Lecture 21 - Malaria Vaccines Flashcards
What are the types of vaccine that are being developed?
3 types:
Pre-erythrocytic
Transmission blocking
Blood stage (Anti-merozoite)
Describe transmission blocking vaccines
Vaccinating people so that Abs are made
Abs are taken up by mosquitoes when taking a blood meal
Mosquitoes are immune to infection
Describe pre-erythrocytic vaccines
RTS.S, in phase 3
Recombinant protein that blocks the process of sporozoites entering the liver
Could make the market
In 14,000 children around Africa
Works a bit, but is not amazing
Describe the RTS,S vaccine phase III trial
- Overall vaccine efficacy, clinical malaria 26% for 3 doses and 39% for 4 doses, declines rapidly and lower in the younger age groups
- Booster essential for efficacy against severe malaria but poorly boosted antibodies
Describe briefly Blood stage vaccines
Blood stage vaccines are a type of vaccine that target the blood stage of the malaria parasite Plasmodium falciparum. During the blood stage, the parasite infects and replicates within red blood cells, causing symptoms such as fever, chills, and anemia.
Blood stage vaccines work by stimulating the immune system to recognize and attack the parasite during the blood stage of the infection. These vaccines typically contain proteins or other components of the parasite that are expressed on the surface of infected red blood cells, which can be recognized by antibodies or T cells.
What do different Plasmodium species prefer?
different RBCs
e.g. P. vivax only likes young RBS, reticulocytes
older RBCs has different surface molecules
P. falciparum recognises all RBCs
How do merozoites invade red blood cells?
First, the merozoite attaches to the red blood cell surface through specialized proteins called ligands. One of the most important of these ligands is called the erythrocyte-binding antigen (EBA), which binds to a receptor on the surface of the red blood cell called glycophorin A.
Once the merozoite is attached to the red blood cell, it reorients itself and begins to actively push its way into the cell. This process is facilitated by a group of proteins known as the apical complex, which includes actin-myosin motor proteins that generate force to drive the merozoite through the red blood cell membrane.
As the merozoite penetrates the red blood cell, it forms a tight junction called the parasitophorous vacuole, which surrounds the parasite and separates it from the host cell cytoplasm. The parasite then begins to take up nutrients from the host cell, replicate, and develop into new merozoites, which are released into the bloodstream to invade additional red blood cells and continue the cycle of infection.
Can knowledge of parasite cell invasion at a molecular level inform a blood-stage malaria vaccine?
- It informs which parasite can infect a specific red blood cell
- P. Falciparum merozoite secrete ligands that bind to red blood cells allowing for the merozoite to invade the cell
- Tight junctions move around the surface until the parasite is fully invaded the RBC, energy dependent mechanism led by a motor
Why is it important that the RBC surface is highly polymorphic?
Different RBCs between different people
different surface molecules at different stages of cell life
Duffy glycoprotein - anyone who is endemic to west africa does not express this protein while most of the rest of the world does
Duffy is essential for P. vivax to invade the cell
so west africa does not have P. vivax at all
instead of just one or two secondary ligands responsible for binding RBCs now have at least 8 proteins in P. falciparum - 4 erythrocyte binding antigens and 4 reticulocyte binding homologue proteins
P. vivax has only one - binds duffy
P. falciparum has alternate ways of entering the RBC
multiple red cell receptors and invasion ligands
causes a problem for vaccine developmont
What are some difficulties in making a blood-stage vaccine?
- The speed of invasion is rapid – barrier
- Pre-invasion step: merozoite starts rolling around and testing/deforming the RBC
What does merozoite invasion involve and the corresponding vaccine targets?
Merozoite invasion involves + vaccine targets
* Secondary interactions
o Microneme/RON adhesins
* Actin-myosin motor
o Motor components/actin regulation machinery
* Ca2+ response
o Calcium sensors
* Ca2+ release
o Novel IP3/cADPR channels
* Signal
o TM proteins, kinases
* Primary contact
o GPI-anchored proteins and partners
* Merozoite egress
o PV proteases
* Recovery from echinocytosis
o Ion pumps
* Re-sealing
o Dynamin
* Secondary ligand shedding
o Rhomboids
* Surface protein shedding
o Sheddase
What can alter receptor-ligand usage?
e.g. the W2mef strain
uses EBA175 to bind to sialic acid on GlyA
if you grow them with NA-treated erythrocytes they can’t invade in the first cycle but will eventually switch entry pathway –> same strain but different entry mechanism
same invasion rates in normal RBCs, different in treated RBCs indicating that they have different invasion mechanisms
What happens if you delete the ligand (EBA175) used by W2mef?
EBA175 (erythrocyte-binding antigen 175) is a ligand used by the malaria parasite Plasmodium falciparum to invade red blood cells. The ligand binds to a receptor on the red blood cell surface, which allows the parasite to enter the cell and replicate.
If EBA175 is deleted or mutated, the parasite’s ability to invade red blood cells may be impaired or abolished. This has been shown in experimental studies using genetically modified parasites that lack EBA175. For example, one study found that a P. falciparum strain lacking EBA175 was unable to invade red blood cells in vitro.
However, the impact of deleting EBA175 in vivo may be more complex, as the parasite has alternate invasion pathways allow parasites to invade via a diverse range of RBC receptors and to avoid immunity
What are alternate invasion pathways for the malaria parasite?
Rh proteins: The Rh (Rhesus) protein family is a group of proteins expressed on the surface of red blood cells. Some members of this family, such as Rh1 and Rh2b, are also expressed on the surface of the malaria parasite and can mediate invasion.
Other erythrocyte-binding antigens (EBAs): In addition to EBA175, P. falciparum expresses other EBAs, such as EBA140 and EBA181, which can also mediate invasion of red blood cells.
PfRh proteins: PfRh (Plasmodium falciparum Reticulocyte-binding Homolog). Some members of this family, such as PfRh1 and PfRh4, can bind to specific receptors on the surface of red blood cells and mediate invasion.
Other proteins: Such as the MSP (Merozoite Surface Protein) family and the AMA1 (Apical Membrane Antigen 1) protein.
What are two broad approaches to blood stage vaccines?
- The obligatory steps
- The alternate ligands
Selective pressure can alter receptor-ligand usage: e.g., the W2mef strain (which uses EBA175 to bind sialic acid on GlyA)
