The use of antimalarial antibodies to measure malaria transmission in low transmission and pre-elimination settings

Global declines in malaria transmission in recent years have refocused efforts towards elimination. An essential part of this effort is adequate detection of transmission patterns. However, meta-analyses have shown that microscopy detects about half of all polymerase chain reaction (PCR)-confirmed infections. To date, the performance of rapid diagnostic tests (RDTs) relative to microscopy and PCR has not been evaluated in a comprehensive meta-analysis. Therefore, the relationship between PCR, RDT and microscopy prevalence estimates in asymptomatic populations was determined using data from cross-sectional surveys in endemic settings (Chapter 3). Overall, RDTs detected 41% of all PCR-confirmed infections, and RDT-undetected (i.e. low-density) infections increased with age and decreasing transmission intensity. Another approach to estimate transmission is to use malaria-specific immune responses of resident populations as a measure of exposure to infection. Antimalarial antibodies, in combination with age, reflect both historical and recent exposure. Until recently, the majority of sero-surveillance data were based on a few well-characterised antigens using enzyme-linked immunosorbent assays (ELISA). However, which antibodies most accurately reflect exposure to recent low-density infections remains largely unknown. To address this, Chapter 4 examined antibody responses in previously naïve, controlled human malaria infections (CHMI) participants using protein microarray. Nearly all participants showed measurable antibody responses to a subset of four antigens one month post-CHMI. In addition to protein microarray, multiplex bead assays (MBAs) enable multiplex detection of antibodies. However, MBA protocols may require further adaptation in scenarios where results must be readily available to inform control and elimination policies. The precision of an adapted MBA protocol with improved throughput and ease-of-use was determined in Chapter 5 using data collected in three large-scale transmission surveys. For some antigens, inter-plate variability seemed to increase during the third survey, possibly due to long-term storage of reagents. Commercially available ELISAs are standardised in their production and have been used to test blood products prior to donation to reduce the risk of transfusion-transmitted malaria. However, their performance in an epidemiological context has not been investigated. In Chapter 6, one of five commercially available ELISAs evaluated, accurately described transmission in a low transmission and pre-elimination setting. A low-cost, high-throughput assay for which results are readily interpretable may help to directly inform control activities targeting areas with remaining transmission

Galectin-9 and CXCL10 as biomarkers for disease activity in juvenile dermatomyositis: a longitudinal cohort study and multi-cohort validation

OBJECTIVE: Objective evaluation of disease activity is challenging in patients with juvenile dermatomyositis (JDM) due to lack of biomarkers, but crucial to avoid both under- and overtreatment. Recently, we identified two proteins that highly correlate with JDM disease activity: galectin-9 and CXCL10. Here, we validate galectin-9 and CXCL10 as biomarkers for disease activity, assess disease-specificity and investigate their potency to predict flares. METHODS: Galectin-9 and CXCL10 were measured in serum samples of 125 unique JDM patients in three international cross-sectional cohorts and a local longitudinal cohort, by multiplex immunoassay. Disease-specificity was examined in 50 adults with (dermato)myositis and 61 patients with other systemic autoimmune diseases. RESULTS: Galectin-9 and CXCL10 outperformed the currently used marker creatine kinase (CK) to distinguish between JDM patients with active disease and remission, both cross-sectionally and longitudinally (area ROC curve: 0.86-0.90 for galectin-9 and CXCL10, 0.66-0.68 for CK). The sensitivity and specificity were 0.84 and 0.92 for galectin-9, and 0.87 and 1.00 for CXCL10. In 10 prospectively followed patients with a flare, continuously elevated or rising biomarker levels suggested an imminent flare up to several months before symptoms, even in absence of elevated CK. Galectin-9 and CXCL10 distinguished between active disease and remission in adults with (dermato)myositis and were suited for measurement in minimally-invasive dried blood spots. CONCLUSIONS: Galectin-9 and CXCL10 were validated as sensitive and reliable biomarkers for disease activity in (J)DM. Implementation of these biomarkers into clinical practice, as tools to monitor disease activity and guide treatment, might facilitate personalized treatment strategies

Reactive community-based self-administered treatment against residual malaria transmission: study protocol for a randomized controlled trial

Background: Systematic treatment of all individuals living in the same compound of a clinical malaria case may clear asymptomatic infections and possibly reduce malaria transmission, where this is focal. High and sustained coverage is extremely important and requires active community engagement. This study explores a communitybased approach to treating malaria case contacts. Methods/design: This is a cluster-randomized trial to determine whether, in low-transmission areas, treating individuals living in the same compound of a clinical malaria case with dihydroartemisinin-piperaquine can reduce parasite carriage and thus residual malaria transmission. Treatment will be administered through the local health system with the approach of encouraging community participation designed and monitored through formative research. The trial goal is to show that this approach can reduce in intervention villages the prevalence of Plasmodium falciparum infection toward the end of the malaria transmission season. Discussion: Adherence and cooperation of the local communities are critical for the success of mass treatment campaigns aimed at reducing malaria transmission. By exploring community perceptions of the changing trends in malaria burden, existing health systems, and reaction to self-administered treatment, this study will develop and adapt a model for community engagement toward malaria elimination that is cost-effective and fits within the existing health system. Trial registration: Clinical trials.gov, NCT02878200. Registered on 25 August 2016

A longitudinal cohort study of malaria exposure and changing serostatus in a malaria endemic area of rural Tanzania.

BACKGROUND: Measurements of anti-malarial antibodies are increasingly used as a proxy of transmission intensity. Most serological surveys are based on the use of cross-sectional data that, when age-stratified, approximates historical patterns of transmission within a population. Comparatively few studies leverage longitudinal data to explicitly relate individual infection events with subsequent antibody responses. METHODS: The occurrence of seroconversion and seroreversion events for two Plasmodium falciparum asexual stage antigens (MSP-1 and AMA-1) was examined using three annual measurements of 691 individuals from a cohort of individuals in a malaria-endemic area of rural east-central Tanzania. Mixed-effect logistic regression models were employed to determine factors associated with changes in serostatus over time. RESULTS: While the expected population-level relationship between seroprevalence and disease incidence was observed, on an individual level the relationship between individual infections and the antibody response was complex. MSP-1 antibody responses were more dynamic in response to the occurrence and resolution of infection events than AMA-1, while the latter was more correlated with consecutive infections. The MSP-1 antibody response to an observed infection seemed to decay faster over time than the corresponding AMA-1 response. Surprisingly, there was no evidence of an age effect on the occurrence of a conversion or reversion event. CONCLUSIONS: While the population-level results concur with previously published sero-epidemiological surveys, the individual-level results highlight the more complex relationship between detected infections and antibody dynamics than can be analysed using cross-sectional data. The longitudinal analysis of serological data may provide a powerful tool for teasing apart the complex relationship between infection events and the corresponding immune response, thereby improving the ability to rapidly assess the success or failure of malaria control programmes