Analysis of Immunity to Febrile Malaria in Children That Distinguishes Immunity from Lack of Exposure

Bejon, Philip; Warimwe, George M.; Mackintosh, Claire; Mackinnon, Margaret J.; Kinyanjui, Sam; Musyoki, Jennifer; Bull, Peter C.; Marsh, Kevin

doi:10.1128/iai.00125-11

Cited by 23 publications

(35 citation statements)

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“…In cross-sectional studies, individuals with current or recent exposure to malaria may have transient antibody levels that add noise to the comparisons. This is in contrast to other studies that suggest comparing only between individuals with a current infection (40). However, based on our findings, comparisons within parasitemic individuals would assume that peak antibody levels are more important than steady-state levels for protection against subsequent malaria challenges.…”

Section: Discussioncontrasting

confidence: 91%

RTS,S Vaccination Is Associated With Serologic Evidence of Decreased Exposure to Plasmodium falciparum Liver- and Blood-Stage Parasites*

Campo

Aponte

Skinner

et al. 2015

Molecular & Cellular Proteomics

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The leading malaria vaccine candidate, RTS,S, targets the sporozoite and liver stages of the Plasmodium falciparum life cycle, yet it provides partial protection against disease associated with the subsequent blood stage of infection. Antibodies against the vaccine target, the circumsporozoite protein, have not shown sufficient correlation with risk of clinical malaria to serve as a surrogate for protection. The mechanism by which a vaccine that targets the asymptomatic sporozoite and liver stages protects against disease caused by blood-stage parasites remains unclear. We hypothesized that vaccination with RTS,S protects from blood-stage disease by reducing the number of parasites emerging from the liver, leading to prolonged exposure to subclinical levels of blood-stage parasites that go undetected and untreated, which in turn boosts pre-existing antibody-mediated blood-stage immunity. To test this hypothesis, we compared antibody responses to 824 P. falciparum antigens by protein array in Mozambican children 6 months after receiving a full course of RTS,S (n ‫؍‬ 291) versus comparator vaccine (n ‫؍‬ 297) in a Phase IIb trial. Moreover, we used a nested case-control design to compare antibody responses of children who did or did not experience febrile malaria. Unexpectedly, we found that the breadth and magnitude of the antibody response to both liver and asexual bloodstage antigens was significantly lower in RTS,S vaccinees, with the exception of only four antigens, including the RTS,S circumsporozoite antigen. Contrary to our initial hypothesis, these findings suggest that RTS,S confers protection against clinical malaria by blocking sporozoite invasion of hepatocytes, thereby reducing exposure to the blood-stage parasites that cause disease. We also found that antibody profiles 6 months after vaccination did not distinguish protected and susceptible children during the subsequent 12-month follow-up period but were strongly associated with exposure.

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Section: Discussioncontrasting

confidence: 91%

RTS,S Vaccination Is Associated With Serologic Evidence of Decreased Exposure to Plasmodium falciparum Liver- and Blood-Stage Parasites*

Campo

Aponte

Skinner

et al. 2015

Molecular & Cellular Proteomics

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“…Transmission was stratified according to re-infection rates measured during the three months following curative anti-malarials, which were 50% and 49% in the two villages in the “high transmission” group, and 39%, 36% and 27% among the three villages in the low transmission group. The parasite rates prior to curative anti-malarials were 78% and 69% in the high transmission group and 65%, 61% and 43% in the low transmission group [22]. Age was analysed by dividing children into two equally sized groups.…”

Section: Methodsmentioning

confidence: 99%

Interactions between Age and ITN Use Determine the Risk of Febrile Malaria in Children

et al. 2009

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BackgroundControl measures which reduce individual exposure to malaria are expected to reduce disease, but also to eventually reduce immunity. Reassuringly, long term data following community wide ITN distribution show sustained benefits at a population level. However, the more common practice in Sub-Saharan Africa is to target ITN distribution on young children. There are few data on the long term outcomes of this practice.Methodology/Principal FindingsEpisodes of febrile malaria were identified by active surveillance in 383 children over 18 months of follow up. In order to compare the short and long term outcomes of ITN use, we examined interactions between ITN use and age (12–42 months of age versus 42–80 months) in determining the risk of febrile malaria. ITN use and older age protected against the first or only episode of malaria (Hazard Ratio [HR] = 0.33, 95%CI 0.17–0.65 and HR = 0.30, 95%CI 0.17–0.51, respectively). The interaction term between ITN use and older age was HR = 2.91, 95%CI 1.02–8.3, p = 0.045, indicating that ITNs did not protect older children. When multiple episodes were included in analysis, ITN use and older age were again protective against malaria episodes (Incident Rate Ratio [IRR] = 0.43 95%CI 0.27–0.7) and IRR = 0.23, 95%CI 0.13–0.42, respectively) and the interaction term indicated that ITNs did not protect older children (IRR = 2.71, 95%CI 1.3–5.7, p = 0.008).Conclusions/SignificanceThese data on age interactions with ITN use suggest that larger scale studies on the long term individual outcomes should be undertaken if the policy of targeted ITN use for vulnerable groups is to continue.

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“…We have also previously identified interactions between Pf-specific Abs and asymptomatic parasitaemia in determining risk of clinical malaria (44,45). The reasons for these interactions are complex, and may reflect confounding by exposure (46), premunition (47), or persistent exposure to antigen (17). Nonetheless, the differential mortality in previously exposed versus unexposed individuals during malaria epidemics in Madagascar (48) suggests that immunological memory may be critical when facing resurgent malaria.…”

Section: Discussionmentioning

confidence: 96%

Memory B cells are a more reliable archive for historical antimalarial responses than plasma antibodies in no-longer exposed children

Ndungu

Olotu

Mwacharo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Humans respond to foreign antigen by generating plasma Abs and memory B cells (MBCs). The Ab response then declines, sometimes to below the limit of detection. In contrast, MBCs are generally thought to be long-lived. We tested and compared Plasmodium falciparum (Pf)-specific Ab and MBC responses in two populations of children: (i) previously exposed children who had documented Pf infections several years ago, but minimal exposure since then; and (ii) persistently exposed children living in a separate but nearby endemic area. We found that although Pf-specific plasma Abs were lower in previously exposed children compared with persistently exposed children, their cognate MBCs were maintained at similar frequencies. We conclude that serological analysis by itself would greatly underestimate the true memory of Pf-specific Ab responses in previously exposed children living in areas where Pf transmission has been reduced or eliminated.immunological | immunity | protection | longevity | maintenance

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Analysis of Immunity to Febrile Malaria in Children That Distinguishes Immunity from Lack of Exposure

Cited by 23 publications

References 0 publications

RTS,S Vaccination Is Associated With Serologic Evidence of Decreased Exposure to Plasmodium falciparum Liver- and Blood-Stage Parasites*

RTS,S Vaccination Is Associated With Serologic Evidence of Decreased Exposure to Plasmodium falciparum Liver- and Blood-Stage Parasites*

Interactions between Age and ITN Use Determine the Risk of Febrile Malaria in Children

Memory B cells are a more reliable archive for historical antimalarial responses than plasma antibodies in no-longer exposed children

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