Accelerating Progress Towards the 2030 Neglected Tropical Diseases Targets: How Can Quantitative Modeling Support Programmatic Decisions?

Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs.

Modelling seasonal household variation in harvested rainwater availability: a case study in Siaya County, Kenya.

Rainwater harvesting reliability, the proportion of days annually when rainwater demand is fully met, is challenging to estimate from cross-sectional household surveys that underpin international monitoring. This study investigated the use of a modelling approach that integrates household surveys with gridded precipitation data to evaluate rainwater harvesting reliability, using two local-scale household surveys in rural Siaya County, Kenya as an illustrative case study. We interviewed 234 households, administering a standard questionnaire that also identified the source of household stored drinking water.

A spatiotemporal analysis of cattle herd movement in relation to drinking-water sources: implications for Cryptosporidium control in rural Kenya.

Given the increasing evidence that domestic contact with livestock is a risk factor for child diarrhoea in low- and middle-income countries, there have been calls for greater quantification of human-livestock contact in such countries. This study aimed to quantify seasonality in cattle proximity to domestic water sources and household compounds and develop a preliminary landscape model of faecal deposition by cattle. A total of 120 cattle in smallholder herds in the Asembo area of Siaya County, Kenya, were tracked over 1 week in April 2018 to July 2018 and November 2018 to February 2019 using GPS tracking devices.

A longitudinal study of the association between domestic contact with livestock and contamination of household point-of-use stored drinking water in rural Siaya County (Kenya).

Background: Emerging evidence suggests close domestic proximity of livestock and humans may lead to microbiological contamination of hands, objects, food and water supplies within domestic environments, adversely impacting public health. However, evidence quantifying the relationship between livestock, domestic animals, humans and microbiological contamination of household stored water remains limited.

Aim: This longitudinal study aimed to examine the relationship between domestic contact with livestock and domestic animals on microbiological contamination of household Point-of-Use (POU) stored drinking water in rural Kenya and assess the influence of choice of faecal indicator on such associations.

An outbreak of cholera in western Kenya, 2015: a case control study.

Introduction: in February 2015, an outbreak of acute watery diarrhea was reported in two sub counties in western Kenya. e 01 serotype Ogawa was isolated from 26 cases and from water samples collected from a river mainly used by residents of the two sub-counties for domestic purposes. We carried out an investigation to determine factors associated with the outbreak.

Intra-articular clearance of labeled dextrans from naive and arthritic rat knee joints.

Objective: Determine the effects of arthritis on the trans-synovial clearance of small and large model compounds following local delivery to the knee joint in a rat model.

Design: Intra-articular delivery was studied in rat knee joints in an osteoarthritis model of joint instability (medial collateral ligament and meniscus transection model or MMT). Fluorescently-labeled 10 kDa or 500 kDa dextran was injected in the arthritic or unoperated control (naive) joints 3 weeks after surgical destabilization, and the temporal clearance pattern was evaluated via in vivo regional fluorescence imaging, dextran concentrations in plasma and draining lymph nodes, and by quantification of fluorescence in histological synovium sections.

Prevalence and correlates of home delivery amongst HIV-infected women attending care at a rural public health facility in Coastal Kenya.

Background: Home delivery, referring to pregnant women giving birth in the absence of a skilled birth attendant, is a significant contributor to maternal mortality, and is encouragingly reported to be on a decline in the general population in resource limited settings. However, much less is known about home delivery amongst HIV-infected women in sub-Saharan Africa (sSA). We described the prevalence and correlates of home delivery among HIV-infected women attending care at a rural public health facility in Kilifi, Coastal Kenya.

Identifying children with excess malaria episodes after adjusting for variation in exposure: identification from a longitudinal study using statistical count models.

Background: The distribution of Plasmodium falciparum clinical malaria episodes is over-dispersed among children in endemic areas, with more children experiencing multiple clinical episodes than would be expected based on a Poisson distribution. There is consistent evidence for micro-epidemiological variation in exposure to P. falciparum.

Synthesis and characterization of silk fibroin microparticles for intra-articular drug delivery.

Objective: To determine the utility of silk fibroin (SF) microparticles as sustained release vehicles for intra-articular delivery.

Design: SF formulations were varied to generate microparticle drug carriers that were characterized in vitro for their physical properties, release kinetics for a conjugated fluorophore (Cy7), and in vivo for intra-articular retention time using live-animal, fluorescence in vivo imaging.

Results: SF microparticle carriers were spherical in shape and ranged from 598 nm to 21.

Combinatorial effects of malaria season, iron deficiency, and inflammation determine plasma hepcidin concentration in African children.

Hepcidin is the master regulatory hormone that governs iron homeostasis and has a role in innate immunity. Although hepcidin has been studied extensively in model systems, there is less information on hepcidin regulation in global health contexts where iron deficiency (ID), anemia, and high infectious burdens (including malaria) all coexist but fluctuate over time. We evaluated iron status, hepcidin levels, and determinants of hepcidin in 2 populations of rural children aged ≤8 years, in the Gambia and Kenya (total n = 848), at the start and end of a malaria season.

In vivo luminescence imaging of NF-κB activity and serum cytokine levels predict pain sensitivities in a rodent model of osteoarthritis.

Objective: To investigate the relationship between NF-κB activity, cytokine levels, and pain sensitivities in a rodent model of osteoarthritis (OA).

Methods: OA was induced in transgenic NF-κB-luciferase reporter mice via intraarticular injection of monosodium iodoacetate (MIA). Using luminescence imaging we evaluated the temporal kinetics of NF-κB activity and its relationship to the development of pain sensitivities and serum cytokine levels in this model.

Transmission-dependent tolerance to multiclonal Plasmodium falciparum infection.

Whether the number of concurrent clones in asymptomatic Plasmodium falciparum infections reflects the degree of host protection was investigated in children living in areas with different levels of transmission on the coast of Kenya. The number of concurrent clones was determined on the basis of polymorphism in msp2, which encodes the vaccine candidate antigen merozoite surface protein 2. In a low-transmission area, most children had monoclonal infections, and diversity did not predict a risk of clinical malaria.

HIV infection, malnutrition, and invasive bacterial infection among children with severe malaria.

Background: Human immunodeficiency virus (HIV) infection, malnutrition, and invasive bacterial infection (IBI) are reported among children with severe malaria. However, it is unclear whether their cooccurrence with falciparum parasitization and severe disease happens by chance or by association among children in areas where malaria is endemic.

Methods: We examined 3068 consecutive children admitted to a Kenyan district hospital with clinical features of severe malaria and 592 control subjects from the community.

Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya.

Background: As efforts to control malaria are expanded across the world, understanding the role of transmission intensity in determining the burden of clinical malaria is crucial to the prediction and measurement of the effectiveness of interventions to reduce transmission. Furthermore, studies comparing several endemic sites led to speculation that as transmission decreases morbidity and mortality caused by severe malaria might increase. We aimed to assess the epidemiological characteristics of malaria in Kilifi, Kenya, during a period of decreasing transmission intensity.

Acquisition of naturally occurring antibody responses to recombinant protein domains of Plasmodium falciparum erythrocyte membrane protein 1.

Background: Antibodies targeting variant antigens expressed on the surface of Plasmodium falciparum infected erythrocytes have been associated with protection from clinical malaria. The precise target for these antibodies is unknown. The best characterized and most likely target is the erythrocyte surface-expressed variant protein family Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1).

Relationship between exposure, clinical malaria, and age in an area of changing transmission intensity.

The relationship between malaria transmission intensity and clinical disease is important for predicting the outcome of control measures that reduce transmission. Comparisons of hospital data between areas of differing transmission intensity suggest that the mean age of hospitalized clinical malaria is higher under relatively lower transmission, but the total number of episodes is similar until transmission drops below a threshold, where the risks of hospitalized malaria decline. These observations have rarely been examined longitudinally in a single community where transmission declines over time.

Failure to respond to the surface of Plasmodium falciparum infected erythrocytes predicts susceptibility to clinical malaria amongst African children.

Following infection with Plasmodium falciparum malaria, children in endemic areas develop antibodies specific to antigens on the parasite-infected red cell surface of the infecting isolate, antibodies associated with protection against subsequent infection with that isolate. In some circumstances induction of antibodies to heterologous parasite isolates also occurs and this has been suggested as evidence for cross-reactivity of responses against the erythrocyte surface. The role of these relatively cross-reactive antibodies in protection from clinical malaria is currently unknown.

Evidence for over-dispersion in the distribution of clinical malaria episodes in children.

Background: It may be assumed that patterns of clinical malaria in children of similar age under the same level of exposure would follow a Poisson distribution with no over-dispersion. Longitudinal studies that have been conducted over many years suggest that some children may experience more episodes of clinical malaria than would be expected. The aim of this study was to identify this group of children and investigate possible causes for this increased susceptibility.

Correlation of memory T cell responses against TRAP with protection from clinical malaria, and CD4 CD25 high T cells with susceptibility in Kenyans.

Background: Immunity to malaria develops naturally in endemic regions, but the protective immune mechanisms are poorly understood. Many vaccination strategies aim to induce T cells against diverse pre-erythrocytic antigens, but correlates of protection in the field have been limited. The objective of this study was to investigate cell-mediated immune correlates of protection in natural malaria.

Breadth and magnitude of antibody responses to multiple Plasmodium falciparum merozoite antigens are associated with protection from clinical malaria.

Individuals living in areas where malaria is endemic are repeatedly exposed to many different malaria parasite antigens. Studies on naturally acquired antibody-mediated immunity to clinical malaria have largely focused on the presence of responses to individual antigens and their associations with decreased morbidity. We hypothesized that the breadth (number of important targets to which antibodies were made) and magnitude (antibody level measured in a random serum sample) of the antibody response were important predictors of protection from clinical malaria.

Helminth infection and eosinophilia and the risk of Plasmodium falciparum malaria in 1- to 6-year-old children in a malaria endemic area.

Background: Helminth infection is common in malaria endemic areas, and an interaction between the two would be of considerable public health importance. Animal models suggest that helminth infections may increase susceptibility to malaria, but epidemiological data has been limited and contradictory.

Methodology/principal Findings: In a vaccine trial, we studied 387 one- to six-year-old children for the effect of helminth infections on febrile Plasmodium falciparum malaria episodes.

Clearing asymptomatic parasitaemia increases the specificity of the definition of mild febrile malaria.

In clinical trials, the specificity of the disease endpoint is critical to an accurate estimate of vaccine efficacy. We used a logistic regression model to analyse parasite densities among children before and after treatment with antimalarials, in order to estimate the impact that clearing asymptomatic parasitaemia had on the specificity of the endpoint of febrile malaria. The malaria attributable fever fraction was higher after antimalarial treatment (i.

The induction and persistence of T cell IFN-gamma responses after vaccination or natural exposure is suppressed by Plasmodium falciparum.

Epidemiological observations suggest that T cell immunity may be suppressed in malaria-endemic areas. In vitro studies, animal models, and limited data in humans link immunosuppression with malaria, malnutrition, and other parasitic infections. However, there are no data to determine whether malaria-induced immunosuppression is significant in the long-term, or relative data comparing it with other factors in malaria-endemic areas, so as to measure the impact of malaria, other parasitic disease, nutritional status, age.

Defining childhood severe falciparum malaria for intervention studies.

Background: Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials.

Extended follow-up following a phase 2b randomized trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya.

Background: "FFM ME-TRAP" is sequential immunisation with two attenuated poxvirus vectors (FP9 and modified vaccinia virus Ankara) delivering the pre-erythrocytic malaria antigen ME-TRAP. Over nine months follow-up in our original study, there was no evidence that FFM ME-TRAP provided protection against malaria. The incidence of malaria was slightly higher in children who received FFM ME-TRAP, but this was not statistically significant (hazard ratio 1.