Impact of maternal antibodies and microbiota development on the immunogenicity of oral rotavirus vaccine in African, Indian, and European infants.

Identifying risk factors for impaired oral rotavirus vaccine (ORV) efficacy in low-income countries may lead to improvements in vaccine design and delivery. In this prospective cohort study, we measure maternal rotavirus antibodies, environmental enteric dysfunction (EED), and bacterial gut microbiota development among infants receiving two doses of Rotarix in India (n = 307), Malawi (n = 119), and the UK (n = 60), using standardised methods across cohorts. We observe ORV shedding and seroconversion rates to be significantly lower in Malawi and India than the UK. Maternal rotavirus-specific antibodies in serum and breastmilk are negatively correlated with ORV response in India and Malawi, mediated partly by a reduction in ORV shedding. In the UK, ORV shedding is not inhibited despite comparable maternal antibody levels to the other cohorts. In both India and Malawi, increased microbiota diversity is negatively correlated with ORV immunogenicity, suggesting that high early-life microbial exposure may contribute to impaired vaccine efficacy.

Persistence of G10P[11] neonatal rotavirus infections in southern India.

BACKGROUND: Neonatal rotavirus infections are predominantly caused by distinct genotypes restricted to this age-group and are mostly asymptomatic. METHOD: Stool samples from neonates admitted for >48 h in neonatal intensive care units (NICUs) in Vellore (2014-2015) and Chennai (2015-2016) in southern India, and from neonates born at hospitals in Vellore but not admitted to NICUs (2015-2016) were tested for rotavirus by ELISA and genotyped by hemi-nested RT-PCR. RESULTS: Of 791 neonates, 150 and 336 were recruited from Vellore and Chennai NICUs, and 305 were born in five hospitals in Vellore. Positivity rates in the three settings were 49.3% (74/150), 29.5% (99/336) and 54% (164/305), respectively. G10P[11] was the commonly identified genotype in 87.8% (65/74), 94.9% (94/99) and 98.2% (161/164) of the neonates in Vellore and Chennai NICUs, and those born at Vellore hospitals, respectively. Neonates delivered by lower segment cesarian section (LSCS) at Vellore hospitals, not admitted to NICUs, had a significantly higher odds of acquiring rotavirus infection compared to those delivered vaginally [p = 0.002, OR = 2.4 (1.4-4.3)]. CONCLUSIONS: This report demonstrates the persistence of G10P[11] strain in Vellore and Chennai, indicating widespread neonatal G10P[11] strain in southern India and their persistence over two decades, leading to interesting questions about strain stability.

Immune predictors of oral poliovirus vaccine immunogenicity among infants in South India.

Identification of the causes of poor oral vaccine immunogenicity in low-income countries might lead to more effective vaccines. We measured mucosal and systemic immune parameters at the time of vaccination with oral poliovirus vaccine (OPV) in 292 Indian infants aged 6-11 months, including plasma cytokines, leukocyte counts, fecal biomarkers of environmental enteropathy and peripheral blood T-cell phenotype, focused on gut-homing regulatory CD4+ populations. We did not find a distinct immune phenotype associated with OPV immunogenicity, although viral pathogens were more prevalent in stool at the time of immunization among infants who failed to seroconvert (63.9% vs. 45.6%, p = 0.002). Using a machine-learning approach, we could predict seroconversion a priori using immune parameters and infection status with a median 58% accuracy (cross-validation IQR: 50-69%) compared with 50% expected by chance. Better identification of immune predictors of OPV immunogenicity is likely to require sampling of mucosal tissue and improved oral poliovirus infection models.

Replantation of Nine Fingers in a Patient: A case report.

Amputation of multiple fingers of both hands is a rare and serious injury. We report a case of a 41-year-old male patient who presented to Khoula Hospital, Muscat, Oman, in 2015 with the amputation of nine fingers due to a workplace injury. With two teams working in tandem, all the amputated fingers were re-attached. A total of seven fingers survived and the patient regained reasonable functionality of his hands. To the best of the authors' knowledge, this is the first case of several finger amputations in Oman.

Dynamic tracking of Purkinje images for the comparison of pseudophakodonesis between in-the-bag and secondary fixated intraocular lenses.

PURPOSE: To compare the pseudophakodonesis of in-the-bag intraocular lens (IOL) and a secondary fixated IOL by tracking the Purkinje image IV. SETTING: Dr. Agarwal's Eye Hospital and Eye Research Centre, Chennai, India. DESIGN: Prospective case series. METHODS: The IOL movement was recorded via slitlamp videography (DC3), streamed in video editor (Pinnacle), and evaluated by ImageJ analysis. The positional difference of Purkinje IV in relation to the stationary image Purkinje I at 3 random timeframes was measured. Pseudophakodonesis was quantified, compared, and correlated clinically. RESULTS: The study comprised 127 eyes that had posterior chamber IOLs (PC IOLs) (n = 50), anterior chamber IOLs (AC IOLs) (n = 20), iris-claw IOLs (n = 20), glued IOLs (n = 30), and sutured scleral-fixated IOLs (n = 7). The iris-claw IOL showed significant difference in Purkinje IV at various timeframes (P = .0418) whereas others showed no significant change. On comparison of the Purkinje IV difference, there was a significant difference between the PC IOL and the iris-claw IOL (P = .0001), the glued IOL and the iris-claw IOL (P = .0020), and the AC IOL and the iris-claw IOL (P = .0302). The iris-claw IOL showed significant exaggeration of the position of Purkinje IV (P = .0395) after saccade. Pseudophakodonesis seemed mild (difference < 0.5 mm) in the PC IOL (68%), glued IOL (53.3%), and AC IOL (50%); moderate in the scleral-fixated IOL (71.4%); and severe (≥ 1.0 mm) in the iris-claw IOL (55%). CONCLUSION: Positional difference in Purkinje IV was highest in iris-claw IOLs and lowest in PC IOLs.

Geographical distribution of soil transmitted helminths and the effects of community type in South Asia and South East Asia - A systematic review.

BACKGROUND: Soil-transmitted helminth (STH) infections are among the most prevalent neglected tropical diseases (NTD) worldwide. Since the publication of the WHO road map to combat NTD in 2012, there has been a renewed commitment to control STH. In this study, we analysed the geographical distribution and effect of community type on prevalence of hookworm, Trichuris and Ascaris in south Asia and south east Asia. METHODOLOGY: We conducted a systematic review of open-access literature published in PubMed Central and the Global Atlas of Helminth Infection. A total of 4182 articles were available and after applying selection criteria, 174 studies from the region were retained for analysis. PRINCIPAL FINDINGS: Ascaris was the commonest STH identified with an overall prevalence of 18% (95% CI, 14-23%) followed by Trichuris (14%, 9-19%) and hookworm (12%, 9-15%). Hookworm prevalence was highest in Laos, Vietnam and Cambodia. We found a geographical overlap in countries with high prevalence rates for Trichuris and Ascaris (Malaysia, Philippines, Myanmar, Vietnam and Bangladesh). When the effect of community type was examined, prevalence rates of hookworm was comparable in rural (19%, 14-24%) and tribal communities (14%, 10-19%). Tribal communities, however, showed higher prevalence of Trichuris (38%, 18-63%) and Ascaris (32%, 23-43%) than rural communities (13%, 9-20% and 14%, 9-20% respectively). Considerable between and within country heterogeneity in the distribution of STH (I2 >90%) was also noted. When available data from school aged children (SAC) were analysed, prevalence of Ascaris (25% 16-31%) and Trichuris (22%, 14-34%) were higher than among the general population while that of hookworm (10%, 7-16%) was comparable. CONCLUSIONS/SIGNIFICANCE: Our analysis showed significant variation in prevalence rates between and within countries in the region. Highlighting the importance of community type in prevalence and species mix, we showed that tribal and rural communities had higher hookworm infections than urban communities and for ascariasis and trichuriasis, tribal populations had higher levels of infection than rural populations. We also found a higher prevalence of ascariasis and trichuriasis in SAC compared to the general population but comparable levels of hookworm infections. These key findings need to be taken into account in planning future MDA and other interventions.

The effect of probiotics and zinc supplementation on the immune response to oral rotavirus vaccine: A randomized, factorial design, placebo-controlled study among Indian infants.

BACKGROUND: Strategies are needed to improve oral rotavirus vaccine (RV), which provides suboptimal protection in developing countries. Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function. METHODS: Infants 5weeks old living in urban Vellore, India were enrolled in a randomized, double-blind, placebo-controlled trial with a 4-arm factorial design to assess the effects of daily zinc (5mg), probiotic (1010Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix®, GlaxoSmithKline Biologicals) given at 6 and 10weeks of age. Infants were eligible for participation if healthy, available for the study duration and without prior receipt of RV or oral poliovirus vaccine other than the birth dose. The primary outcome was seroconversion to rotavirus at 14weeks of age based on detection of VP6-specific IgA at ≥20U/ml in previously seronegative infants or a fourfold rise in concentration. RESULTS: The study took place during July 2012 to February 2013. 620 infants were randomized equally between study arms and 551 (88.9%) completed per protocol. Seroconversion was recorded in 54/137 (39.4%), 42/136 (30.9%), 40/143 (28.0%), and 37/135 (27.4%) infants receiving (1) probiotic and zinc, (2) probiotic and placebo, (3) placebo and zinc, (4) two placebos. Seroconversion showed a modest improvement among infants receiving probiotic (difference between groups 1, 2 and 3, 4 was 7.5% (97.5% Confidence Interval (CI): -1.4%, 16.2%), p=0.066) but not zinc (difference between groups 1, 3 and 2, 4 was 4.4% (97.5% CI: -4.4%, 13.2%), p=0.272). 16 serious adverse events were recorded, none related to study interventions. CONCLUSIONS: Zinc or probiotic supplementation did not significantly improve the low immunogenicity of rotavirus vaccine given to infants in a poor urban community in India. A modest effect of combined supplementation deserves further investigation. TRIAL REGISTRATION: The trial was registered in India (CTRI/2012/05/002677).

Utilization of Preventive and Curative Services in Five Rural Blocks in Vellore, India.

This health utilization survey of 720 children (age <2 y) from 5 rural blocks in Vellore district identified that 80% used government facilities for preventive care while >80% used private facilities for curative services. Only 0.7% were home deliveries, 46% reported illness in the two-week recall, and 83% sought care for these illness.

Natural History of Cryptosporidiosis in a Birth Cohort in Southern India.

BACKGROUND: Cryptosporidium is a leading cause of moderate to severe childhood diarrhea in resource-poor settings. Understanding the natural history of cryptosporidiosis and the correlates of protection are essential to develop effective and sustainable approaches to disease control and prevention. METHODS: Children (N = 497) were recruited at birth in semiurban slums in Vellore, India, and followed for 3 years with twice-weekly home visits. Stool samples were collected every 2 weeks and during diarrheal episodes were tested for Cryptosporidium species by polymerase chain reaction (PCR). Serum samples obtained every 6 months were evaluated for seroconversion, defined as a 4-fold increase in immunoglobulin G directed against Cryptosporidium gp15 and/or Cp23 antigens between consecutive sera. RESULTS: Of 410 children completing follow-up, 397 (97%) acquired cryptosporidiosis by 3 years of age. PCR identified 1053 episodes of cryptosporidiosis, with an overall incidence of 0.86 infections per child-year by stool and serology. The median age for the first infection was 9 (interquartile range, 4-17) months, indicating early exposure. Although infections were mainly asymptomatic (693 [66%]), Cryptosporidium was identified in 9.4% of diarrheal episodes. The proportion of reinfected children was high (81%) and there was clustering of asymptomatic and symptomatic infections (P < .0001 for both). Protection against infection increased with the order of infection but was only 69% after 4 infections. Cryptosporidium hominis (73.3%) was the predominant Cryptosporidium species, and there was no species-specific protection. CONCLUSIONS: There is a high burden of endemic cryptosporidiosis in southern India. Clustering of infection is suggestive of host susceptibility. Multiple reinfections conferred some protection against subsequent infection.

Factors determining anti-poliovirus type 3 antibodies among orally immunised Indian infants.

BACKGROUND: Among the three poliovirus serotypes, the lowest responses after vaccination with trivalent oral polio vaccine (tOPV) are to serotype 3. Although improvements in routine immunisation and supplementary immunisation activities have greatly increased vaccine coverage, there are limited data on antibody prevalence in Indian infants. METHODS: Children aged 5-11months with a history of not having received inactivated polio vaccine were screened for serum antibodies to poliovirus serotype 3 (PV3) by a micro-neutralisation assay according to a modified World Health Organization (WHO) protocol. Limited demographic information was collected to assess risk-factors for a lack of protective antibodies. Student's t-test, logistic regression and multilevel logistic regression (MLR) model were used to estimate model parameters. RESULTS: Of 8454 children screened at a mean age of 8.3 (standard deviation [SD]-1.8) months, 88.1% (95% confidence interval (CI): 87.4-88.8) had protective antibodies to PV3. The number of tOPV doses received was the main determinant of seroprevalence; the maximum likelihood estimate yields a 37.7% (95% CI: 36.2-38.3) increase in seroprevalence per dose of tOPV. In multivariable logistic regression analysis increasing age, male sex, and urban residence were also independently associated with seropositivity (Odds Ratios (OR): 1.17 (95% CI: 1.12-1.23) per month of age, 1.27 (1.11-1.46) and 1.24 (1.05-1.45) respectively). CONCLUSION: Seroprevalence of antibodies to PV3 is associated with age, gender and place of residence, in addition to the number of tOPV doses received. Ensuring high coverage and monitoring of response are essential as long as oral vaccines are used in polio eradication.

Racecadotril in the Management of Rotavirus and Non-rotavirus Diarrhea in Under-five Children: Two Randomized, Double-blind, Placebo-controlled Trials.

OBJECTIVE: To study the effect of racecadotril on reduction in the duration of acute rotavirus and non-rotavirus diarrhea. DESIGN: Two randomized double-blind placebo-controlled trials. SETTING: Community-based trial in an urban area in Vellore, hospital-based trial at a secondary hospital in Vellore. PARTICIPANTS: 199 and 130 3-59 month old children in the community- and hospital-based trials, respectively. METHODS: Racecadotril (1.5 mg/kg/dose, thrice a day for three days) or placebo were given to manage acute diarrhea in both trials. MAIN OUTCOME MEASURE: Median duration of diarrhea. RESULTS: Among 124 children completing the hospital trial, the median duration of diarrhea was 25 h in both arms (P=0.5); median total stool weight was 74 g/kg and 53.5 g/kg in racecadotril group and placebo group, respectively (P=0.4); and average fluid intake per day was 3.6 mL/kg/h and 3mL/kg/h in racecadotril and placebo arms, respectively (P=0.3). Among rotavirus-positive children, median duration of diarrhea was 26.9 h and 30.2 h in racecadotril and placebo arms, respectively (P=0.7). In the community, 196 completed the trial, the median duration of diarrhea was 2 days for both arms (P=0.8) and rotavirus positive children had similar outcomes with median diarrheal duration of 3 d in both arms (P=0.4). CONCLUSIONS: Treatment with racecadotril did not reduce diarrheal duration, stool volume or the requirement for fluid replacement in children with acute gastroenteritis, both with and without rotavirus infection.

Direct Medical Costs in Children with Rotavirus and Non-rotavirus Diarrhea Admitted to a Pediatric Intensive Care Unit and High Dependency Unit in Delhi.

OBJECTIVE: To estimate direct medical costs of diarrheal hospitalization of children <5 years admitted in pediatric intensive care unit (PICU) or high dependency unit (HDU). METHODS: Analysis of medical records and hospital bills of 84 children during two time frames, 2005-08 and 2012-14. RESULTS: Direct medical costs in PICU increased from INR 17,941 to INR 50,663 per child for rotavirus diarrhea and INR 11,614 to INR 27,106 for non-rotavirus diarrhea, and in HDU from approximately INR 5,800 to INR 10,500 per child for all-cause diarrhea between the two time frames. CONCLUSIONS: Costs of PICU and HDU care are high and should be included in cost-effectiveness analysis of vaccination.

Measuring Poverty in Southern India: A Comparison of Socio-Economic Scales Evaluated against Childhood Stunting.

INTRODUCTION: Socioeconomic status (SES) scales measure poverty, wealth and economic inequality in a population to guide appropriate economic and public health policies. Measurement of poverty and comparison of material deprivation across nations is a challenge. This study compared four SES scales which have been used locally and internationally and evaluated them against childhood stunting, used as an indicator of chronic deprivation, in urban southern India. METHODS: A door-to-door survey collected information on socio-demographic indicators such as education, occupation, assets, income and living conditions in a semi-urban slum area in Vellore, Tamil Nadu in southern India. A total of 7925 households were categorized by four SES scales-Kuppuswamy scale, Below Poverty Line scale (BPL), the modified Kuppuswamy scale, and the multidimensional poverty index (MDPI) and the level of agreement compared between scales. Logistic regression was used to test the association of SES scales with stunting. FINDINGS: The Kuppuswamy, BPL, MDPI and modified Kuppuswamy scales classified 7.1%, 1%, 5.5%, and 55.3% of families as low SES respectively, indicating conservative estimation of low SES by the BPL and MDPI scales in comparison with the modified Kuppuswamy scale, which had the highest sensitivity (89%). Children from low SES classified by all scales had higher odds of stunting, but the level of agreement between scales was very poor ranging from 1%-15%. CONCLUSION: There is great non-uniformity between existing SES scales and cautious interpretation of SES scales is needed in the context of social, cultural, and economic realities.

The effect of azithromycin on the immunogenicity of oral poliovirus vaccine: a double-blind randomised placebo-controlled trial in seronegative Indian infants.

BACKGROUND: Oral poliovirus vaccine is less immunogenic and effective in low-income countries than in high-income countries, similarly to other oral vaccines. The high prevalence of intestinal pathogens and associated environmental enteropathy has been proposed to explain this problem. Because administration of an antibiotic has the potential to resolve environmental enteropathy and clear bacterial pathogens, we aimed to assess whether antibiotics would improve oral poliovirus vaccine immunogenicity. METHODS: We did a double-blind, randomised, placebo-controlled trial of the effect of azithromycin on the immunogenicity of serotype-3 monovalent oral poliovirus vaccine given to healthy infants living in 14 blocks of Vellore district, India. Infants were eligible to participate if they were 6-11 months old, available for the study duration, and lacked serum neutralising antibodies to serotype-3 poliovirus. Infants were randomly assigned (1:1) at enrolment to receive oral 10 mg/kg azithromycin or placebo once daily for 3 days, followed by serotype-3 monovalent oral poliovirus vaccine on day 14. The primary outcome was detection of serum neutralising antibodies to serotype-3 poliovirus at a dilution of one in eight or more on day 35 and was assessed in the per-protocol population (ie, all those who received azithromycin or placebo, oral poliovirus vaccine, and provided a blood sample according to the study protocol). Safety outcomes were assessed in all infants enrolled in the study. The trial is registered with the Clinical Trials Registry India, number CTRI/2014/05/004588. FINDINGS: Between Aug 5, 2014, and March 21, 2015, 754 infants were randomly assigned: 376 to receive azithromycin and 378 to placebo. Of these, 348 (93%) of 376 in the azithromycin group and 357 (94%) of 378 infants in the placebo group completed the study per protocol. In the azithromycin group, 175 (50%) seroconverted to serotype-3 poliovirus compared with 192 (54%) in the placebo group (risk ratio 0·94, 95% CI 0·81-1·08; p=0·366). Azithromycin reduced faecal biomarkers of environmental enteropathy (calprotectin, myeloperoxidase, α1-antitrypsin) and the prevalence of bacterial but not viral or eukaryotic pathogens. Viral pathogens were associated with lower seroconversion. Three serious adverse events were reported (two in the azithromycin group and one in the placebo group), but none was considered related to the study interventions. INTERPRETATION: Azithromycin did not improve the immunogenicity of oral poliovirus vaccine despite reducing biomarkers of environmental enteropathy and the prevalence of pathogenic intestinal bacteria. Viral interference and innate antiviral immune mechanisms might be more important determinants of the immunogenicity of live-virus oral vaccines. FUNDING: Bill & Melinda Gates Foundation.

The first 1000†days of life: prenatal and postnatal risk factors for morbidity and growth in a birth cohort in southern India.

OBJECTIVE: To estimate the burden and assess prenatal and postnatal determinants of illnesses experienced by children residing in a semiurban slum, during the first 1000 days of life. DESIGN: Community-based birth cohort SETTING: Southern India PARTICIPANTS: Four hundred and ninety-seven children of 561 pregnant women recruited and followed for 2 years with surveillance and anthropometry. MAIN OUTCOME MEASURE: Incidence rates of illness; rates of clinic visits and hospitalisations; factors associated with low birth weight, various illnesses and growth. RESULTS: Data on 10 377.7 child-months of follow-up estimated an average rate of 14.8 illnesses/child-year. Gastrointestinal and respiratory illnesses were 20.6% and 47.8% of the total disease burden, respectively. The hospitalisation rate reduced from 46/100 child-years during infancy to 19/100 child-years in the second year. Anaemia during pregnancy (OR=2.3, 95% CI=1.08 to 5.18), less than four antenatal visits (OR=6.8, 95% CI=2.1 to 22.5) and preterm birth (OR=3.3, 95% CI=1.1 to 9.7) were independent prenatal risk factors for low birth weight. Female gender (HR=0.88, 95% CI=0.79 to 0.99) and 6 months of exclusive breast feeding (HR=0.76, 95% CI=0.66 to 0.88) offered protection against all morbidity. Average monthly height and weight gain were lower in female child and children exclusively breast fed for 6 months. CONCLUSIONS: The high morbidity in Indian slum children in the first 1000 days of life was mainly due to prenatal factors and gastrointestinal and respiratory illness. Policymakers need disease prevalence and pathways to target high-risk groups with appropriate interventions in the community.