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 Gamet Fertilization In mid-gut Oocysts In mid-gut Sporozoites In salivary glands Sporozoites In tissue Merozoite

Blocking the parasites Sporozoites Liver stage RBC stage Tropozoite Merozoite Schizon Gamet Fertilization In mid-gut Oocysts In mid-gut Sporozoites In salivary glands Sporozoites In tissue Merozoite Adult Larva Eggs DRUGS AND VACCINATION IN 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 Fertilization In mid-gut Oocysts In 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 cycle that could be a vaccine target Mosquito bite Sporozoite injected Mosquito bite Gametocytes transmitted Oocyst developed Mosquito bite Sporozoite injected Erythrocyte stages in human blood Sporozoite in Salivary gland and other tissue of mosquitoes Minimum Level of Ab needed to inactivate parasites during erythrocytic cycles Reserve concentration when the Ab target the weakest points of parasite’s population, Conventional vaccine’s target Alternative vaccine’s target in mosquitoes Alternative vaccine’s target in human Different parasite’s concentration =

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 cycle that could be a vaccine target Mosquito bite Sporozoite injected Mosquito bite Gametocytes transmitted Oocyst developed Mosquito bite Sporozoite injected Erythrocyte stages in human blood Sporozoite in Salivary gland and other tissue of mosquitoes Minimum Level of Ab needed to inactivate parasites during erythrocytic cycles Reserve concentration when the Ab target the weakest points of parasite’s population, Different parasite’s concentration = 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 analysis Cell-based assay Animal experiment Clinical trial

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