Vl 6 - Malaria Vaccines Flashcards
what are the 5 vaccination types?
I) Live-attenuated vaccine:
II) Inactivated vaccine
III) subunit vaccines
IV) gene base vaccines
V) Virus-like particles
immune intervention strategies against malaria
sporozoite stage: humoral immunity: CSP, PfMAEBL
liver stage: cell mediated immunity: CD8+, CD4+T-cells ⇒ CSP, ME-Trap
blood stage: humoral immunity: MSP1, MSP3, AMA1, Rh5
what are approaches to sporozoite immunization and how can arrested Plasmodium liver act stages as potent whole organism vaccines?
3 approaches:
- Chloroquine/Azithromycin attenuated sporozoites: - apicoplast inhibited by Azithromycin (inhibits DNA-replication) ⇒ merozoites leave hepatocyte, then die (apicoplast only important for blood-stage) ⇒ high antigen and biomass diversity to be recognized by immune system
- Early arresting genetically attenuated parasites and irradiated sporozoites: parasite arrested in hepatocyte and dies before it multiplies ⇒ low antigen and biomass diversity to be recognized by immune system
- Late arresting genetically attenuated parasites: schizont arrested ⇒ can’t leave it and die ⇒ high antigen and biomass diversity to be recognized by immune system
Subunit vaccines (+ example)
- Protect against sporozoites or blood stages
- can also block transmission taking place during sexual stages
- Main mediator of protection: antibodies
- example: RTS,S/AS01
Against which plasmodium stage would a malaria vaccination be best suited? Why?
Sporozoites (pre-liver): Still low number of sporozoites, then 30000 times more parasites
Which vaccination types are best suited for each Plasmodium stage? What structures have been targeted for the vaccines? What are the vaccines called?
- Pre-liver (RTS,S/AS01 ⇒ CSP ⇒ inhibition of sporozoite infection)
- (MSP1, pfAMA1-DiCO ⇒ AMA1 ⇒ inhibition of merozoite invasion) are best treated with AK or subunit vaccines (inducing AK production) (humoral immunity).
Liver (ME-TRAP ⇒ TRAP, CSP ⇒ killing infected hepatocytes): CD8+-T are induced Cellular immune response ⇒ with virus-like particles and/or live attenuated vaccines (protect against pre-erythrocytic stages) ⇒ Cellular immune response: activation of phagocytes, antigen-specific cytotoxic T lymphocytes and release of various cytokines in response to antigen.
Against gametes: Inhibition of sexual development (inhibits transmission): Pfs25 VLP: Pfs25 -> virus-like particles.
How does the mode-of-action of the attenuated parasite or RAS (radiation attenuated sporozoite) vaccination work?
travel through spleen ⇒ induce CD8+-T cells via Cd8+-DC antigen presentation ⇒ CD8+-T cells migrate to liver and detect infected hepatocytes via MHC-I-AG presentation ⇒ form IFN-y ⇒ increase in ROS and NO production (in infected and healthy cells)⇒ fewer EEFs.
What effect does azithromycin have on Plasmodium parasites?
- antibiotic which inhibits apicoplast DNA replication
- apicoplast is only vital for blood stage ⇒ liver stage develops, but die as they differentiate to merozoites
What are the obstacles on the way to a complete Sporozoite malaria vaccine? What are the benefits?
Obstacles:
- used sporozoites have to be purified, conserved, aseptic, metabolically active, non replicating, and completely attenuated
- Only intravenous vaccinations (and mosquito bites) trigger specific T-cell responses in the liver
Advantages:
- only sustainable and complete way to protect against P. falciparum
- potential to protect against cross strains and species
- all antigens expressed in right amount at right time
- Antibody and T cell reactions are induced
Against which plasmodium stages do the subunit vaccines protect?
- Sporozoite and blood stages
- CSP ⇒ RTS/S (now in Phase III - vs sporo)
- against TRAP (in Phase II - vs sporo)
- against AMA-1 (in Phase I - vs mero)
Are there any viral vector vaccines?
- Yes (but still in lab)
Example: TRAP vaccine = gene based vaccine: mixed vector immunization with recombinant adenovirus and modified vaccinia virus Ankara (MVA)
Against which antigen are few natural antibodies formed?
- vs alpha Rh5 ⇒ Reason unknown
- Rh5 is needed for the RBC invasion
What type of vaccine is used to produce vaccines that inhibit the development of the sexual stage? What does this do?
- Virus-like particles: Stop the transmission of the disease
Why is the plasmodium sporozoite stage relevant for the development of the vaccine? What is the problem with the production of the vaccine?
- attractive target ⇒ surface continuously covered with the highly immunogenic glycoprotein CSP
- Antibodies against CSP cause a stripping of the CSP coat and thus a loss of infectivity of the sporozoites.
- only few sporozoites after bite ⇒ thousands after proliferating in liver
Problem: migrate very fast (from bite to liver in ~ 15 min) ⇒ vaccine must act very quickly.
What is the molecular basis of the RTS,S/AS01 anti-malaria vaccine candidate?
- B- and T-cell epitopes of CSP introduced into hepatitis B viral particles
- chemical adjuvant (AS01) added to increase immune response
- induction of humoral and cellular immunity with high antibody titers prevent parasite from infecting the liver
⇒ CSP targeted during sporozoite invasion
BUT: only effective in infants (even then, only 65% effective in the first 3 years ⇒ 100% effectiveness imprtant!!!) ⇒ high antibody titers not enough
