Seasonal vaccination with RTS,S/AS01E vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: a double-blind, randomised, controlled, phase 3 trial.

BACKGROUND: Seasonal vaccination with the RTS,S/AS01E vaccine combined with seasonal malaria chemoprevention (SMC) prevented malaria in young children more effectively than either intervention given alone over a 3 year period. The objective of this study was to establish whether the added protection provided by the combination could be sustained for a further 2 years. METHODS: This was a double-blind, individually randomised, controlled, non-inferiority and superiority, phase 3 trial done at two sites: the Bougouni district and neighbouring areas in Mali and Houndé district, Burkina Faso. Children who had been enrolled in the initial 3-year trial when aged 5-17 months were initially randomly assigned individually to receive SMC with sulphadoxine-pyrimethamine and amodiaquine plus control vaccines, RTS,S/AS01E plus placebo SMC, or SMC plus RTS,S/AS01E. They continued to receive the same interventions until the age of 5 years. The primary trial endpoint was the incidence of clinical malaria over the 5-year trial period in both the modified intention-to-treat and per-protocol populations. Over the 5-year period, non-inferiority was defined as a 20% increase in clinical malaria in the RTS,S/AS01E-alone group compared with the SMC alone group. Superiority was defined as a 12% difference in the incidence of clinical malaria between the combined and single intervention groups. The study is registered with ClinicalTrials.gov, NCT04319380, and is complete. FINDINGS: In April, 2020, of 6861 children originally recruited, 5098 (94%) of the 5433 children who completed the initial 3-year follow-up were re-enrolled in the extension study. Over 5 years, the incidence of clinical malaria per 1000 person-years at risk was 313 in the SMC alone group, 320 in the RTS,S/AS01E-alone group, and 133 in the combined group. The combination of RTS,S/AS01E and SMC was superior to SMC (protective efficacy 57·7%, 95% CI 53·3 to 61·7) and to RTS,S/AS01E (protective efficacy 59·0%, 54·7 to 62·8) in preventing clinical malaria. RTS,S/AS01E was non-inferior to SMC (hazard ratio 1·03 [95% CI 0·95 to 1·12]). The protective efficacy of the combination versus SMC over the 5-year period of the study was very similar to that seen in the first 3 years with the protective efficacy of the combination versus SMC being 57·7% (53·3 to 61·7) and versus RTS/AS01E-alone being 59·0% (54·7 to 62·8). The comparable figures for the first 3 years of the study were 62·8% (58·4 to 66·8) and 59·6% (54·7 to 64·0%), respectively. Hospital admissions for WHO-defined severe malaria were reduced by 66·8% (95% CI 40·3 to 81·5), for malarial anaemia by 65·9% (34·1 to 82·4), for blood transfusion by 68·1% (32·6 to 84·9), for all-cause deaths by 44·5% (2·8 to 68·3), for deaths excluding external causes or surgery by 41·1% (-9·2 to 68·3), and for deaths from malaria by 66·8% (-2·7 to 89·3) in the combined group compared with the SMC alone group. No safety signals were detected. INTERPRETATION: Substantial protection against malaria was sustained over 5 years by combining seasonal malaria vaccination with seasonal chemoprevention, offering a potential new approach to malaria control in areas with seasonal malaria transmission. FUNDING: UK Joint Global Health Trials and PATH's Malaria Vaccine Initiative (through a grant from the Bill & Melinda Gates Foundation). TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Higher platelet counts and platelet factors are associated with a reduction in Plasmodium falciparum parasite density in young Malian children.

OBJECTIVES: The association between thrombocytopenia and parasite density or disease severity is described in numerous studies. In recent years, several studies described the protective role of platelets in directly killing Plasmodium parasites, mediated by platelet factor 4 (PF4) binding to Duffy antigen. This study aimed to evaluate the protective role of platelets in young children who are Duffy antigen-negative, such as those in sub-Saharan Africa. METHODS: A zero-inflated negative binomial model was used to relate platelet count and parasite density data collected in a longitudinal birth cohort. Platelet factors were measured by enzyme-linked immunosorbent assay in samples collected from malaria-infected children who participated in a cross-sectional study. RESULTS: We described that an increase of 10,000 platelets/µl was associated with a 2.76% reduction in parasite count. Increasing levels of PF4 and CXCL7 levels were also significantly associated with a reduction in parasite count. CONCLUSIONS: Platelets play a protective role in reducing parasite burden in Duffy-negative children, possibly mediated through activation of the innate immune system.

Spatio-Temporal Determinants of Dengue Epidemics in the Central Region of Burkina Faso.

The aim of this study was to analyze the spatio-temporal distribution and determinants of the 2017 dengue epidemic in Burkina Faso. A principal component analysis of meteorological and environmental factors was performed to reduce dimensions and avoid collinearities. An initial generalized additive model assessed the impact of the components derived from this analysis on dengue incidence. Dengue incidence increased mainly with relative humidity, precipitation, normalized difference vegetation index and minimum temperature with an 8-week lag. A Kulldoff Satscan scan was used to identify high-risk dengue clusters, and a second generalized additive model assessed the risk of a health area being at high risk according to land-use factors. The spatio-temporal distribution of dengue fever was heterogeneous and strongly correlated with meteorological factors. The rural communes of Sabaa and Koubri were the areas most at risk. This study provides useful information for planning targeted dengue control strategies in Burkina Faso.

Additional payment despite free health care in Burkina Faso / Paiement additionnel malgré la gratuité des soins au Burkina Faso

Introduction: Free health care for children under five years of age in Burkina Faso was introduced in 2016 in order to remove the financial barrier to accessing care. Additional health expenses remain despite this free health care, which may compromise access to health services for the poorest patients. Methods: This partial medico-economic evaluation included a descriptive study of additional health expenses paid by parents. Payment receipts and parents' declarations were consulted. Results: The average monthly income of the parents was 73,026.79 FCFA ($132) with 5.08% of the parents having no income. The total direct cost was 6,043,785 FCFA ($10939). The total additional direct cost was 2,181,150 FCFA ($3,950) or 36.09% of the total direct cost. The average percentage of free care was 65.50%. 7.7% of parents were dissatisfied with the free schooling. 34.48% were unprepared for additional expenses, 43.97% of parents had difficulty paying the additional costs and of these 80% reported that they had exhausted their savings to meet the prescriptions. Conclusions: Additional health expenses remain high despite free care. This can compromise the care of the poorest patients. A reorganization of free health care is necessary.

Introduction: La gratuité des soins chez les enfants de moins de 5 ans au Burkina Faso a été introduite en 2016 afin de lever la barrière financière dans l'accès aux soins. Des dépenses de santé additionnelles subsisteraient malgré cette gratuité, ce qui peut compromettre l'accès aux services de santé des patients les plus démunis. Méthodes: Il s'agit d'une évaluation médico-économique partielle, notamment l'étude descriptive des dépenses de santé additionnelles payées par les parents. Nous avons consulté les reçus de paiement et les déclarations des parents. Résultats: Le revenu mensuel des parents était en moyenne de 73 026,79 FCFA (132 $) avec 5,08 % des parents qui n'ont pas de revenu. Le coût direct total était de 6 043 785 FCFA (10 939 $). Le coût direct total additionnel était de 2 181 150 FCFA (3 950 $), soit 36,09 % du coût direct total. Le pourcentage moyen de prise en charge de la gratuité était de 65,50 %. Près de 10 % (7,7 %) des parents étaient insatisfaits de la gratuité ; ils étaient 34,48 % à ne pas être préparés à honorer des dépenses supplémentaires, 43,97 % avaient eu du mal à payer les frais supplémentaires et parmi ces derniers, 80 % ont déclaré avoir épuisé leur économie pour honorer les prescriptions. Conclusions: Les dépenses de santé additionnelles restent élevées malgré la gratuité des soins. Cela peut compromettre la prise en charge des patients les plus pauvres. Une réorganisation de la gratuité des soins s'avère nécessaire.

Delivery strategies for malaria vaccination in areas with seasonal malaria transmission.

BACKGROUND: Seasonal vaccination with the RTS,S/AS01E malaria vaccine given alongside seasonal malaria chemoprevention (SMC) substantially reduces malaria in young children. The WHO has recommended the use of RTS,S/AS01E, including seasonal vaccination, in areas with seasonal malaria transmission. This study aimed to identify potential strategies to deliver RTS,S/AS01E, and assess the considerations and recommendations for delivery of seasonal malaria vaccination in Mali, a country with highly seasonal malaria. METHODS: Potential delivery strategies for RTS,S/AS01E in areas with seasonal malaria were identified through a series of high level discussions with the RTS,S/AS01E plus SMC trial investigators, international and national immunisation and malaria experts, and through the development of a theory of change. These were explored through qualitative in-depth interviews with 108 participants, including national-level, regional-level and district-level malaria and immunisation programme managers, health workers, caregivers of children under 5 years of age, and community stakeholders. A national-level workshop was held to confirm the qualitative findings and work towards consensus on an appropriate strategy. RESULTS: Four delivery strategies were identified: age-based vaccination delivered via the Essential Programme on Immunisation (EPI); seasonal vaccination via EPI mass vaccination campaigns (MVCs); a combination of age-based priming vaccination doses delivered via the EPI clinics and seasonal booster doses delivered via MVCs; and a combination of age-based priming vaccination doses and seasonal booster doses, all delivered via the EPI clinics, which was the preferred strategy for delivery of RTS,S/AS01E in Mali identified during the national workshop. Participants recommended that supportive interventions, including communications and mobilisation, would be needed for this strategy to achieve required coverage. CONCLUSIONS: Four delivery strategies were identified for administration of RTS,S/AS01E alongside SMC in countries with seasonal malaria transmission. Components of these delivery strategies were defined as the vaccination schedule, and the delivery system(s) plus the supportive interventions needed for the strategies to be effective. Further implementation research and evaluation is needed to explore how, where, when and what effective coverage is achievable via these new strategies and their supportive interventions.

Cost of introducing and delivering malaria vaccine (RTS,S/AS01E) in areas of seasonal malaria transmission, Mali and Burkina Faso.

BACKGROUND: The WHO recommends use of the RTS,S/AS01E (RTS,S) malaria vaccine for young children living in areas of moderate to high Plasmodium falciparum malaria transmission and suggests countries consider seasonal vaccination in areas with highly seasonal malaria. Seasonal vaccination is uncommon and may require adaptations with potential cost consequences. This study prospectively estimates cost of seasonal malaria vaccine delivery in Mali and Burkina Faso. METHODS: Three scenarios for seasonal vaccine delivery are costed (1) mass campaign only, (2) routine Expanded Programme on Immunisation (EPI) and (3) mixed delivery (mass campaign and routine EPI)), from the government's perspective. Resource use data are informed by previous new vaccine introductions, supplemented with primary data from a sample of health facilities and administrative units. FINDINGS: At an assumed vaccine price of US $5 per dose, the economic cost per dose administered ranges between $7.73 and $8.68 (mass campaign), $7.04 and $7.38 (routine EPI) and $7.26 and $7.93 (mixed delivery). Excluding commodities, the cost ranges between $1.17 and $2.12 (mass campaign), $0.48 and $0.82 (routine EPI) and $0.70 and $1.37 (mixed delivery). The financial non-commodity cost per dose administered ranges between $0.99 and $1.99 (mass campaign), $0.39 and $0.76 (routine EPI) and $0.58 and $1.28 (mixed delivery). Excluding commodity costs, service delivery is the main cost driver under the mass campaign scenario, accounting for 36% to 55% of the financial cost. Service delivery accounts for 2%-8% and 12%-23% of the total financial cost under routine EPI and mixed delivery scenarios, respectively. CONCLUSION: Vaccine delivery using the mass campaign approach is most costly followed by mixed delivery and routine EPI delivery approaches, in both countries. Our cost estimates provide useful insights for decisions regarding delivery approaches, as countries plan the malaria vaccine rollout.

Correlates of dietary diversity among children aged 6-23 months of head porters in Ghana.

Objective: In many developing countries, most children cannot meet minimum dietary diversity (MDD), defined as the consumption of four or more of the seven food groups. In Ghana, only 35% of children met MDD nationwide in 2017, but rates are worse among the rural poor and resource-constrained individuals like Head Porters (HPs). The current study investigated the correlates of MDD in children of HPs aged 6-23 months old in Ghana. Methods and materials: A cross-sectional survey was carried out in 2021 among 423 HPs selected purposively from eight market centers in two commercial cities. A multi-stage sampling method was used in obtaining the sample, while a structured interview guide was used to collect data from the caregivers. Stata version 15.1 and descriptive and inferential statistics like frequency, percentage, chi-square and logistic regression were used to analyze the data. All results were deemed significant if the p-value was < 0.05 and the odds ratios with a 95% confidence interval. Results: The children had a mean age of 14.3 (±4.9) months, while half of the caregivers (48.2%) were between 15 and 25 years. Approximately 59% (251) had good knowledge of infant and young child feeding practices (IYCF). About 45% of the children consumed a diversified diet. The number of postnatal care (PNC) visits, delivery in a health facility, meeting minimum meal frequency (MMF), and the child's age was independently associated with MDD at the multivariate level. Conclusion: Over a third of the caregivers had poor knowledge of IYCF practices. Furthermore, less than half of the children achieved MDD reflecting the need for more education by the stakeholders. Regular PNC visits and delivery in health facilities were independently associated with MDD; therefore, interventions to combat low MDD should prioritize the relevance of these predictors.

The duration of protection against clinical malaria provided by the combination of seasonal RTS,S/AS01E vaccination and seasonal malaria chemoprevention versus either intervention given alone.

BACKGROUND: A recent trial of 5920 children in Burkina Faso and Mali showed that the combination of seasonal vaccination with the RTS,S/AS01E malaria vaccine (primary series and two seasonal boosters) and seasonal malaria chemoprevention (four monthly cycles per year) was markedly more effective than either intervention given alone in preventing clinical malaria, severe malaria, and deaths from malaria. METHODS: In order to help optimise the timing of these two interventions, trial data were reanalysed to estimate the duration of protection against clinical malaria provided by RTS,S/AS01E when deployed seasonally, by comparing the group who received the combination of SMC and RTS,S/AS01E with the group who received SMC alone. The duration of protection from SMC was also estimated comparing the combined intervention group with the group who received RTS,S/AS01E alone. Three methods were used: Piecewise Cox regression, Flexible parametric survival models and Smoothed Schoenfeld residuals from Cox models, stratifying on the study area and using robust standard errors to control for within-child clustering of multiple episodes. RESULTS: The overall protective efficacy from RTS,S/AS01E over 6 months was at least 60% following the primary series and the two seasonal booster doses and remained at a high level over the full malaria transmission season. Beyond 6 months, protective efficacy appeared to wane more rapidly, but the uncertainty around the estimates increases due to the lower number of cases during this period (coinciding with the onset of the dry season). Protection from SMC exceeded 90% in the first 2-3 weeks post-administration after several cycles, but was not 100%, even immediately post-administration. Efficacy begins to decline from approximately day 21 and then declines more sharply after day 28, indicating the importance of preserving the delivery interval for SMC cycles at a maximum of four weeks. CONCLUSIONS: The efficacy of both interventions was highest immediately post-administration. Understanding differences between these interventions in their peak efficacy and how rapidly efficacy declines over time will help to optimise the scheduling of SMC, malaria vaccination and the combination in areas of seasonal transmission with differing epidemiology, and using different vaccine delivery systems. TRIAL REGISTRATION: The RTS,S-SMC trial in which these data were collected was registered at clinicaltrials.gov: NCT03143218.

Recent malaria does not substantially impact COVID-19 antibody response or rates of symptomatic illness in communities with high malaria and COVID-19 transmission in Mali, West Africa.

Malaria has been hypothesized as a factor that may have reduced the severity of the COVID-19 pandemic in sub-Saharan Africa. To evaluate the effect of recent malaria on COVID-19 we assessed a subgroup of individuals participating in a longitudinal cohort COVID-19 serosurvey that were also undergoing intensive malaria monitoring as part of antimalarial vaccine trials during the 2020 transmission season in Mali. These communities experienced a high incidence of primarily asymptomatic or mild COVID-19 during 2020 and 2021. In 1314 individuals, 711 were parasitemic during the 2020 malaria transmission season; 442 were symptomatic with clinical malaria and 269 had asymptomatic infection. Presence of parasitemia was not associated with new COVID-19 seroconversion (29.7% (211/711) vs. 30.0% (181/603), p=0.9038) or with rates of reported symptomatic seroconversion during the malaria transmission season. In the subsequent dry season, prior parasitemia was not associated with new COVID-19 seroconversion (30.2% (133/441) vs. 31.2% (108/346), p=0.7499), with symptomatic seroconversion, or with reversion from seropositive to seronegative (prior parasitemia: 36.2% (64/177) vs. no parasitemia: 30.1% (37/119), p=0.3842). After excluding participants with asymptomatic infection, clinical malaria was also not associated with COVID-19 serostatus or symptomatic seroconversion when compared to participants with no parasitemia during the monitoring period. In communities with intense seasonal malaria and a high incidence of asymptomatic or mild COVID-19, we did not demonstrate a relationship between recent malaria and subsequent response to COVID-19. Lifetime exposure, rather than recent infection, may be responsible for any effect of malaria on COVID-19 severity.

Climate factors and dengue fever in Burkina Faso from 2017 to 2019.

Dengue is now a major health concern in sub-Saharan Africa. Understanding the influence of local meteorological factors on the incidence of dengue is an important element for better prediction and control of this disease. This study aims to assess the impact of meteorological factors on dengue transmission in the central region of Burkina Faso. We analyzed the lagged effects of meteorological factors on the weekly incidence of dengue from 2017 to 2019 in the central region of Burkina Faso using a General Additive Model. The results show that maximum and minimum temperature, relative humidity, and wind speed have a significant non-linear effect on dengue cases in the region with 83% of case variance explained. The optimal temperature that increases dengue cases was 27°C to 32°C for the maximum temperature and 18°C to 20°C for the minimum temperature with a decrease beyond that. The maximum temperature shifted by six weeks had the best correlation with dengue incidence. The estimated number of dengue cases increases as the maximum relative humidity increases from 15 to 45% and then from 60 to 70%. In general, an increase in daily wind speed is estimated to decrease the number of daily dengue cases. The relationship between rainfall and dengue cases was not significant. This study provides local information about the effect of meteorological factors on dengue that should help improve predictive models of dengue cases in Burkina Faso and contribute to the control of this disease.

Spatiotemporal analysis of dengue fever in Burkina Faso from 2016 to 2019.

BACKGROUND: Burkina Faso experienced an epidemic resurgence of dengue in 2016, which led to the implementation of several control strategies. In order to allow a better adaptation of these strategies, we studied the spatio-temporal distribution of dengue. METHODS: Monthly dengue cases from 2016 to 2019, aggregated at the health district level, were used to map the crude incidence, excess risk, and smoothed incidence of dengue in Burkina Faso with GeoDa software. A Kulldoff scan on Satscan software was then used to identify spatio-temporal clustering of cases. RESULTS: The results show that the distribution of dengue fever across the health districts of Burkina Faso is heterogeneous. Dengue was considered non-endemic in 9 out of the 70 health districts, minimally endemic in 45 districts (< 10 incidences), moderately endemic (10-100 incidences) in 12 districts, and highly endemic (> 100 incidences) in 4 districts. The main cluster covered the health districts of Baskuy, Nongr-massom, Sig-noghin, Boulmiougou, and Bogodogo. The months of October and November corresponded to the peak of cases and a significant temporal cluster in 2017. CONCLUSION: This study identified the spatial and temporal clustering of dengue cases in Burkina Faso. These results may help to develop better preventive strategies.

Impact of seasonal RTS,S/AS01E vaccination plus seasonal malaria chemoprevention on the nutritional status of children in Burkina Faso and Mali.

BACKGROUND: A recent trial in Burkina Faso and Mali showed that combining seasonal RTS,S/AS01E malaria vaccination with seasonal malaria chemoprevention (SMC) substantially reduced the incidence of uncomplicated and severe malaria in young children compared to either intervention alone. Given the possible negative effect of malaria on nutrition, the study investigated whether these children also experienced lower prevalence of acute and chronic malnutrition. METHODS: In Burkina Faso and Mali 5920 children were randomized to receive either SMC alone, RTS,S/AS01E alone, or SMC combined with RTS,S/AS01E for three malaria transmission seasons (2017-2019). After each transmission season, anthropometric measurements were collected from all study children at a cross-sectional survey and used to derive nutritional status indicators, including the binary variables wasted and stunted (weight-for-height and height-for-age z-scores below - 2, respectively). Binary and continuous outcomes between treatment groups were compared by Poisson and linear regression. RESULTS: In 2017, compared to SMC alone, the combined intervention reduced the prevalence of wasting by approximately 12% [prevalence ratio (PR) = 0.88 (95% CI 0.75, 1.03)], and approximately 21% in 2018 [PR = 0.79 (95% CI 0.62, 1.01)]. Point estimates were similar for comparisons with RTS,S/AS01E, but there was stronger evidence of a difference. There was at least a 30% reduction in the point estimates for the prevalence of severe wasting in the combined group compared to the other two groups in 2017 and 2018. There was no difference in the prevalence of moderate or severe wasting between the groups in 2019. The prevalence of stunting, low-MUAC-for-age or being underweight did not differ between groups for any of the three years. The prevalence of severe stunting was higher in the combined group compared to both other groups in 2018, and compared to RTS,S/AS01E alone in 2017; this observation does not have an obvious explanation and may be a chance finding. Overall, malnutrition was very common in this cohort, but declined over the study as the children became older. CONCLUSIONS: Despite a high burden of malnutrition and malaria in the study populations, and a major reduction in the incidence of malaria in children receiving both interventions, this had only a modest impact on nutritional status. Therefore, other interventions are needed to reduce the high burden of malnutrition in these areas. TRIAL REGISTRATION: https://www.clinicaltrials.gov/ct2/show/NCT03143218 , registered 8th May 2017.

The Anti-Circumsporozoite Antibody Response of Children to Seasonal Vaccination With the RTS,S/AS01E Malaria Vaccine.

BACKGROUND: A trial in African children showed that combining seasonal vaccination with the RTS,S/AS01E vaccine with seasonal malaria chemoprevention reduced the incidence of uncomplicated and severe malaria compared with either intervention given alone. Here, we report on the anti-circumsporozoite antibody response to seasonal RTS,S/AS01E vaccination in children in this trial. METHODS: Sera from a randomly selected subset of children collected before and 1 month after 3 priming doses of RTS,S/AS01E and before and 1 month after 2 seasonal booster doses were tested for anti-circumsporozoite antibodies using enzyme-linked immunosorbent assay. The association between post-vaccination antibody titer and incidence of malaria was explored. RESULTS: A strong anti-circumsporozoite antibody response to 3 priming doses of RTS,S/AS01E was seen (geometric mean titer, 368.9 enzyme-linked immunosorbent assay units/mL), but titers fell prior to the first booster dose. A strong antibody response to an annual, pre-malaria transmission season booster dose was observed, but this was lower than after the primary vaccination series and lower after the second than after the first booster dose (ratio of geometric mean rise, 0.66; 95% confidence interval [CI], .57-.77). Children whose antibody response was in the upper tercile post-vaccination had a lower incidence of malaria during the following year than children in the lowest tercile (hazard ratio, 0.43; 95% CI, .28-.66). CONCLUSIONS: Seasonal vaccination with RTS,S/AS01E induced a strong booster antibody response that was lower after the second than after the first booster dose. The diminished antibody response to the second booster dose was not associated with diminished efficacy. CLINICAL TRIALS REGISTRATION: NCT03143218.

Seasonal Malaria Vaccination with or without Seasonal Malaria Chemoprevention.

BACKGROUND: Malaria control remains a challenge in many parts of the Sahel and sub-Sahel regions of Africa. METHODS: We conducted an individually randomized, controlled trial to assess whether seasonal vaccination with RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria and whether the two interventions combined were superior to either one alone in preventing uncomplicated malaria and severe malaria-related outcomes. RESULTS: We randomly assigned 6861 children 5 to 17 months of age to receive sulfadoxine-pyrimethamine and amodiaquine (2287 children [chemoprevention-alone group]), RTS,S/AS01E (2288 children [vaccine-alone group]), or chemoprevention and RTS,S/AS01E (2286 children [combination group]). Of these, 1965, 1988, and 1967 children in the three groups, respectively, received the first dose of the assigned intervention and were followed for 3 years. Febrile seizure developed in 5 children the day after receipt of the vaccine, but the children recovered and had no sequelae. There were 305 events of uncomplicated clinical malaria per 1000 person-years at risk in the chemoprevention-alone group, 278 events per 1000 person-years in the vaccine-alone group, and 113 events per 1000 person-years in the combination group. The hazard ratio for the protective efficacy of RTS,S/AS01E as compared with chemoprevention was 0.92 (95% confidence interval [CI], 0.84 to 1.01), which excluded the prespecified noninferiority margin of 1.20. The protective efficacy of the combination as compared with chemoprevention alone was 62.8% (95% CI, 58.4 to 66.8) against clinical malaria, 70.5% (95% CI, 41.9 to 85.0) against hospital admission with severe malaria according to the World Health Organization definition, and 72.9% (95% CI, 2.9 to 92.4) against death from malaria. The protective efficacy of the combination as compared with the vaccine alone against these outcomes was 59.6% (95% CI, 54.7 to 64.0), 70.6% (95% CI, 42.3 to 85.0), and 75.3% (95% CI, 12.5 to 93.0), respectively. CONCLUSIONS: Administration of RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria. The combination of these interventions resulted in a substantially lower incidence of uncomplicated malaria, severe malaria, and death from malaria than either intervention alone. (Funded by the Joint Global Health Trials and PATH; ClinicalTrials.gov number, NCT03143218.).

Optimal anchoring of a foldamer inhibitor of ASF1 histone chaperone through backbone plasticity.

Sequence-specific oligomers with predictable folding patterns, i.e., foldamers, provide new opportunities to mimic α-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may notably contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as α helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a notable plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with nonpeptide oligourea segments is the resistance to proteolysis in human plasma, which was highly improved compared to the cognate α-helical peptide.

Community Health Worker Program Sustainability in Africa: Evidence From Costing, Financing, and Geospatial Analyses in Mali.

BACKGROUND: In Mali, community health workers (CHWs) deliver essential community care (ECC) to rural populations. The dominance of external funding for the program threatens the sustainability of this critical workforce as donor financing decreases. This article summarizes results of analyses aimed at assisting Mali's decision makers and leaders in initiating a transition to a sustainable CHW program supported by domestic funding through strategic and rational investment. METHODS: Data on ECC implementation norms, workforce, coverage, utilization, cost, and geospatial features were collected between 2016 and 2019. The data informed interlinked CHW financing analyses-situational, services costing, efficiency, and geospatial mapping. Analysis showed distribution of reported expenditures, estimates of required CHW funding, cost-saving options, and spatially visualized discrepancies between spending estimates and normative costs. RESULTS: Thirteen financing sources contributed to CHW program expenditures, 88% of which were from international donors, for a package of 23 curative, preventive, and promotive interventions. In 2015, the CHW program spent US$13.01 million; an estimated US$8.36 million would have been needed to achieve the same service volume under standard care protocols. Medicines and start-up training had US$6.88 million more than needed; supervision, program management, and recurrent training components were underfunded by US$2.2 million. Cost-saving opportunities of US$6.16 million were identified in 41 of 44 districts. Funding reallocation opportunities (after meeting technical efficiency requirements) were identified in 20 of 44 districts (US$2.56 million). Use of geospatial targeting and mapping suggests district- and village-level reallocation options for theoretical funding surpluses. CONCLUSION: CHW costs can be significantly reduced without sacrificing service technical quality. Spending can be geographically targeted to optimize service use by rural populations. Efficiency analyses provide evidence to build stronger engagement, support improved decision making, efficiently prioritize resources, and target investments for sustainable financing of CHW programs.

Climate disturbance impact assessment in West Africa: evidence from field survey and satellite imagery analysis.

Extreme drought events from climate disturbances are weakening livelihood and limiting agriculture and livestock production in the Sahel region. The lack of relevant information to anticipate coping measures has exacerbated impacts leading to climate adaptation failure in most parts. In this regard, the current research paper has collected important datasets with an objective to assess the impact of extreme drought events on household's livelihoods for better understanding impacts, local people's perception, and the changes on vegetation cover in order to support a robust adaptation strategy to drought. The study conducted a household survey and collected satellite data for comparative analysis. The first survey was conducted in 2013 to collect data from 465 household heads through a structured questionnaire. Supplementary focus group discussions (FGDs) were also conducted in 2018 to collect qualitative information from targeted respondents such as village leaders and members of other key groups including women and youth. Descriptive statistics and correlation coefficient matrix were used to characterize the impact on households' main livelihoods and logistic regression to predict people's perception on pasture depletion over the last 20 years. Satellite data were used to derive spectral vegetation of land covers and unsupervised classification indexes. Both individual survey and focus group discussions identified drought as the main climate constraint which reduced crop production, water and pastures. The logistic analysis revealed that if the respondent's major occupation is livestock, the probability to perceive a depletion of pasture will increase by 28%. Concurrently, the satellite image observation in perfect agreement with the field survey showed 6.78% and 6.01% losses of water surface and vegetation cover respectively between 1986 and 2016 in the study area. These findings showed that logistic regression coupled with satellite information can inform on past and future impacts which are extremely crucial for sound adaptation planning in the Sahel region.

Docking proteins and peptides under evolutionary constraints in Critical Assessment of PRediction of Interactions rounds 38 to 45.

Computational structural prediction of macromolecular interactions is a fundamental tool toward the global understanding of cellular processes. The Critical Assessment of PRediction of Interactions (CAPRI) community-wide experiment provides excellent opportunities for blind testing computational docking methods and includes original targets, thus widening the range of docking applications. Our participation in CAPRI rounds 38 to 45 enabled us to expand the way we include evolutionary information in structural predictions beyond our standard free docking InterEvDock pipeline. InterEvDock integrates a coarse-grained potential that accounts for interface coevolution based on joint multiple sequence alignments of two protein partners (co-alignments). However, even though such co-alignments could be built for none of the CAPRI targets in rounds 38 to 45, including host-pathogen and protein-oligosaccharide complexes and a redesigned interface, we identified multiple strategies that can be used to incorporate evolutionary constraints, which helped us to identify the most likely macromolecular binding modes. These strategies include template-based modeling where only local adjustments should be applied when query-template sequence identity is above 30% and larger perturbations are needed below this threshold; covariation-based structure prediction for individual protein partners; and the identification of evolutionarily conserved and structurally recurrent anchoring interface motifs. Overall, we submitted correct predictions among the top 5 models for 12 out of 19 interface challenges, including four High- and five Medium-quality predictions. Our top 20 models included correct predictions for three out of the five targets we missed in the top 5, including two targets for which misleading biological data led us to downgrade correct free docking models.

A Teledermatology Pilot Programme for the Management of Skin Diseases in Primary Health Care Centres: Experiences from a Resource-Limited Country (Mali, West Africa).

In sub-Saharan Africa, in particular in rural areas, patients have limited access to doctors with specialist skills in skin diseases. To address this issue, a teledermatology pilot programme focused on primary health centres was set up in Mali. This study was aimed at investigating the feasibility of this programme and its impact on the management of skin diseases. The programme was based on the store-and-forward model. Health care providers from 10 primary centres were trained to manage common skin diseases, to capture images of skin lesions, and to use an e-platform to post all cases beyond their expertise for dermatologists in order to obtain diagnosis and treatment recommendations. After training, the cases of 180 patients were posted by trained health workers on the platform. Ninety-six per cent of these patients were properly managed via the responses given by dermatologists. The mean time to receive the expert's response was 32 h (range: 13 min to 20 days). Analysis of all diseases diagnosed via the platform revealed a wide range of skin disorders. Our initiative hugely improved the management of all skin diseases in the targeted health centres. In developing countries, Internet accessibility and connection quality represent the main challenges when conducting teledermatology programmes.

Deterministic Search Methods for Computational Protein Design.

One main challenge in Computational Protein Design (CPD) lies in the exploration of the amino-acid sequence space, while considering, to some extent, side chain flexibility. The exorbitant size of the search space urges for the development of efficient exact deterministic search methods enabling identification of low-energy sequence-conformation models, corresponding either to the global minimum energy conformation (GMEC) or an ensemble of guaranteed near-optimal solutions. In contrast to stochastic local search methods that are not guaranteed to find the GMEC, exact deterministic approaches always identify the GMEC and prove its optimality in finite but exponential worst-case time. After a brief overview on these two classes of methods, we discuss the grounds and merits of four deterministic methods that have been applied to solve CPD problems. These approaches are based either on the Dead-End-Elimination theorem combined with A* algorithm (DEE/A*), on Cost Function Networks algorithms (CFN), on Integer Linear Programming solvers (ILP) or on Markov Random Fields solvers (MRF). The way two of these methods (DEE/A* and CFN) can be used in practice to identify low-energy sequence-conformation models starting from a pairwise decomposed energy matrix is detailed in this review.