Malaria Vaccine Candidates

7/31/2019 Malaria Vaccine Candidates

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WHY THERE IS NEED OF MALARIA VACCINE?

DUE TO DRUG-RESISTANT PARASITES

INSECTICIDE RESISTANT VECTORSRESULTING IN RESURGENCE OF

MALARIA

NEW MALARIA DRUGS LIKE CHEMICALDERIVATIVES OF ARTEMISIN ARE TOO

EXPENSIVE TO BE AFFORDABLE BYPOOR COUNTRIES AND STILL IN

LIMITED SUPPLY.


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Early malaria vaccine development effortsfocused on the parasite's pre-erythrocytic stage the period during which theorganism, in the form of a sporozoite ,enters a person's blood stream and headsfor the liver, where it matures and begins aprolific multiplication process.Breaking erythrocytic stage.Interrupting life cycle to effect maturationof parasite .
http://www.malariavaccine.org/malvac-glossary.phphttp://www.malariavaccine.org/malvac-glossary.phphttp://www.malariavaccine.org/malvac-glossary.phphttp://www.malariavaccine.org/malvac-glossary.phphttp://www.malariavaccine.org/malvac-glossary.phphttp://www.malariavaccine.org/malvac-glossary.phphttp://www.malariavaccine.org/malvac-lifecycle.php


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http://www.malariavaccine.org/malvac-lifecycle.php


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TYPES OF MALARIA VACCINES:

PRE-ERYTHROCYTIC VACCINES

ERYTHROCYTIC VACCINES

TRANSMISSION BLOCKING VACCINES


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More than 50% of the approximately 75 candidate vaccines in activedevelopment today, are based on just

three antigens that were cloned 20 years ago : the circumsporozoiteprotein (CSP), the merozoite surfaceprotein (MSP) and the apicalmembrane antigen 1 (AMA1) .


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Pre-erythrocytic vaccine candidates aim to protectagainst the early stage of malaria infection thestage at which the parasite enters or matures in aninfected person's liver cells. These vaccines wouldelicit an immune response that would either

prevent infection or attack the infected liver cell ifinfection does occur. These candidates include:Recombinant or genetically engineered proteins orantigens from the surface of the parasite or fromthe infected liver cell.DNA vaccines that contain the genetic informationfor producing the vaccine antigen in the vaccinerecipient.Live, attenuated vaccines that consist of aweakened form of the whole parasite (thesporozoite) as the vaccine's main component.


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CS-NANPCS102

RTS,S

ME-TRAP(THROMBOSPONDIN RELATED ADHESIVEPROTEIN)ICC-1132LSA-1(LIVER STAGE ANTIGEN)

LSA-6STARP(SPOROZOITE THREONINE AND ASPARAGINE RICHPROTEIN)

Pfs-16


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CS-NANP

Two different constructs containing theNANP epitope of theCS protein were used in the three trialsof CS-NANP vaccines.

Guiguemde 1990 used three syntheticNANP repeats conjugatedto tetanus toxoid; the control wastetanus toxoid


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There was no evidence foreffectiveness of CS-NANPvaccinesin the three trials. Thecombined risk ratio for

reduction of newinfections in the threetrials was 1.05 (95% CI 0.82to 1.35; 307participants,


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CS 102

REPRESENTS THE C-TERMINUS OF CSP(CIRCUMSPOROZOITE PROTEIN OF

PLASMODIUM FALCIPARUM)

THIS VACCINE UNDERWENTPHASE 1 AND PHASE 2a

CLINICAL TRIALS

THIS VACCINE HAS FAILED TO SHOW PROTECTIONAGAINST EXPERIMENTAL MALARIA CHALLENGE.

DRAWBACK


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ICC-1132

CSP-HBc PARTICLE VACCINE

WAS DEVELOPED BY APOVIA IN THEU.S.A.

NO EVIDENCE OF PROTECTION WASFOUND IN PHASE 2 STUDY AND THIS

APPROACH WAS DISCONTINUED.

DRAWBACK


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RTS,S

WAS DEVELOPED BY GLAXO SMITH KLINE (GSK) INCOLLABORATION WITH WALTER REED ARMY INSTITUTE OF

RESEARCH(WRAIR)

IT COMPRISES C-TERMINUS OF CSP FROMP.FALCIPARUM FUSEDTO HEPATITIS B SURFACE ANTIGEN AND EXPRESSED IN THE FORM

OF VIRUS LIKE PARTICLES(VLPs) INSaccharomyces cerevisiae.


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RTS,S IS DEVELOPED WITH ADJUVANT-AS02 WHICH IS AN

OIL-IN-WATER EMULSION PLUS

MPL(MONOPHOSPHORYL LIPID A) AND

QS21.


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RTS,S AS02 IS THE ONLY VACCINE THAT

HAS PASSED MAJOR PHASE TRIALS ANDENTERED PHASE 3 CLINICAL TRIAL INAFRICAN CHILDREN.


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Blood-stage vaccine candidates target the malariaparasite at its most destructive stage the rapidreplication of the organism in human red bloodcells.

Blood-stage vaccines do not aim to block allinfection. They are expected to decrease thenumber of parasites in the blood, and in so doing,reduce the severity of disease. Evidence suggeststhat people who have survived regular exposureto malaria develop natural immunity over time.The goal of a vaccine that contains antigens orproteins from the surface of the blood-stageparasite (the merozoite) would be to allow thebody to develop that natural immunity with muchless risk of getting ill .


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BLOOD STAGE VACCINECANDIDATES:

MSP-1MSP-2 AMA-1SERA GLURP (glutamate

rich protein)

Spf-66


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MSP 1=MEROZOITE SURFACE PROTEIN 1CONTAINS TWO CYSTEINE RICH

EPIDERMAL GROWTH FACTOR LIKEDOMAINS THAT GENERATE PROTECTIVEANTIBODIES AND ARE CONSERVED

ACROSS ALL SPECIES OFPLASMODIUM.

AMA 1=APICAL MEMBRANE ANTIGENBLOCK PARASITE INVASION OF RBCsin

vitro and is natural target of protective responses in vivo.


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A phase I AMA1 vaccine trial

in humans has commenced,and the vaccine is consideredsafe and sufficiently

immunogenic to be used in

field trials


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Transmission-blocking vaccine candidates seek tointerrupt the life cycle of the parasite by inducingantibodies that prevent the parasite from maturingin the mosquito after it takes a blood meal from avaccinated person.These vaccines would not prevent a person fromgetting malaria, nor would they lessen thesymptoms of disease.They would, however, limit the spread of infectionby preventing mosquitoes that fed on an infectedperson from spreading malaria to new hosts.A successful transmission-blocking vaccine would

be expected to reduce deaths and illness related tomalaria in at-risk communities .


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TRANSMISSION BLOCKING VACCINE CANDIDATES:

Pfs25 Pfs26

Pfs45 Pfs48

Pfs230Pvs25

Pvs28


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Pfs25 and 28 containsp.falciparum ookinete surface antigens and p.vivax homologues in

Pvs25 and 28.These are developed at the national institute of

health(NIH) in the U.S.A. as recombinant

yeast-secretedproteins( S.cerevisiae)


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INITIAL HUMAN PHASE 1 TRIALS THAT WERE

CONDUCTED FOR Pvs25DEMONSTRATED SAFETY AND A MODEST

IMMUNOGENICITY.


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An attempt to develop an attenuated sporozoitevaccine has been undertaken by Sanaria, Inc.,with the support from the Bill and Melinda GatesFoundation and the NIH.Finally, the glycosylphosphatidylinositol(GPI)anchor, which tethers several of the Plasmodiumantigens to the membrane, has been shown to behighly toxic in mouse models.An anti-toxic vaccine is currently beingdeveloped as a carbohydrate anti-GPI vaccine.An proof-of-principle study testing synthetic GPIas a vaccine in rodent models of malaria showedthat the candidate vaccine was immunogenic andprotected the animals from significant malariapathology and mortality.


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Adjuvants and malaria vaccine development

Adjuvants are substances that enhance immuneresponses to vaccines, promoting the induction of long-lasting humoral and cellular immunity. Theymodulate the immune system by up-regulating certaintypes of cytokines, preserving the conformationalintegrity of an antigen, delivering an immunogen toimmune effector cells and generating a depot of antigen. Substances that are used as adjuvants

include small solid particles, aluminium salts, water-in-oil emulsions, oil-in-water emulsions, immunestimulating complexes (ISCOM), liposomes, saponins,bacterial toxins and cytokines. The identification of effective adjuvants is very important for the

development of a successful malaria vaccine


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The ability of adjuvants to influenceimmune responses to blood stage malariavaccines has been demonstrated. Someadjuvants such as saponin and pertussisenhance protection in mice that areimmunized with whole P. yoelii vaccinesby inducing the production of IgG2a

Ab.Mice immunized with the samevaccines combined with adjuvants whichdo not augment IgG2a productionsuccumb to infection.Successfulimmunization of mice with MSP1 has

been shown to be dependent on both theadjuvant used and the genotype of theresponding host


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Mice that are vaccinated withMSP119 in various formulations showdifferent degrees of protectionagainst P. yoelii , which correlateswith the levels and isotypes of Abproduced.The formulations that areeffective in BALB/c mice cannotinduce protection in Swiss/Webstermice, suggesting that the finespecificity of the protectiveresponse is influence by both thehost MHC haplotype and by theadjuvant.


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As adjuvants can alter the quality of immune responses,selection of an appropriate formulation of antigens/adjuvant is a crucial step in malaria vaccinedesign. Further investigation is required to identify aneffective adjuvant for use in humans, which shouldstrongly enhance the protective immune response andhave an acceptably low level of side-effects .


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THANKS

Malaria Vaccine Candidates

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