BACKGROUND
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.
METHODS
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).
FINDINGS
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.
INTERPRETATION
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.
BACKGROUND
In settings with low Pneumoccocal Conjugate Vaccine (PCV) coverage, mass campaigns targeting multi-age cohorts (MAC) might accelerate herd protection but ould be costly. Campaigns using fractional dose PCV would decrease cost and increase access.
METHODS
We conducted a cluster-randomized trial in Niger to evaluate the effect of a mass campaign targeting children aged 1-9 years on pneumococcal carriage. 63 villages were randomized in a 3:3:1 ratio to receive campaigns with a single full dose of a 10-valent PCV (Pneumosil®), a single 1/5th fractional dose, or no campaign. We conducted two independent carriage surveys among a total of 2268 households 6 months before and 6 months after vaccination, collecting a nasopharyngeal swab from a child aged 1-9 years for culture and serotyping. If the full-dose campaign was shown superior to control in carriage reduction, the non-inferiority of fractional-dose campaign was to be evaluated, with the lower bound of the 95%CI > -7.5%. Registration: NCT05175014, PACTR20211257448484
RESULTS
Surveys were conducted between December 22, 2021, and 18 March, 2022, and December 12, 2022, and March 9, 2023. The vaccination campaign was June 15-August 2, 2022. Participant characteristics were similar between the two surveys and across arms. Pre-vaccination, vaccine-type (VT) carriage was 15.6% in the full-dose arm, 17.9% in the fractional dose arm, and 18.8% in the control arm. Post-
vaccination, VT carriage was 4.6% in the full-dose arm, 8.0% in the fractional dose arm, and 16.5% in the control arm. In the primary analysis, the risk difference between the full dose and the control arms was -12.0% [-19.0; -5.0], p=0.001, and between the full dose and fractional dose arms it was -3.5% [-5.8; -1.1], meeting the prespecified non-inferiority criterion. Similar results were seen after adjustment for age, vaccine coverage and other factors.
CONCLUSION
MAC campaigns had a marked impact on VT 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.
Rotavirus vaccination is recommended in all countries to reduce the burden of diarrhea-related morbidity and mortality in children. In resource-limited settings, rotavirus vaccination in the national immunization program has important cost implications, and evidence for protection beyond the first year of life and against the evolving variety of rotavirus strains is important. We assessed the extended and strain-specific vaccine efficacy of a heat-stable, affordable oral rotavirus vaccine (Rotasiil, Serum Institute of India, Pune, India) against severe rotavirus gastroenteritis (SRVGE) among healthy infants in Niger.
METHODS AND FINDINGS
From August 2014 to November 2015, infants were randomized in a 1:1 ratio to receive 3 doses of Rotasiil or placebo at approximately 6, 10, and 14 weeks of age. Episodes of gastroenteritis were assessed through active and passive surveillance and graded using the Vesikari score. The primary endpoint was vaccine efficacy of 3 doses of vaccine versus placebo against a first episode of laboratory-confirmed SRVGE (Vesikari score ≥ 11) from 28 days after dose 3, as previously reported. At the time of the primary analysis, median age was 9.8 months. In the present paper, analyses of extended efficacy were undertaken for 3 periods (28 days after dose 3 to 1 year of age, 1 to 2 years of age, and the combined period 28 days after dose 3 to 2 years of age) and by individual rotavirus G type. Among the 3,508 infants included in the per-protocol efficacy analysis (mean age at first dose 6.5 weeks; 49% male), the vaccine provided significant protection against SRVGE through the first year of life (3.96 and 9.98 cases per 100 person-years for vaccine and placebo, respectively; vaccine efficacy 60.3%, 95% CI 43.6% to 72.1%) and over the entire efficacy follow-up period up to 2 years of age (2.13 and 4.69 cases per 100 person-years for vaccine and placebo, respectively; vaccine efficacy 54.7%, 95% CI 38.1% to 66.8%), but the difference was not statistically significant in the second year of life. Up to 2 years of age, rotavirus vaccination prevented 2.56 episodes of SRVGE per 100 child-years. Estimates of efficacy against SRVGE by individual rotavirus genotype were consistent with the overall protective efficacy. Study limitations include limited generalizability to settings with administration of oral polio virus due to low concomitant administration, limited power to assess vaccine efficacy in the second year of life owing to a low number of events among older children, potential bias due to censoring of placebo children at the time of study vaccine receipt, and suboptimal adapted severity scoring based on the Vesikari score, which was designed for use in settings with high parental literacy.
CONCLUSIONS
Rotasiil provided protection against SRVGE in infants through an extended follow-up period of approximately 2 years. Protection was significant in the first year of life, when the disease burden and risk of death are highest, and against a changing pattern of rotavirus strains during the 2-year efficacy period. Rotavirus vaccines that are safe, effective, and protective against multiple strains represent the best hope for preventing the severe consequences of rotavirus infection, especially in resource-limited settings, where access to care may be limited. Studies such as this provide valuable information for the planning of national immunization programs and future vaccine development.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02145000.
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
The first 1000 days of life, from conception until a child's second birthday, is a crucial period during which life-long foundations for good health, growth, and development are established. It has been shown that poor maternal weight gain can contribute to adverse birth outcomes, such as low birth weight, small for gestational age, and prematurity, and such adverse birth outcomes can place children at greater risk for developing wasting and stunting as they age. While it has been suggested that the development of wasting and stunting may be related, the relative impact of poor birth outcomes on weight and height attainment over time is not clear. The objective of this study is to use recently collected longitudinal data to explore the inter-relationships between prenatal weight gain, birth outcomes, and postnatal risk of both wasting and stunting over time.
Methods
Using longitudinal data nested within a large randomized trial conducted in Madarounfa, Niger, we describe prenatal weight gain, the risk of adverse birth outcomes (preterm, small for gestational age, and low birthweight) and postnatal child growth (weight and length/height) up to 2 years of age. We use binomial regression to examine the relationship between prenatal weight gain and adverse birth outcomes. We use generalized estimating equations to examine the risk of wasting and stunting over time and evaluate potential effect modification of postnatal growth by birth outcomes.
Results
We followed 2796 mother-child pairs from pregnancy through 2 years of age. We found that 55.9% of the children were born preterm, 6.4% were born small for gestational weight, and 6.8% were born with low birth weight. Using longitudinal analysis, we are examining the relationship between the risk of wasting and stunting over time.
Conclusions
This analysis will provide evidence to describe the inter-relationships between prenatal weight gain, adverse birth outcomes, and risk of both wasting and stunting over time, with special attention to the inter-relationships between prenatal and postnatal growth.
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
At two years of follow-up, RotaSIIL was found to be safe.
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.
OBJECTIVE
To compare the effect of prenatal MMS, medium-quantity LNS (MQ-LNS), and IFA on child growth up to 2 years of age.
DESIGN
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 weeks to 24 months of age. We assessed the effect of prenatal MMS and MQ-LNS compared to IFA and the effect of prenatal MMS compared to 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 months of age using generalized linear models. In secondary analyses, we used mixed effects models to assess the trajectory of anthropometric Z-scores longitudinally from 6-8 weeks to 24 months.
RESULTS
Compared to IFA, MMS and MQ-LNS had no effect on child LAZ, WAZ, or WLZ at 24 months of age (P-values >0.05). Children in the MQ-LNS arm had significantly higher MUAC at 24 months than children in the MMS arm: mean difference 0.50 cm (95% CI 0.10, 0.91). WAZ and WLZ trajectories were more negative in the MQ-LNS arm compared to IFA and MMS, with lower Z-scores from 14 to 20 months of age. However, WAZ and WLZ trajectories converged after 20 months of age, and there were no differences by 24 months of age.
CONCLUSIONS
Prenatal MMS and MQ-LNS had limited effect on anthropometric measures of child growth up to 24 months of age as compared to IFA in rural Niger.