Development of Malarial Vaccines

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Malaria is an arthropod-borne blood infection transmitted by the female anopheline mosquito and caused by protozoan parasites of the Plasmodium genus. Four species of Plasmodium are infectious to humans; P.falciparum, P.vivax, P.malariae and P.ovale. P.falciparum is the most prevalent organism and frequently causes severe and fatal infections amidst the young, the pregnant and the immune-compromised and accounts for at least 5% of the 750 million cases occurring each year in Tropical Africa. Although the mortality rate of P.vivax is much lower than that of P.falciparum it causes an extremely incapacitating disease and represents the prevalent form of recurring malaria. P.vivax alongside P.falciparum accounts for almost all of the 100 million cases which arise each year out with Africa.

Since the latter part of the 0th Century it has been a goal of the WHO alongside many pharmaceutical companies and charities to develop vaccines against these two species of malaria. However, due to the complexity of the life cycle and the continuously changing morphology and antigen expression of the parasite, the development of a globally effective and long lasting vaccine has become somewhat of a challenge. Currently there are three stages of development against which vaccines are being developed.

The first of these stages is the pre-erythrocytic phase where vaccines are produced against the parasite from the sporozoite infected mosquito as they enter the liver. The aims of these vaccines are to stop sporozoites entering liver cells i.e. hepatocytes and developing into schizonts thus preventing further transmission of the parasite to the mosquito and clinical expression of the disease.

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Antibodies which have been immunised with irradiated sporozoites recognise a protein known as the circumsporozoite (CS) protein that is expressed on the liver sporozoites surface and cause a precipitation reaction (CSP) which stops invasion of hepatocytes.

Several P.falciparum vaccine candidates' antigens have been identified and studied by using cells and sera from individuals immunised with irradiated sporozoites. The number of these antigens is increasing e.g. CS, LSA1//, SSP/TRAP, SALSA etc for P.falciparum but in the case of P.vivax only the CS and SSP/TRAP proteins are targets.

Passive transfer of CS-specific T cells from immunised mice to animals susceptible to the disease confers protection from the parasitic challenge. A monoclonal antibody (mAb) specific to the AGDR sequence of the P.vivax CS protein protects sporozoite challenges in Samini monkeys. Moreover immunisation of human volunteers using a recombinant protein containing the carboxyl flank of P.falciparum CS protein protects human volunteers against sporozoites.

long peptides, one containing the CS B cell, Th and CD8 T cell epitopes recognised by humans, the second a synthetic polypeptide corresponding to the N- and C-terminal domains of CS produced and safety tested on Aotus monkeys and the third called peptide R consists of a dimer of peptide p11 from the central domain of CS and ppt0 which is a tetanus toxin derived epitope have been produced. These three long peptides induced vigorous Ab responses in monkeys and a phase I clinical vaccine trial is currently being conducted in naïve humans.

SSP/TRAP proteins participate in sporozoite motility and invasion and Abs directed against them prevent sporozoites binding to the hepatocyte membrane therefore preventing invasion in P.falciparum. Specific anti-TRAP Abs and CD8 T cells can also contribute to malarial protection. The P.vivax SSP gene has recently been used to construct a nucleic acid vaccine which induces high levels of specific Abs in mice.

An example of a vaccine against antigens at this stage of infection is the C.S.P vaccine which induces anti-sporozoite antibody and was found to be protective in Kenyan trials.

The second stage to which vaccines can be produced is the asexual blood stage which begins when the infected hepatocytes burst and release merozoites that enter the circulation and quickly invade red blood cells. Then after - days the parasite develops into a mature schizont which ruptures the erythrocyte releasing more merozoite thus continuing the cycle. The goal of a blood stage vaccine is to halt undue parasitic expansion thus containing the disease.

There are several antigens that are specific for this stage of development. One of these is a polymorphic protein profusely expressed on the surface of merozoites, called merozoite surface protein, MSP-1. An internal processing mechanism of this protein results in production of small fragments such as MSP-1/1 which participates in erythrocytic invasion and MSP-1/4 which is derived from the carboxyl end of the protein. Vaccine trials using monkey models with recombinant products of these two protein fragments have offered diverse protective efficacy.

Merozoites have also been found to rely on the Duffy blood group in order to invade erythrocytes. It has been discovered that individuals who don't possess this blood group are protected by infection from P.vivax. The parasite ligand for this receptor is the Duffy Binding Protein (DBP) and is currently being tested as a vaccine candidate. Initial experiments in rabbits and mice show high immunogenicity relating to a DNA vaccine, a recombinant protein and synthetic peptides corresponding to the DBP ligand domain.

The Apical membrane protein (AMA-1) is a 66-8kDa protein found on the surface of merozoites. AMA-1 provides a protective capacity in rhesus monkeys when challenged with the P.knowlesi parasite and is currently being examined as a contender for a malarial vaccine.

Patarroyo and colleagues designed a synthetic peptide vaccine called SPF66, which contained sequences from MSP-1 and two other blood-stage antigens along with tetra peptide repeats for the CS protein. The efficacy of the vaccine was worked out to be 75% after Phase I experimental challenges however after several Phase II and III trials the efficacy against P.falciparum ranged between 8.% and 60.%. Formal testing of the vaccine in Phase III trials also showed varying results dependant on age and location. Studies in Columbian adults and children and Tanzanian children showed the vaccine prevented approximately % of the clinical episodes expected however no significant protection was seen in Gambian infants or Thai children. Presently development of a second generation subunit SPf66 vaccine is being undertaken in order to increase efficacy and to confer global protection.

The third stage to which malarial vaccines are being developed is the sexual stage. The aim here is to prevent transmission of malaria in humans and mosquitoes and thus vaccines produced against this stage are called transmission blocking vaccines, TBVs. The main target antigens are surface proteins of the extra-cellular male and female gamete, zygote and ookinete stages of the parasite which fall into two distinct classes.

The first class includes two major surface proteins found on the gametes. These molecules, Pfs48/45 and Pfs0 are thought to be ligands in the fertilisation process and monoclonal antibodies against them can block infectivity of the parasites to the mosquito. However problems due to the small size of these molecules and in discovering the exact location of their epitopes have halted advancement of developing a TBV against them.

In the second class two possible targets are the Ps5 and Ps8 groups of molecules expressed on the surface of zygotes and mature ookinetes. Pfs5 and Pv5 i.e. the Ps5 form of P.falciparum and P.vivax respectively, have been expressed on immunogenic form in yeast and used to generate immune sera in mice which has strong transmission blocking activity against gametocytes of the corresponding species.

A modified version of Pfs5 has been tested in Phase I trials in humans for safety and immunogenicity and has caused a 50% reduction in infectivity of P.falciparum to mosquitoes compared to controls while only causing a mild localised reaction at the injection site.

The NYVAC-Pf. 7 vaccine blocks transmission of the parasite from the vertebrate host to the mosquito and incorporates seven of the antigens already mentioned. Trials with rhesus monkeys show the vaccine to be safe and well tolerated and at presented human trials are underway.

Recently a new approach to vaccination against malaria is . This vaccine is based on glycosylphosphatidylinositol (GPI) a glycolypid which has the characteristics of a toxin produced by malarial parasites. Vaccinating mice with synthetic GPI induces protection from acidosis, pulmonary oedema and fatality. If immunogenic in humans, GPI could perpetuate the development of an antitoxin vaccine for malaria. Vaccinating with GPI at an early stage in children could provide them with "sufficient clinical protection to withstand their first few malarial infections, while at the same time, developing acquired immunity for life-long protection" ( Bradbury 00 ).

Thus due to detailed work being employed in the field of genomics and by being able to determine the epitopes present on the antigens present of the parasites surface at different stages of its life cycle more and more possible targets for an anti-malarial vaccine are developing.

There are as mentioned already several quite different vaccines currently undergoing clinical trials as well as a second generation of SPf66 vaccine being developed the possibility of discovering a global high efficacy vaccine for malaria is growing ever nearer.

Indeed the goal of the Medicines for Malaria Venture, a non-profit foundation based in Geneva, in to bring a new anti-malarial drug onto the market every five years with the first new drug in production by 010.

The Lancet

Volume 60, Issue , 17 August 00, Page 551

Jane Bradbury Antitoxin vaccine could provide new way to fight malaria.

Molecular Immunology

Volume 8, Issue 6, December 001, Pages 44-455

Plasmodium vivax malaria vaccine development.

Vaccine

Volume 1, Issues 17-1 March 001, Pages 0-14

Transmission blocking malarial vaccines.

The Lancet

Volume 50, Issue 0, 17, Pages 166-1701

Development of a malarial vaccine.

New England Journal of Medicine 17, 6, No.

Current opinion in Immunology

15,7 Pages 607-611

Malaria vaccines

Malarial vaccine- www.malariasite.com/malaria/malaria_vaccine.html

The Harvard Malarial Iniative- www.hsph.harvard.edu/press/releases/press417001.html

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