Draft proposal and concept for malarial

vaccine.

Basic concept for vaccines

• Reachable target Ag• Inhibition of targets can block the life cycle of parasites• The target has high immunogenic capability to stimulate immune

responses• High ratio of Ab : target Ag • Enough titer to inactivate the target• Target parasite stage at the lowest density

• Could be maintained at high effective titer for protection

REACHABLE TARGETS

Reachable target: Surface Ag

• Available in body fluid• Not in erithrocytes• Position at the

surface of parasites

Antibody bind to the surface protein of a sporozoite

BLOCKING THE LIFE CYCLE

Life cycle of Plasmodium parasites

Sporozoites

Liver stage

RBC stage

Tropozoite

Merozoite Schizon

GametFertilizationIn mid-gut

OocystsIn mid-gut

Sporozoites In salivary glands

SporozoitesIn tissue

Merozoite

Blocking the parasites

Sporozoites

Liver stage

RBC stage

Tropozoite

Merozoite Schizon

GametFertilizationIn mid-gut

OocystsIn mid-gut

Sporozoites In salivary

glands

SporozoitesIn tissue

Merozoite

Adult

Larva Eggs

DRUGS AND VACCINATIONIN HUMAN

BLOCKING ENTERIC STAGE IN MOSQUITO

VECTOR CONTROL

Study plans?

• Adult mosquito target: Transmission-blocking Ab for the enteric stage of parasites:

• Ab againts gametocyites and oocyst ready in infected blood, • Ab against mosquito intestinal cell’s surface protein.

• Larval mosquito target: the IgY antibodies from chicken egg yolk targeting larval enteric cell or larval nature enteric bacteria

• Human target: Optimize sporozoite-based vaccine with regular booster to get high ratio of Ab: Ag target

Blocking the parasites

Sporozoites

Liver stage

RBC stage

Gamet FertilizationIn mid-gut

OocystsIn mid-gut

Sporozoites In salivary

glands Adult

Larva Eggs

Surface sporozoite Ag-based vaccine with regular

booster

Ab to gametocytes or oocyst ready in patient

blood

Chicken Egg Yolk IgY as a larvacide

IMMUNOGENIC ANTIGENS

What factor influence the immunogenic nature of an antigen?

• Substance contents of the Ag: LPS, protein, Nucleic acid?• 3D Structures of the Ag?• Adjuvant?

HIGH RATIO OF AB : TARGET AG

Dynamic of parasites in the life cyclethat could be a vaccine target

Mosquito biteSporozoite

injected

Mosquito biteGametocytes transmitted

Oocyst developed

Mosquito biteSporozoite

injected

Erythrocyte stages in human

blood

Sporozoite in Salivary gland and

other tissue of mosquitoes

Minimum Level of Ab needed to inactivate 1012 parasites during erythrocytic cycles

Reserve concentration when the Ab target the weakest points of parasite’s population, 100 - 103

Conventional vaccine’s target

Alternative vaccine’s target in mosquitoes

Alternative vaccine’s target

in human

Alternative vaccine’s target

in human

Different parasite’s concentration =1012 - 103

MAINTAIN THE HIGH TITER AB IN BLOOD

Prevalence Ab terhadap surface Ag sporozoit menurut kelompok umur pada daerah low transmission area dan high transmission area. Titer yang tinggi pada semua kelompok umur hanya pada daerah high transmission area menunjukkan perlunya booster regular vaksin sporozoit yang diaplikasikan untuk menjamin tingkat proteksi.

REGULAR VACCINATION BOOSTER

MAY MIMIC THE HIGH TRANSMISSION AREA EFFECTS TO BLOOD TITER OF THE ANTIBODY

AGAINST THE ANTIGEN

Dynamic of parasites in the life cyclethat could be a vaccine target

Mosquito biteSporozoite

injected

Mosquito biteGametocytes transmitted

Oocyst developed

Mosquito biteSporozoite

injected

Erythrocyte stages in human

blood

Sporozoite in Salivary gland and

other tissue of mosquitoes

Minimum Level of Ab needed to inactivate 1012 parasites during erythrocytic cycles

Reserve concentration when the Ab target the weakest points of parasite’s population, 100 - 103

Different parasite’s concentration =1012 - 103

High ratio of Ab:Ag target can be maintained with regular vaccination

booster (e.g. every 6 months)

WHAT IS THE STRATEGY

• Adult peoples in high transmission area usually have enough protective immunity to malaria parasites and show less clinical symptoms. No need for vaccines?• Neonatus and children in high transmission area my have more risk to get

severe malaria since they have only have low titer of Ab, hence need to get early vaccination with regular booster• Peoples in low transmission area may need early vaccination with regular

booster too• Susceptible peoples that visit in to an endemic area may need:

• Vaccination 3 month prior to long visit (e.g. 1-2 year)• Get vaccination booster every 6 month during in the area• If plan to have regular visit, same regular booster needed

TESTING THE VACCINE CANDIDATE

Molecular design and analysisCell-based assay

Animal experimentClinical trial

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