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While pesticides and antimalarial drugs are important tools in the fight against malaria, most experts believe that the only permanent solution to the malaria problem is to develop a malaria vaccine (Marshall, 2000). Not only is vaccination the single most effective medical procedure in terms of saving lives, but it is also the most cost effective (Henderson, 1997). While more and more people are beginning to look for a malaria vaccine, the process has been a slow one. Much of the problem has been a lack of resources. Not only have people been uninterested in a disease that primarily affects poorer countries (Vogel 431), but there are also financial difficulties: it can take over ten years and a quarter of a billion dollars to research and market an effective vaccine (Vogel, 2000; Taubes, 2000).
The scientific obstacles to a malaria vaccine are equally challenging. The primary problem is the complexity of Plasmodium: it is a protozoan with 14 chromosomes, 7,000 genes, and a four-stage life cycle. Not only has no one ever developed a vaccine that is effective against a protozoan, a truly effective vaccine will have to be able to attack all four stages of the parasite's life cycle and overcome its techniques for evading the immune response. Finally, because malaria parasites multiply in every step of the infection process, even 99% of the parasites in the body are eliminated, the remaining 1% can turn into enough parasites to reinfect a person (Taubes, 2000). Despite the challenges facing them, researchers have made significant progress towards developing a vaccine, primarily due to the complete sequencing of the Plasmodium and Anopheles genomes in 2002 (NIH, 2007).
Vaccine Research and Development
The majority of researchers focus on attacking sporozoites for two reasons: first, it is the most direct approach, in that it is the first stage of Plasmodium’s life cycle and will prevent the liver from being infected; and secondly, using attenuated sporozoites provides complete protection from malaria (Honigsbaum, 2002). According to the attenuated sporozoite model, when mosquitoes carrying malaria parasites are exposed to x-rays, the sporozoites are deactivated. They are still alive and can trigger an immune response, but cannot invade liver or red blood cells. Unfortunately, there is no practical way to use this method, because live mosquitoes have to be used—if the sporozoites were extracted from the mosquitoes, they died and had no effect on the immune response—and constructing “a massive insectary to deliver the vaccine was obviously impractical” (Honigsbaum. 2002). However, this research paved the way for further research that found that the circumsporozoite (CS) protein in Plasmodium is partially responsible for the activation of the human immune response (Honigsbaum, 2002; Taubes, 2000). Since this discovery, researches have attempted to develop a vaccine that works by boosting the immune response to the CS protein, but none have been successful.
CS Protein Vaccines
Most CS protein vaccines work by “ambushing” Plasmodium at its weakest point: after it has left the liver but before it enters the red blood cells. A vaccine that successfully attacks parasites at this point would prevent the cycle of red blood cell infection and reinfection that causes malaria’s symptoms (Taubes, 2000).
One of the first such vaccines was SPf66, a synthetic chemical vaccine developed by Manuel Elkin Patarroyo. However, in trials in The Gambia and Tanzania in 1995r, SPf66 had no effect on the children it was tested on. In further testing on 1,200 children in Thailand in 1996, those who were given SPf66 were no more protected than those who had taken a placebo. According to Patarroyo, the reason for these failures is that there are variations between the strains of Plasmodium tested in the laboratory and in the field. Since 1995, he has been working on a modified version of SPf66 that targets binding proteins of Plasmodium’s surface that are common to all strains of the parasite (Honigsbaum, 2002).
In 1996, after a decade of testing nearly two dozen vaccines, the Walter Reed Army Institute of Research (WRAIR) discovered a CS protein vaccine called RTS,S
that conferred protection to six out of seven test subjects for over three weeks. They followed this with a field trial in 306 adults in The Gambia, and the results were unprecedented—71% were protected after two months (Taubes, 2000). Although the number dropped to 16% after another two months, RTS,S, was the first vaccine to ever provide protection in the field, and significantly, it had worked in The Gambia, “the place where many previous vaccines…had met their Waterloo” (Honigsbaum, 2002). Since then, researchers have continued to improve the immune response produced by the vaccine and tested it in younger and younger subjects. If the vaccines remain effective and safe, they hope to soon be able to test them in children (Taubes, 2000).
The most promising vaccine thus far attacks Plasmodium in the liver and has a significant ability to reduce clinical symptoms. The vaccine consists of the RTS,S antigen and the AS02A adjuvant, which enhances RTS,S’s effect. Based on data that shows that the effects of this vaccine last for 18 months, the Gates Foundation has given WRAIR over $100 million for further tests and development (USAID, 2006)
The most advanced blood-stage vaccine is FMP1/AS02A, which was also developed by WRAIR and is currently undergoing trials. If it is ineffective in comparison to RTS,S/AS02A, it may be used as in comibination with current control measures, and WRAIR will continue to research blood-stage vaccines. If, however, FMP1/AS02A is as effective as RTS,S/AS02A, WRAIR plans to combine the two in hopes that the protection conferred would be more complete than that from either vaccine alone. If it is clearly more effective that RTS,S/AS02A, FMP1/AS02A will be developed as a first-line malaria vaccine, and RTS,S/AS02A would be used as a second-line option (USAID, 2006).
Transmission-blocking vaccines would create antibodies against malaria gametocytes, thereby preventing the mosquito from transmitting parasites to another human host. However, gametocytes can only be attacked when they are actually inside the mosquito, because they stay in red blood cells until they detect a decrease in temperature which signals that it is safely in the mosquito’s gut, at which point it emerges, reproduces, and is able to infect humans again. Scientists at the U.S. National Institutes of Health (NIH) are attempting to develop a “Trojan horse" method of vaccination by creating antibodies that can be taken into the mosquito’s gut along with the Plasmodium gametocytes.
DNA vaccines are composed of a gene from the pathogen that has been incorporated into a bacterial plasmid. In order to create a DNA vaccine effective against Plasmodium, one would have to select DNA from the parasite that encodes for the primary antigens, splice it into a plasmid, and inject it into the body, where cells would begin making the proteins the malaria parasite generates in the liver and red blood cells. In theory, when a person is next infected with malaria, their immune system would recognize the proteins and intitiate the immune response (Honigsbaum, 2002).
The primary advantage of DNA vaccines is that they are relatively easy to make, and they directly activate the killer T cells, which then destroy infected liver cells, a reaction that scientists have not yet been able to induce with any other malaria treatments (Taubes 436). In addition, DNA vaccines can be tailored to be as complex as desired. Ideally, enough genes from Plasmodium will be spliced into the plasmid that the human immune system will recognize all four stages of the parasite’s life cycle and thereby defeat its ability to evade the body's immune response (Honigsbaum, 2002). A DNA vaccine would be the most practical malaria treatment for several reasons: they produce long-term immune responses and would therefore only need to be given once; they are extremely stable; and they can be stored under a wide range of conditions, either dried or in solution at room temperature. These qualities will make it possible to vaccinate people in even the most remote parts of the world (Henahan, 1997).
P. falciparum home
Henahan, Sean. 1997. “DNA vaccine outlook.” Access Excellence.<http://www.accessexcellence.org/WN/SUA11/dnavax1297.html>. Accessed 2007 May 3.
Henderson, Donald A. 1997. “The miracle of vaccination.” Notes and Records of the Royal Society of London 51: 235-45.
Honigsbaum, Mark. 2002. The Fever Trail: In Search of the Cure for Malaria. New York: Farrar, Straus, & Giroux.
Marshall, Eliot. 2000. “A renewed assault on an old and deadly foe.” Science, New Series 290: 428-430.
National Institutes of Health (NIH). 2007 Feb. “Understanding malaria: fighting an ancient scourge.” U.S. Department of Health and Human Services. <http://www.niaid.nih.gov/publications/malaria/pdf/malaria.pdf>. Accessed 2007 May 3.
Taubes, Gary. 2000. “Searching for a parasite’s weak spot.” Science, New Series 290: 434-37.
USAID. 2006. “Report to Congress: health-related research and development activities at USAID.” <http://pdf.usaid.gov/pdf_docs/PDACH111.pdf>. Accessed 2007 May 3.
Vogel, Gretchen. 2000. “Against all odds, victories from the front lines.” Science, New Series 290: 431-33.
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