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<0·0001), although 354 92% reactions were mild. Obstetrical and non-obstetrical serious adverse events were reported in 60 (3%) women in the quadrivalent meningococcal vaccine group and 61 (3%) women in the trivalent inactivated influenza vaccine group. Presumed neonatal infection was more common in infants in the trivalent inactivated influenza vaccine group than in those in the quadrivalent meningococcal vaccine group (n=60 vs n=37; p=0·02). No serious adverse events were related to vaccination. Interpretation Vaccination of pregnant women with trivalent inactivated influenza vaccine in Mali—a poorly resourced country with high infant mortality—was technically and logistically feasible and protected infants from laboratory-confirmed influenza for 4 months. With adequate financing to procure the vaccine, implementation will parallel the access to antenatal care and immunisation coverage of pregnant women with tetanus toxoid. Funding Bill & Melinda Gates Foundation.
Summary Background The 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). Methods In 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). Findings Between 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. Interpretation 1 × 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). Funding Wellcome 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.
Abstract
Background
Few studies describe the respiratory syncytial virus (RSV) burden in African populations, and most have utilized hospital-based surveillance. In Mali, no community-based studies ...exist of the incidence or epidemiology of RSV infection. This study provides the first estimates of RSV incidence in Mali.
Methods
In a cohort of infants enrolled in a clinical trial of maternal influenza vaccination, we estimate incidence of RSV-associated febrile illness in the first 6 months of life and identify risk factors for RSV infection and progression to severe disease. Infants (N = 1871) were followed from birth to 6 months of age and visited weekly to detect pneumonia and influenza-like illness. Baseline covariates were explored as risk factors for RSV febrile illness and RSV pneumonia or hospitalization.
Results
Incidence of RSV illness was estimated at 536.8 per 1000 person-years, and 86% (131/153) of RSV illness episodes were positive for RSV-B. RSV illness was most frequent in the fifth month of life and associated with having older mothers and with lower parity. The incidence of RSV-associated hospitalizations was 45.6 per 1000 person-years. Among infants with RSV illness, males were more likely to be hospitalized. The incidence of RSV pneumonia was 29 cases per 1000 person-years.
Conclusions
In the first 6 months of life, Malian infants have a high incidence of RSV illness, primarily caused by RSV-B. Prevention of early RSV will require passive protection via maternal immunization in pregnancy. Mali is the first country where RSV-B has been identified as the dominant subtype, with potential implications for vaccine development.
This first report of community-based surveillance for respiratory syncytial virus (RSV) infection in Mali showed that RSV-B was the dominant subtype, in contrast to other regions. Incidence was high early in life, before infant vaccination is a viable strategy.
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.
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.
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.
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.
ObjectiveThe objective was to assess the association between nutritional and clinical characteristics and quantitative PCR (qPCR)-diagnosis of bacterial diarrhoea in a multicentre cohort of children ...under 2 years of age with moderate to severe diarrhoea (MSD).DesignA secondary cross-sectional analysis of baseline data collected from the AntiBiotics for Children with Diarrhoea trial (NCT03130114).PatientsChildren with MSD (defined as >3 loose stools within 24 hours and presenting with at least one of the following: some/severe dehydration, moderate acute malnutrition (MAM) or severe stunting) enrolled in the ABCD trial and collected stool sample.Study periodJune 2017–July 2019.InterventionsNone.Main outcome measuresLikely bacterial aetiology of diarrhoea. Secondary outcomes included specific diarrhoea aetiology.ResultsA total of 6692 children with MSD had qPCR results available and 28% had likely bacterial diarrhoea aetiology. Compared with children with severe stunting, children with MAM (adjusted OR (aOR) (95% CI) 1.56 (1.18 to 2.08)), some/severe dehydration (aOR (95% CI) 1.66 (1.25 to 2.22)) or both (aOR (95% CI) 2.21 (1.61 to 3.06)), had higher odds of having likely bacterial diarrhoea aetiology. Similar trends were noted for stable toxin-enterotoxigenic Escherichia coli aetiology. Clinical correlates including fever and prolonged duration of diarrhoea were not associated with likely bacterial aetiology; children with more than six stools in the previous 24 hours had higher odds of likely bacterial diarrhoea (aOR (95% CI) 1.20 (1.05 to 1.36)) compared with those with fewer stools.ConclusionThe presence of MAM, dehydration or high stool frequency may be helpful in identifying children with MSD who might benefit from antibiotics.
Respiratory syncytial virus (RSV) is the most common cause of early childhood lower respiratory tract infection (LRTI) in low- and middle-income countries (LMICs). Maternal vaccines, birth-dose ...extended half-life monoclonal antibodies (mAbs), and pediatric vaccines are under development for prevention of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in young children. We analyzed the health and economic impact of RSV interventions used alone or in combinations in Mali. We modeled age-specific and season-specific risks of RSV LRTI in children through three years, using WHO Preferred Product Characteristics and data generated in Mali. Health outcomes included RSV LRTI cases, hospitalizations, deaths, and disability-adjusted life-years (DALYs). We identified the optimal combination of products across a range of scenarios. We found that mAb delivered at birth could avert 878 DALYs per birth cohort at an incremental cost-effectiveness ratio (ICER) of $597 per DALY averted compared to no intervention if the product were available at $1 per dose. Combining mAb with pediatric vaccine administered at 10/14 weeks, 1947 DALYs would be prevented. The ICER of this combination strategy is $1514 per DALY averted compared to mAb alone. Incorporating parameter uncertainty, mAb alone is likely to be optimal from the societal perspective at efficacy against RSV LRTI above 66%. The optimal strategy was sensitive to economic considerations, including product prices and willingness-to-pay for DALYs. For example, the combination of mAb and pediatric vaccine would be optimal from the government perspective at a willingness-to-pay above $775 per DALY. Maternal vaccine alone or in combination with other interventions was never the optimal strategy, even for high vaccine efficacy. The same was true for pediatric vaccine administered at 6/7 months. At prices comparable to existing vaccine products, extended half-life RSV mAbs would be impactful and efficient components of prevention strategies in LMICs such as Mali.
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) in young children and is associated with subsequent recurrent wheezing illness and asthma ...(wheeze/asthma). RSV prevention may therefore reduce wheeze/asthma prevalence.
We estimated the contribution of RSV LRTI and the impact of RSV prevention on recurrent wheeze/asthma in Mali.
We simulated 12 consecutive monthly birth cohorts in Mali and estimated RSV LRTI cases through 2 years and recurrent wheeze/asthma prevalence at 6 years under different RSV prevention scenarios: status quo, seasonal birth-dose extended half-life mAb, and seasonal birth-dose extended half-life mAb followed by 2 doses of pediatric vaccine (mAb + vaccine). We used World Health Organization (WHO) Preferred Product Characteristics for RSV prevention, demographic and RSV epidemiologic data from Mali, regional recurrent wheeze/asthma prevalence, and relative risk of recurrent wheeze/asthma given early childhood RSV LRTI.
Among the simulated cohort of 778,680 live births, 10.0% had RSV LRTI by 2 years and 89.6% survived to 6 years. We estimated that 13.4% of all recurrent wheeze/asthma at 6 years was attributable to RSV LRTI. Recurrent wheeze/asthma prevalence at 6 years was 145.0 per 10,000 persons (RSV LRTI attributable) and 1084.2 per 10,000 persons (total). In mAb and mAb + vaccine scenarios, RSV LRTI cases decreased by 11.8% and 44.4%, respectively, and recurrent wheeze/asthma prevalence decreased by 11.8% and 44.4% (RSV LRTI attributable) and 1.6% and 5.9% (total).
In Mali, RSV prevention programs may have a meaningful impact on chronic respiratory disease, strengthening the case for investment in RSV prevention.
Preterm birth is a primary outcome of interest in maternal vaccination trials but determination of gestational age is challenging in limited-resource settings. This study compares the New Ballard ...Score and fundal height measurements with the current standard of early ultrasound for sensitivity of predicting preterm birth. A trial of maternal influenza vaccination was conducted in Bamako, Mali. The New Ballard Score and fundal height were collected on 4038 infants born in the trial, ultrasound data were available for 1893 of those infants. New Ballard Score and fundal height were compared, consecutively, to all ultrasound results, early ultrasound results from the first trimester, and the date of last menstrual period for estimation of gestational age. Sensitivity of the New Ballard Score for identifying preterm infants was 0.33 compared with early ultrasound and 0.1 compared with the last menstrual period based estimates of gestational age. Sensitivity of low birth weight alone was 0.43 compared with early ultrasound. New Ballard Score estimated gestational age within 1 week of ultrasound more frequently than fundal height (53% compared with 7.6%, respectively) yet New Ballard Score identified few infants as preterm (1.8% vs 5.8% by early ultrasound), and was biased toward categorizing low birth weight infants and infants requiring hospitalization as preterm. New Ballard Score is not an ideal measure for identifying preterm births in low-resource settings. Despite the time and cost of training required for correct measurement of New Ballard Score, measurement of low birth weight alone performed better than New Ballard Score for identifying preterm infants.
Abstract
Background
Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for dysentery or ...suspected cholera.
Methods
AntiBiotics for Children with severe Diarrhea was a 7-country, placebo-controlled, double-blind efficacy trial of azithromycin in children 2–23 months of age with watery diarrhea accompanied by dehydration or malnutrition. We tested fecal samples for enteric pathogens utilizing quantitative polymerase chain reaction to identify likely and possible bacterial etiologies and employed pathogen-specific cutoffs based on genomic target quantity in previous case-control diarrhea etiology studies to identify likely and possible bacterial etiologies.
Results
Among 6692 children, the leading likely etiologies were rotavirus (21.1%), enterotoxigenic Escherichia coli encoding heat-stable toxin (13.3%), Shigella (12.6%), and Cryptosporidium (9.6%). More than one-quarter (1894 28.3%) had a likely and 1153 (17.3%) a possible bacterial etiology. Day 3 diarrhea was less common in those randomized to azithromycin versus placebo among children with a likely bacterial etiology (risk difference RDlikely, −11.6 95% confidence interval {CI}, −15.6 to −7.6) and possible bacterial etiology (RDpossible, −8.7 95% CI, −13.0 to −4.4) but not in other children (RDunlikely, −0.3% 95% CI, −2.9% to 2.3%). A similar association was observed for 90-day hospitalization or death (RDlikely, −3.1 95% CI, −5.3 to −1.0; RDpossible, −2.3 95% CI, −4.5 to −.01; RDunlikely, −0.6 95% CI, −1.9 to .6). The magnitude of risk differences was similar among specific likely bacterial etiologies, including Shigella.
Conclusions
Acute watery diarrhea confirmed or presumed to be of bacterial etiology may benefit from azithromycin treatment.
Clinical Trials Registration
NCT03130114.
Improved clinical outcomes among children with acute watery diarrhea of bacterial etiology in this reanalysis of the ABCD trial suggest that a short course of azithromycin may be warranted if bacterial etiologies could be identified at the point of care.
Rotavirus vaccines given to infants are safe and efficacious. A booster dose of rotavirus vaccine could extend protection into the second year of life in low-resource countries.
We conducted an ...open-label, individual-randomized trial in Bamako, Mali. We assigned 600 infants aged 9-11 months to receive measles vaccine (MV), yellow fever vaccine (YFV), and meningococcal A conjugate vaccine (MenAV) with or without pentavalent rotavirus vaccine (PRV). We assessed the noninferiority (defined as a difference of ≤10%) of seroconversion and seroresponse rates to MV, YFV, and MenAV. We compared the seroresponse to PRV.
Seroconversion to MV occurred in 255 of 261 PRV recipients (97.7%) and 246 of 252 control infants (97.6%; difference, 0.1% 95% confidence interval {CI}, -4.0%-4.2%). Seroresponse to YFV occurred in 48.1% of PRV recipients (141 of 293), compared with 52.2% of controls (153 of 293; difference, -4.1% 95% CI, -12.2%-4.0%). A 4-fold rise in meningococcus A bactericidal titer was observed in 273 of 292 PRV recipients (93.5%) and 276 of 293 controls (94.2%; difference, -0.7% 95% CI, -5.2%-3.8%). Rises in geometric mean concentrations of immunoglobulin A and immunoglobulin G antibodies to rotavirus were higher among PRV recipients (118 95% CI, 91-154 and 364 95% CI, 294-450, respectively), compared with controls (68 95% CI, 50-92 and 153 95% CI, 114-207, respectively).
PRV did not interfere with MV and MenAV; this study could not rule out interference with YFV. PRV increased serum rotavirus antibody levels.
NCT02286895.
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