • Abdominal pain

    • Elevated levels of many cytokines in serum, referred to as a "cytokine storm".

Integral Hypothesis of Dengue

  • Key factors influencing observed differences in individuals include:

    • Viral Risk Factors

    • Serotype, genotype/clade

    • Number of susceptibles

    • Vector density

    • Virus circulation

    • Hyper-endemicity

  • Individual Risk Factors

    • Age

    • Sex

    • Race

    • Nutritional status

    • Chronic diseases

    • Co-morbidities

    • Immune status

Clinical Presentations of Zika

  • Subject to similar transformations with onset of symptoms typically around Day 1 post-infection, lasting until approximately Day 5.

  • Symptoms include:

    • Maculopapular rash

    • Conjunctivitis

    • Fever

    • Arthralgia and myalgia

  • Rare symptoms can include vomiting, edema.

  • Complications include Guillain-Barré Syndrome and Microcephaly & Congenital Zika Syndrome.

Nicaraguan Cohort Study

Overview

  • Study investigates imprinting effects of pre-existing antibodies against DENV and ZIKV on subsequent infections and outcomes, highlighting interactions between these viruses.

  • Involves a longitudinal cohort of 4,000 children aged 2-17, tracking infections and antibody responses over several years.

Imprinting Effects & Antibody Dependent Enhancement (ADE)

  • Impacts of prior infections:

    • DENV infection on future dengue disease severity and responses due to pre-existing ZIKV antibodies.

    • Related studies from Guzman et al. and Katzelnick et al. are annotated.

Statistical Models and Observations

  • Risk models used include generalized linear mixed models to evaluate how prior infections influence clinical outcomes for children in Nicaragua. Findings articulate a correlation between antibody titers and dengue disease severity.

Implications for Vaccine Development

Issues Identified

  • Analysis reveals high risk for hospitalized dengue in previously seronegative vaccinated individuals, emphasizing vigilance in potential vaccine applications.

  • The interaction between prior ZIKV immunization could predestine higher risks when considering subsequent DENV exposures.

Future Strategies and Directions

  • Next-generation immunogens are being developed that aim to minimize the generation of enhancing antibodies, thus preserving future safety and efficacy in vaccinations against both Zika and Dengue.

  • Continued identification and study of protective correlates is essential for understanding the differences amongst serotypes.

Conclusions

  • There are complex immunological and epidemiological interactions between DENV and ZIKV stressing the necessity for detailed understanding to thrive towards innovative vaccine strategies.

  • The order of infection plays a critical role in dictating the immunological landscape, which can mediate disease outcomes effectively.

Acknowledgments

  • Research and cooperation contributions from several institutions and individuals, highlighting the collaborative effort at UC Berkeley and through partnerships in Nicaragua.