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A serogroup A meningococcal polysaccharide–tetanus toxoid conjugate vaccine (PsA–TT, MenAfriVac) was licensed in India in 2009, and pre-qualified by WHO in 2010, on the basis of its safety and immunogenicity. This vaccine is now being deployed across the African meningitis belt. We studied the effect of PsA–TT on meningococcal meningitis and carriage in Chad during a serogroup A meningococcal meningitis epidemic. We obtained data for the incidence of meningitis before and after vaccination from national records between January, 2009, and June, 2012. In 2012, surveillance was enhanced in regions where vaccination with PsA–TT had been undertaken in 2011, and in one district where a reactive vaccination campaign in response to an outbreak of meningitis was undertaken. Meningococcal carriage was studied in an age-stratified sample of residents aged 1–29 years of a rural area roughly 13–15 and 2–4 months before and 4–6 months after vaccination. Meningococci obtained from cerebrospinal fluid or oropharyngeal swabs were characterised by conventional microbiological and molecular methods. Roughly 1·8 million individuals aged 1–29 years received one dose of PsA–TT during a vaccination campaign in three regions of Chad in and around the capital N'Djamena during 10 days in December, 2011. The incidence of meningitis during the 2012 meningitis season in these three regions was 2·48 per 100 000 (57 cases in the 2·3 million population), whereas in regions without mass vaccination, incidence was 43·8 per 100 000 (3809 cases per 8·7 million population), a 94% difference in crude incidence (p<0·0001), and an incidence rate ratio of 0·096 (95% CI 0·046–0·198). Despite enhanced surveillance, no case of serogroup A meningococcal meningitis was reported in the three vaccinated regions. 32 serogroup A carriers were identified in 4278 age-stratified individuals (0·75%) living in a rural area near the capital 2–4 months before vaccination, whereas only one serogroup A meningococcus was isolated in 5001 people living in the same community 4–6 months after vaccination (adjusted odds ratio 0·019, 95% CI 0·002–0·138; p<0·0001). PSA–TT was highly effective at prevention of serogroup A invasive meningococcal disease and carriage in Chad. How long this protection will persist needs to be established. The Bill & Melinda Gates Foundation, the Wellcome Trust, and Médecins Sans Frontères.

In settings with low pneumococcal conjugate vaccine (PCV) coverage, multi-age cohort mass campaigns could increase population immunity, and fractional dosing could increase affordability. We aimed to evaluate the effect of mass campaigns on nasopharyngeal pneumococcal carriage of Pneumosil (PCV10) in children aged 1–9 years in Niger. In this three-arm, open-label, cluster-randomised trial, 63 clusters of one to four villages in Niger were randomly assigned (3:3:1) using block randomisation to receive campaigns consisting of a single full dose of a 10-valent PCV (Pneumosil), a single one-fifth dose of Pneumosil, or no campaign. Independently sampled carriage surveys were done among 2268 households 6 months before and after vaccination, collecting nasopharyngeal swabs from healthy children for culture and serotyping; those with contraindication to nasopharyngeal swabbing were excluded. The primary outcome was nasopharyngeal carriage of vaccine-serotype pneumococcus. We tested whether vaccine-type carriage was reduced in full-dose versus control clusters; and whether fractional doses were non-inferior to full-doses (lower bound 95% CI more than –7·5%), using generalised estimating equations to analyse cluster summaries at baseline and follow-up, controlling for covariates to estimate risk differences and their 95% CIs. The study is registered with ClinicalTrials.gov (NCT05175014) and the Pan-African Clinical Trials Registry (PACTR20211257448484). Surveys were done between Dec 22, 2021, and March 18, 2022, and between Dec 12, 2022, and March 9, 2023. The vaccination campaign ran from June 15 to Aug 2, 2022. Participants' characteristics were consistent across surveys and groups. Pre-vaccination, vaccine-type carriage was 15·6% (149 of 955 participants) in the full-dose group, 17·9% (170 of 948) in the fractional-dose group, and 18·8% (60 of 320) in the control group. Post-vaccination, vaccine-type carriage was 4·6% (44 of 967) in the full-dose group, 8·0% (77 of 962) in the fractional-dose group, and 16·5% (53 of 321) in the control group. The primary analysis showed a risk difference of –16·2% (95% CI –28·6 to –3·0) between the full-dose group and control group (p=0·002 for superiority), and –3·8% (–6·1 to –1·6) between the full-dose group and fractional-dose group, meeting the non-inferiority criteria. No adverse events were judged to be related to vaccination. Multi-age cohort campaigns had a marked effect on vaccine-type carriage and fractional-dose campaigns met non-inferiority criteria. Such campaigns should be considered in low-coverage settings, including humanitarian emergencies, to accelerate population protection. EDCTP2 programme supported by the EU. For the French translation of the abstract see Supplementary Materials section.

International recommendations advise against the use of intravenous rehydration therapy in children with severe acute malnutrition because of the concern about fluid overload, but evidence to support this concern is lacking. Given the high mortality associated with the current recommendations, the adoption of intravenous rehydration strategies might improve outcomes. We conducted a factorial, open-label superiority trial in four countries in Africa. Children 6 months to 12 years of age with severe acute malnutrition with gastroenteritis and dehydration underwent randomization in a 2:1:1 ratio to one of three rehydration strategies: oral rehydration, plus intravenous boluses for shock; a rapid intravenous strategy that consisted of lactated Ringer's solution (100 ml per kilogram of body weight) administered over a period of 3 to 6 hours, with boluses for shock; or a slow intravenous strategy that consisted of the same solution administered over a period of 8 hours, with no boluses. The primary end point was death at 96 hours. A total of 272 children underwent randomization; 138 were assigned to the oral strategy, 67 to the rapid intravenous strategy, and 67 to the slow intravenous strategy. Participants were followed for 28 days. A nasogastric tube was used for oral rehydration in 126 of 135 participants (93%) in the oral group and in 82 of 126 (65%) in the intravenous groups. Intravenous boluses were administered at admission in 12 participants (9%) in the oral group, 7 (10%) in the rapid intravenous group, and none in the slow intravenous group. At 96 hours, 11 participants (8%) in the oral group and 9 (7%) in the intravenous groups (5 in the rapid group and 4 in the slow group) had died (risk ratio, 1.02; 95% confidence interval [CI], 0.41 to 2.52; P = 0.69). At 28 days, 17 participants (12%) in the oral group and 14 (10%) in the intravenous groups had died (hazard ratio, 0.85; 95% CI, 0.41 to 1.78). Serious adverse events occurred in 32 participants (23%) in the oral group, 14 (21%) in the rapid intravenous group, and 10 (15%) in the slow intravenous group. No evidence of pulmonary edema, heart failure, or fluid overload was noted. Among children with severe acute malnutrition and gastroenteritis, no evidence of a difference in mortality at 96 hours was noted between oral and intravenous rehydration strategies. (Funded by the Joint Global Health Trials scheme and others; GASTROSAM Current Controlled Trials number, ISRCTN76149273.).

Antibiotic prophylaxis for contacts of meningitis cases is not recommended during outbreaks in the African meningitis belt. We assessed the effectiveness of single-dose oral ciprofloxacin administered to household contacts and in village-wide distributions on the overall attack rate (AR) in an outbreak of meningococcal meningitis. In this 3-arm, open-label, cluster-randomized trial during a meningococcal meningitis outbreak in Madarounfa District, Niger, villages notifying a suspected case were randomly assigned (1:1:1) to standard care (the control arm), single-dose oral ciprofloxacin for household contacts within 24 hours of case notification, or village-wide distribution of ciprofloxacin within 72 hours of first case notification. The primary outcome was the overall AR of suspected meningitis after inclusion. A random sample of 20 participating villages was enrolled to document any changes in fecal carriage prevalence of ciprofloxacin-resistant and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae before and after the intervention. Between April 22 and May 18, 2017, 49 villages were included: 17 to the control arm, 17 to household prophylaxis, and 15 to village-wide prophylaxis. A total of 248 cases were notified in the study after the index cases. The AR was 451 per 100,000 persons in the control arm, 386 per 100,000 persons in the household prophylaxis arm (t test versus control p = 0.68), and 190 per 100,000 persons in the village-wide prophylaxis arm (t test versus control p = 0.032). The adjusted AR ratio between the household prophylaxis arm and the control arm was 0.94 (95% CI 0.52-1.73, p = 0.85), and the adjusted AR ratio between the village-wide prophylaxis arm and the control arm was 0.40 (95% CI 0.19‒0.87, p = 0.022). No adverse events were notified. Baseline carriage prevalence of ciprofloxacin-resistant Enterobacteriaceae was 95% and of ESBL-producing Enterobacteriaceae was >90%, and did not change post-intervention. One limitation of the study was the small number of cerebrospinal fluid samples sent for confirmatory testing. Village-wide distribution of single-dose oral ciprofloxacin within 72 hours of case notification reduced overall meningitis AR. Distributions of ciprofloxacin could be an effective tool in future meningitis outbreak responses, but further studies investigating length of protection, effectiveness in urban settings, and potential impact on antimicrobial resistance patterns should be carried out. ClinicalTrials.gov NCT02724046.

A diphtheria outbreak occurred from February to November 2011 in the village of Kimba and its surrounding settlements, in Borno State, northeastern Nigeria. We conducted a retrospective outbreak investigation in Kimba village and the surrounding settlements to better describe the extent and clinical characteristics of this outbreak. Ninety-eight cases met the criteria of the case definition of diphtheria, 63 (64·3%) of whom were children aged <10 years; 98% of cases had never been immunized against diphtheria. None of the 98 cases received diphtheria antitoxin, penicillin, or erythromycin during their illness. The overall case-fatality ratio was 21·4%, and was highest in children aged 10–4 years (42·9%). Low rates of immunization, delayed clinical recognition of diphtheria and absence of treatment with antitoxin and appropriate antibiotics contributed to this epidemic and its severity.

•RotaSIIL has been shown effective against severe rotavirus gastroenteritis in Niger.•Two-year follow-up of the intention-to-treat population shows no safety concerns.•Overall mortality was very low for the region.•One case of intussusception was notified, and was unrelated to RotaSIIL. Rotavirus remains a major cause of diarrhea among children under 5 years of age. The efficacy of RotaSIIL, a pentavalent rotavirus vaccine, was shown in an event-driven trial in Niger. We describe the two-year safety follow-up of this trial. Follow-up of safety outcomes began upon administration of the first dose of RotaSIIL or placebo. Adverse events were followed until 28 days after the third dose, and serious adverse events were followed until 2 years of age. Suspected cases of intussusception were evaluated at first point of contact and then referred to hospital for surgical evaluation. Causes of death were obtained by chart review and verbal autopsy. Passive surveillance was carried out in health centers. Community health workers carried out active surveillance in villages. Between-group differences were evaluated using the chi-squared test and Fisher’s exact test. A total of 4092 children were randomized, and 4086 received at least one dose of RotaSIIL or placebo, constituting the intention-to-treat population, who accrued a total of 7385 child-years of follow-up time. At two years of follow-up, 58 (2.8%) participants who received RotaSIIL and 49 (2.4%) participants who received placebo had died (p = 0.38). Most deaths were due to infectious causes common to the study area. One participant had confirmed intussusception, 542 days after receiving the third dose of RotaSIIL. A total of 395 (19.3%) participants receiving RotaSIIL and 419 (20.5%) participants receiving placebo experienced any serious adverse event (p = 0.36). Most serious adverse events were hospitalizations due to infection (malaria, lower respiratory tract infection and gastroenteritis) or marasmus. Overall, 1474 (72.1%) participants receiving RotaSIIL and 1456 (71.1%) participants receiving placebo had at least one adverse event (p = 0.49) in the follow-up period. At two years of follow-up, RotaSIIL was found to be safe. Trial registration: ClinicalTrials.gov: NCT02145000.

Background Epidemics of meningococcal meningitis are common in the “African meningitis belt.” Current response strategies include reactive vaccination campaigns, which are often organized too late to have maximal impact. A novel strain of Neisseria meningitidis serogroup C has been circulating in recent years, and vaccine supplies are limited. An evaluation of chemoprophylaxis with single-dose ciprofloxacin for household contacts of meningitis cases has therefore been recommended. Methods/design A three-arm cluster-randomized trial has been designed for implementation during a meningococcal meningitis epidemic in a health district in Niger in which at least two Health Zones (HZs) have met the weekly epidemic threshold. The primary outcome is the incidence (attack rate) of meningitis during the epidemic. Villages will be randomized in a 1:1:1 ratio to one of three different arms: standard care, household-level prophylaxis, or village-wide prophylaxis. After study launch, when a case of meningococcal meningitis is identified in an HZ, the first reported case from a village will trigger the inclusion and randomization of the village. Household-level prophylaxis with single-dose ciprofloxacin will be offered in the home to all household members within 24 hours of the notification of the case, and village-wide distributions will occur within 72 hours of the notification of the case. The sample size necessary to detect differences between each of the two intervention arms and the standard care arm will be set after 4 weeks of data collection, in order to quantify multiple variables that could be particular to a given area. The primary analysis will compare attack rates at the end of the epidemic in each of the three arms. A nested sub-study will assess the effects of ciprofloxacin prophylaxis on the prevalence of ciprofloxacin-resistant enterobacteriaceae. A total of 200 participants in the standard care arm and 200 in the village-wide prophylaxis arm will provide stool samples at days 0, 7, and 28 following their village’s inclusion in the study. Discussion An innovative trial is proposed for implementation during an epidemic that will assess the impact of a novel strategy for meningitis outbreak response. In parallel, we will describe potential negative effects of the intervention. Trial registration ClinicalTrials.gov, NCT02724046 . Registered on 15 March 2016. Last updated on 13 June 2017.

A global core outcome measurement set for snakebite clinical trialsBackground. Snakebite clinical trials have often used heterogeneous outcome measures and there is an urgent need for standardisation.Method. A globally representative group of key stakeholders came together to reach consensus on a globally relevant set of core outcome measurements. Outcome domains and outcome measurement instruments were identified through searching the literature and a systematic review of snakebite clinical trials. Outcome domains were shortlisted by use of a questionnaire and consensus was reached among stakeholders and the patient group through facilitated discussions and voting.Results. Five universal core outcome measures should be included in all future snakebite clinical trials: mortality, WHO disability assessment scale, patient-specific functional scale, acute allergic reaction by Brown criteria, and serum sickness by formal criteria. Additional syndrome-specific core outcome measures should be used depending on the biting species.Conclusion. This core outcome measurement set provides global standardisation, supports the priorities of patients and clinicians, enables meta-analysis, and is appropriate for use in low-income and middle-income settings.Définition d’un jeu universel de critères de décision de base pour les essais cliniques sur les morsures de serpentContexte. Les essais cliniques sur les morsures de serpent ont souvent utilisé des critères de décision hétérogènes qui demandent à être standardisés.Méthode. Un groupe d’acteurs clés mondialement représentatifs s’est réuni pour parvenir à un consensus sur un jeu universel de critères de décision de base. Les domaines d’intérêt et les instruments d’évaluation des critères de décision ont été identifiés à partir d’une recherche documentaire et d’un examen systématique des essais cliniques concernant les envenimations par morsure de serpent. Les domaines d’intérêt ont été présélectionnés à l’aide d’un questionnaire et un consensus a été obtenu entre le groupe d’acteurs et un groupe représentatif de patients à la suite de discussions orientées et d’un vote.Résultats. Cinq critères de décision de base universels devraient être inclus dans tous les futurs essais cliniques sur les morsures de serpent : la mortalité, l’échelle d’évaluation du handicap de l’OMS, l’échelle fonctionnelle propre à chaque patient, la réaction allergique immédiate selon les critères de Brown et la maladie sérique en fonction de critères formels. D’autres critères de décision spécifiques aux différents syndromes observés lors des envenimations par morsure de serpent doivent être utilisés en fonction de l’espèce responsable de la morsure.Conclusion. Ce jeu universel de critères de décision de base permet une standardisation mondiale, répond aux priorités des patients et des cliniciens, favorise des méta-analyses et est compatible avec une utilisation dans les pays à revenu faible ou intermédiaire.