Vaccine equity: Past, present, and future.

The term "vaccine equity" primarily points to the enormous imbalance in global COVID-19 vaccine distribution. Vaccine equity should adopt a normative approach toward "health equity," and various stakeholders across the vaccine life cycle must practice it. The momentum gathered during this pandemic must be used to correct these structural imbalances.

Disentangling a complex nationwide Salmonella Dublin outbreak associated with raw-milk cheese consumption, France, 2015 to 2016.

On 18 January 2016, the French National Reference Centre for Salmonella reported to Santé publique France an excess of Salmonella enterica serotype Dublin (S. Dublin) infections. We investigated to identify the source of infection and implement control measures. Whole genome sequencing (WGS) and multilocus variable-number tandem repeat analysis (MLVA) were performed to identify microbiological clusters and links among cases, animal and food sources. Clusters were defined as isolates with less than 15 single nucleotide polymorphisms determined by WGS and/or with identical MLVA pattern. We compared different clusters of cases with other cases (case-case study) and controls recruited from a web-based cohort (case-control study) in terms of food consumption. We interviewed 63/83 (76%) cases; 2,914 controls completed a questionnaire. Both studies' findings indicated that successive S. Dublin outbreaks from different sources had occurred between November 2015 and March 2016. In the case-control study, cases of distinct WGS clusters were more likely to have consumed Morbier (adjusted odds ratio (aOR): 14; 95% confidence interval (CI): 4.8-42) or Vacherin Mont d'Or (aOR: 27; 95% CI: 6.8-105), two bovine raw-milk cheeses. Based on these results, the Ministry of Agriculture launched a reinforced control plan for processing plants of raw-milk cheeses in the production region, to prevent future outbreaks.

Factors associated with high heterogeneity of malaria at fine spatial scale in the Western Kenyan highlands.

BACKGROUND: The East African highlands are fringe regions between stable and unstable malaria transmission. What factors contribute to the heterogeneity of malaria exposure on different spatial scales within larger foci has not been extensively studied. In a comprehensive, community-based cross-sectional survey an attempt was made to identify factors that drive the macro- and micro epidemiology of malaria in a fringe region using parasitological and serological outcomes. METHODS: A large cross-sectional survey including 17,503 individuals was conducted across all age groups in a 100 km(2) area in the Western Kenyan highlands of Rachuonyo South district. Households were geo-located and prevalence of malaria parasites and malaria-specific antibodies were determined by PCR and ELISA. Household and individual risk-factors were recorded. Geographical characteristics of the study area were digitally derived using high-resolution satellite images. RESULTS: Malaria antibody prevalence strongly related to altitude (1350-1600 m, p < 0.001). A strong negative association with increasing altitude and PCR parasite prevalence was found. Parasite carriage was detected at all altitudes and in all age groups; 93.2 % (2481/2663) of malaria infections were apparently asymptomatic. Malaria parasite prevalence was associated with age, bed net use, house construction features, altitude and topographical wetness index. Antibody prevalence was associated with all these factors and distance to the nearest water body. CONCLUSION: Altitude was a major driver of malaria transmission in this study area, even across narrow altitude bands. The large proportion of asymptomatic parasite carriers at all altitudes and the age-dependent acquisition of malaria antibodies indicate stable malaria transmission; the strong correlation between current parasite carriage and serological markers of malaria exposure indicate temporal stability of spatially heterogeneous transmission.

The Impact of Hotspot-Targeted Interventions on Malaria Transmission in Rachuonyo South District in the Western Kenyan Highlands: A Cluster-Randomized Controlled Trial.

BACKGROUND: Malaria transmission is highly heterogeneous, generating malaria hotspots that can fuel malaria transmission across a wider area. Targeting hotspots may represent an efficacious strategy for reducing malaria transmission. We determined the impact of interventions targeted to serologically defined malaria hotspots on malaria transmission both inside hotspots and in surrounding communities. METHODS AND FINDINGS: Twenty-seven serologically defined malaria hotspots were detected in a survey conducted from 24 June to 31 July 2011 that included 17,503 individuals from 3,213 compounds in a 100-km2 area in Rachuonyo South District, Kenya. In a cluster-randomized trial from 22 March to 15 April 2012, we randomly allocated five clusters to hotspot-targeted interventions with larviciding, distribution of long-lasting insecticide-treated nets, indoor residual spraying, and focal mass drug administration (2,082 individuals in 432 compounds); five control clusters received malaria control following Kenyan national policy (2,468 individuals in 512 compounds). Our primary outcome measure was parasite prevalence in evaluation zones up to 500 m outside hotspots, determined by nested PCR (nPCR) at baseline and 8 wk (16 June-6 July 2012) and 16 wk (21 August-10 September 2012) post-intervention by technicians blinded to the intervention arm. Secondary outcome measures were parasite prevalence inside hotpots, parasite prevalence in the evaluation zone as a function of distance from the hotspot boundary, Anopheles mosquito density, mosquito breeding site productivity, malaria incidence by passive case detection, and the safety and acceptability of the interventions. Intervention coverage exceeded 87% for all interventions. Hotspot-targeted interventions did not result in a change in nPCR parasite prevalence outside hotspot boundaries (p ≥ 0.187). We observed an average reduction in nPCR parasite prevalence of 10.2% (95% CI -1.3 to 21.7%) inside hotspots 8 wk post-intervention that was statistically significant after adjustment for covariates (p = 0.024), but not 16 wk post-intervention (p = 0.265). We observed no statistically significant trend in the effect of the intervention on nPCR parasite prevalence in the evaluation zone in relation to distance from the hotspot boundary 8 wk (p = 0.27) or 16 wk post-intervention (p = 0.75). Thirty-six patients with clinical malaria confirmed by rapid diagnostic test could be located to intervention or control clusters, with no apparent difference between the study arms. In intervention clusters we caught an average of 1.14 female anophelines inside hotspots and 0.47 in evaluation zones; in control clusters we caught an average of 0.90 female anophelines inside hotspots and 0.50 in evaluation zones, with no apparent difference between study arms. Our trial was not powered to detect subtle effects of hotspot-targeted interventions nor designed to detect effects of interventions over multiple transmission seasons. CONCLUSIONS: Despite high coverage, the impact of interventions targeting malaria vectors and human infections on nPCR parasite prevalence was modest, transient, and restricted to the targeted hotspot areas. Our findings suggest that transmission may not primarily occur from hotspots to the surrounding areas and that areas with highly heterogeneous but widespread malaria transmission may currently benefit most from an untargeted community-wide approach. Hotspot-targeted approaches may have more validity in settings where human settlement is more nuclear. TRIAL REGISTRATION: ClinicalTrials.gov NCT01575613.

Is asymptomatic malaria really asymptomatic? Hematological, vascular and inflammatory effects of asymptomatic malaria parasitemia.

Asymptomatic malaria infections are highly prevalent in malaria endemic regions and most of these infections remain undiagnosed and untreated. Whereas conventional malaria symptoms are by definition absent, little is known on the more subtle health consequences of these infections. The aim of our study was to analyze the hematologic, vascular and inflammatory effects of patent and subpatent asymptomatic malaria parasitemia in children and adults on the Indonesian island Sumba. Both children and adults with parasitemia had increased high-sensitive C-reactive protein levels compared to aparasitemic individuals. In addition, children, but not adults with parasitemia also had lower platelet counts and Hb levels and higher levels of von Willebrand factor and platelet factor-4, markers of endothelial and platelet activation, respectively. These findings suggest that asymptomatic malaria infections have subtle health consequences, especially in children, and should be regarded as potentially harmful.

Focal Screening to Identify the Subpatent Parasite Reservoir in an Area of Low and Heterogeneous Transmission in the Kenya Highlands.

BACKGROUND: Mass screening and treatment currently fails to identify a considerable fraction of low parasite density infections, while mass treatment exposes many uninfected individuals to antimalarial drugs. Here we test a hybrid approach to screen a sentinel population to identify clusters of subpatent infections in the Kenya highlands with low, heterogeneous malaria transmission. METHODS: Two thousand eighty-two inhabitants were screened for parasitemia by nested polymerase chain reaction (nPCR). Children aged ≤ 15 years and febrile adults were also tested for malaria by rapid diagnostic test (RDT) and served as sentinel members to identify subpatent infections within the household. All parasitemic individuals were assessed for multiplicity of infections by nPCR and gametocyte carriage by nucleic acid sequence-based amplification. RESULTS: Households with RDT-positive individuals in the sentinel population were more likely to have nPCR-positive individuals (odds ratio: 1.71, 95% confidence interval, 1.60-1.84). The sentinel population identified 64.5% (locality range: 31.6%-81.2%) of nPCR-positive households and 77.3% (locality range: 24.2%-91.0%) of nPCR-positive individuals. The sensitivity of the sentinel screening approach was positively associated with transmission intensity (P = .037). CONCLUSIONS: In this low endemic area, a focal screening approach with RDTs prior to the high transmission season was able to identify the majority of the subpatent parasite reservoirs.

Modeling the cost effectiveness of malaria control interventions in the highlands of western Kenya.

INTRODUCTION: Tools that allow for in silico optimization of available malaria control strategies can assist the decision-making process for prioritizing interventions. The OpenMalaria stochastic simulation modeling platform can be applied to simulate the impact of interventions singly and in combination as implemented in Rachuonyo South District, western Kenya, to support this goal. METHODS: Combinations of malaria interventions were simulated using a previously-published, validated model of malaria epidemiology and control in the study area. An economic model of the costs of case management and malaria control interventions in Kenya was applied to simulation results and cost-effectiveness of each intervention combination compared to the corresponding simulated outputs of a scenario without interventions. Uncertainty was evaluated by varying health system and intervention delivery parameters. RESULTS: The intervention strategy with the greatest simulated health impact employed long lasting insecticide treated net (LLIN) use by 80% of the population, 90% of households covered by indoor residual spraying (IRS) with deployment starting in April, and intermittent screen and treat (IST) of school children using Artemether lumefantrine (AL) with 80% coverage twice per term. However, the current malaria control strategy in the study area including LLIN use of 56% and IRS coverage of 70% was the most cost effective at reducing disability-adjusted life years (DALYs) over a five year period. CONCLUSIONS: All the simulated intervention combinations can be considered cost effective in the context of available resources for health in Kenya. Increasing coverage of vector control interventions has a larger simulated impact compared to adding IST to the current implementation strategy, suggesting that transmission in the study area is not at a level to warrant replacing vector control to a school-based screen and treat program. These results have the potential to assist malaria control program managers in the study area in adding new or changing implementation of current interventions.

Malaria transmission after artemether-lumefantrine and dihydroartemisinin-piperaquine: a randomized trial.

BACKGROUND: Artemisinin-based combination therapy (ACT) reduces the potential for malaria transmission, compared with non-ACTs. It is unclear whether this effect differs between ACTs. METHODS: A total of 298 children (age, 6 months to 10 years) with uncomplicated falciparum malaria were randomized to artemether-lumefantrine (AL; n = 153) or dihydroartemisinin-piperaquine (DP; n = 145) in Mbita, a community in western Kenya. Gametocyte carriage was determined by molecular methods on days 0, 1, 2, 3, 7, 14, 28, and 42 after treatment initiation. The gametocyte infectiousness to mosquitoes was determined by mosquito-feeding assays on day 7 after beginning therapy. RESULTS: The cumulative risk of recurrent parasitemia on day 42 after initiation of treatment, unadjusted by polymerase chain reaction findings, was 20.7% (95% confidence interval [CI], 14.4-28.2) for AL, compared with 3.7% (95% CI, 1.2-8.5) for DP (P < .001). The mean duration of gametocyte carriage was 5.5 days (95% CI, 3.6-8.5) for AL and 15.3 days (95% CI, 9.7-24.2) for DP (P = .001). The proportion of mosquitoes that became infected after feeding on blood from AL-treated children was 1.88% (43 of 2293), compared with 3.50% (83 of 2371) for those that fed on blood from DP-treated children (P = .06); the oocyst burden among mosquitoes was lower among those that fed on blood from AL-treated children (P = .005) CONCLUSIONS: While DP was associated with a longer prophylactic time after treatment, gametocyte carriage and malaria transmission to mosquitoes was lower after AL treatment. CLINICAL TRIALS REGISTRATION: NCT00868465.

Effect of α(+)-thalassaemia on episodes of fever due to malaria and other causes: a community-based cohort study in Tanzania.

BACKGROUND: It is controversial to what degree α(+)-thalassaemia protects against episodes of uncomplicated malaria and febrile disease due to infections other than Plasmodium. METHODS: In Tanzania, in children aged 6-60 months and height-for-age z-score < -1.5 SD (n = 612), rates of fevers due to malaria and other causes were compared between those with heterozygous or homozygotes α(+)-thalassaemia and those with a normal genotype, using Cox regression models that accounted for multiple events per child. RESULTS: The overall incidence of malaria was 3.0/child-year (1, 572/526 child-years); no differences were found in malaria rates between genotypes (hazard ratios, 95% CI: 0.93, 0.82-1.06 and 0.91, 0.73-1.14 for heterozygotes and homozygotes respectively, adjusted for baseline factors that were predictive for outcome). However, this association strongly depended on age: among children aged 6-17 months, those with α(+)-thalassaemia experienced episodes more frequently than those with a normal genotype (1.30, 1.02-1.65 and 1.15, 0.80-1.65 for heterozygotes and homozygotes respectively), whereas among their peers aged 18-60 months, α(+)-thalassaemia protected against malaria (0.80, 0.68-0.95 and 0.78, 0.60-1.03; p-value for interaction 0.001 and 0.10 for hetero- and homozygotes respectively). No effect was observed on non-malarial febrile episodes. CONCLUSIONS: In this population, the association between α(+)-thalassaemia and malaria depends on age. Our data suggest that protection by α(+)-thalassaemia is conferred by more efficient acquisition of malaria-specific immunity.