Four Species of Plasmodium Can Cause the Disease in Humans Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium

dium malariae. P. falciparum is the most prevalent and pathogenic, leading to more than 2 million deaths per year. Mosquito Vectors and the Plasmodium Life Cycle 5 The parasite's primary (Definitive) hosts and transmission vectors are female mosquitoes of the Anopheles genus.

INTRODUCTION Malaria is a global disease, caused by a protozoan parasite of the genus Plasmodium. Even today more than 3 billion people are at risk of Plasmodium falciparum disease. More than 500 million cases occur per year with 1 2 million deaths each year mainly in young children and pregnant women 90% in subSaharan Africa 1, 2. In addition 7080 million cases of relapsing Plasmodium vivax malaria occur per year adding to the morbidity even if not to the mortality 3, 4.

Abstracts: Malaria has remained a major public health concern in the developing world, caused by a protozoan parasite of the genus Plasmodium. More than 600 million people are infected annually resulting in more than three million deaths, mostly children in Africa. Increased resistance to malaria drugs has made the situation worse and control of the disease will require rapid development of new control methods, so development of vaccines against malaria is one of the most effective modes of treatment available. An effective vaccine against malaria that would protect non-immune individuals from the disease has long been a dream.

Malaria Vaccine Development: A Challenge Facing Pathway for Eradication of Malaria

Rajeev Sharma 1*, Balak D Kurmi1, Alok Pal Jain1

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Key Words: Malaria, Plasmodium, Vaccine, Antigen.

Clinical Aspects of Severe Malaria Severe malaria defines infection with manifestations and complications that are potentially fatal in man causing 15 to 20% mortality in spite of effective drugs and correct medical aid. Annually, 5 to 10 million infected individuals develop complications during infection, manifested as coma (cerebral malaria), metabolic acidosis, hypoglycemia, severe anemia, renal failure and lung edema, with frequency varying according to the level of malaria transmission in the area6. Antigen Vaccines contain antigen that serve as target for the immune system. Different antigenic targets on the parasite are expressed at different stages of its life cycle, and genetic diversity between parasite strains makes some antigens immunologically distinct. The
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SOME ANTIGEN EXPRESSED BY PLASMODIUM IN ITS LIFE CYCLE WITH THERE IMMUNE RESPONSE 6, 7 Pre-Erythrocytic Stage Circumsporozoite protein (CS or CSP, Main sporozite coat protein), Promotes strong B-cell immune response Abs that block sporozites in culture. Induce CD8+ and CD4+ CTL response in mice 8. Sporozite surface protein2 (SSP2, Found on sporozites of P. yeoli), Mice immunized with CS and SSP2 expressing cells were protected by CD8+ CTLs. Liver stage-specific antigen 1 (LSA-1, Found in Infected liver cells.), 17 A. A. repeat causes CTL (Cytotoxic-TLymphocytes). Immune responses in Africans that gave protection to serve malaria. Glycoproteins (Released by the destruction of infected hepatocyte), Induce the release of TNF (Tumor necrosis factor) which may cause malaria related illness.

parasites have also adapted to the human immune system and learned to hinder it. These factors complicate the process of determining which antigens to use in vaccine formulations.

Transmission Blocking 9 Pfs25 (found on Surface of P. Falciparum zygotes and ookinetes), Can block, development stages and sporozoite development.

Erythrocytic membrane proteins1 (PfEMP1, Infected erythrocytes), Involved in sequestration of infected erythrocyte. Sequestin (erythrocytes), recognition protein expressed by vascular epithelium.

Vaccine A vaccine is any preparation intended to produce immunity to a disease by stimulating the production of antibodies. Vaccines include, for example, suspensions of killed or attenuated microorganisms, or products or derivatives of microorganisms. The most common method of administering vaccines is by inoculation, but some are given by mouth or nasal spray.

Development of an Effective Vaccine for Malaria Is Challenging Because The pathogens antigenic composition during different stages of the life cycle is complex. There is multiplicity of epidemiology and clinical end points. The candidate vaccine antigens exhibit genetic diversity and variation. We lack a complete understanding of the characteristics of naturally acquired immunity and the mechanism of protection.

Ramdas Khalsa Institute of Science & Technology (Pharmacy), Jabalpur- 482001, M.P. India. E-mail: rajeevs472@gmail.com *Corresponding author

Erthrocytic Stage Merozoite surface protein 1 (MSP-1 or MSA-1, Major surface antigen of merozoites.), 195-kDa protein breakes down to 19-kDa. Abs to 19-kDA reduce efficiency erythrocyte invasion. Merozoite surface protein 2 (MSP-2 or MSA-2, Second merozoite surface antigen unrelated to MSP-1), No immunologenicity known. Erythrocyte binding antigen antigen 175 (EBA-175, found on Surface of merozoites.), Immunizing rabbits with this protein can give blocking effect to merozoite invasion. Ring infected erythrocyte surface antigen (RESA, Expressed on erythrocytes infected with ring stage parasites.), Causes humoral immune response. Apical merozoite antigen (AMA-1, Apical region of the merozoite. May be involved in erythrocyte invasion), Known to stimulate humoral response in patients with chronic malaria.

Innate Immune Responses to Malaria Infection The development of effective adaptive immunity to malaria occurs through repetitive infections during childhood 10. Native individuals, on malaria infection, the hosts ability to control rapidly growing parasites relies on the defensive actions of the innate immune system. Otherwise, the parasite could grow exponentially and cause death. During malaria infection, the host produces high levels of many proinflammatory cytokines, including tumor necrosis factor (TNF)-a, interleukin (IL)-1, IL-6, IL-12 and interferon (IFN)-g, that have important roles in controlling parasite growth [816]. TNF-a, IL-12 and IFN-g activate macrophages to produce reactive
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An Ideal Malaria Vaccine Encompasses Mainly Three Essential Characteristics It is multi-stage incorporating antigenic characteristics at multiple stages It is multivalent containing multiple epitopes restricted by different MHC molecules, which would help in overcoming the genetic restriction and allelic and antigenic variations. It is a multi-immune inducing more than one type of immune response, comprising both cell-mediated and humoral immunity.

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Table 1; Definition of Malaria Control, Elimination and Eradication Term Definition Control Malaria no longer a significant clinical problem but transmission of malaria continues. Elimination Malaria transmission is interrupted at a national or regional level. Eradication Cessation of natural malaria transmission across the globe may be species specific or refer to all human malaria parasites.

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Recent Advances in Malaria Vaccine Development Malaria vaccine development has been an active field of research for over 2 decades, with a primary focus on Plasmodium falciparum, the deadliest of the 4 species of Plasmodia parasites that infect man. A recent WHO review of the portfolio of candidate malaria vaccines currently in development has identified more than 80 vaccines at the preclinical development stage. More than 30 malaria vaccines have entered clinical testing. Two vaccines have reached phase 2b efficacy evaluation in endemic regions, in adult volunteers and one malaria vaccine is now undergoing phase 2b evaluation in a paediatric endemic setting. Malaria vaccine development strategies are based on the complex life cycle of the parasite 14.
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oxygen and nitrogen radicals, which kill parasites 11. IFN-g primes macrophages and dendritic cells (DCs) for the efficient production of cytokines, chemokines and other inflammatory mediators 12. IL-12 is involved in the production of IFN-g by natural killer (NK) cells, the promotion of cell-mediated adaptive immune responses and the modulation of humoral responses by the induction of antibody- isotype switching 13.Thus; pro-inflammatory cytokines modulate parasite-specific adaptive immunity for efficient parasite clearance and for sustained and effective protection against disease pathology. In fact, the early cytokine expression pattern is believed to govern the specificity and effectiveness of adaptive immunity.

Figure1: Life cycle of malaria [Source: http://ocw.jhsph.edu/]

SOME EXAMPLES OF SOME MALARIAL VACCINES C.S.P. Vaccine Studies concluded that CSP vaccine induced antisporozoite antibody is not protective. Encouraging results have been reported with a CSP-HBs Ag Hybrid Vaccine (U.S. Army and SKB).

Figure 2: A graphic view of the various stages in malaria transmission

Elkin Patarroyo in 1987, a combination of antigens from the sporozoite (using CS repeats) and merozoite parasites.

CDC/NII MLVAC-1 It is a candidate vaccine that codes for nine different antigens that the plasmodium expresses during its development is liver, blood and circulation in the hosts. The vaccine stood the challenge on rabbit trial.

NYVAC-Pf.7 This vaccine blocks transmission of the parasite from vertebrate host to mosquitoes. The highly attenuated NYVAC vaccinia virus strain has been utilized to develop a multiantigen, multistage vaccine attempted to use different technology, incorporating seven P.falciparum antigenic genes.

RTS, S This is the most recently developed recombinant vaccine. It consists of the P. falciparum cirumsporozoite protein from the pre-erythrocytic stage 15.

Patorraya Vaccine (Cocktail vaccine): This is the basis for adopting an ''antigenic cocktail'' approach toward obtaining a synthetic or recombinant subunit vaccine such as the synthetic Colombian Malaria vaccine SPf 66. SPf 66 consists of 3 peptide epitopes from 3 blood stage proteins (35 KD, 55KD, 83 KD) intercalated with NANP sequence. SPf66 This is the first vaccine developed that has undergone field trials, developed by Manuel

Vaccine Development Strategies for the Future The development of a vaccine of therapeutic and protective benefit against the malaria parasite requires a novel approach as to date there are no vaccines available that effectively target a parasitic infection. The focus so far has been predominately on the use of sub-unit vaccines. The use of live, inactivated or attenuated whole parasites is not feasible and therefore antigenic particles, or subunits, from the parasite are isolated and tested for immunogenicity i.e. the ability to elicit an immune response. The most recent advances in the field of sub-unit vaccine development include the use of DNA vaccination 16. This approach involves removing sections of DNA from the parasitic genome and inserting the sequences into a vector, examples including plasmid genomes, attenuated DNA viral genomes, liposomes or proteoliposes, and other nanocarrier complex molecules. The approach of potentially allowing the modification of vaccine candidates to improve development techniques and further scientific understanding is known as iterative development.
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CONCLUSION A successful vaccine strategy requires an appreciation of how the human host immune response interacts with the parasite. One malaria vaccine, RTS, S/AS02, has shown promise in endemic areas and will shortly enter further trials. Other vaccines (SPf 66, CDC/NII MLVAC-1) are being studied in clinical trials 17, but it will probably be at least 10 years before a malaria vaccine is ready for widespread use Finally, there seems to be some light at the end of the long and mostly dark malaria vaccine development tunnel. The road to a safe, efficient and affordable malaria vaccine will be dreadfully long, but our refined road maps seem to tell us for the first time how to get there. REFERENCES AND NOTES
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Acknowledgement: Author thankful to Guru Ramdas Khalsa Institute of Science & Technology (Pharmacy), Jabalpur (M.P.) for providing facilities for reviewing this article.

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