Prof Kevin Marsh

Research Area: Global Health
Scientific Themes: Tropical Medicine & Global Health
Keywords: malaria, immunology and epidemiology
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Professor Kevin Marsh has a broad research interest in child health in the tropics, with a particular focus in the immune epidemiology of malaria. As well as directing the KEMRI Wellcome Programme in Kenya, Kevin also coordinates the KEMRI Molecular Parasitology group. The Programme’s research focuses on four main areas: (1) Identifying the protective immune response to malaria (2) the regulation of immune responses (3) Determinants of virulence and (4) Mechanisms of anti malarial drug action and resistance.
Kevin’s particular interest is in capacity building for science in Africa. He has recently secured a major strategic award, from the Wellcome Trust, to support doctoral and post doctoral career development for East African Scientists. Kevin is also a member of many global health advisory groups.

Name Department Institution Country
Prof Chris I Newbold (RDM) Investigative Medicine Division University of Oxford United Kingdom
Prof Adrian VS Hill Jenner Institute University of Oxford United Kingdom
Prof David Roberts (RDM) Nuffield Division of Clinical Laboratory Sciences University of Oxford United Kingdom
David Conway MRC Laboratories Gambia
S Polley London School of Hygiene and Tropical Medicine United Kingdom
Paul Milligan London School of Hygiene and Tropical Medicine United Kingdom
Tony Holder National Institute of Medical Research Mill Hill United Kingdom
Jean Langhorne National Institute of Medical Research Mill Hill United Kingdom
Dr Alex Rowe Centers for Disease Control United States
James Beeson Walter and Eliza Hall Institute Melbourne Australia
Anna Farnert Karolinska Institute Stockholm Sweden
Ibrahim Ei Hassan Institute of Endemic Diseases Khartoum Sudan
Gilbert Kokwaro University of Nairobi Kenya

Bull PC, Pain A, Ndungu FM, Kinyanjui SM, Roberts DJ, Newbold CI, Marsh K. 2005. Plasmodium falciparum antigenic variation: relationships between in vivo selection, acquired antibody response, and disease severity. J Infect Dis, 192 (6), pp. 1119-1126. Read abstract | Read more

BACKGROUND: Variant surface antigens (VSA) on Plasmodium falciparum-infected erythrocytes are potentially important targets of immunity to malaria. We previously identified a VSA phenotype--VSA with a high frequency of antibody recognition (VSA(FoRH))--that is associated with young host age and severe malaria. We hypothesized that VSA(FoRH) are positively selected by host molecules such as intercellular adhesion molecule 1 (ICAM1) and CD36 and dominate in the absence of an effective immune response. Here, we assessed, in 115 Kenyan children, the potential role played by in vivo selection pressures in either favoring or selecting against VSA(FoRH) among parasites that cause malaria. METHODS: We tested for associations between VSA(FoRH) and (1) the repertoire of VSA antibodies carried by children at the time of acute malaria and (2) polymorphisms in ICAM1 (K29M) and CD36 (T188G) that could potentially reduce the positive selection of VSA(FoRH). RESULTS: An expected negative association between VSA antibody repertoire and VSA(FoRH) was observed in children with nonsevere malaria. However, this association did not extend to children with severe malaria, many of whom apparently had well-developed VSA antibody responses despite being infected by parasites expressing VSA(FoRH). There was no evidence for involvement of CD36 or ICAM1 in positive selection of VSA(FoRH). On the contrary, a weak positive association between carriage of the CD36 (T188G) allele and VSA(FoRH) was observed in children with severe malaria. CONCLUSION: The association between the VSA(FoRH) parasite phenotype and severe malaria cannot be explained simply in terms of the total repertoire of VSA antibodies carried at the time of acute disease. Hide abstract

Mwangi TW, Ross A, Snow RW, Marsh K. 2005. Case definitions of clinical malaria under different transmission conditions in Kilifi District, Kenya. J Infect Dis, 191 (11), pp. 1932-1939. Read abstract | Read more

BACKGROUND: Clear case definitions of malaria are an essential means of evaluating the effectiveness of present and proposed interventions in malaria. The clinical signs of malaria are nonspecific, and parasitemia accompanied by a fever may not be sufficient to define an episode of clinical malaria in endemic areas. We defined and quantified cases of malaria in people of different age groups from 2 areas with different rates of transmission of malaria. METHODS: A total of 1602 people were followed up weekly for 2 years, and all the cases of fever accompanied by parasitemia were identified. Logistic regression methods were used to derive case definitions of malaria. RESULTS: Two case definitions of malaria were derived: 1 for children 1-14 years old and 1 for infants (<1 year old) and older children and adults (> or =15 years old). We also found a higher number of episodes of clinical malaria per person per year in people from an area of low transmission of malaria, compared with the number of episodes in those from an area of higher transmission (0.84 vs. 0.55 episodes/person/year; incidence rate ratio, 0.66 [95% confidence interval, 0.61-0.72]; P<.001). CONCLUSIONS: Case definitions of malaria are bound to be altered by factors that affect immunity, such as age and transmission. Case definitions may, however, be affected by other immunity-altering factors, such as HIV and vaccination status, and this needs to be borne in mind during vaccine trials. Hide abstract

Dorfman JR, Bejon P, Ndungu FM, Langhorne J, Kortok MM, Lowe BS, Mwangi TW, Williams TN, Marsh K. 2005. B cell memory to 3 Plasmodium falciparum blood-stage antigens in a malaria-endemic area. J Infect Dis, 191 (10), pp. 1623-1630. Read abstract | Read more

To gain insight into why antibody responses to malarial antigens tend to be short lived, we studied antigen-specific memory B cells from donors in an area where malaria is endemic. We compared antibody and memory B cell responses to tetanus toxoid with those to 3 Plasmodium falciparum candidate vaccine antigens: the C-terminal portion of merozoite surface protein 1 (MSP1(19)), apical membrane antigen 1 (AMA1), and the cysteine-rich interdomain region 1 alpha (CIDR1 alpha ) of a protein from the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. These data are the first to be generated on memory B cells in children who are in the process of acquiring antimalarial immunity, and they reveal defects in B cell memory to P. falciparum antigens. Compared with the results for tetanus toxoid, more donors who were positive for antibody to AMA1 and CIDR1 alpha were negative for memory B cells. These data imply that some exposures to malaria do not result in the establishment of stable populations of circulating antigen-specific memory B cells, suggesting possible mechanisms for the short-lived nature of many anti-malarial antibody responses. Hide abstract

Williams TN, Mwangi TW, Roberts DJ, Alexander ND, Weatherall DJ, Wambua S, Kortok M, Snow RW, Marsh K. 2005. An immune basis for malaria protection by the sickle cell trait. PLoS Med, 2 (5), pp. e128. Read abstract | Read more

BACKGROUND: Malaria resistance by the sickle cell trait (genotype HbAS) has served as the prime example of genetic selection for over half a century. Nevertheless, the mechanism of this resistance remains the subject of considerable debate. While it probably involves innate factors such as the reduced ability of Plasmodium falciparum parasites to grow and multiply in HbAS erythrocytes, recent observations suggest that it might also involve the accelerated acquisition of malaria-specific immunity. METHODS AND FINDINGS: We studied the age-specific protection afforded by HbAS against clinical malaria in children living on the coast of Kenya. We found that protection increased with age from only 20% in the first 2 y of life to a maximum of 56% by the age of 10 y, returning thereafter to 30% in participants greater than 10 y old. CONCLUSIONS: Our observations suggest that malaria protection by HbAS involves the enhancement of not only innate but also of acquired immunity to the parasite. A better understanding of the underlying mechanisms might yield important insights into both these processes. Hide abstract

Snow RW, Marsh K. 2002. The consequences of reducing transmission of Plasmodium falciparum in Africa. Adv Parasitol, 52 pp. 235-264. Read abstract | Read more

Malaria transmission intensity in Africa varies over several log orders, from less than one infected bite per year to more than one thousand. In this review we examine the consequences in terms of age pattern, clinical spectrum and overall burden of disease and discuss the possible implications for interventions that reduce exposure to infected bites. With very low transmission intensity, all age groups are susceptible to severe malaria. With increasing transmission intensities, older children and adults suffer less severe disease and with high transmission rates the majority of severe cases occur in infants under one year of age. This pattern reflects the increasingly rapid acquisition of immune responses that limit the life-threatening effects of malaria with increasing exposure to the parasite. The clinical spectrum of severe malaria varies with transmission: with high transmission, severe malarial anaemia dominates and cerebral malaria is rare. As one moves towards lower transmission rates, cerebral malaria accounts for an increasingly large proportion of cases. Although the population risk of severe disease falls with age, the risk of death at an individual level may rise with age after an initial fall from very high case fatality rates in children aged under 6 months. Of central interest to malaria control is how the overall amount of disease in childhood varies with transmission. Data from a number of sources suggest that, with low transmission, the amount of malarial disease rises with increasing exposure but that this saturates relatively early. A key issue is whether the same pattern obtains for deaths, both those directly due to malaria and those from all causes. The methodological limitations of ecological comparisons between different areas are discussed before presenting a review of attempts to use this approach in Africa. This suggests that children living in areas of low malarial endemicity have all-cause mortality rates about half of those of children living in areas of moderate to high transmission. Deaths in the first year of life rise linearly with increasing exposure to malaria over a wide range of transmission intensities; by contrast all-cause mortality in children aged 0-4 years appears to saturate at relatively low transmission intensities. These data suggest that interventions that reduce exposure to malaria parasites, such as insecticide-treated bed nets (ITNs), will have the greatest chance of a sustained effect when used in areas where disease burdens are high but the frequency of parasite exposure is low-to-moderate. In conditions of high transmission, initial reductions in mortality may prove difficult to sustain as the reduced level of transmission may still lie on the part of the curve where mortality has saturated. However, at all levels of transmission the overall balance of benefits, including reduced load on families and health services from non-life-threatening malaria, favours the widespread introduction of ITNs in endemic areas of Africa. Hide abstract

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