Dengue virus immunity and vaccination- Part II

• LO:


  • To appreciate the challenges around dengue vaccine design
  • To describe pros & cons of the different vaccine platforms
  • To evaluate the most suitable vaccine platform for the design of a dengue vaccine
  • To describe the current landscape for dengue vaccines
• Dengue control requires multiple strategies


  • Vector control
  • Host-directed therapies
  • Anti-viral drugs
  • Vaccines
• Dengue: opportunities for treatment


  CHALLENGES

  • Severe dengue manifests late (≥d4)
  • Severe dengue occurs after virus is cleared
  • Viraemia subsides ∼day 5

  Therapeutic window:

  • Anti-virals: <day 5
  • Host immunmodulator: <day 6/7

  
• Secondary heterologous infections are at highest risk for severe dengue

  
• Challenges for dengue vaccine development

  • Tetravalent vaccines needs to elicit equal immunity to all 4 DENV serotypes

  
• DENV vaccine candidates


  Live attenuated vaccines

  ✓ Sustained/broad immunity

  ✗ Balanced immunity to all 4 DENV serotypes

  Virus-vectored vaccines

  ✓ Safe, broad immunity

  ✗ Efficacy

  “Non-infectious” vaccines

  ✓ Safe, balanced immunity to 4 DENV serotypes

  ✗ Sustained/broad immunity

  
• Live attenuated virus vaccines (LAV)


  • Successful vaccines are LAVS: Japanese encephalitis (JEV) and Yellow fever (YFV)
  • Attenuation is achieved by:

  1. passaging of virus in non-human cell lines (e.g. PDK, primary dog kidney cell line)
  2. DNA recombination technology

  • Pros:

  1. They replicate in the host thus mimicking a natural infection
  2. They elicit a broad and sustained immune response(Abs, T cells)

  • Cons:

  1. Competition between viral strains leads to unbalanced immunity
  2. Risk of genetic reversion to the WT pathogenic strain

  
• Dengvaxia® (CYD-TDV) 


  • Overall vaccine efficacy in participants:

  1. > 9 years: 65.6% (81.9%seropositive versus 52.5% seronegative)
  2. < 9 years: 44.6% (70.1% seropositive versus 14.1seronegative)

  • Increased rates of hospitalization in year3 for vaccinated children <age 9

  
• Increased hospitalization in year 3 in vaccinated kids < 9 years

  
• “Dengue vaccine fiasco leads to criminal charges”

  • 2015: Dengvaxia® vaccination programme rolled out in Philippine school children
  • 19 vaccinated children died following a natural dengue infection
  • 830,000 children received the vaccine before the programme was halted
  • WHO now recommends the vaccine is administered only to seropositive individuals (9-16 years)
• TAK-003


  • Well tolerated vaccine
  • Induces neutralizing antibodies against all 4 DENV serotypes
  • Induces DENV 2-specific CD8+ T cells
  • Induces cross-reactive CD8+ T cells to DENC 1, 3, 4

  
• Serotype-specific antibody titers to TAK-003

  
• 3-year efficacy of Takeda’s TAK-003

  
• TAK-003 vaccine efficacy during year 3

  
• WHO SAGE recommendations for TAK-003 Sept 2023


  • To be considered for introduction in settings with high dengue disease burden and high transmission intensity
  • To be introduced to children aged 6 to 16 years of age
  • Administration in a 2-dose schedule with a 3-month interval between doses
  • Vaccine introduction should be accompanied by a well-designed communication strategy and community engagement
• TV003-TV005 


  • Clinical Phase III (Butantan), II (Medigen Vaccine Biologics Co), phase I (Merck)
  • Well tolerated vaccine
  • Induces neutralizing antibodies against all 4 DENV serotypes
  • Induces tetravalent CD4+ and CD8+ T cell response

  
• T cell responses to DENV 1-4 after monovalent vaccination

  
• T cell responses after tetravalent TV003 targets highly conserved regions

  
• TV003 elicits protection in a human dengue challenge

  
• Butantan phase 3 trials for TV003


  • Instituto Butantan, U.S. NIH, and Merck (MSD) reported the first results from a phase III trial in Brazil with over 16,000 participants (2-59 years), started 2016 with at least 2 years of disease surveillance
  • Single dose
  • No severe cases or cases with clinical warning signs reported
  • Low circulation of DENV 3 and 4 in the region

  
• Challenges to dengue vaccine development

  • Four DENV serotypes (DENV 1–4)
  • Tetravalent vaccine needs to induce a balanced immune response to DENV 1-4
  • No validated immune correlates of protection
  • No animal model which accurately recapitulates human dengue
  • Immunologic assays are unable to precisely define DENV serotypes pecific immune responses
  • Requirement for very large clinical trials to demonstrate benefit across diverse populations
• Virus vectored vaccines

  
• E85 Venezuelan equine encephalitis virus replicon particles (VRP)


  • Elicits neutralizing antibodies and T cell responses in mice and NHPs
  • Protects NHPs upon challenge with DENV

  
• E85 VRP induces neutralizing antibodies against DENV-1 to 4 after 2 doses

  
• E85 VRP induces a protective immune response in NHP

  
• “Non-infectious” vaccines

  
• TDENV Purified Inactivated vaccine (PIV)

  • Used with GSK adjuvants (AS01, AS03) or aluminium hydroxide (alum)
  • Elicits tetravalent neutralizing antibodies in NHP
  • Reduces viremia after challenge with DENV2 in NHP
  • Phase I (A03, A05 or alum) and phase II (AS03)

  
• DSV4 Virus Like Particles (VLP)

  • Monovalent DENV 1-3 formulations induce neutralizing antibodies and confer protection against lethal challenge in mice
  • Tetravalent formulation induces neutralizing antibodies in mice
  • Tetravalent formulation is under investigation in NHPs

  
• DENV vaccine candidates

  
• Summary


  • Different vaccine platforms exist •
  • LAVs are at the most advanced phase of development for dengue
  • Dengvaxia® and Qdenga® (TAK-003) are the first licensed dengue vaccines
  • Both vaccines show higher vaccine efficacies in individuals who are seropositive at baseline
  • Both vaccines elicit unbalanced immunity to DENV 1-4 and variable protection across DENVserotypes
  • Dengvaxia® shows increased hospitalization in children < 9 years: evidence of ADE?
  • Other vaccines are in development that are not based on LAVs