Dengue Virus

Question 1

What is dengue virus?

Answer 1

Tropical disease
Caused by dengue virus
Transmitted by Aedes aegypti mosquitos

Question 2

How can dengue disease manifest?

Answer 2

Rash
Eye pain
Headache
Muscle pain
Bone pain
Nausea/vomiting
Joint pain

Question 3

Describe the epidemiology of dengue

Answer 3

Mortality relatively low (<1%) but huge economic impact
Severe dengue has high mortality (>20%)
Endemic in over 100 countries
Affects 500 million people worldwide
0.5 million cases of severe dengue
Approximately 40,000 deaths
4th most significant infectious disease after TB, HIV and Malaria (before covid)

Question 4

What type of virus is dengue?

Answer 4

RNA virus

Question 5

What family does dengue virus belong to?

Answer 5

Flaviviridae, genus flavivirus

Question 6

How are most flaviviruses transmitted?

Answer 6

By arthropods (mosquitos or ticks) - known as arboviruses

Question 7

Name some other significant flaviviruses

Answer 7

Yellow fever virus
Chickungunya
Japanese encephalitis virus
West Nile virus
Zika virus

Question 8

Describe how DENV replicates

Answer 8

Binds to receptor and enters into cell by endocytosis
Uncoating of virus and transport to ER
Viral RNA replication and protein translation
Immature virion assembly
Transport to golgi where virion matures
Exocytosis and virion release

Question 9

What is the receptor that DENV binds to?

Answer 9

Not known but several candidates:
- heparin sulphate
- DC-SIGN
- mannose receptor
- HSPs

Question 10

What cells does DENV infect?

Answer 10

Myeloid cells
Endothelial cells
Hepatocytes
Other cells

Question 11

Describe the immune response to dengue

Answer 11

Tissue resident CD8 cells patrol skin for virus infected APCs
Killing of virus infected MHC-1-expressing cells by cytotoxic CD8
Killing of virus infected MHC-2-expressing cells by cytotoxic CD4
Promote/suppress inflammatory immune response depending on cytokines released
CD4 Tfh cells provides B cell help to produce high affinity antibodies

Question 12

How many serotypes of dengue are there?

Answer 12

4
Less characterised serotype 5 recently reported

Question 13

Describe infection with different serotypes

Answer 13

All serotypes can cause full spectrum disease
Infection with 1 serotype provides life-long protection against that serotype but only transient protection against others
Infection with 1 serotype can make infection with others worse

Question 14

What is the typical incubation period of dengue?

Answer 14

4-7 days

Question 15

What are the clinical symptoms of dengue infection?

Answer 15

Asymptomatic or mild fever (80%)
More severe illness (5%)
In small proportion it is life theratening - dengue haemorrhagic fever (DHF); bleeding, low levels of platelets, blood plasma leakage into tissues
Dengue shock syndrome (DSS) - dangerously low BP

Question 16

What are warning signs of severe dengue disease?

Answer 16

Abdominal pains
Muscle, joint and bone pain
Frequent vomiting
Hepatomegaly
Mucosal bleeding
Lethargy

Question 17

What are direct methods of dengue diagnosis?

Answer 17

Virus isolation
Genome detection
NS1 detection
These have high confidence but low accessibility

Question 18

What are indirect methods of dengue diagnosis?

Answer 18

Serology IgM
Serology IgG
High accessibility but low confidence

Question 19

What can be done in place of treatment of dengue?

Answer 19

No cure or specific treatment, can only relieve symptoms until infection has gone
e.g. taking paracetamol to relieve pain and fever, do not take aspirin or ibuprofen as can cause bleeding problems, drink plenty fluids to prevent dehydration, get plenty of rest

Question 20

What are the issues with vaccine development of dengue virus?

Answer 20

Dengue virus infected cells are located in the mucosal tissue so need a mucosal vaccine
4 antigenically distinct serotypes of dengue virus so need a vaccine that protects against all
Dengue infection has antibody-dependent enhancement meaning ab will bind to pathogen but not prevent infection

Question 21

Describe ADE of dengue

Answer 21

Abs against 1 serotype provide long term protection but subsequent infection with a different serotype means existing abs are not sufficiently neutralising
Instead, they form immune complexes with the virus which is still functional and these immune complexes are targeted to host Fc receptors and virus gains access to cell
Results in antibody-dependent enhancement of infection

Question 22

What is the current status of a dengue vaccine?

Answer 22

1 licensed vaccine (CYD-TDV)
2 stage 3 vaccines - DENVax, TV003/TV005
A stage 2 vaccine - TDENV
A stage 1 vaccine - DEV-80E
Potential novel vaccine

Question 23

What is the CYD-TDV vaccine?

Answer 23

Live attenuated tetravalent chimeric vaccine

Question 24

What is denvaxia?

Answer 24

First dengue vaccine approved in more than 10 countries
Recommended for use in adults and children older than 9 pre-exposed to dengue

Question 25

What is the TDV vaccine?

Answer 25

LATV chimeric dengue vaccine based on DENV-2
Recently approved by EMA