Dengue Virus Flashcards
Describe Dengue
Pathogen: Dengue Virus, arbovirus, An RNA virus from the family of Flaviviridae, genus Flavivirus
Epidemiology: Tropical climates
Vector: Aedes aegypti mosquito. Humans are the reservoir for dengue virus
Morphology: icosahedral nucleocapsid surrounded by an envelope and a single-stranded, positive-polarity RNA genome. 40 to 50 nm in diameter
Dengue disease manifestations?
-High-fever (saddleback fever)
-retro-orbital pain
-Severe pains in muscles (myalgia) and joints (arthralgia, breakbone)
-Profound leukopenia
-Moderately lymphadenopathy
-May have protracted convalescence
-Erythematous rash followed by morbilliform rash starting on extremities
What cells and receptors are targetted by DENV?
Receptor not known but Several candidates:
* Heparin sulphate
* DC-SIGN
* Mannose receptor
* HSPs
Infects:
* Myeloid cells
* Endothelial cells
* Hepatocytes
* Other cells
Immune response to dengue?
Describe the Dengue serotypes
- There are 4 well-known dengue serotypes (1-4)
- Less characterised serotype 5 recently reported
- All serotype can cause full spectrum disease
- Infection with one serotype provides life-long protection against that serotype but only transient protection against others
- Infection with one serotype can make infection with others worse
Describe the Spectrum of Clinical Symptoms of dengue infection
- The incubation period is typically 4-7 days
- Asymptomatic or mild fever (80%) (Dengue fever, DF)
- More severe illness (5%)
- In a small proportion it is life threatening
- Dengue haemorrhagic fever, DHF (bleeding, low level of platelets, blood plasma leakage into tissues)
- Dengue shock syndrome, DSS (dangerously low blood pressure)
Warning signs of severe dengue disease
- Abdominal pains
- Muscle, joint and bone pain
- Frequent vomiting
- Hepatomegaly
- Mucosal bleeding
- Lethargy
Dengue diagnosis
DIRECT METHODS (HIGH CONFIDENCE):
(RT-PCR)-based methods are available for rapid identification and serotyping of dengue virus in acute-phase serum
- Virus isolation
- Genome detection e.g. Nucleic acid detection
- NS1 detection
- Antigen detection
INDIRECT METHODS (HIGH ACCESSIBILITY):
Serologic diagnosis is complicated by cross-reactivity of IgG antibodies to heterologous flavivirus antigens = LOW CONFIDENCE
-Serology of IgM and IgG
- IgG ELISA and the HI test
- IgM ELISA
- IgM rapid test
Treatment for dengue?
There’s no cure or specific treatment for dengue. You can only relieve the symptoms until the infection has gone.
The following may help:
* take paracetamol to relieve pain and fever. Do not take aspirin or ibuprofen, as these can cause bleeding problems in people with dengue
* drink plenty of fluids to prevent dehydration – if you’re currently abroad, only drink bottled water from a bottle that was properly sealed
* get plenty of rest
Control of Dengue virus transmission
Control depends on antimosquito measures, including the use of insecticides.
Screened windows and doors can reduce exposure to the vectors.
Outbreaks are controlled by draining stagnant water that serves as the breeding place for the
mosquitoes. Personal protection includes using mosquito repellent and wearing clothing that covers the entire body
Describe the pathogenesis of dengue hemorrhagic fever or dengue shock syndrome
The key pathological feature of dengue hemorrhagic fever is increased vascular permeability with plasma leakage into the interstitial spaces associated with increased levels of vasoactive cytokines. This can lead
to life-threatening shock in some patients. Monocytes are the major target cell in the blood for dengue virus infection.
The pathogenesis of the severe syndrome involves preexisting dengue antibody.
Issues with dengue infection and vaccine development?
The need for protection against all:
- Four antigenically distinct serotypes of dengue virus (65-70% homology)
No Antibody-dependent Enhancement:
- (cross-reactive & sub-optimal Ab)
The need for Mucosal vaccines:
- Dengue virus infected cells located in mucosal tissue
Describe Antibody dependent enhancement of infection (ADE)
- Antibodies against one serotype give a long term protection against that serotype
- However, if an individual is subsequently infected with a different serotype, the existing antibodies are not sufficiently neutralising.
- Instead, they form immune complexes (IC) with the virus which is still functional
- This IC are then targeted to host cell Fc receptors and the virus gains access to cell
- This results in antibody-dependent enhancement of infection, ADE
- ADE is an issue with natural multiple infections and vaccines
- A vaccine that induces weak antibodies against one serotype can potentially make infection with that serotype worse due to ADE
Dengue vaccine: current status
CYD-TDV (Licensed):
* Sanofi Pasteur
* DengvaxiaTM
* Recombinant attenuated
(YF-based)
* Partial protection
DENVax (TDV):
* Takeda
* Recombinant attenuated
(DENV-2 & DENV-2-based recombinant DENV-1, -3 and -4)
TV003/TV005:
* US NIH, Instituto de Butantan
* Recombinant attenuated (DENV-1, -3 and -4 & DENV-4-based recombinant DENV-2)
TDENV:
* GSK/US WRAIR/Fiocruz
* Inactivated
DEV80E:
* Merck
* Subunit
CYD-TDV?
- Live attenuated tetravalent chimeric vaccine
- administered as 3 doses on a 0/6/12 month schedule
Advantages of using Poly-Immunoglobulin G Scaffold (PIGS)
- Multiple Ag presentation ( ~ 12 Ags in one molecule)
- Enhancement of immunity (Self-adjuvanticity)
- Exposure of Ag to APCs (Increase an efficiency)
- Stable polymerization (Disulfide bond)
D-PIGS induced neutralising antibodies against all serotypes
