Malaria Vaccine

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Why do we need a Vaccine?

Endemic in over 90 countries (~40% of the

worlds population)

More than 300 to 500 million individuals

worldwide are infected with Plasmodium spp

1.5 to 2.7 million people a year, most of whom

are children, die from the infection.

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Causative Agent
P. vivax, P.

falciparum, P. malariae and P. Ovale are the common species which infect humans most widespread), P. falciparum ~ 15%

P. vivax ~ 80% (the

5th species has also

been identified Plasmodium knowlesi

Plasmodium falciparum photomicrograph of a blood smear

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P. vivax and P. ovale have Hypnozoites a dormant stage

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Symptoms

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Drugs Used in the US

Most drugs used in treatment are active

against the parasite forms in the blood (the form that causes disease) and include:
Chloroquine Atovaquone-proguanil (Malarone) Artemether-lumefantrine (Coartem) Mefloquine (Lariam) Quinine Qinidine Doxycycline (used in combination with quinine)
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Clindamycin (used in combination with quinine)

Vaccine Approaches
Data in animal models support the concept of

developing a malaria vaccine that can improve on natural immunity by either

(1) Inducing more robust and potent immune

responses against a selected panel of antigens recognized as immuno dominant in the context of natural infection. large number of parasite antigens.

(2) Inducing a broader immune response against a

For (2) strategies include a renewed interest

in whole parasite vaccines which include

()irradiated sporozoite vaccine ()asexual blood-stage vaccine

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Recombinant Protein Subunit Vaccines

Parts of or complete antigens are identified

from a pathogens proteome, which can induce protective immunity to the whole pathogen on vaccination. immunogenicity

Problem - proteins vary greatly in their These are generally poor at induction of

effector T-cell responses, such as CD8+ cytotoxic T lymphocytes, that are necessary for elimination of intracellular pathogens such as liver-stagemalaria parasites
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Pre-erythrocytic vaccines
An ideal vaccine could be one that either

prevents invasion of the sporozites or blocks the formation of liver merozites. also block transmission.

Most ideal for Anti-Infection vaccine would Attenuated Plasmodium sporozites have been

shown to confer sterile protection against malaria.

large scale production en masse vaccination
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Limitations for using whole organism here

The lead candidate vaccine of this type is

RTS,Sa recombinant protein vaccine.

Hep B surface antigen DNA was fused to DNA

encoding a large part of the best characterised pre-erythrocytic malaria antigen, the circumsporozoite (CS) protein.

When expressed in yeast, the fusion product

(RTS) binds hepatitis B surface antigen (S) to form RTS,S particles.

These particles are mixed with an adjuvant,

AS02a mixture of deacylated monophosphoryl lipid A, QS21, and an emulsionand given intramuscularly on two 4/21/12 to three occasions.

ICC-1132 A hepatitis B core particle, genetically

engineered to include a region of CS for high titre antibody induction.

Presently in Phase I trials Heterologous Prime Boosting Vaccine 2 diff

vaccine vectors encoding same Ag given sequentially.

boosting

Viral vectors can be used for both priming and DNA vectors poor boosters.

Example Virosomal Vaccine PEV3A and FP9-

MVA ME-TRAP (MVA modified 4/21/12 vaccine virus

 Other CS-based candidate vaccines that have been

tested in phase-I studies include

A multiple antigen peptide A type of synthetic delivery system, which induced

strong antibody responses

A polyoxime construct, containing a universal Tcell

epitope
A long synthetic peptide in an oil-based adjuvant,

which induced detectable antibody and CD4+ and CD8+ T-cell responses with a good safety profile.

(Information a bit old 2004)

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Blood-stage vaccines
Two possible classes of blood-stage vaccine:

antiinvasion and anticomplication. symptoms.

Blood stage is the one which causes the main So it is believed that if BS vaccines work not

to a great extent even then they would greatly reduce morbidity and mortality.
PE and BS together could have a synergistic

role.
Target antigens
Merozite surface protein 1 (MSP 4/21/12 1)

Combination B - MSP 1, MSP 2 and Ring

infected erythrocyte surface antigen (RESA) and two on efficacy have been done.

Five clinical trials on safety (217 participants) No severe or systemic adverse effects

reported at 13-15 g of each antigen (39 45 g total) significantly reduced parasite density but only in children who hadnt been pre-treated with sulfadoxine pyrimethamine.

In the second efficacy trial Combination B

An anti-invasion vaccine based on MSP-1

known as falciparum malaria protein (FMP-1) 4/21/12 is being clinically assessed and has

Transmission Blocking Vaccines Sexual Stage being vaccinated but stop the Wouldnt Protect the person
spread.
Based on Ags on the surface of the sexual gamete and/or

in mosquito mid-gut stages (MTBV) of malarial parasite. mosquito blood meal. the mosquito.

Ab induced by vaccination would be ingested during Ab prevent fertilization or inhibit parasite development in Antigen examples Pfs 25 and Pvs 25 -In Phase I trial But systemic adverse events occurred in volunteers. Others in preclinical developments.

4/21/12 MTBV antigens trypsin, Carpoxy Peptidase B Anopheles

gambiae 1 (CPBAg1), Anopheles gambiae Amino Peptidase

Factors Hindering Development

Lack of understanding of the host mediators

of natural immunity

Lack of appropriate assays and surrogates for

vaccine safety and efficacy

A limited number of antigens being pursued

as vaccine candidates
A limited number of immune-enhancing

adjuvants

Limited vaccine delivery platforms available. Co-infection with other tropical infectious
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References
Malaria, L S Garcia, Clinics in Laboratory

Medicine, March 2010, Vol 30 (93-129) al, Jan 10 (2010), The Lancet, Vol 363

Malaria vaccine developments, V S Moorthy et Malaria Vaccine Design : Immunological

Considerations, M F Good et al, October 29 (2010), Immunity, Vol 33

Malaria vaccine: Latest updates and

challenges ahead, R Chattopadhyay et al, Indian Journal of Emperimental Biology, July 2009, Vol 47 (527-536)
http://www.clinicaltrials.gov
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