BIOL 305
Can Erythrocyte Binding Antigen-175 decrease the morbidity levels of children living in severe malarial holoendemic regions?
Introduction
The malaria disease is often transmitted through the bite of a female mosquito. Severe malaria is most commonly caused by infection with the parasite Plasmodium falciparum. The parasitic Plasmodium species causing severe forms of malaria persist despite the availability of instruments for treatment. These instruments consist of an array of drugs – Artenusate (AS) being a common medication for treatment – , diagnostics, and insecticides (used in bed netting).

As of today, there is no effective vaccine for malaria. This is impart due to the technical complexities of developing a vaccine against a parasite. Malaria is a disease that is prevalent and whose cure is much needed especially in certain sub-Saharan African nations who often bear the burden of this disease. A large percentage (75%) of deaths due to malaria are of children. Several studies of these deaths in sub-Saharan African nations have been classified to occur in holoendemic patterns. A disease, malaria in this case, is classified as holoendemic when basically each individual in a population is infected. As the disease appears all over the area, the young are more likely to exhibit pathogenic symptoms (morbidity), whilst older individual hosts carry the disease asymptomatically. In certain cases, the older hosts exhibit reduced damage because of the acquisition of adaptive immunity.
There is a limited knowledge of the mechanism of acquired immunity in children living in these holoendemic regions and thus there is a need to research possible pathways to facilitating immunity and thus reducing morbidity levels.
Background
Once Plasmodium falciparum malaria takes a severe trajectory, there are multiple organs affected and mortality levels are high (Reyburn et al., 2005). Severe anemia, hypoglycemia and cerebral malaria are features of severe malaria more commonly seen in children than in adults. This stage of the disease is defined by clinical or laboratory evidence of vital organ dysfunction. Every year, an estimated 1.21 million people die of severe malaria (Richards et al., 2010). Children under 5 years of age are one of most vulnerable groups affected by malaria. In a certain number of African countries, about 285 000 children died before their fifth birthdays in 2016. In African children diagnosed with malaria, the presence of impaired consciousness or any respiratory difficulties can identify those at a higher risk for death.

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“As malaria transmission declines, it becomes increasingly focal and prone to outbreaks. Pockets of transmission, or ‘hot spots’, characterize low transmission areas, and must be identified and cleared for an area to be declared malaria-free” (Larsen et al., 2015, pg. 2)
In areas with low transmission, severe malaria occurs in all age groups, but young adults are the most affected; at this stage, cerebral malaria, renal failure, severe jaundice, and pulmonary edema are the main manifestations (Dondrop et al.,2008). There has been evidence that suggests during a time of low transmission, there is an increase in overall morbidity and mortality from severe malaria such as anemia malaria and cerebral malaria (O’Meara et al., 2008).

Immunity to malaria can be acquired quickly in older individual, and severe malaria is rarely seen in children older than five years old. Naturally acquired immunity is directed against numerous merozoite (motile infective stage of a malaria parasite’s life cycle) antigens, but it remains unclear which of these organisms, if any, mediate protection in humans. Antibodies against merozoite antigens are likely important in mediating protection, but specific targets and effector responses are largely unknown.

Erythrocyte-binding antigens (EBAs) are important erythrocyte invasion ligands (molecules) used by merozoites and may be targets of protective immunity (Richards et al., 2010). Erythrocyte-binding antigens (EBAs), in association with high levels of immunoglobulin G(IgG) showed signs of protection by way of lack of ‘reinfection risk’ and thus provides a possible pathway to immunization (Richards et al., 2010). The EBAs (erythrocyte binding antigens) are particularly promising vaccines because of their known role in erythrocyte invasion and established erythrocyte-binding receptors; EBA-175. In a study by McCarra et al. (2011) concentrated (high-titer) antibodies to EBA-175 were associated with protection from clinical malaria in children in a malaria holoendemic area of Kenya.
Proposed Research
In this proposed study, I will test the hypothesis, based on prior studies, that EBA-175 administration can decrease the morbidity levels of children living in holoendemic low transmission malarial areas by providing a possible pathway to immunization. I will do so by using a treatment-reinfection design developed by Richards et al. (2010) and thus address the following aims:
Distinguish new infections(reinfections) from treatment failures
Determine the parasite load which indicates the virulence of the malarial infection
Analyze the parasite load (measure of the number and severity of the parasites that a host organism has) in a statistically quantifiable manner
I will study the blood samples of 200 children living in a malarial holoendemic region of Kenya. Particularly, age would range from 5-14 years (Richards et al., 2010). All child participants will be assessed in accordance with the WHO categorization of severe malaria. I will administer a combination of EBA-175 and the common Artesunate (AS) drug used to treat malaria. I will enroll the control children group on a 7-day oral treatment of AS, while administering the combined EBA-175 – AS drug to the second treatment group. I will review the treatment efficacy every two weeks for a 6 month period. An instance of reinfection in the treatment group suggests a failure to acquire immunity from EBA-175.

A Plasmodium falciparum parasite load of more than 100 000 parasites/µl, defined as an indicator of a severe clinical episode in a low transmission setting. In the study by (Richards et al., 2010), the use of MSP2 genotyping aided in differentiating between new infections and treatment failure. Major Surface Protein 2 (MSP2) is a target of protective immune response during an infection.
The frequency of the occurrence of infections and treatment can be statistically analyzed by using the Chi-square test. ELISA assays will be taken to further measure the levels of EBAs in the blood samples of the treatment group and accurately measure the appropriate amount to administer if proven to be successful in reducing morbidity. A one-way ANOVA test will be used to analyze the variance in parasite load between the control and treatment groups. A fractionally high percentage of high parasite load indicates a reinfection.

Literature cited
Reyburn, H., Mbatia, R., Drakeley, C., Bruce, J., Carneiro, I., Olomi, R., Cox, J., Nkya., Lemnge, M., Greenwood, B.M., Riley, E. M. 2005; Association of Transmission Intensity and Age with Clinical Manifestations and Case Fatality of Severe Plasmodium falciparum Malaria. JAMA. 2005; 293:1461-1470
O’Meara, W.P., Bejon, P., Mwangi, T.W., Okiro, E.A., Peshu, N., Snow,R. W., Newton, C.R.J.C., Marsh, K.2008. E?ect of a fall in malaria transmission on morbidity and mortality in Kili?, Kenya. Lancet 2008; 372: 1555–62
Dondorp, A.M., Lee, S.J., Faiz, M.A.,Mishra,S., Price, R., Tjitra, E., Than,M., Htut,Y., Mohanty,S.. Yunus,E., Rahman,R., Nosten,F., M. Anstey, Nicholas P. J. Day and N, J.2008. White The Relationship between Age and the Manifestations of and Mortality Associated with Severe Malaria. CID 2008:47
Jack S. Richards, Danielle I. Stanisic, Freya J. I. Fowkes, Livingstone Tavul, Elijah Dabod, Jennifer K. Thompson, Sanjeev Kumar, Chetan E. Chitnis, David L. Narum, Pascal Michon, Peter M. Siba, Alan F. Cowman, Ivo Mueller, James G. Beeson.2010; Association between Naturally Acquired Antibodies to Erythrocyte-Binding Antigens of Plasmodium falciparum and Protection from Malaria and High-Density Parasitemia, Clinical Infectious Diseases 2010;51:8
Sturrock, H.J.W., Bennett A.F., Midekisa A., Gosling R.D., Gething P.W., Greenhouse B.2016;
Mapping Malaria Risk in Low Transmission Settings: Challenges and Opportunities. Trends in Parasitology. 2016; 32 (8) 635-645
McCarra, Matthew B., Ayodo, George., Sumba, Peter O., Kazura, James W., Moormann, Ann M., Narum, David L., John, Chandy C. 2011; Antibodies to Plasmodium falciparum Erythrocyte-binding Antigen-175 are Associated With Protection From Clinical Malaria. The Pediatric Infectious Disease Journal. 2011;30

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