alaria: Science still in search of cost-effective vaccine

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Sun News Publishing

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By AZOMA CHIKWE

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Tue, 04/26/2011 - 16:40

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World’s most infectious disease in Nigeria

Malaria vaccines are an area of intensive research, however, no affective vaccines has yet been introduced into clinical practice.
Malaria, a sickness caused by a parasite, plasmodium, that has infected the saliva glands of a female is has been a major health issue in many African and developing nations including Nigeria.

The sickness is characterized by cyctes of chills, fever, pain and sweating. Lately, the Artemisinin Combination Therapy (ACT) anti-malarials were developed to give a double bared attack on malaria, however, popular opinion maintain that malaria vaccine will easily eradicate the disease.

The task of developing a vaccine that is of potentially preventive benefit for malaria is a complex process. There are a number of consideration to be made concerning what strategy a potential vaccine should adopt. This is because the diversity of the parasite continuous to be a stumbling black in the drive to develop a vaccine.
Plasmodium falciparum, the parasite that causes malaria has demonstrated the capability, through the development of multiple drug-resistance parasites, of evolutionary change. “The plasmodium species has a very high rate of replication, much higher than that actually needed to ensure transmission in the parasite’s life cycte,” experts say.

“This enables pharmaceutical treatments that are effective in reducing the reproduction rate but not halting it to exert a high selection pressure, thus favouring the development of resistance.”
According to scientists, there are many antigens present throughout the parasite life cycle that potentially could act as targets for the vaccine. More than 30 of these are currently being researched by teams all over the world in the hope of identifying a combination that can elicit immunity in the inoculated individual.

Some of the approaches involve surface expression of the antigen, inhibitory effects of specific antibodies on the life cycle and the protective effects through immunization or passive transfer of antibodies between an immune and a non-immune host. The majority of research into malarial vaccines has focused on the Plasmodium falciparum strain due to the high mortality caused by the parasite and the ease of a carrying out in vitro/in vivo studies. The earliest vaccines attempted to use the parasitic circumsporozoite (CS) protein. This is the most dominant surface antigen of the initial pre-erythrocytic phase. However, problems were encountered due to low efficacy, reactogenicity and low immunogenicity.

The first vaccine developed that has undergone field trials, is the SPf66, developed by Manuel Elkin Patarroyo in 1987. It presents a combination of antigens from the sporozoite and merozoite parasites. During phase I trials a 75% efficacy rate was demonstrated and the vaccine appeared to be well tolerated by subjects and immunogenic. The phase IIb and III trials were less promising, with the efficacy falling to between 38.8% and 60.2%. A trial was carried out in Tanzania in 1993 demonstrating the efficacy to be 31% after a year of follow up, however the most recent (though controversial) study was carried out in Gambia.

It did not show any effect despite the relatively long trial periods and the number of studies carried out. It is still not known how the SPf66 vaccine confers immunity; it therefore remains an unlikely solution to malaria. The CSP was the next vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporoziote protein, but additionally has the recombinant protein covalently bound to a purified Pseudomonas aeruginosa toxin. However at an early stage, a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia whilst the control group only had an 89% incidence.

The vaccine intended to cause an increased T-lymphocyte response in those exposed, this was also not observed. The NYVAC-Pf7 multistage vaccine attempted to use different technology, incorporating seven P.falciparum antigenic genes. These came from a variety of stages during the life cycle. CSP and sporozoite surface protein 2 (called PfSSP2) were derived from the sporozoite phase. The liver stage antigen 1 (LSA1), three from the erythrocytic stage (merozoite surface protein 1, serine repeat antigen and AMA-1) and one sexual stage antigen (the 25-kDa Pfs25) were included.

This was first investigated using Rhesus monkeys and produced encouraging results: 4 out of the 7 antigens produced specific antibody responses (CSP, PfSSP2, MSP1 and PFs25). Later trials in humans, despite demonstrating cellular immune responses in over 90% of the subjects had very poor antibody responses. Despite this, following administration of the vaccine some candidates had complete protection when challenged with P.falciparum. This result has warranted ongoing trials.

In 1995 a field trial involving [NANP]19-5.1 proved to be very successful. Out of 194 children vaccinated none developed symptomatic malaria in the 12 week follow up period and only 8 failed to have higher levels of antibody present. The vaccine consists of the schizont export protein (5.1) and 19 repeats of the sporozoite surface protein [NANP]. Limitations of the technology exist as it contains only 20% peptide and has low levels of immunogenicity. It also does not contain any immunodominant T-cell epitopes.

RTS,S is the most recently developed recombinant vaccine. It consists of the P. falciparum cirumsporozoite protein from the pre-erythrocytic stage. The CSP antigen causes the production of antibodies capable of preventing the invasion of hepatocytes and additionally elicits a cellular response enabling the destruction of infected hepatocytes. The CSP vaccine presented problems in trials due to its poor immunogenicity. The RTS,S attempted to avoid these by fusing the protein with a surface antigen from Hepatitis B, hence creating a more potent and immunogenic vaccine. When tested in trials an emulsion of oil in water and the added adjuvants of monophosphoryl A and QS21 (SBAS2), the vaccine gave 7 out of 8 volunteers challenged with P. falciparum protective immunity.

The global burden of P. falciparum malaria increased through the 1990s due to drug-resistant parasites and insecticide-resistant mosquitoes; this is illustrated by re-emergence of the disease in areas that had been previously malaria-free. The first decade of the 21st century has seen reductions in morbidity and mortality in many settings. Though the reasons are not entirely clear, improving socioeconomic indices, deployment of artemisinin-combination drugs and insecticide-treated bednets are all likely to have contributed. There has been a major scaling-up in distribution of malaria control measures particularly since the advent of The Global Fund to Fight AIDS, Tuberculosis and Malaria.

It is unclear what the future will hold for disease burden trends. If political will and funding is maintained, the disease burden could drop further; if as in the past funding lapses or clinically significant resistance develops to the main antimalarial drugs and insecticides used, then the disease burden may rise again. Early evidence of resistance to artemisinins, the most important class of antimalarials, is now confirmed, having manifested as delayed parasite clearance times in the western region of Cambodia on the border with Thailand.

This is also the region where resistance to earlier antimalarial drugs emerged and then subsequently spread throughout much of the world in the case of chloroquine. The Bill and Melinda Gates Foundation has launched a call for the aim of the malaria community to shift from sustained control to eradication. It is agreed that eradication is not possible with current tools and that research and development of new drugs, diagnostics, insecticides and a cost-effective deployable vaccine will be needed to facilitate eradication. There has been a great increase in funding for such research in the 21st century.