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Background The association between childhood diarrheal disease and linear growth faltering in developing countries is well described. However, the impact attributed to specific pathogens has not been elucidated, nor has the impact of recommended antibiotic treatment. Methods The Global Enteric Multicenter Study enrolled children with moderate to severe diarrhea (MSD) seeking healthcare at 7 sites in sub-Saharan Africa and South Asia. At enrollment, we collected stool samples to identify enteropathogens. Length/height was measured at enrollment and follow-up, approximately 60 days later, to calculate change in height-for-age z scores (ΔHAZ). The association of pathogens with ΔHAZ was tested using linear mixed effects regression models. Results Among 8077 MSD cases analyzed, the proportion with stunting (HAZ below −1) increased from 59% at enrollment to 65% at follow-up (P < .0001). Pathogens significantly associated with linear growth decline included Cryptosporidium (P < .001), typical enteropathogenic Escherichia coli (P = .01), and untreated Shigella (P = .009) among infants (aged 0–11 months) and enterotoxigenic E. coli encoding heat-stable toxin (P < .001) and Cryptosporidium (P = .03) among toddlers (aged 12–23 months). Shigella-infected toddlers given antibiotics had improved linear growth (P = .02). Conclusions Linear growth faltering among children aged 0–23 months with MSD is associated with specific pathogens and can be mitigated with targeted treatment strategies, as demonstrated for Shigella.

Summary Background Maternal influenza immunisation can reduce morbidity and mortality associated with influenza infection in pregnant women and young infants. We aimed to determine the vaccine efficacy of maternal influenza immunisation against maternal and infant PCR-confirmed influenza, duration of protection, and the effect of gestational age at vaccination on vaccine efficacy, birth outcomes, and infant growth up to 6 months of age. Methods We did a pooled analysis of three randomised controlled trials done in Nepal (2011–2014), Mali (2011–2014), and South Africa (2011–2013). Pregnant women, gestational age 17–34 weeks in Nepal, 28 weeks or more in Mali, and 20–36 weeks in South Africa, were enrolled. Women were randomly assigned 1:1 to a study group, in which they received trivalent inactivated influenza vaccine (IIV) in all three trials, or a control group, in which they received saline placebo in Nepal and South Africa or quadrivalent meningococcal conjugate vaccine in Mali. Enrolment at all sites was complete by April 24, 2013. Infants and women were assessed for respiratory illness, and samples from those that met the case definition were tested for influenza by PCR testing. Growth measurements, including length and weight, were obtained at birth at all sites, at 24 weeks in South Africa, and at 6 months in Nepal and Mali. The three trials are registered with ClinicalTrials.gov , numbers NCT01430689 , NCT01034254 , and NCT02465190 . Findings 10 002 women and 9800 liveborn infants were included. Pooled efficacy of maternal vaccination to prevent infant PCR-confirmed influenza up to 6 months of age was 35% (95% CI 19 to 47). The pooled estimate was 56% (28 to 73) within the first 2 months of life, 39% (11 to 58) between 2 and 4 months, and 19% (–9 to 40) between 4 and 6 months. In women, from enrolment during pregnancy to the end of follow-up at 6 months postpartum, the vaccine was 50% (95% CI 32–63) efficacious against PCR-confirmed influenza. Efficacy was 42% (12 to 61) during pregnancy and 60% (36 to 75) postpartum. In women vaccinated before 29 weeks gestational age, the estimated efficacy was 30% (–2 to 52), and in women vaccinated at or after 29 weeks, efficacy was 71% (50 to 83). Efficacy was similar in infants born to mothers vaccinated before or after 29 weeks gestation (34% [95% CI 12 to 51] vs 35% [11 to 52]). There was no overall association between maternal vaccination and low birthweight, stillbirth, preterm birth, and small for gestational age. At 6 months of age, the intervention and control groups were similar in terms of underweight (weight-for-age), stunted (length-for-age), and wasted (weight-for-length). Median centile change from birth to 6 months of age was similar between the intervention and the control groups for both weight and length. Interpretation The assessment of efficacy for women vaccinated before 29 weeks gestational age might have been underpowered, because the point estimate suggests that there might be efficacy despite wide CIs. Estimates of efficacy against PCR-confirmed influenza and safety in terms of adverse birth outcomes should be incorporated into any further consideration of maternal influenza immunisation recommendations. Funding Bill & Melinda Gates Foundation.

Summary Background Diarrheal diseases remain a leading cause of illness and death among children younger than 5 years in low-income and middle-income countries. The Global Enteric Multicenter Study (GEMS) has described the incidence, aetiology, and sequelae of medically attended moderate-to-severe diarrhoea (MSD) among children aged 0–59 months residing in censused populations in sub-Saharan Africa and south Asia, where most child deaths occur. To further characterise this disease burden and guide interventions, we extended this study to include children with episodes of less-severe diarrhoea (LSD) seeking care at health centres serving six GEMS sites. Methods We report a 1-year, multisite, age-stratified, matched case-control study following on to the GEMS study. Six sites (Bamako, Mali; Manhica, Mozambique; Basse, The Gambia; Mirzapur, Bangladesh; Kolkata, India; and Bin Qasim Town, Karachi, Pakistan) participated in this study. Children aged 0–59 months at each site who sought care at a sentinel hospital or health centre during a 12-month period were screened for diarrhoea. New (onset after ≥7 diarrhoea-free days) and acute (onset within the previous 7 days) episodes of diarrhoea in children who had sunken eyes, whose skin lost turgor, who received intravenous hydration, who had dysentery, or who were hospitalised were eligible for inclusion as MSD. The remaining new and acute diarrhoea episodes among children who sought care at the same health centres were considered LSD. We aimed to enrol the first eight or nine eligible children with MSD and LSD at each site during each fortnight in three age strata: infants (aged 0–11 months), toddlers (aged 12–23 months), and young children (aged 24–59 months). For each included case of MSD or LSD, we enrolled one to three community control children without diarrhoea during the previous 7 days. From patients and controls we collected clinical and epidemiological data, anthropometric measurements, and faecal samples to identify enteropathogens at enrolment, and we performed a follow-up home visit about 60 days later to ascertain vital status, clinical outcome, and interval growth. Primary outcomes were to characterise, for MSD and LSD, the pathogen-specific attributable risk and population-based incidence values, and to assess the frequency of adverse clinical consequences associated with these two diarrhoeal syndromes. Findings From Oct 31, 2011, to Nov 14, 2012, we recruited 2368 children with MSD, 3174 with LSD, and one to three randomly selected community control children without diarrhoea matched to cases with MSD (n=3597) or LSD (n=4236). Weighted adjusted population attributable fractions showed that most attributable cases of MSD and LSD were due to rotavirus, Cryptosporidium spp, enterotoxigenic Escherichia coli encoding heat-stable toxin (with or without genes encoding heat-labile enterotoxin), and Shigella spp. The attributable incidence per 100 child-years for LSD versus MSD, by age stratum, for rotavirus was 22·3 versus 5·5 (0–11 months), 9·8 versus 2·9 (12–23 months), and 0·5 versus 0·2 (24–59 months); for Cryptosporidium spp was 3·6 versus 2·3 (0–11 months), 4·3 versus 0·6 (12–23 months), and 0·3 versus 0·1 (24–59 months); for enterotoxigenic E coli encoding heat-stable toxin was 4·2 versus 0·1 (0–11 months), 5·2 versus 0·0 (12–23 months), and 1·1 versus 0·2 (24–59 months); and for Shigella spp was 1·0 versus 1·3 (0–11 months), 3·1 versus 2·4 (12–23 months), and 0·8 versus 0·7 (24–59 months). Participants with both MSD and LSD had significantly more linear growth faltering than controls at follow-up. Interpretation Inclusion of participants with LSD markedly expands the population of children who experience adverse clinical and nutritional outcomes from acute diarrhoeal diseases. Since MSD and LSD have similar aetiologies, interventions targeting rotavirus, Shigella spp, enterotoxigenic E coli producing heat-stable toxin, and Cryptosporidium spp might substantially reduce the diarrhoeal disease burden and its associated nutritional faltering. Funding Bill & Melinda Gates Foundation.

Background: The Global Enteric Multicenter Study (GEMS) was a 3-year case-control study that measured the burden, aetiology, and consequences of moderate-to-severe diarrhoea (MSD) in children aged 0–59 months. GEMS-1A, a 12-month follow-on study, comprised two parallel case-control studies, one assessing MSD and the other less-severe diarrhoea (LSD). In this report, we analyse the risk of death with each diarrhoea type and the specific pathogens associated with fatal outcomes. Methods: GEMS was a prospective, age-stratified, matched case-control study done at seven sites in Africa and Asia. Children aged 0–59 months with MSD seeking care at sentinel health centres were recruited along with one to three randomly selected matched community control children without diarrhoea. In the 12-month GEMS-1A follow-on study, children with LSD and matched controls, in addition to children with MSD and matched controls, were recruited at six of the seven sites; only cases of MSD and controls were enrolled at the seventh site. We compared risk of death during the period between enrolment and one follow-up household visit done about 60 days later (range 50–90 days) in children with MSD and LSD and in their respective controls. Approximately 50 pathogens were detected using, as appropriate, classic bacteriology, immunoassays, gel-based PCR and reverse transcriptase PCR, and quantitative real-time PCR (qPCR). Specimens from a subset of GEMS cases and controls were also tested by a TaqMan Array Card that compartmentalised probe-based qPCR for 32 enteropathogens. Findings: 223 (2·0%) of 11 108 children with MSD and 43 (0·3%) of 16369 matched controls died between study enrolment and the follow-up visit at about 60 days (hazard ratio [HR] 8·16, 95% CI 5·69–11·68, p

Nontyphoidal Salmonella (NTS) are the leading cause of foodborne infections worldwide and a major cause of bloodstream infections in infants and HIV-infected adults in sub-Saharan Africa (SSA). Salmonella Typhimurium (serogroup B) and Salmonella Enteritidis (serogroup D) are the most common serovars in this region. However, data describing rarer invasive NTS serovars, particularly those belonging to serogroups C1 and C2, circulating in SSA are lacking. We previously conducted systematic blood culture surveillance on pediatric patients in Bamako, Mali, from 2002 to 2014, and the results showed that serovars Typhimurium and Enteritidis accounted for 32% and 36% of isolates, respectively. Here, we present data on 27 Salmonella serogroup C1 strains that were isolated during this previous study. The strains were typed by serum agglutination and multilocus sequence typing (MLST). Sixteen strains were Salmonella Paratyphi C, four were Salmonella Colindale, and two were Salmonella Virchow. Interestingly, five strains were identified as the very rare Salmonella Brazzaville using a combination of serum agglutination and flagellin gene typing. Phenotypic characterization showed that Salmonella Brazzaville produced biofilm and exhibited catalase activity, which were not statistically different from the gastroenteritis-associated Salmonella Typhimurium sequence type (ST) 19. All tested Salmonella Paratyphi C strains were poor biofilm producers and showed significantly less catalase activity than Salmonella Typhimurium ST19. Overall, our study provides insight into the Salmonella serogroup C1 serovars that cause invasive disease in infants in Mali. In addition, we show that MLST and flagellin gene sequencing, in association with traditional serum agglutination, are invaluable tools to help identify rare Salmonella serovars.

Background Lack of a gold standard for identifying bacterial and viral etiologies of pneumonia has limited evaluation of C-reactive protein (CRP) for identifying bacterial pneumonia. We evaluated the sensitivity and specificity of CRP for identifying bacterial vs respiratory syncytial virus (RSV) pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) multicenter case-control study. Methods We measured serum CRP levels in cases with World Health Organization–defined severe or very severe pneumonia and a subset of community controls. We evaluated the sensitivity and specificity of elevated CRP for “confirmed” bacterial pneumonia (positive blood culture or positive lung aspirate or pleural fluid culture or polymerase chain reaction [PCR]) compared to “RSV pneumonia” (nasopharyngeal/oropharyngeal or induced sputum PCR-positive without confirmed/suspected bacterial pneumonia). Receiver operating characteristic (ROC) curves were constructed to assess the performance of elevated CRP in distinguishing these cases. Results Among 601 human immunodeficiency virus (HIV)–negative tested controls, 3% had CRP ≥40 mg/L. Among 119 HIV-negative cases with confirmed bacterial pneumonia, 77% had CRP ≥40 mg/L compared with 17% of 556 RSV pneumonia cases. The ROC analysis produced an area under the curve of 0.87, indicating very good discrimination; a cut-point of 37.1 mg/L best discriminated confirmed bacterial pneumonia (sensitivity 77%) from RSV pneumonia (specificity 82%). CRP ≥100 mg/L substantially improved specificity over CRP ≥40 mg/L, though at a loss to sensitivity. Conclusions Elevated CRP was positively associated with confirmed bacterial pneumonia and negatively associated with RSV pneumonia in PERCH. CRP may be useful for distinguishing bacterial from RSV-associated pneumonia, although its role in discriminating against other respiratory viral-associated pneumonia needs further study.

Background Enterotoxigenic Escherichia coli (ETEC) encoding heat-stable enterotoxin (ST) alone or with heat-labile enterotoxin (LT) cause moderate-to-severe diarrhea (MSD) in developing country children. The Global Enteric Multicenter Study (GEMS) identified ETEC encoding ST among the top four enteropathogens. Since the GEMS objective was to provide evidence to guide development and implementation of enteric vaccines and other interventions to diminish diarrheal disease morbidity and mortality, we examined colonization factor (CF) prevalence among ETEC isolates from children age, Author summary Enterotoxigenic Escherichia coli (“ETEC”) were found to be one of the four most consistently important agents that cause moderate-to-severe diarrhea among children

Summary Background Despite the heightened risk of serious influenza during infancy, vaccination is not recommended in infants younger than 6 months. We aimed to assess the safety, immunogenicity, and efficacy of maternal immunisation with trivalent inactivated influenza vaccine for protection of infants against a first episode of laboratory-confirmed influenza. Methods We did this prospective, active-controlled, observer-blind, randomised phase 4 trial at six referral centres and community health centres in Bamako, Mali. Third-trimester pregnant women (≥28 weeks' gestation) were randomly assigned (1:1), via a computer-generated, centre-specific list with alternate block sizes of six or 12, to receive either trivalent inactivated influenza vaccine or quadrivalent meningococcal vaccine. Study personnel administering vaccines were not masked to treatment allocation, but allocation was concealed from clinicians, laboratory personnel, and participants. Infants were visited weekly until age 6 months to detect influenza-like illness; laboratory-confirmed influenza diagnosed with RT-PCR. We assessed two coprimary objectives: vaccine efficacy against laboratory-confirmed influenza in infants born to women immunised any time prepartum (intention-to-treat population), and vaccine efficacy in infants born to women immunised at least 14 days prepartum (per-protocol population). The primary outcome was the occurrence of a first case of laboratory-confirmed influenza by age 6 months. This trial is registered with ClinicalTrials.gov, number NCT01430689. Findings We did this trial from Sept 12, 2011, to Jan 28, 2014. Between Sept 12, 2011, and April 18, 2013, we randomly assigned 4193 women to receive trivalent inactivated influenza vaccine (n=2108) or quadrivalent meningococcal vaccine (n=2085). There were 4105 livebirths; 1797 (87%) of 2064 infants in the trivalent inactivated influenza vaccine group and 1793 (88%) of 2041 infants in the quadrivalent meningococcal vaccine group were followed up until age 6 months. We recorded 5279 influenza-like illness episodes in 2789 (68%) infants, of which 131 (2%) episodes were laboratory-confirmed influenza. 129 (98%) cases of laboratory-confirmed influenza were first episodes (n=77 in the quadrivalent meningococcal vaccine group vs n=52 in the trivalent inactivated influenza vaccine group). In the intention-to-treat population, overall infant vaccine efficacy was 33·1% (95% CI 3·7–53·9); in the per-protocol population, vaccine efficacy was 37·3% (7·6–57·8). Vaccine efficacy remained robust during the first 4 months of follow-up (67·9% [95% CI 35·1–85·3] by intention to treat and 70·2% [35·7–87·6] by per protocol), before diminishing during the fifth month (57·3% [30·6–74·4] and 60·7 [33·8–77·5], respectively). Adverse event rates in women and infants were similar among groups. Pain at the injection site was more common in women given quadrivalent meningococcal vaccine than in those given trivalent inactivated influenza vaccine (n=253 vs n=132; p

Efforts to prevent the large-scale outbreaks of meningococcal disease that have led to significant morbidity and mortality in the African meningitis belt, a region stretching from Senegal to Ethiopia, changed dramatically in 2010 when a newly developed group A meningococcal polysaccharide–tetanus toxoid protein conjugate vaccine, PsA-TT or MenAfriVac, was introduced in the first-ever preventive mass vaccination campaign in Burkina Faso, Mali, and Niger [1–4]. Developed by the Meningitis Vaccine Project, a partnership between the World Health Organization (WHO) and PATH with funding from the Bill & Melinda Gates Foundation, PsA-TT transformed the reactive vaccination strategy in place in the Meningitis Belt since the 1970s, which utilized polysaccharide meningococcal vaccines to respond to meningococcal disease outbreaks, into a preventive campaign that is implementing mass vaccination of individuals aged 1–29 years in >25 countries in Africa [5]. Evidence has indicated that PsA-TT is highly immunogenic; the vaccine was licensed based on immunogenicity alone [2, 6–8]. By the end of 2014, >217 million people in 15 countries had been vaccinated with PsA-TT [9]. The introduction of PsA-TT has dramatically altered the epidemiology of meningococcal disease in Africa, and significant reductions in the incidence of meningococcal A disease [10, 11] and meningococcal A carriage [12, 13] have been achieved in countries where the vaccine has been introduced. As with all recently developed and newly introduced vaccines, questions remain about the duration of protection provided by PsA-TT. Assessing the duration of protection has been identified as a priority for the prevention and control of meningitis in Africa [14]. Evaluating antibody persistence both in the context of clinical trials and in population-based epidemiologic studies is an important component of investigating the impact conjugate meningococcal A vaccination has had on immunity in this region. Meningococcal conjugate vaccines including PsA-TT join together polysaccharides from the outer membrane of Neisseria meningitidis to a protein carrier such as tetanus toxoid. Conjugate vaccines elicit a more robust immune response than polysaccharide-only vaccines, which are limited in that immunity wanes after 3–5 years and in that they are not immunogenic in very young children [15–17]. Although conjugate meningococcal C and ACWY vaccines provide a longer duration of immunity than comparable polysaccharide vaccines, antibody levels have been shown to wane rapidly following vaccination [18, 19]. Booster doses have been added to vaccination schedules in both the United States, where meningococcal ACWY conjugate vaccine is recommended for 11- and 12-year-olds with a booster dose at age 16 years [20], and the United Kingdom, where meningococcal C conjugate vaccine is recommended for infants and booster doses are given at 12 months and around 14 years [21]. Booster doses for these meningococcal conjugate vaccines have been recommended due to concerns about waning immunity during periods of high risk [18, 22–24], further emphasizing the need to understand the duration of immunity following PsA-TT introduction has been introduced in areas where meningococcal disease is highly endemic. To assess the duration of protection and changes in population-level immunity over time following the 2010 introduction of PsA-TT, we established a cohort in 2012 among residents of Bamako, Mali. Here we report the results of the first seroprevalence survey undertaken in the cohort, 2 years after the PsA-TT mass vaccination campaign.

Reactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically naive individuals during virgin soil epidemics, when cholera reaches immunologically naive populations that have not experienced cholera for decades, would facilitate cholera control. One dose of attenuated Vibrio cholerae O1 classical Inaba vaccine CVD 103-HgR (Vaxchora) containing ≥2 × 10 8 CFU induces vibriocidal antibody seroconversion (a correlate of protection) in >90% of U.S. adults. A previous CVD 103-HgR commercial formulation required ≥2 × 10 9 CFU to elicit high levels of seroconversion in populations in developing countries. We compared the vibriocidal responses of Malians (individuals 18 to 45 years old) randomized to ingest a single ≥2 × 10 8 -CFU standard dose ( n = 50) or a ≥2 × 10 9 -CFU high dose ( n = 50) of PaxVax CVD 103-HgR with buffer or two doses ( n = 50) of Shanchol inactivated cholera vaccine (the immunologic comparator). To maintain blinding, participants were dosed twice 2 weeks apart; CVD 103-HgR recipients ingested placebo 2 weeks before or after ingesting vaccine. Seroconversion (a ≥4-fold vibriocidal titer rise) between the baseline and 14 days after CVD 103-HgR ingestion and following the first and second doses of Shanchol were the main outcomes measured. By day 14 postvaccination, the rates of seroconversion after ingestion of a single standard dose and a high dose of CVD 103-HgR were 71.7% (33/46 participants) and 83.3% (40/48 participants), respectively. The rate of seroconversion following the first dose of Shanchol, 56.0% (28/50 participants), was significantly lower than that following the high dose of CVD 103-HgR ( P = 0.003). The vibriocidal geometric mean titer (GMT) of the high dose of CVD 103-HgR exceeded the GMT of the standard dose at day 14 (214 versus 95, P = 0.045) and was ∼2-fold higher than the GMT on day 7 and day 14 following the first Shanchol dose ( P > 0.05). High-dose CVD 103-HgR is recommended for accelerated evaluation in developing countries to assess its efficacy and practicality in field situations. (This study has been registered at ClinicalTrials.gov under registration no. NCT02145377.)

Diarrhea is a leading cause of child mortality worldwide. Early recognition of symptoms and referral to medical treatment are essential. In 2007, we conducted a Healthcare Utilization and Attitudes Survey (HUAS) of 1,000 children randomly selected from a population census to define care-seeking patterns for diarrheal disease in Bamako, Mali, in preparation for the Global Enteric Multicenter Study (GEMS). We found that 57% of caretakers sought care for their child's diarrheal illness from traditional healers, and 27% of caretakers sought care from the government health center (GHC). Weighted logistic regression showed that seeking care from a traditional healer was associated with more severe reported diarrheal disease, like decreased urination (odds ratio [OR] = 3.35, 95% confidence interval [95% CI] = 1.19–9.41) and mucus or pus in stool (OR = 4.42, 95% CI = 1.35–14.51), along with other indicators of perceived susceptibility. A locally designed traditional healer referral system was, therefore, created that emphasized more severe disease. This system may serve as a model for health systems in West Africa.

Beyond the morbidity and mortality burden of childhood diarrhea in sub-Saharan African are significant economic costs to affected households. Using survey data from 3 of the 4 sites in sub-Saharan Africa (Gambia, Kenya, Mali) participating in the Global Enteric Multicenter Study (GEMS), we estimated the direct medical, direct nonmedical, and indirect (productivity losses) costs borne by households due to diarrhea in young children. Mean cost per episode was $2.63 in Gambia, $6.24 in Kenya, and $4.11 in Mali. Direct medical costs accounted for less than half of these costs. Mean costs understate the distribution of costs, with 10% of cases exceeding $6.50, $11.05, and $13.84 in Gambia, Kenya, and Mali. In all countries there was a trend toward lower costs among poorer households and in 2 of the countries for diarrheal illness affecting girls. For poor children and girls, this may reflect reduced household investment in care, which may result in increased risks of mortality.

The oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rotavirus gastroenteritis (RVGE) in young children in two multi-site, randomized, placebo-controlled field trials; one in Asia (Vietnam and Bangladesh) and the other in sub-Saharan Africa (Ghana, Kenya and Mali). The efficacy results for the Mali site of the multi-country trial are presented here. We randomly assigned infants in a 1:1 ratio to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age. Gastroenteritis episodes were captured passively at the local health centers and by home visits. The primary study outcome was severe RVGE, as defined by a score of ≥ 11 using the Vesikari Clinical Scoring System occurring ≥ 14 days after the third dose until the end of the study. Other efficacy analyses included efficacy against severe RVGE through the first year and during the second years of life, as well as efficacy after receiving at least one dose of vaccine. In total, 1960 infants were enrolled in the trial at the Mali site and sera were collected on a subset of infants (approximately 150) for immunogenicity testing. In the first year of follow-up, largely due to cultural practices to visit traditional healers as the first point of care, the point estimate of efficacy was unreliable: the per protocol vaccine efficacy against severe RVGE was 1% (95% confidence interval [CI]: -431.7, 81.6); the intention-to-treat vaccine efficacy was 42.9% (95% CI: -125.7, 87.7). During the second year of follow-up, after the surveillance system was modified to adapt to local customs and health care seeking practices, the point estimate of per-protocol vaccine efficacy was 19.2% (95% CI: -23.1,47.3%). 82.5% of Malian infants (95% CI: 70.1,91.3%) who received PRV mounted a seroresponse (≥ 3-fold rise from baseline (prevaccination) to post-dose 3 vaccination) of anti-rotavirus immunoglobulin A antibody, with a post third-dose geometric mean titer (GMT) of 31.3 units/mL. By contrast, only 20.0% of placebo recipients (95% CI: 10.0, 33.7%) developed a seroresponse and the post-third dose GMT was 3.2 units/mL. None of the serious clinical adverse events observed were considered to be vaccine-related.

Background. In 2002, following establishment of a clinical microbiology laboratory in the government hospital that admits children with severe illnesses in Bamako, Mali, surveillance to identify pathogens causing invasive bacterial infections (septicemia, bacteremia, meningitis, etc) was initiated. Methods. Parents/guardians of children aged

Background. In 2010, mass vaccination with a then-new meningococcal A polysaccharide–tetanus toxoid protein conjugate vaccine (PsA-TT, or MenAfriVac) was undertaken in 1- to 29-year-olds in Bamako, Mali. Whether vaccination with PsA-TT effectively boosts tetanus immunity in a population with heterogeneous baseline tetanus immunity is not known. We assessed the impact of PsA-TT on tetanus toxoid (TT) immunity by quantifying age- and sex-specific immunity prior to and 2 years after introduction. Methods. Using a household-based, age-stratified design, we randomly selected participants for a prevaccination serological survey in 2010 and a postvaccination survey in 2012. TT immunoglobulin G (IgG) antibodies were quantified and geometric mean concentrations (GMCs) pre- and postvaccination among all age groups targeted for vaccination were compared. The probability of TT IgG levels ≥0.1 IU/mL (indicating short-term protection) and ≥1.0 IU/mL (indicating long-term protection) by age and sex was determined using logistic regression models. Results. Analysis of 793 prevaccination and 800 postvaccination sera indicated that while GMCs were low pre–PsA-TT, significantly higher GMCs in all age–sex strata were observed 2 years after PsA-TT introduction. The percentage with short-term immunity increased from 57.1% to 88.4% (31.3-point increase; 95% confidence interval [CI], 26.6–36.0;, P < .0001) and with long-term immunity increased from 20.0% to 58.5% (38.5-point increase; 95% CI, 33.7–43.3; P < .0001) pre- and postvaccination. Conclusions. Significantly higher TT immunity was observed among vaccine-targeted age groups up to 2 years after Mali's PsA-TT mass vaccination campaign. Our results, combined with evidence from clinical trials, strongly suggest that conjugate vaccines containing TT such as PsA-TT should be considered bivalent vaccines because of their ability to boost tetanus immunity.

BACKGROUND Group A streptococcus (GAS) pharyngitis is associated with high rates of rheumatic heart disease in developing countries. We sought to identify guidelines for empiric treatment of pharyngitis in low-resource settings. To inform the design of GAS vaccines, we determined the emm types associated with pharyngitis among African schoolchildren. METHODS Surveillance for pharyngitis was conducted among children 5-16 years of age attending schools in Bamako, Mali. Students were encouraged to visit a study clinician when they had a sore throat. Enrollees underwent evaluation and throat swab for isolation of GAS. Strains were emm typed by standard methods. RESULTS GAS was isolated from 449 (25.5%) of the 1,759 sore throat episodes. Painful cervical adenopathy was identified in 403 children (89.8%) with GAS infection and was absent in 369 uninfected children (28.2%). Emm type was determined in 396 (88.2%) of the 449 culture-positive children; 70 types were represented and 14 types accounted for 49% of isolates. Based on the proportion of the 449 isolates bearing emm types included in the 30-valent vaccine (31.0%) plus nonvaccine types previously shown to react to vaccine-induced bactericidal antibodies (44.1%), the vaccine could protect against almost 75% of GAS infections among Bamako schoolchildren. CONCLUSIONS Two promising strategies could reduce rheumatic heart disease in low-resource settings. Administering antibiotics to children with sore throat and tender cervical adenopathy could treat most GAS-positive children while reducing use of unnecessary antibiotics for uninfected children. Broad coverage against M types associated with pharyngitis in Bamako schoolchildren might be achieved with the 30-valent GAS vaccine under development.

Background Maternal influenza immunization has gained traction as a strategy to diminish maternal and neonatal mortality. However, efforts to vaccinate pregnant women against influenza in developing countries will require substantial investment. We present cost-effectiveness estimates of maternal influenza immunization based on clinical trial data from Bamako, Mali. Methods We parameterized a decision-tree model using prospectively collected trial data on influenza incidence, vaccine efficacy, and direct and indirect influenza-related healthcare expenditures. Since clinical trial participants likely had better access to care than the general Malian population, we also simulated scenarios with poor access to care, including decreased healthcare resource utilization and worse influenza-related outcomes. Results Under base-case assumptions, a maternal influenza immunization program in Mali would cost $857 (95% UI: $188-$2358) per disability-adjusted life year (DALY) saved. Adjusting for poor access to care yielded a cost-effectiveness ratio of $486 (95% UI: $105-$1425) per DALY saved. Cost-effectiveness ratios were most sensitive to changes in the cost of a maternal vaccination program and to the proportion of laboratory-confirmed influenza among infants warranting hospitalization. Mean cost-effectiveness estimates fell below Mali’s GDP per capita when the cost per pregnant woman vaccinated was $1.00 or less with no adjustment for access to care or $1.67 for those with poor access to care. Healthcare expenditures for lab-confirmed influenza were not significantly different than the cost of influenza-like illness. Conclusions Maternal influenza immunization in Mali would be cost-effective in most settings if vaccine can be obtained, managed, and administered for ≤$1.00 per pregnant woman.

Diarrhoeal diseases cause illness and death among children younger than 5 years in low-income countries. We designed the Global Enteric Multicenter Study (GEMS) to identify the aetiology and population-based burden of paediatric diarrhoeal disease in sub-Saharan Africa and south Asia.The GEMS is a 3-year, prospective, age-stratified, matched case-control study of moderate-to-severe diarrhoea in children aged 0-59 months residing in censused populations at four sites in Africa and three in Asia. We recruited children with moderate-to-severe diarrhoea seeking care at health centres along with one to three randomly selected matched community control children without diarrhoea. From patients with moderate-to-severe diarrhoea and controls, we obtained clinical and epidemiological data, anthropometric measurements, and a faecal sample to identify enteropathogens at enrolment; one follow-up home visit was made about 60 days later to ascertain vital status, clinical outcome, and interval growth.We enrolled 9439 children with moderate-to-severe diarrhoea and 13,129 control children without diarrhoea. By analysing adjusted population attributable fractions, most attributable cases of moderate-to-severe diarrhoea were due to four pathogens: rotavirus, Cryptosporidium, enterotoxigenic Escherichia coli producing heat-stable toxin (ST-ETEC; with or without co-expression of heat-labile enterotoxin), and Shigella. Other pathogens were important in selected sites (eg, Aeromonas, Vibrio cholerae O1, Campylobacter jejuni). Odds of dying during follow-up were 8·5-fold higher in patients with moderate-to-severe diarrhoea than in controls (odd ratio 8·5, 95% CI 5·8-12·5, p0·0001); most deaths (167 [87·9%]) occurred during the first 2 years of life. Pathogens associated with increased risk of case death were ST-ETEC (hazard ratio [HR] 1·9; 0·99-3·5) and typical enteropathogenic E coli (HR 2·6; 1·6-4·1) in infants aged 0-11 months, and Cryptosporidium (HR 2·3; 1·3-4·3) in toddlers aged 12-23 months.Interventions targeting five pathogens (rotavirus, Shigella, ST-ETEC, Cryptosporidium, typical enteropathogenic E coli) can substantially reduce the burden of moderate-to-severe diarrhoea. New methods and accelerated implementation of existing interventions (rotavirus vaccine and zinc) are needed to prevent disease and improve outcomes.The BillMelinda Gates Foundation.

SummaryBackgroundThe 2014 west African Zaire Ebola virus epidemic prompted worldwide partners to accelerate clinical development of replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein (ChAd3-EBO-Z). We aimed to investigate the safety, tolerability, and immunogenicity of ChAd3-EBO-Z in Malian and US adults, and assess the effect of boosting of Malians with modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo).MethodsIn the phase 1, single-blind, randomised trial of ChAd3-EBO-Z in the USA, we recruited adults aged 18–65 years from the University of Maryland medical community and the Baltimore community. In the phase 1b, open-label and double-blind, dose-escalation trial of ChAd3-EBO-Z in Mali, we recruited adults 18–50 years of age from six hospitals and health centres in Bamako (Mali), some of whom were also eligible for a nested, randomised, double-blind, placebo-controlled trial of MVA-BN-Filo. For randomised segments of the Malian trial and for the US trial, we randomly allocated participants (1:1; block size of six [Malian] or four [US]; ARB produced computer-generated randomisation lists; clinical staff did randomisation) to different single doses of intramuscular immunisation with ChAd3-EBO-Z: Malians received 1 × 1010 viral particle units (pu), 2·5 × 1010 pu, 5 × 1010 pu, or 1 × 1011 pu; US participants received 1 × 1010 pu or 1 × 1011 pu. We randomly allocated Malians in the nested trial (1:1) to receive a single dose of 2 × 108 plaque-forming units of MVA-BN-Filo or saline placebo. In the double-blind segments of the Malian trial, investigators, clinical staff, participants, and immunology laboratory staff were masked, but the study pharmacist (MK), vaccine administrator, and study statistician (ARB) were unmasked. In the US trial, investigators were not masked, but participants were. Analyses were per protocol. The primary outcome was safety, measured with occurrence of adverse events for 7 days after vaccination. Both trials are registered with ClinicalTrials.gov, numbers NCT02231866 (US) and NCT02267109 (Malian).FindingsBetween Oct 8, 2014, and Feb 16, 2015, we randomly allocated 91 participants in Mali (ten [11%] to 1 × 1010 pu, 35 [38%] to 2·5 × 1010 pu, 35 [38%] to 5 × 1010 pu, and 11 [12%] to 1 × 1011 pu) and 20 in the USA (ten [50%] to 1 × 1010 pu and ten [50%] to 1 × 1011 pu), and boosted 52 Malians with MVA-BN-Filo (27 [52%]) or saline (25 [48%]). We identified no safety concerns with either vaccine: seven (8%) of 91 participants in Mali (five [5%] received 5 × 1010 and two [2%] received 1 × 1011 pu) and four (20%) of 20 in the USA (all received 1 × 1011 pu) given ChAd3-EBO-Z had fever lasting for less than 24 h, and 15 (56%) of 27 Malians boosted with MVA-BN-Filo had injection-site pain or tenderness.Interpretation1 × 1011 pu single-dose ChAd3-EBO-Z could suffice for phase 3 efficacy trials of ring-vaccination containment needing short-term, high-level protection to interrupt transmission. MVA-BN-Filo boosting, although a complex regimen, could confer long-lived protection if needed (eg, for health-care workers).FundingWellcome Trust, Medical Research Council UK, Department for International Development UK, National Cancer Institute, Frederick National Laboratory for Cancer Research, Federal Funds from National Institute of Allergy and Infectious Diseases.

Background The importance of Cryptosporidium as a pediatric enteropathogen in developing countries is recognized. Methods Data from the Global Enteric Multicenter Study (GEMS), a 3-year, 7-site, case-control study of moderate-to-severe diarrhea (MSD) and GEMS-1A (1-year study of MSD and less-severe diarrhea [LSD]) were analyzed. Stools from 12,110 MSD and 3,174 LSD cases among children aged, Author Summary Cryptosporidium is a protozoan that causes diarrhea and malnutrition in young children in developing countries, and is associated with diarrhea cases and outbreaks in developed countries. To date, limited information exists on the burden of Cryptosporidium diarrheal disease in sub-Saharan Africa and South Asia, where most diarrheal disease deaths occur. We estimated the burden of Cryptosporidium-diarrhea and associated deaths in these regions using data from the Global Enteric Multicenter Study (GEMS). Cryptosporidium was associated with diarrhea mainly in children aged

To investigate potential risk factors for acquisition in seven countries of the meningitis belt.Households were followed up every 2 weeks for 2 months, then monthly for a further 4 months. Pharyngeal swabs were collected from all available household members at each visit and questionnaires completed. Risks of acquisition over the whole study period and for each visit were analysed by a series of logistic regressions.Over the course of the study, acquisition was higher in: (i) 5-to 14-year olds, as compared with those 30 years or older (OR 3.6, 95% CI 1.4-9.9); (ii) smokers (OR 3.6, 95% CI 0.98-13); and (iii) those exposed to wood smoke at home (OR 2.6 95% CI 1.3-5.6). The risk of acquisition from one visit to the next was higher in those reporting a sore throat during the dry season (OR 3.7, 95% CI 2.0-6.7) and lower in those reporting antibiotic use (OR 0.17, 95% CI 0.03-0.56).Acquisition of meningococcal carriage peaked in school age children. Recent symptoms of sore throat during the dry season, but not during the rainy season, were associated with a higher risk of acquisition. Upper respiratory tract infections may be an important driver of epidemics in the meningitis belt.Investiguer les facteurs de risque potentiels d'acquisition dans sept pays de la ceinture de la méningite. MÉTHODES: Des ménages ont été suivis toutes les deux semaines pendant deux mois, puis tous les mois pendant quatre mois. Des prélèvements pharyngés sur écouvillons ont été collectés auprès de tous les membres disponibles du ménage à chaque visite et des questionnaires ont été remplis. Les risques d'acquisition sur l'ensemble de la période d’étude et pour chaque visite ont été analysés par une série de régressions logistiques. RÉSULTATS: Au cours de l’étude, l'acquisition a été plus élevée chez: (i) les 5-14 ans, par rapport à ceux âgés de 30 ans ou plus (OR = 3,6; IC95%: 1,4-9,9); (ii) les fumeurs (OR = 3,6; IC95%: 0,98-13); et (iii) les personnes exposées à la fumée de bois à la maison (OR = 2,6; IC95%: 1,3-5,6). Le risque d'acquisition d'une visite à l'autre était plus élevé chez les personnes signalant un mal de gorge pendant la saison sèche (OR = 3,7; IC95%: 2,0-6,7) et plus faible chez celles signalant une utilisation d'antibiotique (OR = 0,17; IC95%: 0,03-0,56).L'acquisition du portage du méningocoque a culminé chez les enfants d’âge scolaire. Les symptômes récents de maux de gorge pendant la saison sèche, mais pas pendant la saison des pluies, étaient associés à un risque d'acquisition plus élevé. Les infections des voies respiratoires supérieures pourraient être un facteur important d’épidémies dans la ceinture de la méningite.

International audience; Background. Study of meningococcal carriage is essential to understanding the epidemiology of Neisseria meningitidis infection.Methods. Twenty cross-sectional carriage surveys were conducted in 7 countries in the African meningitis belt; 5 surveys were conducted after introduction of a new serogroup A meningococcal conjugate vaccine (MenAfriVac). Pharyngeal swab specimens were collected, and Neisseria species were identified by microbiological and molecular techniques.Results. A total of 1687 of 48 490 participants (3.4%; 95% confidence interval [CI], 3.2%–3.6%) carried meningococci. Carriage was more frequent in individuals aged 5–14 years, relative to those aged 15–29 years (adjusted odds ratio [OR], 1.41; 95% CI, 1.25–1.60); in males, relative to females (adjusted OR, 1.17; 95% CI, 1.10–1.24); in individuals in rural areas, relative to those in urban areas (adjusted OR, 1.44; 95% CI, 1.28–1.63); and in the dry season, relative to the rainy season (adjusted OR, 1.54; 95% CI, 1.37–1.75). Forty-eight percent of isolates had genes encoding disease-associated polysaccharide capsules; genogroup W predominated, and genogroup A was rare. Strain diversity was lower in countries in the center of the meningitis belt than in Senegal or Ethiopia. The prevalence of genogroup A fell from 0.7% to 0.02% in Chad following mass vaccination with MenAfriVac.Conclusions. The prevalence of meningococcal carriage in the African meningitis belt is lower than in industrialized countries and is very diverse and dynamic, even in the absence of vaccination.