Transcriptomic signatures were identified in human peripheral blood mononuclear cells (PBMCs) and breast milk lymphocyte (BML) cells induced by trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV) administered after delivery. We performed an RNA-Seq analysis on blood and breast milk samples from a subset of subjects enrolled in a randomized, double-blind controlled study in breastfeeding women who received either intranasal LAIV and intramuscular placebo, or intramuscular TIV and intranasal placebo (LAIV, n = 10 and TIV, n = 6). Differentially expressed genes, gene clusters, and enriched pathways were identified. We observed increased innate immune signaling responses in BML but not in PBMC at Day 28 for the LAIV group. We hypothesize that breastfeeding extended the innate response to LAIV via mucosal immunity. An association between an increased IgG antibody response in TIV vs. LAIV identified in the parent study using ELISA corresponded to IGHG1 immunoglobulin gene expression in Day 28 PBMCs.

BACKGROUND:Risk factors of infant mortality in Africa and south Asian countries have been broadly discussed. However, infant morbidity is largely underestimated. We analyzed the data from a randomized vaccine trial in Bangladesh to identify and assess the effect of risk factors on infant morbidity. METHODS:Pregnant women were randomly assigned to receive either inactivated influenza vaccine or pneumococcal polysaccharide vaccine and the infants were randomly assigned to receive 7-valent pneumococcal conjugate vaccine or Hib conjugate vaccine at week 6, 10 and 14. The data were collected from August 2004 through December 2005. Each pair of infant and mother were followed for 24 weeks after birth with weekly visits. Generalized estimating equations (GEE) for repeated measurements and Poisson regression models were used to identify the risk factors and evaluate their effect on the longitudinal incidence and total number of episodes of respiratory illness with fever (RIF), diarrhea disease, ear problem and pneumonia. RESULTS:A total of 340 pregnant women were randomized with mean age of 25 years. The baseline mother and infant characteristics were similar between two treatment groups. Exclusive breastfeeding and higher paternal education level were common factors associated with lower infant morbidity of RIF (adjusted OR = 0.40 and 0.94 with p < 0.01 and p = 0.02, respectively), diarrhea disease (adjusted OR = 0.39 and 0.95 with p < 0.01 and p = 0.04, respectively), and ear problem (adjusted OR = 0.20 and 0.76 with p < 0.01 and p < 0.01, respectively). Maternal influenza vaccine significantly reduced the incidence of RIF (adjusted OR = 0.54; p < 0.01) but not diarrhea disease or ear problem (p > 0.05). Female infants had lower incidence of diarrhea disease (adjusted OR = 0.67; p = 0.01) and ear problem (adjusted OR = 0.12; p = 0.01). CONCLUSIONS:Maternal influenza vaccination, exclusive breastfeeding, female children, and higher paternal education level significantly reduced the infant morbidity within the 24 weeks after birth in Bangladesh.

Context: Influenza infection in pregnancy causes 4%–8% case fatality and five times more perinatal mortality. Influenza is a major contributor to mortality in developing countries; however, the morbidity has largely been underestimated. Public health interventions for prevention are also lacking. Aims: This study aimed to determine the seasonality of influenza in pregnant Indian women and to estimate the maternal and perinatal morbidity after treatment with oseltamivir. Settings and Design: This was a prospective observational cohort study, conducted in a tertiary hospital. Subjects and Methods: Pregnant women with ILI (influenza-like illness) were recruited into Cohort 1 (polymerase chain reaction [PCR] positive) and Cohort 2 (PCR negative). Gestational age-matched asymptomatic controls formed Cohort 3. Women in Cohort 1 received oseltamivir for 5 days. The incidence of small-for-gestational age (SGA) and preterm birth were the primary outcomes. Maternal and neonatal morbidity formed the secondary outcomes. Statistical Analysis: Unmatched (Cohort 1 and 2) and matched analysis (Cohort 1 and 3) were done. Student's t-test and Chi-square test were used to compare between variables. Results: Year-round incidence of influenza was recorded. Severe illness was more in Cohort 1 compared to Cohort 2 (36.2% vs. 6.3%; P < 0.001). SGA was comparable in all the cohorts (13%). Preterm birth (7.8% vs. 3.3%; P < 0.08; relative risk-2.75) was considerably high in Cohort 1. Secondary maternal and neonatal outcomes were similar between the groups. Conclusion: Influenza in pregnancy showed year-round incidence and increased maternal and neonatal morbidity despite treatment with oseltamivir. We suggest the need for newer interventions to curtail the illness in pregnancy.

BACKGROUND:Respiratory viruses cause significant morbidity and death in infants; 99% of such deaths occur in resource-limited settings. Risk factors for initial and repeated respiratory viral infections in young infants in resource-limited settings have not been well described. METHODS:From 2011 to 2014, a birth cohort of infants in rural Nepal was enrolled and followed with weekly household-based active surveillance for respiratory symptoms until 6 months of age. Respiratory illness was defined as having any of the following: fever, cough, wheeze, difficulty breathing, and/or a draining ear. We tested nasal swabs of infants with respiratory illness for multiple respiratory viruses by using a reverse transcription polymerase chain reaction assay. The risk of primary and repeated infections with the same virus was evaluated using Poisson regression. RESULTS:Of 3528 infants, 1726 (49%) had a primary infection, and 419 (12%) had a repeated infection. The incidences of respiratory viral infection in infants were 1816 per 1000 person-years for primary infections and 1204 per 1000 person-years for repeated infection with the same virus. Exposure to other children and male sex were each associated with an increased risk for primary infection (risk ratios, 1.13 [95% confidence interval (CI), 1.06-1.20] and 1.14 [95% CI, 1.02-1.27], respectively), whereas higher maternal education was associated with a decreased risk for both primary and repeated infections (risk ratio, 0.96 [95% CI, 0.95-0.98]). The incidence of subsequent infection did not change when previous infection with the same or another respiratory virus occurred. Illness duration and severity were not significantly different in the infants between the first and second episodes for any respiratory virus tested. CONCLUSIONS:In infants in rural Nepal, repeated respiratory virus infections were frequent, and we found no decrease in illness severity with repeated infections and no evidence of replacement with another virus. Vaccine strategies and public health interventions that provide durable protection in the first 6 months of life could decrease the burden of repeated infections by multiple respiratory viruses, particularly in low-resource countries.

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. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.

Abstract Background Maternal influenza vaccination has been demonstrated to reduce influenza infections in infants. Influenza infections generally peak during the winter season, and several studies support the association between low levels of vitamin D during winter months and an increase in respiratory infections, including influenza. We examined the effects of vitamin D and maternal influenza vaccination status on laboratory confirmed influenza infections in infants less than 6 months of age. Methods Pregnant Bangladeshi mothers were randomized to receive influenza vaccine or pneumococcal vaccine as part of the Mother’s Gift study. Mothers reported breastfeeding frequency, along with episodes of infant respiratory illness with fever, every week for the first 6 months of life. If a respiratory illness with fever was reported, nasal swabs were obtained from the infant and tested with a commercial rapid influenza test. Infants with confirmed influenza disease were matched with four controls by birth month and sex, for a total of 84 controls. We measured 25-hydroxyvitamin D levels from cord blood in all cases and controls. A conditional logistic regression was performed to test the effect of vitamin D on the odds of laboratory confirmed influenza while controlling for birth weight, gestational age, crowding, number of siblings, and socioeconomic status score. Results A total of 21 infants had laboratory confirmed influenza disease. There were no significant differences in birth weight, crowding, family size, gestational age, socioeconomic status score, infant gender, and smokers in the home between cases and controls (Table 1). Frequency of maternal influenza vaccine was lower in cases when compared with controls (23.81% vs. 58.33%). Serum vitamin D was lower in cases than in controls (8.73 ± 3.34 vs. 10.67 ± 4.08, Table 2). Conclusion Both vitamin D levels and maternal vaccination status have medically relevant, and statistically significant, independent effects on the odds of infants contracting influenza. Although the vitamin D levels in the infants at birth were low, there was a significant association of lower levels at birth with an increased risk of influenza virus infection. Further study with a larger sample-size is needed to explore these effects. Disclosures All authors: No reported disclosures.

Background: Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are both licensed for administration to nursing mothers. Little is known about the potential for transmission of LAIV viruses from the mother to the infant and the comparative breast milk antibody responses to LAIV and IIV. Methods: We performed a randomized, double-blind study comparing the immunogenicity of LAW to IIV when administered to nursing mothers. The safety of LAIV to IIV in women and their infants was also compared. Women received LAIV + intramuscular placebo, or IIV + intranasal placebo on Day 0. Breast milk and nasal swabs (from women and infants) were collected on Days 0, 2, and 8 for detection of LAIV. Breast milk and serum antibody responses were measured at Days 0 and 28. The primary hypothesis was that LAIV would provide superior induction of breast milk IgA responses to influenza as compared to IIV when administered to nursing mothers. Results: Breast milk IgG, breast milk IgA (H1N1 only), serum hemagglutination inhibition (HAI), and serum IgG responses were significantly higher following administration of IIV compared to LAIV. Receipt of either LAIV or IIV was safe in women and their infants. One (1%) LAIV recipient transmitted vaccine virus to her infant who remained well. No influenza virus was detected in breast milk. Conclusions: Breast milk and serum antibody responses were higher for IIV compared to LAIV. LAIV and IIV were safe for nursing women but there was one (1%) possible transmission of LAIV to an infant. This study suggests that IIV may be the preferred vaccine for nursing mothers. (C) 2018 Elsevier Ltd. All rights reserved.

We sought to compare seroprevalence of protective measles and rubella-specific antibody in mother-infant pairs across two populations: a pre-disease elimination Nepal population with recently introduced rubella vaccine and post-disease elimination U.S. population. Qualitative measles and rubella immunoglobulin G was assessed in maternal serum and cord blood from 258 pairs in Nepal, 2012-2013 and 49 pairs in Seattle, WA, 2014-2015. High rates of protective antibody were observed in both populations. Two hundred and forty-four (95%) pregnant women in Nepal had protective measles antibody versus 44 (92%) in Seattle (P = 0.42). Ninety-six percent of infants in Nepal (N = 246) and Seattle (N = 43) had protective measles antibody (P = 0.75). Ninety-four percentage of pregnant women in Nepal (N = 242) and Seattle (N = 45) had protective rubella antibody (P = 0.23). Two hundred and thirty-eight (93%) infants in Nepal had protective rubella antibody versus 44 (98%) in Seattle (P = 0.12). Continued surveillance will be necessary to ensure protective immunity, inform progress toward disease elimination in Nepal and avoid reemergence in the United States.

Influenza immunization of pregnant women provides protection of the infant against influenza disease. A potential mechanism of protection is prevention of maternal illness that may result in secondary transmission to infants. We aim to characterize influenza transmission in mother–infant pairs. Pregnant mothers were enrolled in a randomized controlled trial of influenza immunization in rural Nepal from April 2011 to April 2013. Mothers and infants were surveyed weekly until 180 days post-partum for respiratory illness and mid-nasal swabs were collected at time of illness and tested for influenza virus by reverse-transcriptase polymerase chain reaction (RT-PCR). We defined a transmission episode as a mother–infant pair with an influenza-positive illness within 14 days of each other. Influenza viruses were strain-typed by RT-PCR and/or mass spectrometry. Seventeen mother–infant transmission episodes occurred with maternal illness preceding infant illness in 12 (70.6%). Of transmission pairs, 12 (70.6%) were influenza B, three (17.6%) H3N2 influenza A, one (5.9%) H1N1 influenza A, and one (5.9%) unspecified influenza A. Five (29.4%) mothers received the influenza vaccine. Successful strain-typing with RT-PCR/mass spectrometry of 11 pairs revealed that 10 (90.9%) were synonymous strains. Figure 1 shows the start of respiratory symptoms and virus type associated with influenza illness in the 17 mother–infant pairs. Mothers are an important source of infant influenza infection. Transmission was confirmed with nearly all paired transmissions demonstrating a similar strain. The majority of transmission events occurred in nonvaccinated mother–infant pairs. Figure 1: Influenza transmission events in mother–infant pairs. Symbols represent first day of respiratory symptoms associated with influenza-positive illness. J. Englund, GlaxoSmithKline: Investigator, Research grant. MedImmune: Investigator, Research grant. Gilead: Investigator, Research grant. Novavax: Investigator, Research grant. Chimerix: Investigator, Research grant. Alios: Investigator, Research grant. H. Chu, Sanofi-Pasteur: Grant Investigator, Grant recipient.

Background:Knowledge of risk factors for symptomatic human coronavirus (HCoV) infections in children in community settings is limited. We estimated the disease burden and impact of birth-related, maternal, household, and seasonal factors on HCoV infections among children from birth to 6 months old in rural Nepal.Methods:Prospective, active, weekly surveillance for acute respiratory infections (ARIs) was conducted in infants over a period of 3 years during 2 consecutive, population-based randomized trials of maternal influenza immunization. Midnasal swabs were collected for acute respiratory symptoms and tested for HCoV and other viruses by reverse-transcription polymerase chain reaction. Association between HCoV incidence and potential risk factors was modeled using Poisson regression.Results:Overall, 282 of 3505 (8%) infants experienced an HCoV ARI within the first 6 months of life. HCoV incidence overall was 255.6 (95% confidence interval [CI], 227.3-286.5) per 1000 person-years, and was more than twice as high among nonneonates than among neonates (incidence rate ratio [IRR], 2.53; 95% CI, 1.52-4.21). HCoV ARI incidence was also positively associated with the number of children <5 years of age per room in a household (IRR, 1.13; 95% CI, 1.01-1.28). Of the 296 HCoV infections detected, 46% were coinfections with other respiratory viruses. While HCoVs were detected throughout the study period, seasonal variation was also observed, with incidence peaking in 2 winters (December-February) and 1 autumn (September-November).Conclusions:HCoV is associated with a substantial proportion of illnesses among young infants in rural Nepal. There is an increased risk of HCoV infection beyond the first month of life.

Background:Transplacental respiratory syncytial virus (RSV) antibody transfer has been characterized, but little is known about the protective effect of breast milk RSV-specific antibodies. Serum antibodies against the prefusion RSV fusion protein (pre-F) exhibit high neutralizing activity. We investigate protection of breast milk pre-F antibodies against RSV acute respiratory infection (ARI).Methods:Breast milk at 1, 3, and 6 months postpartum and midnasal swabs during infant illness episodes were collected in mother-infant pairs in Nepal. One hundred seventy-four infants with and without RSV ARI were matched 1:1 by risk factors for RSV ARI. Pre-F immunoglobulin A (IgA) and immunoglobulin G (IgG) antibody levels were measured in breast milk.Results:The median breast milk pre-F IgG antibody concentration before illness was lower in mothers of infants with RSV ARI (1.4 [interquartile range {IQR}, 1.1-1.6] log10 ng/mL) than without RSV ARI (1.5 [IQR, 1.3-1.8] log10 ng/mL) (P = .001). There was no difference in median maternal pre-F IgA antibody concentrations in cases vs controls (1.7 [IQR, 0.0-2.2] log10 ng/mL vs 1.7 [IQR, 1.2-2.2] log10 ng/mL, respectively; P = .58).Conclusions:Low breast milk pre-F IgG antibodies before RSV ARI support a potential role for pre-F IgG as a correlate of protection against RSV ARI. Induction of breast milk pre-F IgG may be a mechanism of protection for maternal RSV vaccines.

Abstract Background Pneumococcal pneumonia after a preceding respiratory viral illness is associated with morbidity and mortality in infants. Our study sought to determine how pneumococcal carriage impacted illness severity due to respiratory syncytial virus (RSV) or human metapneumovirus (hMPV) in infants 0–6 months in a low resource setting in South Asia without pneumococcal vaccination. Previous studies in this population found an overall 79.4% prevalence of pneumococcal carriage in ages 1–36 months with higher rates of carriage among healthy controls when compared with those with respiratory illness. Methods Infants were enrolled at the time of birth in a maternal influenza immunization trial conducted in rural Nepal from 2011 to 2014. Weekly household-based active surveillance was performed from birth to 6 months to assess for infant respiratory illness, defined as fever, cough, difficulty breathing, wheeze, or otorrhea. Mid-nasal swabs were collected and tested by PCR for RSV, hMPV, and streptococcus pneumoniae with inclusion of first illness episode in the surveillance period. Disease severity was defined using the World Health Organization Integrated Management of Childhood Illness criteria. Results Altogether, 247 (73.5%) of 336 infants with RSV and 154 (83.7%) of 184 infants with hMPV had S. pneumoniae detected. Mean age at RSV illness with concurrent pneumococcal carriage was 97.0 days (91.3–102.6) versus 72.8 days (63.3–82.4) for infants without carriage (P < 0.001). Mean age at hMPV illness with concurrent pneumococcal carriage was 101.3 days (93.9–108.7) versus 77.2 days (56.5–98.0) for infants without carriage (P = 0.01). Frequency of reported lower respiratory tract infection did not differ with or without carriage (RSV: 64.4% vs. 65.2% respectively; P = 0.89, hMPV: 52.6% vs. 50.0% P = 0.79). S. pneumoniae PCR cycle threshold value did not differ by duration or severity of RSV or hMPV illness episode. Conclusion High rates of pneumococcal carriage were observed with RSV and hMPV illness episodes in a birth cohort of infants in rural Nepal. The majority of infants with RSV or hMPV illness had pneumococcus detected at the time of first observed illness. However, no increase in RSV or hMPV illness severity or duration was seen with pneumococcal carriage. Disclosures H. Y. Chu, sanofi pasteur: Grant Investigator, Grant recipient. Novavax: Grant Investigator, Grant to co-investigator’s institution.

Background: To evaluate the effect of antenatal influenza vaccination on all-cause severe infant pneumonia, we performed pooled analysis of 3 randomized controlled trials conducted in Nepal, Mali and South Africa. Methods: The trials were coordinated from the planning phase. The follow-up period was 0–6 months postpartum in Nepal and Mali and 0–24 weeks in South Africa. Pregnant women with gestational age 17–34 weeks in Nepal, ≥28 weeks in Mali and 20–36 weeks in South Africa were enrolled. Trivalent inactivated influenza vaccine (IIV) was compared with either saline placebo (Nepal and South Africa) or quadrivalent meningococcal conjugate vaccine (Mali). In South Africa, cases were hospitalized and were therefore considered to have severe pneumonia. In Nepal and Mali, severe infant pneumonia diagnosis was based on the WHO Integrated Management of Childhood Illness definition. Results: A total of 10,002 mothers and 9801 live-born eligible infants were included in the present analysis. There was a 31% lower incidence rate of severe pneumonia in the IIV group compared with the control group in Nepal [incidence rate ratio (IRR): 0.69; 95% CI: 0.50–0.94; Table 1]. In South Africa, there was a 43% lower incidence rate of severe pneumonia in the IIV group versus the control group (IRR: 0.57; 95% CI: 0.33–1.0). There was no difference in incidence rates between the IIV group and the control group in Mali. Overall, incidence rate of severe pneumonia was 20% lower in the IIV group compared with the control group (IRR: 0.80; 95% CI: 0.66–0.99; P = 0.04). Protection was highest in the high influenza circulation period (IRR: 0.44; 95% CI: 0.23–0.84). Conclusions: Maternal influenza immunization may reduce severe pneumonia episodes among infants—particularly those too young to be completely vaccinated against Streptococcus pneumoniae and influenza.

We used RT-PCR-electrospray ionization-mass spectrometry to identify subtypes and strains of influenza viruses detected during a maternal influenza immunization study in Nepal from May 2011 to April 2014. Hemagglutinin (HA) gene amino acid (aa) sequences of inferred reference strains were compared to those of the vaccines to determine impact of aa relatedness on vaccine efficacy (VE) and disease severity. Three influenza subtypes and many strains were identified. A(H3N2) strains with less than 13 aa differences in HA compared to vaccine strains (matched) showed higher VE than strains with 13 or more differences (mismatched). Yamagata lineage B strains, which were mismatched to the Victoria strain in the vaccine, demonstrated lower VE compared to Victoria strains. Differences in VE were not statistically significant. All A(H1N1pdm) matched the vaccine strain, with 10 or fewer aa differences. Except for women infected with vaccine-matched strains of influenza A, clinical signs and symptoms did not differ between vaccinated and unvaccinated participants.

ObjectiveTo describe the effect of maternal vaccination on birth outcomes in rural Nepal, modified by timing of vaccination in pregnancy and influenza virus activity. MethodsA secondary analysis was conducted using data from two annual cohorts of a randomized controlled trial. A total of 3693 pregnant women from Sarlahi District were enrolled between April 25, 2011, and September 9, 2013. All participants were aged 15-40years and received a trivalent inactivated influenza vaccine or placebo. The outcome measures included birth weight, pregnancy length, low birth weight (<2500g), preterm birth, and small-for-gestational-age birth. ResultsData were available on birth weight for 2741 births and on pregnancy length for 3623 births. Maternal vaccination increased mean birthweight by 42g (95% confidence interval [CI] 8-76). The magnitude of this increase varied by season but was greatest among pregnancies with high influenza virus circulation during the third trimester. Birth weight increased by 111g (95% CI -51 to 273) when 75%-100% of apregnancy's third trimester had high influenza virus circulation versus 38g (95% CI -6 to 81) when 0%-25% of a pregnancy's third trimester had high influenza virus circulation. However, these results were nonsignificant. ConclusionSeasonal maternal influenza vaccination in rural Nepal increased birth weight; the magnitude appeared larger during periods of high influenza virus circulation. ClinicalTrials.govNCT01034254. Maternal influenza vaccination in rural Nepal increased birth weight, particularly among pregnancies with high levels of influenza virus circulation during the third trimester.

BackgroundIn the growing embryo, the vitamin A requirement is tightly regulated. Maternal vitamin A deficiency during pregnancy may alter maternal immune function to accommodate the fetus.ObjectiveOur primary objective was to determine the effect of oral vitamin A supplementation (VAS) during pregnancy and until 6 mo postpartum on pandemic H1N1-vaccine responses in mothers and their infants at 6 mo of age.MethodsIn this randomized controlled clinical trial, pregnant women (n = 112) during the second trimester (mean ± SD: 14 ± 1 wk) were assigned to receive either an oral dose of 10,000 IU vitamin A or placebo weekly until 6 mo postpartum. During the third trimester, mothers received a single dose of inactivated pandemic H1N1-influenza vaccine. Hemagglutination-inhibition (HAI) titer was measured in cord, infant, and maternal blood samples. Multivariate regressions with adjustments were used for data analysis.ResultsSeventy-six percent of women had low plasma retinol concentrations (<1.05 μmol/L) in their second trimester. VAS of mothers increased vitamin A concentrations in cord blood by 21.4% and in colostrum by 40.7%. At 6 mo postpartum, women in the vitamin A group had 38.7% higher HAI titers and a higher proportion of HAI titer of ≥1:40 of the cutoff compared with the placebo group. A total of 54.5% of infants had an HAI titer ≥1:40 at 6 mo of age, but there was no difference in HAI titer in infants between groups. Overall, HAI in cord blood did not differ between groups, but in the placebo group, cord blood HAI was negatively associated with maternal "vaccination-to-delivery intervals" (rs = -0.401; P = 0.5), and maternal VAS increased cord blood HAI 6-fold if antenatal immunization was administered ≥10 wk before delivery.ConclusionsIn a community with low vitamin A status, weekly maternal VAS during pregnancy and postpartum increases the breast-milk vitamin A concentration and enhances prenatal H1N1-vaccine responses in mothers, but the benefits of maternal VAS in transplacental antibody transfer may depend on the time of gestation when mothers were vaccinated. This trial was registered at clinicaltrials.gov as NCT00817661.

Background. Maternal influenza vaccination protects mothers and their infants in low resource settings, but little is known about whether the protection varies by gestational age at vaccination. Methods. Women of childbearing age in rural southern Nepal were surveilled for pregnancy, consented and randomized to receive maternal influenza vaccination or placebo, with randomization stratified on gestational age (17-25 or 26-34 weeks). Enrollment occurred in 2 annual cohorts, and vaccinations occurred from April 2011 through September 2013. Results. In sum, 3693 women consented and enrolled, resulting in 3646 live births. Although cord blood antibody tilers and the rise in maternal titers were generally greater when women were vaccinated later in pregnancy, this was not statistically significant. The incidence risk ratio (IRR) for maternal influenza in pregnancy through 6 months postpartum was 0.62 (95% confidence interval [CI]: 0.35, 1.10) for those vaccinated 17-25 weeks gestation and 0.89 (95% CI: 0.39, 2.00) for those 26-34 weeks. Infant influenza IRRs were 0.73 (95% CI: 0.51, 1.05) for those whose mothers were vaccinated earlier in gestation, and 0.63 (95% CI: 0.37, 1.08) for those later. Relative risks (RR) for low birthweighl were 0.83 (95% CI: 0.71, 0.98) and 0.90 (95% CI: 0.72, 1.12) for 17-25 and 26-34 weeks gestation at vaccination, respectively. IRRs did not differ for small-for-gestational age or preterm. No RRs were statistically different by timing of vaccine receipt. Conclusions. Vaccine efficacy did not vary by gestational age at vaccination, making maternal influenza immunization programs easier to implement where women present for care late in pregnancy.

Background: Infants are at greatest risk for pertussis morbidity and mortality. Maternal vaccination during pregnancy has been shown to prevent pertussis in young infants in high-and middle-income countries. However, data on the levels of maternal pertussis antibodies and the efficiency of transplacental transfer in low-income South Asian settings are limited. Objective: To estimate the prevalence of maternal pertussis antibodies and the efficiency of transplacental transfer in rural southern Nepal. Design/methods: Paired maternal-infant blood samples were collected from a subsample of participants in a randomized, controlled trial of maternal influenza immunization (n = 291 pairs). Sera were tested by enzyme-linked immunosorbent assays for pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae. Maternal and infant pertussis antibody levels and transplacental transfer efficiency were determined and potential factors associated with both were assessed. Results: Elevated maternal antibodies to pertussis toxin, suggesting recent pertussis infection, were rarely detected (4%, tested n = 305). However, paired maternal-cord sera were highly correlated across all antibodies; transplacental antibody transfer ratios for pertussis toxin were 1.14 (n = 291, 95% CI 1.07-1.20); filamentous hemagglutinin 1.10 (n = 120, 95% CI: 1.01-1.20); fimbriae 2/3 1.05 (n = 120, 95% CI: 0.96-1.15) and pertactin 0.96 (n = 289, 95% CI: 0.91-1.00). Older gestational age was associated with increased pertussis toxin and decreased fimbriae 2/3 antibody transport. Conclusions: A low prevalence of maternal antibody to all four pertussis antigens was noted in Nepal, but transplacental antibody transfer was efficient. No consistent demographic factors were associated with elevated maternal antibody levels or efficiency of transplacental transfer. If an increase in infant pertussis disease burden was detected in this population, maternal immunization could be an effective intervention to prevent disease in early infancy. (C) 2017 The Author(s). Published by Elsevier Ltd.

Background: Pneumonia is a leading cause of morbidity and mortality in children worldwide; however, its diagnosis can be challenging, especially in settings where skilled clinicians or standard imaging are unavailable. We sought to determine the diagnostic accuracy of lung ultrasound when compared to radiographically-confirmed clinical pediatric pneumonia.Methods: Between January 2012 and September 2013, we consecutively enrolled children aged 2-59 months with primary respiratory complaints at the outpatient clinics, emergency department, and inpatient wards of the Institute Nacional de Salud del Nino in Lima, Peru. All participants underwent clinical evaluation by a pediatrician and lung ultrasonography by one of three general practitioners. We also consecutively enrolled children without respiratory symptoms. Children with respiratory symptoms had a chest radiograph. We obtained ancillary laboratory testing in a subset.Results: Final clinical diagnoses included 453 children with pneumonia, 133 with asthma, 103 with bronchiolitis, and 143 with upper respiratory infections. In total, CXR confirmed the diagnosis in 191 (42%) of 453 children with clinical pneumonia. A consolidation on lung ultrasound, which is our primary endpoint for pneumonia, had a sensitivity of 88.5%, specificity of 100%, and an area under-the-curve of 0.94 (95% CI 0.92-0.97) when compared to radiographically-confirmed clinical pneumonia. When any abnormality on lung ultrasound was compared to radiographically-confirmed clinical pneumonia the sensitivity increased to 92.2% and the specificity decreased to 95.2%, with an area under-the-curve of 0.94 (95% CI 0.91-0.96).Conclusions: Lung ultrasound had high diagnostic accuracy for the diagnosis of radiographically confirmed pneumonia. Added benefits of lung ultrasound include rapid testing and high inter-rater agreement. Lung ultrasound may serve as an alternative tool for the diagnosis of pediatric pneumonia. (C) 2017 The Author(s). Published by Elsevier Ltd.

Abstract Background Incidence of respiratory syncytial virus (RSV) and rhinovirus (RHV) varies throughout the year. We aim to quantify the relationship between weather variables (temperature, humidity, precipitation, and aerosol concentration) and disease incidence in order to quantify how outbreaks of RSV and RHV are related to seasonal or sub-seasonal meteorology, and if these relationships can predict viral outbreaks of RSV and RHV. Methods Health data were collected in a community-based, prospective randomized trial of maternal influenza immunization of pregnant women and their infants conducted in rural Nepal from 2011–2014. Adult illness episodes were defined as fever plus cough, sore throat, runny nose, and/or myalgia, with infant illness defined similarly but without fever requirement. Cases were identified through longitudinal household-based weekly surveillance. Temperature, humidity, precipitation, and fine particulate matter (PM 2.5) data come from reanalysis data products NCEP, Era-Interim, and Merra-2, which are produced by assimilating historical in-situ and satellite-based observations into a weather model. Results RSV exhibits a relationship with temperature after removing the seasonal cycle (r = -0.16, N = 208, P = 0.02), and RHV exhibits a strong relationship to daily temperature (r =-0.14, N =208, P = 0.05). When lagging meteorology by up to 15 weeks, correlations with disease count and weather improve (RSV: r_max = 0.45, P < 0.05; RHV: r_max = 0.15, P = 0.05). We use an SIR model forced by lagged meteorological variables to predict RSV and RHV, suggesting that disease burden can be predicted at lead times of weeks to months. Conclusion Meteorological variables are associated with RSV and RHV incidence in rural Nepal and can be used to drive predictive models with a lead time of several months. Disclosures J. Englund, Gilead: Consultant and Investigator, Research support Chimerix: Investigator, Research support Alios: Investigator, Research support Novavax: Investigator, Research support MedImmune: Investigator, Research support GlaxoSmithKline: Investigator, Research support