R.Sathish Kumar Altheanz ‘09© RSK

prevent the infection at the first instance and if this is not possible, should decrease the intensity of infection and should be successful in preventing malaria transmission.

Reduce the clinical disease severity Reduce the transmission

Due to Multiple drug resistance of the parasitic

species plasmodium due to a very high rate of replication

Insecticide resistant female anopheles mosquito.

Moreover the task of developing a preventative vaccine for malaria is a complex process.

Majority of research into malarial vaccine are focused on P.falciparum strain due to high mortality rate caused by them.

Stage of plasmodium

Antigens

Pre-erythrocytic Irradiated sporozoites , Circum Sporozoite Protein (CSP) or peptides, Liver stage Antigens -1 (LSA-1)

Merozoite and Erythrocytes

Erythrocyte Binding Antigen (EBA-175), Merozoite Surface Antigen 1&2 (MSA-1&2) ; Ring Infected Erythrocyte Surface Antigen (RESA); Serine Repeat Antigen (SERA); Rhoptry Associated Protein (RAP); Histidine Rich Protein (HRP); Apical Membrane Antigen-1 (AMA-1)

Gametocytes & gametes

Pfs 25, 48/45k, Pfs 230

Combined vaccine (cocktail)

SPf 66 (based on pre-erythrocytic and asexual blood stage proteins of Pf)

Source- WHO

The use of whole parasite either live or attenuated as a vaccine is not recommended because it is not feasible.

So subunit vaccines are preferred ,isolated and tested for Immunogenicity. The subunits may be

A. surface antigensB. parasitic proteinC. recombinant protein derived from the

parasite D. combined antigens

The first vaccine developed that has undergone field trials

Developed by Manuel Elkin Patarroyo in 1987. It presents a combination of antigens from the

sporozoite (using CS repeats) and merozoite parasites. During phase I trials a 75% efficacy rate was

demonstrated and the vaccine appeared to be well tolerated by subjects and immunogenic.

The phase IIb and III trials were less promising, with the efficacy falling to between 38.8% and 60.2%.

Despite the relatively long trial periods and the number of studies carried out, it is still not known how the SPf66 vaccine confers immunity; it therefore remains an unlikely solution to malaria

Based on the circumsporoziote protein, but additionally has the recombinant protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9).

It is the most dominant surface antigen of the initial pre-erythrocytic phase.

A complete lack of protective immunity was demonstrated in those inoculated at early stage.

LIMITATIONS Low efficacy , low immunogenicity.

Blocks transmission of the parasite from vertebrate host to mosquitoes.

Genes encoding seven Pf antigens derived from the sporozoite (CSP and sporozoite surface protein 2), Liver (liver stage antigen 1), blood (merozoite surface protein 1, serine repeat antigen, and

apical membrane antigen 1), sexual (25-kDa sexual-stage antigen)

inserted into a single NYVAC genome to generate NYVAC-Pf7. safe and well tolerated.o Specific antibody responses against four [out of 7] of the P.

falciparum antigens were characterized during 1a clinical trial.

Vaccine consists of - schizont export protein (5.1)

- 19 repeats of sporozoite surface protein (NANP)

Out of 194 children vaccinated in trials none developed symptomatic malaria.

LIMITATIONS

has low levels of immunogenicity Doesn’t contain any immuno dominant T-cell

epitopes.

Most recently developed recombinant DNA vaccine

The RTS,S attempted by fusing the protein CPS with a surface antigen from Hepatitis B, hence creating a more potent and immunogenic vaccine. When tested in trials an emulsion of oil in water and the added adjuvants of monophosphoryl A the vaccine gave 7 out of 8 volunteers challenged with P. falciparum protective immunity

Recent RTS,S Phase 2 trials (3 repeated doses administered in 6 months leading up to period of highest malarial transmission).

on Children ages 1-4 in Mozambique

reduced clinical malaria episodes by 35% with vaccine efficacy of approximately 71% during first two months falling to zero% in last 6 weeks

Efficacy = 41% source- AMANET

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Days after vaccination

Efficacy data for RTS,S one two and three doses

controlRTS,S

Increased rate of malarial transmission during final follow up period.

Decrease in prroduction given by the last vaccine booster.

Polymorphism and clonal variation in antigens of plasmodium

Parasite induced immuno-suppression Intracellular parasites

Difficulty of evaluation Parasites’ ingenious ways of avoiding

hosts’ immune response Complexity of conducting clinical and

field trials Mutation of the parasites Antigenic variations e.g. CSP has 6

variants Multiple antigens, specific to species

and stage

MVI is working with the International Centre for Genetic Engineering and Biotechnology (ICGEB) in New Delhi, India, to develop a vaccine against malaria.This development effort includes Bharat Biotech International Ltd. (Hyderabad), which will manufacture the vaccine for preclinical testing followed by initial safety trials in adults.