WHY THERE IS NEED OF MALARIA VACCINE?

DUE TO DRUG-RESISTANT PARASITES INSECTICIDE RESISTANT VECTORS RESULTING IN RESURGENCE OF MALARIA NEW MALARIA DRUGS LIKE CHEMICAL DERIVATIVES OF ARTEMISIN ARE TOO EXPENSIVE TO BE AFFORDABLE BY POOR COUNTRIES AND STILL IN LIMITED SUPPLY.

Early malaria vaccine development efforts focused on the parasite's pre-erythrocytic stagethe period during which the organism, in the form of a sporozoite, enters a person's blood stream and heads for the liver, where it matures and begins a prolific multiplication process. Breaking erythrocytic stage. Interrupting life cycle to effect maturation of parasite.

TYPES OF MALARIA VACCINES:

PRE-ERYTHROCYTIC VACCINES

ERYTHROCYTIC VACCINES

TRANSMISSION BLOCKING VACCINES

More than 50% of the approximately 75 candidate vaccines in active development today, are based on just three antigens that were cloned 20 years ago : the circumsporozoite protein (CSP), the merozoite surface protein (MSP) and the apical membrane antigen 1 (AMA1) .

Pre-erythrocytic vaccine candidates aim to protect against the early stage of malaria infectionthe stage at which the parasite enters or matures in an infected person's liver cells. These vaccines would elicit an immune response that would either prevent infection or attack the infected liver cell if infection does occur. These candidates include: Recombinant or genetically engineered proteins or antigens from the surface of the parasite or from the infected liver cell. DNA vaccines that contain the genetic information for producing the vaccine antigen in the vaccine recipient. Live, attenuated vaccines that consist of a weakened form of the whole parasite (the sporozoite) as the vaccine's main component.

CS-NANP CS102 RTS,S ME-TRAP(THROMBOSPONDIN RELATED ADHESIVE PROTEIN) ICC-1132 LSA-1(LIVER STAGE ANTIGEN) LSA-6 STARP(SPOROZOITE THREONINE AND ASPARAGINE RICH

PROTEIN)

Pfs-16

CS-NANP

Two different constructs containing the NANP epitope of the CS protein were used in the three trials of CS-NANP vaccines. Guiguemde 1990 used three synthetic NANP repeats conjugated to tetanus toxoid; the control was tetanus toxoid

There was no evidence for effectiveness of CS-NANP vaccines in the three trials. The combined risk ratio for reduction of new infections in the three trials was 1.05 (95% CI 0.82 to 1.35; 307 participants,

CS 102
REPRESENTS THE C-TERMINUS OF CSP (CIRCUMSPOROZOITE PROTEIN OF PLASMODIUM FALCIPARUM)

THIS VACCINE UNDERWENT PHASE 1 AND PHASE 2a CLINICAL TRIALS

DRAWBACK

THIS VACCINE HAS FAILED TO SHOW PROTECTION AGAINST EXPERIMENTAL MALARIA CHALLENGE.

ICC-1132
CSP-HBc PARTICLE VACCINE

WAS DEVELOPED BY APOVIA IN THE U.S.A.

DRAWBACK

NO EVIDENCE OF PROTECTION WAS FOUND IN PHASE 2 STUDY AND THIS APPROACH WAS DISCONTINUED.

RTS,S

WAS DEVELOPED BY GLAXO SMITH KLINE (GSK) IN COLLABORATION WITH WALTER REED ARMY INSTITUTE OF RESEARCH(WRAIR)

IT COMPRISES C-TERMINUS OF CSP FROM P.FALCIPARUM FUSED TO HEPATITIS B SURFACE ANTIGEN AND EXPRESSED IN THE FORM OF VIRUS LIKE PARTICLES(VLPs) IN Saccharomyces cerevisiae.

RTS,S IS DEVELOPED WITH ADJUVANTAS02 WHICH IS AN OIL-IN-WATER EMULSION PLUS MPL(MONOPHOSPHO RYL LIPID A) AND QS21.

RTS,S AS02 IS THE ONLY VACCINE THAT HAS PASSED MAJOR PHASE TRIALS AND ENTERED PHASE 3 CLINICAL TRIAL IN AFRICAN CHILDREN.

Blood-stage vaccine candidates target the malaria parasite at its most destructive stagethe rapid replication of the organism in human red blood cells. Blood-stage vaccines do not aim to block all infection. They are expected to decrease the number of parasites in the blood, and in so doing, reduce the severity of disease. Evidence suggests that people who have survived regular exposure to malaria develop natural immunity over time. The goal of a vaccine that contains antigens or proteins from the surface of the blood-stage parasite (the merozoite) would be to allow the body to develop that natural immunity with much less risk of getting ill.

BLOOD STAGE VACCINE CANDIDATES: MSP-1 MSP-2 AMA-1 SERA GLURP(glutamate

rich protein)

Spf-66

SPF-66
WAS DEVELOPED IN COLUMBIA AS A SYNTHETIC,MULTIEPITOPT,MULTI-STAGE PEPTIDE VACCINE MIXED WITH ALUM AS AN ADJUVANT. DRAWBACK

IT WAS TESTED IN SEVERAL PHASE 6 FIELD TRIALS INVOLVING THOUSANDS OF VOLUNTEERS, BUT ITS REPOTED EFFICACY WAS TOO LOW TO WARRANT FURTHER DEVELOPMENT, ALTHOUGH ONE MAY SUSPECT THAT THE VACCINE WOULD HAVE FARED BETTER WITH MORE POTENT ADJUVANTS.

MSP 1=MEROZOITE SURFACE PROTEIN 1 CONTAINS TWO CYSTEINE RICH EPIDERMAL GROWTH FACTOR LIKE DOMAINS THAT GENERATE PROTECTIVE ANTIBODIES AND ARE CONSERVED ACROSS ALL SPECIES OF PLASMODIUM.

AMA 1=APICAL MEMBRANE ANTIGEN BLOCK PARASITE INVASION OF RBCs in vitro and is natural target of protective responses in vivo.

A phase I AMA1 vaccine trial in humans has commenced, and the vaccine is considered safe and sufficiently immunogenic to be used in field trials

Transmission-blocking vaccine candidates seek to interrupt the life cycle of the parasite by inducing antibodies that prevent the parasite from maturing in the mosquito after it takes a blood meal from a vaccinated person. These vaccines would not prevent a person from getting malaria, nor would they lessen the symptoms of disease. They would, however, limit the spread of infection by preventing mosquitoes that fed on an infected person from spreading malaria to new hosts. A successful transmission-blocking vaccine would be expected to reduce deaths and illness related to malaria in at-risk communities.

TRANSMISSION BLOCKING VACCINE CANDIDATES:

Pfs25

Pfs26

Pfs45

Pfs48

Pfs230 Pvs25 Pvs28

Pfs25 and 28 contains

p.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-secreted proteins(S.cerevisiae)

INITIAL HUMAN PHASE 1 TRIALS THAT WERE CONDUCTED FOR Pvs25 DEMONSTRATED SAFETY AND A MODEST IMMUNOGENICITY.

An attempt to develop an attenuated sporozoite vaccine has been undertaken by Sanaria, Inc., with the support from the Bill and Melinda Gates Foundation and the NIH. Finally, the glycosylphosphatidylinositol(GPI) anchor, which tethers several of the Plasmodium antigens to the membrane, has been shown to be highly toxic in mouse models. An anti-toxic vaccine is currently being developed as a carbohydrate anti-GPI vaccine. An proof-of-principle study testing synthetic GPI as a vaccine in rodent models of malaria showed that the candidate vaccine was immunogenic and protected the animals from significant malaria pathology and mortality.

Adjuvants and malaria vaccine development

Adjuvants are substances that enhance immune responses to vaccines, promoting the induction of long-lasting humoral and cellular immunity. They modulate the immune system by up-regulating certain types of cytokines, preserving the conformational integrity of an antigen, delivering an immunogen to immune effector cells and generating a depot of antigen. Substances that are used as adjuvants include small solid particles, aluminium salts, waterin-oil emulsions, oil-in-water emulsions, immune stimulating complexes (ISCOM), liposomes, saponins, bacterial toxins and cytokines. The identification of effective adjuvants is very important for the development of a successful malaria vaccine

The ability of adjuvants to influence immune responses to blood stage malaria vaccines has been demonstrated. Some adjuvants such as saponin and pertussis enhance protection in mice that are immunized with whole P. yoelii vaccines by inducing the production of IgG2a Ab.Mice immunized with the same vaccines combined with adjuvants which do not augment IgG2a production succumb to infection.Successful immunization of mice with MSP1 has been shown to be dependent on both the adjuvant used and the genotype of the responding host

Mice that are vaccinated with MSP119 in various formulations show different degrees of protection against P. yoelii, which correlates with the levels and isotypes of Ab produced.The formulations that are effective in BALB/c mice cannot induce protection in Swiss/Webster mice, suggesting that the fine specificity of the protective response is influence by both the host MHC haplotype and by the adjuvant.

As adjuvants can alter the quality of immune responses, selection of an appropriate formulation of antigens/adjuvant is a crucial step in malaria vaccine design. Further investigation is required to identify an effective adjuvant for use in humans, which should strongly enhance the protective immune response and have an acceptably low level of side-effects.

THANKS