11. Dengue virus immunity and vaccination 2 Flashcards
What does dengue control require?
- Multiple strategies and a more holistic approach.
- This includes vaccines to prevent severe disease.
- Controlling the mosquito vectors possibly through genetic engineering.
- Anti-viral drugs to treat patients.
- Host directed therapies
Why could host directed therapies work well for dengue?
- Dengue is an immune mediated disease especially for severe disease.
- This means targeting the immune system could be a better therapy.
What are the challenges for treating dengue?
- Severe dengue manifests late.
- Severe dengue occurs after the virus is cleared.
- Viremia subsides around day 5
- All antivirals for dengue have not been made to the clinic for various reasons.
What has a larger treatment window than antivirals?
Targeting the immune system
What is the biggest challenge for dengue vaccine development?
- We want immunity to all 4 serotypes of dengue.
- This means once they encounter dengue in real life they will have alow risk infection.
- Most dengue vaccines only give partial immunity. This is a potential higher risk then if they were naive.
- This is especially a problem with live attenuated vaccines.
What is the ideal dengue virus vaccine?
- A tetravalent vaccine that gives equal and balanced protection to all 4 serotypes.
- This can be tricky as the correlates of protection are unknown and this number is different for different serotypes.
What are the advantages and disadvantages of live attenuated dengue vaccine?
Advantages:
1. 2 have been licensed
2. They cause sustained and broad immunity.
3. They don’t cause disease but replicate to mimic infection
Disadvantages:
1. They don’t cause balanced immunity to all 4 serotypes.
2. Mixing all 4 live virus strains causes 1 to try and outcompete the others and leads to imbalanced immunity.
What are the advantages and disadvantages of virus vector dengue vaccine?
Advantages:
1. They are non replicating so they are very safe.
2. They cause broad immunity
Disadvantages:
1. There is mixed efficacy to get a long lasting response.
What are the advantages and disadvantages of Non-infectious dengue vaccine?
Advantages:
1. These are nucleic acid or subunit based so they are inactivated.
2. Very safe and balanced immunity to all 4 serotypes.
Disadvantages:
1. It is a challenge to create sustained T cell and antibody immunity.
What are some successful examples of live attenuated flavivirus vaccines?
- Japanese encephalitis vaccine
- Yellow fever vaccine
What are the 2 ways attenuation of viruses can be achieved?
- By passage of the virus in non-human cells lines.
- Using DNA recombination technology to insert mutations in regions important for replication and pathogenesis.
What are the pros of flavivirus live attenuated vaccines?
- They replicate in the host and mimic a natural infection.
- They elicit a broad and sustained immune response similar to a natural infection.
What are the cons of flavivirus live attenuated vaccines?
- There is competition between viral strains which leads to an imbalanced immune response.
- There is a risk of genetic reversion to the WT pathogenic strain. This hasn’t actually been seen but is a risk.
What are the 3 main live attenuated dengue vaccines?
- Dengvaxia
- TAK-003
- TV003 (in clinical trials)
What is the Dengvaxia vaccine based on?
- The yellow fever vaccine backbone.
- Both viruses are flaviviruses so there is homology.
- The yellow fever vaccine has some proteins added from dengue.
What is the structure of the dengvaxia virus?
- The non-structural proteins and capsid are from yellow fever virus.
- This means it might not create a cross reactive immune response to all strains of dengue.
- prM and E proteins are from Dengue.
What is the efficacy of dengvaxia?
- In children over 9 years efficacy is 65.6%
- In children under 9 efficacy is 44.6%.
- There is decent protection but it was rolled out before long term follow ups were done.
- However there were increased hospitalisation rates in the 3 year follow up for children under 9.
What was big problem with Dengvaxia?
It caused increased hospitalisation in year 3 in vaccinated kids under 9.
How was the problem with Dengvaxia discovered?
- There were 3 follow up trials to see how the vaccine worked over long periods of time.
- These happened after the vaccine was licensed.
- All 3 trials showed more cases of dengue and hospitalisations in the vaccine group than in the control group.
- This occurred in seronegative patients and mostly in younger age groups.
- It was thought that the vaccine was causing dengue disease enhancement.
What happen once the problem with Dengvaxica was discovered?
- Large scale roll out had already begun especially in the Philippines.
- 19 vaccinated children died following a natural dengue infection.
- There was not direct link that the vaccine had aided the deaths it just didn’t offer the protection it should have.
- Most adverse affects were in seronegative patients. This was discovered in later trials as it was not initially measured.
- It was thought imbalanced immunity was increasing the risk of enhanced infection.
- This was a major step back for dengue vaccine development.
Who is Dengvaxia currently recommended for?
- Only seropositive patients
- Older children from 9-16 years old
What is the structure of the TAK003 Takeda dengue vaccine?
- It uses a strain of dengue 2 called PDK-53
- This means it has the dengue 2 non-structural proteins and capsid.
- Then, versions have been made containing the prM and E proteins from all four serotypes.
What protection does the TAK003 dengue vaccine provide?
- It is a well tolerated vaccine that induces neutralising antibodies against all 4 dengue serotypes.
- It induces dengue 2 specific CD8+ T cells.
- It induces cross reactive CD8 T cells for all 4 dengue serotypes.
What antibody response does TAK003 induce?
- It generates neutralising antibodies against all 4 serotypes.
- It generates more antibodies to dengue 2 especially in seronegative patients.
- There is still the problem of an imbalance immune response to the 4 serotypes.
What was the 3 year efficacy of TAK003?
- The overall efficacy is 62%.
- This is protection from getting infection.
- There is lower efficacy in younger patients (42%) and seronegative patients (54%).
- It protects well against hospitalisation up to 85% efficacy. Again this is lower in younger and seronegative patients.
What was the efficacy of the TAK003 vaccine after 3 years?
- Efficacy decreases somewhat more so in seronegative patients.
- It provided good protection for dengue 1 and 2.
- Efficacy for dengue 3 and 4 was very low.
What are the possible reasons TAK003 provide limited protection to dengue 3 or 4?
- The vaccine could be causing enhancement of dengue 3 or 4 infection.
- It could also be due to no circulating dengue 3 or 4 in the tested areas.
- More studies are needed to understand the levels of protection for these serotypes.
Who is the TAK003 dengue vaccine recommended for?
- For use in places with high dengue disease burden and high transmission intensity.
- Not just in areas with high dengue 1 and 2.
- Given to children 6-16 years old.
- Given in a 2 dose schedule with 3 months between doses.
- Needs to be given alongside well-designed communication and community engagement to ensure understanding of the vaccine and benefits.
- There have been no reported adverse events.
What is the TV003/TV005 dengue vaccine?
- It is a dengue vaccine developed by NIAID.
- It uses rational approaches to mutate and attenuate the live vaccine.
What is the structure of TV003-TV005 dengue vaccine?
- Mutations in the 3’ UTR to create attenuation of the virus.
- It worked well for dengue 1 and 4.
- Dengue 3 required an extra 31 nt deletion to get sufficient attenuation.
- Dengue 2 didn’t work so the dengue 4 backbone with the dengue 2 prM and E proteins added.
- These four dengue strains were then introduced as a tetravalent vaccine for prM and E.
What immunity does TV003-TV005 induce?
- It induces neutralising antibodies against all 4 dengue serotypes.
- It induces a tetravalent CD4+ and CD8+ T cell response.
What did each individual strain of the TV003-TV005 produce?
- They were first tested as 4 separate vaccines.
- There were good T cell responses to each serotypes when given individually.
- There was recognition of structural and non-structural proteins.
What immune response is generated from the tetravalent TV003 dengue vaccine?
- T cells to highly conserved antigens are generated for all 4 serotypes.
- These are cross reactive T cells.
- These T cells are mainly to NS3 and NS5.
- This helps remove the risk of Antibody dependent enhancement and antigen sin.
- 93% of responses were targeting conserved regions between the serotypes.
What does TV003 show in a dengue human challenge trial?
- A TV003 vaccinated group and a control group were exposed to a challenge strain of dengue.
- This was done around 6 months post vaccination
- 100% of control group developed dengue
- 0% of the vaccinated group develop dengue. (0% viremia)
- There was also a limited or no boost in antibody response suggesting the vaccine is completely blocking viral replication and giving sterilising immunity.
What are dengue human challenge trials used for?
- To assess the efficacy of the vaccine.
- This is done before larger clinical trials are carried out before companies commit and invest money.
What challenge strain of dengue was used in the TV003 trial?
- Dengue 2 delta 40
- It was initially developed as a vaccine but it caused too much disease.
What is an advantage of a single dose vaccine?
- It’s affordable
- You avoid the problems of getting people to come back and get a 2nd dose.
What did the randomised control trial for TV003 show (the Butantan trial)?
- Dengue 3 and 4 protection couldn’t be assessed due to lack of circulating disease.
- overall efficacy of 67%.
- It has a higher efficacy for dengue 1 (75%).
- protection for dengue 2 of around 59%.
- It is a good vaccine for dengue 1.
What are the challenges to dengue vaccine development?
- 4 different serotypes.
- Tetravalent vaccine need to induce a balanced immune response to all 4 serotypes.
- There is no validated immune correlates of protection so when we measure antibodies and T cells we don’t know what we are looking for.
- There is no animal models to accurately replicate human dengue.
- Immunological assays are unable to define dengue serotypes specific immune responses precisely.
- Requires very large clinical trials to demonstrate the benefit across diverse populations.
Why is there no good animal model for dengue virus?
- Mice don’t get dengue as it is a specialised human pathogen.
- In order to make mice get dengue so create an animal model you have to knock out the type 1 IFN receptor.
- This creates a severely immunocompromised mouse, so it is hard to study the immune response in it.
What is the E85 VRP dengue vaccine?
- A virus replicon particle vaccine
- Genetic information for all 4 serotypes of dengue E protein is inserted.
- E protein dimers are produced which is good as it is the native conformation.
- It has been shown to induce neutralising antibodies and T cell responses in nonhuman primates.
What are virus replicon particles?
- Virus particles based on Venezuelan equine encephalitis virus
- It is able to do a single round of replication and infection
- It is missing the packaging proteins so it cannot replicate and transmit the infection.
What did challenge trials of E85 VRP with dengue show?
- Done in nonhuman primates.
- E85 VRP produced strong neutralising antibodies to all 4 serotypes of dengue
- There was complete protection for dengue 3 and 4.
- There was good protection for dengue 1 and 2.
- It looks like a promising vaccine but has different protection for the different serotypes
What are the non-infectious dengue vaccine candidates?
- TDENV purified inactivated vaccine
- DSV4 virus like particle vaccine
What is the TDENV purified inactivated vaccine?
- This is a tetravalent dead vaccine.
- Uses prM and E proteins alongside different adjuvants.
- It induces neutralising antibodies in nonhuman primates and reduces viremia.
- It is currently in phase 1 and 2 trials.
- Limitation is it only contains a few antigens from the virus and only structural proteins.
What is the DSV4 virus like particle dengue vaccine?
- It uses the key ED3 domain of the E protein that is important in inducing neutralising antibodies.
- ED3 is then stuck on a HBS antigen scaffold from HBV.
- There are 4 monovalent versions and a tetravalent version
- Induces neutralising antibodies and confers protection against challenge in mice.
What are the 4 main dengue virus vaccine candidates?
- Live attenuated Dengvaxia and TAK003.
- Live attenuated TV003
- Non infections PIV
- Viral vector vaccine
