Dengue virus immunity and vaccination- Part I

• LO:


  • To describe the characteristics and global burden of dengue
  • To describe the host adaptive immune response to dengue virus
  • |To describe the role of altered adaptive immune responses in dengue pathology (antibody-dependent enhancement and original antigenic sin)
• The global burdenof dengue

  • Most abundant and rapidly spreading arboviral infection
  • Current estimates: 390 million infections (96 million clinically apparent)
  • 500,000 cases of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS)
  • ≈20,000 deaths annually

  
• The spread ofDengue


  • Flavivirus (zika, Yellow fever, West Nile Virus), ssRNA virus
  • Transmitted by the Aedes mosquitoes
  • Four Infectious serotypes (DENV 1-4)
  • Notherapeutic
  • Partially protective vaccines (Dengvaxia® by Sanofi-Pasteur, Qdenga® by Takeda)

  
• Dengue is spreading geographically

  2023: As of 2nd Oct 2023: >4.2 million cases & >3,000 dengue-related deaths reported from 79 countries

  
• Spectrum of dengue disease


  Clinical features:

  • Asymptomatic
  • Self-limiting dengue fever (DF)
  • Severe dengue: dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS)
  • 36% dengue cases: dengue fever
• Spectrum of dengue disease


  Clinical features:

  • Asymptomatic
  • Self-limiting dengue fever (DF)
  • Severe dengue: dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS)
  • 36% dengue cases: dengue fever

  
• WHO dengue classification (2009)

  
• Potential complications of dengue


  • Minor/severe bleeding
  • Fluid accumulation and respiratory stress
  • Sin rash
  • Muscle & joint pain
  • Abdominal pain
  • retro-orbital pain
  • persistent vomiting
  • liver englargement
  • severe haemorrhage usually follows prolonged shock
• Host risk factors for severe dengue


  • Secondary dengue infection
  • Age
  • Co-morbidities (hypertension and diabetes)
  • Obesity/overweight1
  • Genetic polymorphisms:

  1. MICB, PLCE12 (GWAS study)
  2. TNF-α, IL-103
  3. HLA class I and II4,5
• Secondary heterologous infections are at highest risk for severe dengue

  
• The adaptive immune response


  • Develops as an adaptation to infection with a pathogen
  • Consists of T and B lymphocytes and their secreted products
  • Sophisticated antigen-specific defense system
  • Key feature: immunological memory

  
• T cell recognition of viral antigens

  
• 3 phases of a primary T cell response

  
• The cellular basis of immunological memory

  Memory T cells:

  • Clonally expanded from naïve precursors
  • Low activation threshold Mount secondary responses and confer immediate protection • Persist for a lifetime in the absence of antigen • Heterogeneous for effector functions and migratory capacities
• Immune response during dengue infection

  
• Higher plasma viremia in severe dengue


  Viremia is defined as the level of circulating viral RNA copies and quantified as DENV-3 genome equivalents per ml (cDNA copies/mL)

  
• Dengue virus proteome and structure

  
• Breadth and magnitude of dengue-specific T cell responses

  
• CD4+ and CD8+ T cells target distinct dengue viral proteins

  
• Immunodominant regions for T cells of the dengue virus polyprotein

  
• Immunity to dengue virus initiates in the skin

  
• Antibody-dependent enhancement (ADE) of dengue infection

  
• Antibody-dependent enhancement (ADE) of dengue infection (#2)

  
• Extrinsic and intrinsic ADE in dengue

  
• DENV binds to LILRB1 and inhibits the FcR-induced anti-viral response

  
• A narrow range of pre-existing antibodies increases risk of severe dengue

  
• Increased levels of afucosylated IgG in severe dengue

  
• Potential effects of afucosylated IgG in dengue

  
• Original antigenic sin in dengue infection

  
• Controversial role of T cells during dengue

  
• Dengue-specific T cell responses in DF and DHF

  
• NS3-specific T cells in primary and secondary dengue infections
• NS3-specific T cells in primary and secondary dengue infections

  
• GWAS identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1

  
• Summary


  • Dengue virus is a mosquito-borne flavivirus that is estimated to infect 390 million people each year
  • Infections lead to a wide range of disease manifestations: asymptomatic, dengue fever, severe dengue
  • Adaptive immune responses (B cell/antibodies & T cells) are needed to clear dengue infection
  • Pre-existing antibodies may increase risk of severe dengue infection (ADE)
  • Sub-optimal pre-existing memory T cells may contribute to immunopathology (OAS)