Perceptions, attitudes, and willingness of healthcare and frontline workers to participate in an Ebola vaccine trial in Uganda.

BACKGROUND: Understanding the knowledge, perception and attitudes towards Ebola vaccines is an important factor in ensuring future use of these vaccines. A qualitative methods study embedded in an Ebola vaccine immunogenicity and safety trial (NCT04028349) was conducted to explore the knowledge and perceptions of healthcare (HCWs) and frontline workers (FLWs), about Ebola vaccines and their willingness to participate or recommend participation in Uganda. METHOD: We carried out focus group discussions and semi-structured interviews before and after vaccination, with 70 HCWs and FLWs who consented to participate in the trial, and in the qualitative component, from August to September 2019. Data were analysed using thematic content analysis. RESULTS: Respondents showed good knowledge about Ebola and the vaccines in general, and had wide access to information through several channels, including the study team. On prevention, particular attention was given to effective communication within health facilities. Misconceptions were mainly around route of transmission, animal origin and types of vaccines. Previous fears were based on rumours circulating in the community, mainly about the presence of the virus in the vaccine, side effects and intention to harm (e.g. by "the whites"), ultimately insisting on transparency, trust and involvement of local leaders. Acceptability of participation was motivated by the need to protect self and others, and the willingness to advance research. Majority were willing to recommend participation to their community. CONCLUSIONS: Overall, information sharing leads to a better understanding and acceptance of vaccine trials and a positive vaccination experience can be a deciding factor in the acceptance of others. Particular attention should be paid to involving the community in addressing misconceptions and fears, while ensuring that participants have access to vaccination sites in terms of transport, and that they are properly accommodated at the study site including staying for a reasonable period of time.

Correction: Effectiveness of a monthly schedule of follow-up for the treatment of uncomplicated severe acute malnutrition in Sokoto, Nigeria: A cluster randomized crossover trial.

[This corrects the article DOI: 10.1371/journal.pmed.1003923.].

Effect of amoxicillin on the gut microbiome of children with severe acute malnutrition in Madarounfa, Niger: a retrospective metagenomic analysis of a placebo-controlled trial.

BACKGROUND: Children with severe acute malnutrition are treated with antibiotics as outpatients. We aimed to determine the effect of 7 days of amoxicillin on acute and long-term changes to the gut microbiome and antibiotic resistome in children treated for severe acute malnutrition. METHODS: We conducted a secondary analysis of a randomised, double-blinded, placebo-controlled trial (NCT01613547) of amoxicillin in children (aged 6-59 months) with severe acute malnutrition treated as outpatients in Madarounfa, Niger. We randomly selected 161 children from the overall cohort (n=2399) for initial 12-week follow-up from Sept 23, 2013 to Feb 3, 2014. We selected a convenience sample of those 161 children, on the basis of anthropometric measures, for follow-up 2 years later (Sept 28 to Oct 27, 2015). Children provided faecal samples at baseline, week 1, week 4, week 8, week 12, and, for those in the 2-year follow-up cohort, week 104. We conducted metagenomic sequencing followed by microbiome and resistome profiling of faecal samples. 38 children without severe acute malnutrition and six children with severe acute malnutrition matching the baseline ages of the original cohort were used as reference controls. FINDINGS: In the 12-week follow-up group, amoxicillin led to an immediate decrease in gut microbiome richness from 37·6 species (95% CI 32·6-42·7) and Shannon diversity index (SDI) 2·18 (95% CI 1·97-2·39) at baseline to 27·7 species (95% CI 22·9-32·6) species and SDI 1·55 (95% CI 1·35-1·75) at week 1. Amoxicillin increased gut antibiotic resistance gene abundance to 6044 reads per kilobase million (95% CI 4704-7384) at week 1, up from 4800 (3391-6208) at baseline, which returned to baseline 3 weeks later. 35 children were included in the 2-year follow-up; the amoxicillin-treated children (n=22) had increased number of species in the gut microbiome compared with placebo-treated children (n=13; 60·7 [95% CI 54·7-66·6] vs 36·9 [29·4-44·3]). Amoxicillin-treated children had increased Prevotella spp and decreased Bifidobacterium spp relative to age-matched placebo-treated children, indicating a more mature, adult-like microbiome. INTERPRETATION: Amoxicillin treatment led to acute but not sustained increases in antimicrobial resistance genes and improved gut microbiome maturation 2 years after severe acute malnutrition treatment. FUNDING: Bill & Melinda Gates Foundation; Médecins sans Frontières Operational Center Paris; National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Edward Mallinckrodt Jr Foundation; Doris Duke Foundation.

Reflections on Participation in a Trial on Hydroxychloroquine as Prevention for COVID-19 among Health Workers in Niger.

In 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a rapidly emerging virus causing the coronavirus disease 2019 (COVID-19) pandemic, had no known effective prophylaxis and no widely available proven effective antiviral treatment. Hydroxychloroquine/Chloroquine was identified as an early potential therapeutic candidate drawing on evidence from reports of both in vitro and in vivo testing. A multicountry placebo-controlled randomized trial was set to evaluate the use of hydroxychloroquine/chloroquine to prevent infection in healthcare workers and staff working in a health facility involved in COVID-19 management. One of the sites of this trial was in Niger. In Niger, of the 240 persons who were provided information about the study and with whom participation was discussed, only five participants provided their informed consent. In this article, we describe the key difficulties encountered in the conduct of this trial from the perspective of the site study team. Among the difficulties, we recognize that the epidemic context, controversy surrounding hydroxychloroquine, vaccine rollout, participants' perspectives, and trial design had a major impact on participation.

Immunogenicity and safety of fractional doses of 17D-213 yellow fever vaccine in HIV-infected people in Kenya (YEFE): a randomised, double-blind, non-inferiority substudy of a phase 4 trial.

BACKGROUND: Evidence indicates that fractional doses of yellow fever vaccine are safe and sufficiently immunogenic for use during yellow fever outbreaks. However, there are no data on the generalisability of this observation to populations living with HIV. Therefore, we aimed to evaluate the immunogenicity of fractional and standard doses of yellow fever vaccine in HIV-positive adults. METHODS: We conducted a randomised, double-blind, non-inferiority substudy in Kilifi, coastal Kenya to compare the immunogenicity and safety of a fractional dose (one-fifth of the standard dose) versus the standard dose of 17D-213 yellow fever vaccine among HIV-positive volunteers. HIV-positive participants aged 18-59 years, with baseline CD4+ T-cell count of at least 200 cells per mL, and who were not pregnant, had no previous history of yellow fever vaccination or infection, and had no contraindication for yellow fever vaccination were recruited from the community. Participants were randomly assigned 1:1 in blocks (variable block sizes) to either a fractional dose or a standard dose of the 17D-213 yellow fever vaccine. Vaccines were administered subcutaneously by an unblinded nurse and pharmacist; all other study personnel were blinded to the vaccine allocation. The primary outcome of the study was the proportion of participants who seroconverted by the plaque reduction neutralisation test (PRNT50) 28 days after vaccination for the fractional dose versus the standard dose in the per-protocol population. Secondary outcomes were assessment of adverse events and immunogenicity during the 1-year follow-up period. Participants were considered to have seroconverted if the post-vaccination antibody titre was at least 4 times greater than the pre-vaccination titre. We set a non-inferiority margin of not less than a 17% decrease in seroconversion in the fractional dose compared with the standard dose. This study is registered with ClinicalTrials.gov, NCT02991495. FINDINGS: Between Jan 29, 2019, and May 17, 2019, 303 participants were screened, and 250 participants were included and vaccinated; 126 participants were assigned to the fractional dose and 124 to the standard dose. 28 days after vaccination, 112 (96%, 95% CI 90-99) of 117 participants in the fractional dose group and 115 (98%, 94-100) of 117 in the standard dose group seroconverted by PRNT50. The difference in seroconversion between the fractional dose and the standard dose was -3% (95% CI -7 to 2). Fractional dosing therefore met the non-inferiority criterion, and non-inferiority was maintained for 1 year. The most common adverse events were headache (n=31 [12%]), fatigue (n=23 [9%]), myalgia (n=23 [9%]), and cough (n=14 [6%]). Reported adverse events were either mild (182 [97%] of 187 adverse events) or moderate (5 [3%]) and were self-limiting. INTERPRETATION: Fractional doses of the 17D-213 yellow fever vaccine were sufficiently immunogenic and safe demonstrating non-inferiority to the standard vaccine dose in HIV-infected individuals with CD4+ T cell counts of at least 200 cells per mL. These results provide confidence that fractional dose recommendations are applicable to populations with high HIV prevalence. FUNDING: Wellcome Trust, Médecins Sans Frontières Foundation, and the UK Department for International Development.

Immunogenicity and safety of fractional doses of 17D-213 yellow fever vaccine in children (YEFE): a randomised, double-blind, non-inferiority substudy of a phase 4 trial.

BACKGROUND: Current supply shortages constrain yellow fever vaccination activities, particularly outbreak response. Although fractional doses of all WHO-prequalified yellow fever vaccines have been shown to be safe and immunogenic in a randomised controlled trial in adults, they have not been evaluated in a randomised controlled trial in young children (9-59 months old). We aimed to assess the immunogenicity and safety of fractional doses compared with standard doses of the WHO-prequalified 17D-213 vaccine in young children. METHODS: This substudy of the YEFE phase 4 study was conducted at the Epicentre Mbarara Research Centre (Mbarara, Uganda). Eligible children were aged 9-59 months without contraindications for vaccination, without history of previous yellow fever vaccination or infection and not requiring yellow fever vaccination for travelling. Participants were randomly assigned, using block randomisation, 1:1 to standard or fractional (one-fifth) dose of yellow fever vaccine. Investigators, participants, and laboratory personnel were blinded to group allocation. Participants were followed for immunogenicity and safety at 10 days, 28 days, and 1 year after vaccination. The primary outcome was non-inferiority in seroconversion (-10 percentage point margin) 28 days after vaccination measured by 50% plaque reduction neutralisation test (PRNT50) in the per-protocol population. Safety and seroconversion at 10 days and 12-16 months after vaccination (given COVID-19 resctrictions) were secondary outcomes. This study is registered with ClinicalTrials.gov, NCT02991495. FINDINGS: Between Feb 20, 2019, and Sept 9, 2019, 433 children were assessed, and 420 were randomly assigned to fractional dose (n=210) and to standard dose (n=210) 17D-213 vaccination. 28 days after vaccination, 202 (97%, 95% CI 95-99) of 207 participants in the fractional dose group and 191 (100%, 98-100) of 191 in the standard dose group seroconverted. The absolute difference in seroconversion between the study groups in the per-protocol population was -2 percentage points (95% CI -5 to 1). 154 (73%) of 210 participants in the fractional dose group and 168 (80%) of 210 in the standard dose group reported at least one adverse event 28 days after vaccination. At 10 days follow-up, seroconversion was lower in the fractional dose group than in the standard dose group. The most common adverse events were upper respiratory tract infections (n=221 [53%]), diarrhoea (n=68 [16%]), rhinorrhoea (n=49 [12%]), and conjunctivitis (n=28 [7%]). No difference was observed in incidence of adverse events and serious adverse events between study groups. CONCLUSIONS: Fractional doses of the 17D-213 vaccine were non-inferior to standard doses in inducing seroconversion 28 days after vaccination in children aged 9-59 months when assessed with PRNT50, but we found fewer children seroconverted at 10 days. The results support consideration of the use of fractional dose of yellow fever vaccines in WHO recommendations for outbreak response in the event of a yellow fever vaccine shortage to include children. FUNDING: Médecins Sans Frontières Foundation.

Immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine (ERVEBO®) in African clinical trial participants by age, sex, and baseline GP-ELISA titer: A post hoc analysis of three Phase 2/3 trials.

BACKGROUND: ERVEBO®, a live recombinant vesicular stomatitis virus (VSV) vaccine containing the Zaire ebolavirus glycoprotein (GP) in place of the VSV GP (rVSVΔG-ZEBOV-GP), was advanced through clinical development by Merck & Co., Inc., Rahway, NJ, USA in collaboration with multiple partners to prevent Ebola virus disease (EVD) and has been approved for human use in several countries. METHODS: We evaluated data from three Phase 2/3 clinical trials conducted in Liberia (PREVAIL), Guinea (FLW), and Sierra Leone (STRIVE) during the 2013-2016 West African EVD outbreak to assess immune responses using validated assays. We performed a post hoc analysis of the association of vaccine response with sex, age (18-50 yrs & >50 yrs), and baseline (BL) GP-enzyme-linked immunosorbent assay (ELISA) titer (<200 & ≥200 EU/mL), including individual study (PREVAIL, FLW, or STRIVE) data and pooled data from all 3 studies. The endpoints were total IgG antibody response (EU/mL) measured by the GP-ELISA and neutralizing antibody response measured by the plaque reduction neutralization test (PRNT) to rVSVΔG-ZEBOV-GP at Days 28, 180, and 365 postvaccination. RESULTS: In the overall pooled population, in all subgroups, and in each trial independently, GP-ELISA and PRNT geometric mean titers increased from BL, generally peaking at Day 28 and persisting through Day 365. Immune responses were greater in women and participants with BL GP-ELISA ≥ 200 EU/mL, but did not differ across age groups. CONCLUSION: These data demonstrate that rVSVΔG-ZEBOV-GP elicits a robust and durable immune response through 12 months postvaccination in participants regardless of age, sex, or BL GP-ELISA titer. The higher immune responses observed in women and participants with pre-existing immunity are consistent with those described previously and for other vaccines. Trials were registered as follows: PREVAIL: ClinicalTrials.gov NCT02344407; FLW: Pan African Clinical Trials Registry PACTR201503001057193; STRIVE: ClinicalTrials.gov NCT02378753. Protocols V920-009, 011, and 018.

Impact and cost-effectiveness of rotavirus vaccination in Niger: a modelling study evaluating alternative rotavirus vaccines.

OBJECTIVES: To evaluate the cost-effectiveness of alternative rotavirus vaccines in Niger, using UNIVAC, a proportionate outcomes model. SETTING: The study leverages global, regional and local data to inform cost-effectiveness modelling. Local data were collected as part of a clinical trial taking place in the Madarounfa district, Maradi region, Niger. PARTICIPANTS: The study models impact of infants vaccination on rotavirus gastroenteritis in children under 5 years of age. INTERVENTIONS: We compared the use of ROTARIX (GlaxoSmithKline, Belgium), ROTAVAC (Bharat Biotech, India) and ROTASIIL (Serum Institute, India) to no vaccination and to each other over a 10-year period starting in 2021. RESULTS: We estimated that ROTARIX, ROTAVAC and ROTASIIL would each prevent 13 million cases and 20 000 deaths of children under 5 years over a 10-year period in Niger. Compared with no vaccination, the cost to avert a disability-adjusted life-year was US$146 with ROTARIX, US$107 with ROTASIIL and US$76 with ROTAVAC from the government perspective. ROTAVAC dominated ROTARIX and ROTASIIL (eg, provided similar or higher benefits at a lower cost) and had 90% chance to be cost-effective at a US$100 willingness-to-pay threshold. CONCLUSIONS: This study can inform decision-making around rotavirus vaccination policy in Niger, demonstrating that ROTAVAC is likely the most cost-effective option. Alternative products (ROTASIIL and ROTARIX) may also be considered by decision-makers if they are priced more competitively, or if their cold chain requirements could bring additional economic benefits.

Cost-effectiveness of routine versus indicated antibiotic therapy in the management of severe wasting in children.

BACKGROUND: In the outpatient management of severe wasting, routine antibiotic therapy is recommended for all children upon admission regardless of whether clinical signs of infection are present. Indicated antibiotic therapy, where antibiotics are provided only upon presentation of clinical signs of infection, may be considered for its potential to allow for more prudent antibiotic use and greater program coverage, reducing the risk of antibiotic resistance as well as costs and logistical burdens associated with treatment. We therefore conducted a cost-effectiveness analysis to measure the effects of indicated antibiotic therapy compared to routine antibiotic therapy in terms of incremental cost-per-life-year saved in Niger. METHODS: We used a cohort model to conduct a cost-effectiveness analysis from a healthcare system perspective to project and weigh the lifetime discounted costs and effects of indicated antibiotic therapy compared to routine antibiotic therapy in the treatment of uncomplicated severe wasting in children in Niger. We calculated incremental cost-effectiveness ratios (ICERs) in terms of treatment-related healthcare costs per discounted life-years saved (LYS), and conducted program coverage scenario and sensitivity analyses to assess model uncertainty. RESULTS: The ICER for indicated antibiotic therapy compared to routine antibiotic therapy was $8.5/LYS, which is under the cost-effectiveness threshold for Niger. The probability of the indicated strategy being optimal was 76.1% when program coverage was equal to coverage associated with routine therapy but was 100% likely to be optimal in probabilistic sensitivity analysis scenarios where indicated program coverage improved 5 percentage points. CONCLUSIONS: Indicated antibiotic therapy likely represents a cost-effective strategy, particularly if indicated treatment can result in expanded coverage. With the risk of increasing antibiotic resistance worldwide, antibiotic stewardship and simplified treatment protocols for severe wasting using indicated antibiotic therapy may represent good value for money in some low risk populations.

Burden and risk factors for relapse following successful treatment of uncomplicated severe acute malnutrition in young children: Secondary analysis from a randomised trial in Niger.

This study aimed to quantify the burden of relapse following successful treatment for uncomplicated severe acute malnutrition (SAM) and to identify associated risk factors in rural Niger. We used data from 1490 children aged 6-59 months discharged as recovered from an outpatient nutritional programme for SAM and followed for up to 12 weeks after admission. Postdischarge SAM relapse was defined as weight-for-height Z-score <-3, mid-upper arm circumference (MUAC) <115 mm or bipedal oedema after having been discharged as recovered. Postdischarge hospitalisation was defined as admission to inpatient SAM treatment or hospitalisation for any cause after having been discharged as recovered. We used multivariate log-binomial models to identify independent risk factors. After programmatic discharge, 114 (8%) children relapsed to SAM and 89 (6%) were hospitalised. Factors associated with SAM relapse were discharge during the lean season (relative risk [RR] = 1.80 [95% confidence interval [CI] = 1.22-2.67]) and larger household size (RR = 1.56 [95% CI = 1.01-2.41]), whereas older child age (RR = 0.94 [95% CI = 0.88-1.00]), higher child MUAC at discharge (RR = 0.93 [95% CI = 0.87-1.00]) and maternal literacy (RR = 0.54 [95% CI = 0.29-0.98]) were protective factors. Discharge during the lean season (RR = 2.27 [95% CI = 1.46-3.51]) was independently associated with postdischarge hospitalisation. Future nutritional programmes in the context of Niger may consider modification of anthropometric discharge criteria or the provision of additional home support or follow-up during the lean season as potential interventions to prevent relapse. More research including postdischarge follow-up is needed to better understand the sustainability of treatment outcomes after discharge and the type of intervention that may best sustain recovery over time. Clinical Trial Registration: ClinicalTrials.gov number, NCT01613547.

Evaluation of multiple micronutrient supplementation and medium-quantity lipid-based nutrient supplementation in pregnancy on child development in rural Niger: A secondary analysis of a cluster randomized controlled trial.

BACKGROUND: It is estimated that over 250 million children under 5 years of age in low- and middle-income countries (LMICs) do not reach their full developmental potential. Poor maternal diet, anemia, and micronutrient deficiencies during pregnancy are associated with suboptimal neurodevelopmental outcomes in children. However, the effect of prenatal macronutrient and micronutrient supplementation on child development in LMIC settings remains unclear due to limited evidence from randomized trials. METHODS AND FINDINGS: We conducted a 3-arm cluster-randomized trial (n = 53 clusters) that evaluated the efficacy of (1) prenatal multiple micronutrient supplementation (MMS; n = 18 clusters) and (2) lipid-based nutrient supplementation (LNS; n = 18 clusters) as compared to (3) routine iron-folic acid (IFA) supplementation (n = 17 clusters) among pregnant women in the rural district of Madarounfa, Niger, from March 2015 to August 2019 (ClinicalTrials.gov identifier NCT02145000). Children were followed until 2 years of age, and the Bayley Scales of Infant and Toddler Development III (BSID-III) were administered to children every 3 months from 6 to 24 months of age. Maternal report of WHO gross motor milestone achievement was assessed monthly from 3 to 24 months of age. An intention-to-treat analysis was followed. Child BSID-III data were available for 559, 492, and 581 singleton children in the MMS, LNS, and IFA groups, respectively. Child WHO motor milestone data were available for 691, 781, and 753 singleton children in the MMS, LNS, and IFA groups, respectively. Prenatal MMS had no effect on child BSID-III cognitive (standardized mean difference [SMD]: 0.21; 95% CI: -0.20, 0.62; p = 0.32), language (SMD: 0.16; 95% CI: -0.30, 0.61; p = 0.50) or motor scores (SMD: 0.18; 95% CI: -0.39, 0.74; p = 0.54) or on time to achievement of the WHO gross motor milestones as compared to IFA. Prenatal LNS had no effect on child BSID-III cognitive (SMD: 0.17; 95% CI: -0.15, 0.49; p = 0.29), language (SMD: 0.11; 95% CI: -0.22, 0.44; p = 0.53) or motor scores (SMD: -0.04; 95% CI: -0.46, 0.37; p = 0.85) at the 24-month endline visit as compared to IFA. However, the trajectory of BSID-III cognitive scores during the first 2 years of life differed between the groups with children in the LNS group having higher cognitive scores at 18 and 21 months (approximately 0.35 SD) as compared to the IFA group (p-value for difference in trajectory <0.001). Children whose mothers received LNS also had earlier achievement of sitting alone (hazard ratio [HR]: 1.57; 95% CI: 1.10 to 2.24; p = 0.01) and walking alone (1.52; 95% CI: 1.14 to 2.03; p = 0.004) as compared to IFA, but there was no effect on time to achievement of other motor milestones. A limitation of our study is that we assessed child development up to 2 years of age, and, therefore, we may have not captured effects that are easier to detect or emerge at older ages. CONCLUSIONS: There was no benefit of prenatal MMS on child development outcomes up to 2 years of age as compared to IFA. There was evidence of an apparent positive effect of prenatal LNS on cognitive development trajectory and time to achievement of selected gross motor milestones. TRIAL REGISTRATION: ClinicalTrials.gov NCT02145000.

Risk of community- and hospital-acquired bacteremia and profile of antibiotic resistance in children hospitalized with severe acute malnutrition in Niger.

OBJECTIVE: To estimate the prevalence and antibiotic resistance profile of community- and hospital-acquired bacteremia among hospitalized children with severe acute malnutrition in Niger. METHODS: A descriptive, longitudinal study was conducted in an intensive nutritional rehabilitation center in Madarounfa, Niger. Children aged 6 to 59 months admitted for inpatient treatment of complicated severe acute malnutrition (n=2187) had blood specimens drawn at admission to assess prevalence of community-acquired bacteremia. Subsequent specimens were drawn per physician discretion to assess incidence of hospital-acquired bacteremia. Antibiotic susceptibility testing was performed on positive blood cultures. RESULTS: The prevalence of community-acquired bacteremia at admission was at least 9.1% (95% confidence interval [CI]: 8.1, 10.4%), with non-typhoid Salmonella identified in over half (57.8%) of cases. The cumulative incidence of hospital-acquired bacteremia was estimated at 1.2% (95% CI: 0.8, 1.7%), among which the most common organisms were Klebsiella pneumoniae (19.4%), Acinetobacter baumannii (16.1%), Enterococcus faecalis (12.9%), and Escherichia coli (12.9%). In community-acquired bacteremia, 58% cases were resistant to amoxicillin-clavulanate; 100% of hospital-acquired bacteremia cases were resistant to amoxicillin and amoxicillin-clavulanate. Mortality risk was elevated among children with hospital-acquired bacteremia (risk ratio [RR] = 9.32) and community-acquired bacteremia (RR = 2.67). CONCLUSION: Bacteremia was a significant contributor to mortality. Antibiotic resistance poses a challenge to effective clinical management of severe acute malnutrition.

Protocol for a phase 3 trial to evaluate the effectiveness and safety of a heterologous, two-dose vaccine for Ebola virus disease in the Democratic Republic of the Congo.

INTRODUCTION: Ebola virus disease (EVD) continues to be a significant public health problem in sub-Saharan Africa, especially in the Democratic Republic of the Congo (DRC). Large-scale vaccination during outbreaks may reduce virus transmission. We established a large population-based clinical trial of a heterologous, two-dose prophylactic vaccine during an outbreak in eastern DRC to determine vaccine effectiveness. METHODS AND ANALYSIS: This open-label, non-randomised, population-based trial enrolled eligible adults and children aged 1 year and above. Participants were offered the two-dose candidate EVD vaccine regimen VAC52150 (Ad26.ZEBOV, Modified Vaccinia Ankara (MVA)-BN-Filo), with the doses being given 56 days apart. After vaccination, serious adverse events (SAEs) were passively recorded until 1 month post dose 2. 1000 safety subset participants were telephoned at 1 month post dose 2 to collect SAEs. 500 pregnancy subset participants were contacted to collect SAEs at D7 and D21 post dose 1 and at D7, 1 month, 3 months and 6 months post dose 2, unless delivery was before these time points. The first 100 infants born to these women were given a clinical examination 3 months post delivery. Due to COVID-19 and temporary suspension of dose 2 vaccinations, at least 50 paediatric and 50 adult participants were enrolled into an immunogenicity subset to examine immune responses following a delayed second dose. Samples collected predose 2 and at 21 days post dose 2 will be tested using the Ebola viruses glycoprotein Filovirus Animal Non-Clinical Group ELISA. For qualitative research, in-depth interviews and focus group discussions were being conducted with participants or parents/care providers of paediatric participants. ETHICS AND DISSEMINATION: Approved by Comité National d'Ethique et de la Santé du Ministère de la santé de RDC, Comité d'Ethique de l'Ecole de Santé Publique de l'Université de Kinshasa, the LSHTM Ethics Committee and the MSF Ethics Review Board. Findings will be presented to stakeholders and conferences. Study data will be made available for open access. TRIAL REGISTRATION NUMBER: NCT04152486.

Effectiveness of a monthly schedule of follow-up for the treatment of uncomplicated severe acute malnutrition in Sokoto, Nigeria: A cluster randomized crossover trial.

BACKGROUND: Community-based management of severe acute malnutrition (SAM) involves weekly or biweekly outpatient clinic visits for clinical surveillance and distribution of therapeutic foods. Distance to outpatient clinics and high opportunity costs for caregivers can represent major barriers to access. Reducing the frequency of outpatient visits while providing training to caregivers to recognize clinical danger signs at home between outpatient visits may increase acceptability, coverage, and public health impact of SAM treatment. We investigated the effectiveness of monthly clinic visits compared to the standard weekly follow-up in the outpatient treatment of uncomplicated SAM in northwestern Nigeria. METHODS AND FINDINGS: We conducted a cluster randomized crossover trial to test the noninferiority of nutritional recovery in children with uncomplicated SAM receiving monthly follow-up compared to the standard weekly schedule. From January 2018 to November 2019, 3,945 children aged 6 to 59 months were enrolled at 10 health centers (5 assigned to monthly follow-up and 5 assigned to weekly follow-up) in Sokoto, Nigeria. In total, 96% of children (n = 1,976 in the monthly follow-up group and 1,802 in the weekly follow-up group) were followed until program discharge, and 91% (n = 1,873 in the monthly follow-up group and 1,721 in the weekly follow-up group) were followed to 3 months postdischarge. The mean age at admission was 15.8 months (standard deviation [SD] 7.1), 2,097/3,945 (53.2%) were girls, and the mean midupper arm circumference (MUAC) at admission was 105.8 mm (SD 6.0). In a modified intention-to-treat analysis, the primary outcome of nutritional recovery, defined as having MUAC ≥125 mm on 2 consecutive visits, was analyzed using generalized linear models, with generalized estimating equations to account for clustering. Nutritional recovery was lower in the monthly follow-up group compared to the weekly group (1,036/1,976, 52.4% versus 1,059/1,802, 58.8%; risk difference: -6.8%), and noninferiority was not demonstrated (lower bound of the confidence interval [CI] was -11.5%, lower than the noninferiority margin of 10%). The proportion of children defaulting was lower in the monthly group than in the weekly group (109/1,976, 5.5% versus 151/1,802, 8.4%, p = 0.03). Three months postdischarge, children in the monthly group were less likely to relapse compared to those in the weekly group (58/976, 5.9% versus 78/1,005, 7.8%, p = 0.03), but cumulative mortality at 3 months postdischarge was higher in the monthly group (159/1,873, 8.5% versus 106/1,721, 6.2%, p < 0.001). Study results may depend on context-specific factors including baseline level of care and the clinical status of children presenting to health centers, and, thus, generalizability of these results may be limited. CONCLUSIONS: Where feasible, a weekly schedule of clinic visits should be preferred to maintain effectiveness of SAM treatment. Where geographic coverage of programs is low or frequent travel to outpatient clinics is difficult or impossible, a monthly schedule of visits may provide an alternative model to deliver treatment to those in need. Modifications to the outpatient follow-up schedule, for example, weekly clinic visits until initial weight gain has been achieved followed by monthly visits, could increase the effectiveness of the model and add flexibility for program delivery. TRIAL REGISTRATION: ClinicalTrials.gov NCT03140904.

Cost-effectiveness of monthly follow-up for the treatment of uncomplicated severe acute malnutrition: An economic evaluation of a randomized controlled trial.

Severe acute malnutrition (SAM) is a major source of mortality for children in low resource settings. Alternative treatment models that improve acceptability and reduce caregiver burden are needed to improve treatment access. We assessed costs and cost-effectiveness of monthly vs. weekly follow-up (standard-of-care) for treating uncomplicated SAM in children 6-59 months of age. To do so, we conducted a cost-effectiveness analysis of a cluster-randomized trial of treatment for newly-diagnosed uncomplicated SAM in northwestern Nigeria (clinicaltrials.gov ID NCT03140904). We collected empirical costing data from enrollment up to 3 months post-discharge. We quantified health outcomes as the fraction of children recovered at discharge (primary cost-effectiveness outcome), the fraction recovered 3 months post-discharge, and total DALYs due to acute malnutrition. We estimated cost-effectiveness from both provider and societal perspectives. Costs are reported in 2019 US dollars. Provider costs per child were $67.07 (95% confidence interval: $64.79, $69.29) under standard-of-care, and $78.74 ($77.06, $80.66) under monthly follow-up. Patient costs per child were $21.04 ($18.18, $23.51) under standard-of-care, and $14.16 ($12.79, $15.25) under monthly follow-up. Monthly follow-up performed worse than standard-of-care for each health outcome assessed and was dominated (produced worse health outcomes at higher cost) by the standard-of-care in cost-effectiveness analyses. This result was robust to statistical uncertainty and to alternative costing assumptions. These findings provide evidence against monthly follow-up for treatment of uncomplicated SAM in situations where weekly follow-up of patients is feasible. While monthly follow-up may reduce burdens on caregivers and providers, other approaches are needed to do so while maintaining the effectiveness of care.

Prenatal supplementation with multiple micronutrient supplements or medium-quantity lipid-based nutrient supplements has limited effects on child growth up to 24 months in rural Niger: a secondary analysis of a cluster randomized trial.

BACKGROUND: Prenatal multiple micronutrient supplementation (MMS) and lipid-based nutrient supplementation (LNS) can improve birth outcomes relative to iron-folic acid supplementation (IFA); however, effects on child postnatal growth remain unclear. OBJECTIVES: The aim was to compare the effect of prenatal MMS, medium-quantity LNS (MQ-LNS), and IFA on child growth up to 2 y of age. METHODS: We conducted a cluster randomized controlled trial of prenatal nutritional supplementation in Madarounfa, Niger. Villages were randomly assigned for pregnant women to receive IFA (17 villages, 1105 women), MMS (18 villages, 1083 women) or MQ-LNS (18 villages, 1144 women). Pregnant women received nutritional supplements weekly until delivery, and children were followed up monthly from 6-8 wk to 24 mo of age. We assessed the effect of prenatal MMS and MQ-LNS compared with IFA and the effect of prenatal MMS compared with MQ-LNS on child length-for-age z scores (LAZ), weight-for-age z scores (WAZ), and weight-for-length z scores (WLZ) at 24 mo of age using generalized linear models. In secondary analyses, we used mixed-effects models to assess the trajectories of anthropometric z scores longitudinally from 6-8 wk to 24 mo. RESULTS: Compared with IFA, MMS and MQ-LNS had no effect on child LAZ, WAZ, or WLZ at 24 mo of age (P > 0.05). Children in the MQ-LNS arm had significantly higher mid-upper arm circumference at 24 mo than children in the MMS arm: mean difference 0.50 cm (95% CI 0.10, 0.91 cm). WAZ and WLZ trajectories were more negative in the MQ-LNS arm compared with IFA and MMS, with lower z scores from 14 to 20 mo of age. However, WAZ and WLZ trajectories converged after 20 mo of age, and there were no differences by 24 mo of age. CONCLUSIONS: Prenatal MMS and MQ-LNS had limited effect on anthropometric measures of child growth up to 24 mo of age as compared with IFA in rural Niger.

An exploratory qualitative study of caregivers' knowledge, perceptions and practices related to hospital hygiene in rural Niger.

BACKGROUND: The risk of healthcare-associated infections is exacerbated by poor hygiene practices in health care facilities and can contribute to increased patient morbidity and mortality. In low-income settings, caregivers play a key role in maintaining proper hygiene during inpatient stays. We aimed to explore caregivers' knowledge, perceptions and practices related to hospital hygiene in a rural, sub-Saharan African setting. METHODS: We conducted an exploratory qualitative study among caregivers of children admitted to an inpatient therapeutic feeding center in Madarounfa, Niger. Individual interviews with 28 caregivers of hospitalized children were conducted to explore their knowledge, perceptions and practices of hygiene in the health facility. FINDINGS: Caregivers described a broad understanding of hygiene and reported knowledge of its importance in the hospital, particularly to prevent disease transmission and protect child health. Hygiene was perceived as a collective rather than individual responsibility. Caregivers reported on the poor hygiene practice of others and cited a lack of space and hygiene materials as barriers to correct hygiene practice. Caregivers described educational sessions and informal sharing with other caregivers as tools to gain knowledge and improve practice. CONCLUSION: This exploratory study is unique in describing the perspective of caregivers in a low-resource hospital setting, a group often underrepresented when designing health interventions to improve hospital hygiene. Our findings suggest a strong knowledge of hospital hygiene among caregivers in this setting, with positive perception of its importance in health promotion. Poor individual practice was reported but may be improved through additional education and provision of hygiene materials.

Correction: Immunogenicity of an oral rotavirus vaccine administered with prenatal nutritional support in Niger: A cluster randomized clinical trial.

[This corrects the article DOI: 10.1371/journal.pmed.1003720.].