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  Section: General Biotechnology / Genes & Genetic Engineering
 
 
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Genetic Engineering for Human Welfare

 
     
 

Malaria vaccines
According to WHO estimates 4 billion people are at the risk of developing malaria and about 500 million cases occur each year resulting in one million death each year mainly of children of 5 years age and pregnant women. In addition, development of resistance against drugs by the species of Plasmodium, and insecticides by mosquitoes have been reported. Therefore, threat of malaria disease is still increasing for humans. Therefore, for control of malaria use of vaccines and vector control programmes would be successful. Much work is going on at Indian Institute of Immunology (New Delhi) and ICGEB on development of malaria vaccine by using modern methodologies. All kind of vaccine development through recombinant antigens, synthetic peptides and direct use of DNA are being attempted. All these attempts indicate that development of malaria vaccine is largely complex process. However, progress towards the development of a malaria vaccine has been slow due to several reasons, one of which has been the lack of in vitro correlates and the suitable animal models for malaria vaccine trials. Plasmodium-vhesus monkey is one of the models for malaria vaccine development.

Malaria vaccines are being developed at three distinct developmental stages of the parasite : (i) pre-erythrocytic stage (to eliminate infection by blocking the sporozoites from entering hepatocytes or by destroying the infected hepatocytes), (ii) blood stage of parasite (to prevent disease or reduce parasitic load), and (iii) sexual stage parasite (to limit transmission of disease).

In India 60-70% malaria is due to P. vivex which do not kill host but results discomfort and morbidity. It is more prevalent throughout Asia; but less is known about immune response of host against P. vivex as it resisted all attempts of culturing the parasite. P. cynomolgi is a simian malaria which is closely related to P. vivex in taxonomy and morphology. Hence it is regarded as a good model to study P. vivex infection as both share a similar clinical course of infection. At present vaccines are being developed at ICGEB against all stages of life cycle of the parasite but it is believed that an asexual blood stage vaccine is most likely to have the greatest impact on the disease.

(i) Expression of vaccine target antigens. The most successful vaccines have been based on attenuated or killed pathogens. Malaria vaccine is limited to well defined molecules which can induce protective immune responses and easily produced by recombinant DNA technology in various systems. Three important vaccine target antigens such as thrombospondin related adhesive protein (TRAP), apical membrane antigen (AMA) and erythrocyte binding protein (EBP) from P. cynomolgi have been cloned and sequenced (Table 5.1). To evaluate their vaccine potential, these antigens have been expressed in E.coli using pQE expression system. Each of these proteins was expressed at high levels as insoluble inclusion bodies. Protocols for the large scale production of the correctly folded PcTRAP have been developed. TRAP has a multidomain structure and localized on the cell surface of P. falciparum sporozoites.

(ii) Animal trials of malaria vaccines. The rhesus monkeys were immunized with recombinant PcTRAP, parasite lysate or adjuvant to study the protective efficacy. The antigens were delivered intramuscularly in three doses (500mg each) on 0, 42, and 62 days. Blood from immunized and unimmunized monkeys was collected on days 1, 14, 29, 52 and 70. High antibody titers (8-16 * 105 and above) were detected against PcTRAP and parasite lysate as measured by ELISA technique. Then immunized monkeys after injection with P. cynomolgi sporozoites (3 * 104) were protected from malaria (ICGEB, 1998).
 

Content

Cloned genes and production of chemicals

 

Human peptide hormone genes

 

 

Insulines

 

 

Somatotropin

 

 

Somatostatin

 

 

b-endorphin

 

Human interferon genes

 

Genes for vaccines

 

 

Vaccine for hepatitis-B virus

 

 

Vaccines for Rabies virus

 

 

Vaccines for poliovirus

 

 

Vaccine for foot and mouth disease virus

 

 

Vaccines for small pox virus

 

 

Malaria vaccines

 

 

DNA vaccines

 

Genes associated with genetic diseases

 

 

Phenylketonuria

 

 

Urokinase

 

 

Thalassaemia

 

 

Hemophilia

 

Enzyme engineering

 

Commercial chemicals

Prevention, diagnosis and cure of diseases

 

Prevention of diseases

 

Diagnosis of diseases

 

 

Parasitic diseases

 

 

Monoclonal antibodies

 

 

Antenatal diagnosis

 

Gene therapy

 

 

Types of gene therapy

 

 

Methods of gene therapy

 

 

Success of gene therapy

 

 

Potential of gene delivering system

 

 

Future needs of gene therapy in India

DNA profiling (fingerprinting)

 

Methods of DNA profiling

 

Application of DNA profiling

 

 

Genetic databank

 

 

Reuniting the lost children

 

 

Solving disputed problems of parentage, identity of criminals, rapists, etc

 

 

Immigrant dispute

 

Hurdles of DNA profiling

Animal and plant improvement

 

Transgenic Farm Animals

 

Crop Improvements

 

 

Transgenic plants

 

 

Nif gene transfer

 

 

Phaseolin gene transfer

 

 

Conversion of C3 plants to C4 plants

 

 

Herbicide resistant plants

 

 

Insect pest resistant plants

 

 

Plant improvement through genetic transformation

 

Crop Protection

 

 

Use of antagonists

 

 

Use of insecticides

Abatement of pollution


Table 5.1. Asexual stages vaccine target antigens.
 

Antigens

Appropriate Size

Location

Sporozoite stage

 

 

Circum sporozoite surface protein (CSP)

60 Kda

Sporozoite surface

Sporozoite surface protein-2 (SSP-2)

63 Kda

Sporozoite surface

Liver stage antigen-1 (LSA-1)

200 Kda

Parasitophorous vacuole

Sporozoite threonine asparagine rich protein (STARP)

70 Kda

Sporozoite surface

Blood stage

 

 

Merozoite surface antigen-1 (MSA-1)

195 Kda

Merozoite surface

MSA-2

45 Kda

Merozoite surface

Apical membrane antigen-l(AMA-l)

83 Kda

Rhoptry organelle

Acid base rich antigen (ABRA)

75 Kda

Parasitophorous vacuole

Serine repeat antigen (SERA)

110 Kda

Released at rupture

Erythrocyte binding antigen-175 (EBA-175)

175 Kda

Parasitized erythrocyte surface

Throbospondin related anonymous protein (TRAP)

63 Kda

?

Source: Chauhan (1996).

Merozoite surface protein-1 (MSP-119), the cysteine rich C-terminal domain of MSP-1 on the surface of P. falciparum is a leading malaria vaccine candidate. This is the only part of protein which remains bound to the merozoite membrane after invasion. Similarly the expression and purification of P. falciparum acidic basic repeat antigen (ABRA) and its fragments from E.coli has also been done. The purified recombinant proteins have been used to assess the antibody responses in human populations living in malaria endemic areas from Kalka village of Raurkela (Orissa), and from Nigeria. It has also showed protective efficacy in immunized rabbits.

Spf66 was the first recognized DNA vaccine for malaria developed by joining three merozoite derived proteins with repetitive sequences derived from the circumsporozoite protein of P. falciparum. This vaccine has given equivocal results on human trials in more than one location. Through Indo-US collaboration a recombinant multistage P. falciparum candidate vaccine has been developed (Padmanaban, 1996). For detail discussion see DNA vaccines.

 
     
 
 
     



     
 
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