Designing primary healthcare systems for future in India.

Changing epidemiology, rapid urbanization, and rising expectations of populations are creating new challenges and opportunities for India's primary healthcare system. A group of primary care experts, practitioners, and researchers got together to design key elements of primary healthcare models for the future that would address these challenges and make use of emergent opportunities in rural and urban India. Based on experiences and evidence from India and across the globe shared in the consultation, the article lays out a vision and components of India's primary healthcare for future. It provides answers to questions such as how will healthcare be financed and organized, what mechanisms will assure quality of services, who will provide primary healthcare, and what role will technology have. Finally, it provides an agenda for primary healthcare practitioners and researchers to translate this vision into action.

Research priorities in Maternal, Newborn, & Child Health & Nutrition for India: An Indian Council of Medical Research-INCLEN Initiative.

In India, research prioritization in Maternal, Newborn, and Child Health and Nutrition (MNCHN) themes has traditionally involved only a handful of experts mostly from major cities. The Indian Council of Medical Research (ICMR)-INCLEN collaboration undertook a nationwide exercise engaging faculty from 256 institutions to identify top research priorities in the MNCHN themes for 2016-2025. The Child Health and Nutrition Research Initiative method of priority setting was adapted. The context of the exercise was defined by a National Steering Group (NSG) and guided by four Thematic Research Subcommittees. Research ideas were pooled from 498 experts located in different parts of India, iteratively consolidated into research options, scored by 893 experts against five pre-defined criteria (answerability, relevance, equity, investment and innovation) and weighed by a larger reference group. Ranked lists of priorities were generated for each of the four themes at national and three subnational (regional) levels [Empowered Action Group & North-Eastern States, Southern and Western States, & Northern States (including West Bengal)]. Research priorities differed between regions and from overall national priorities. Delivery domain of research which included implementation research constituted about 70 per cent of the top ten research options under all four themes. The results were endorsed in the NSG meeting. There was unanimity that the research priorities should be considered by different governmental and non-governmental agencies for investment with prioritization on implementation research and issues cutting across themes.

Rotavirus gastroenteritis in India, 2011-2013: revised estimates of disease burden and potential impact of vaccines.

While improvements in oral rehydration use and access to healthcare have contributed to impressive gains in child survival, diarrheal diseases remain the second most important cause of child mortality in India. Pathogen specific disease rates, while key to deciding on the utility of specific public health interventions such as vaccines, are extremely difficult to obtain in developing country settings with less than optimal health access, diagnostic services and information systems. This study combined disease burden within five cohorts of infants followed up for diarrheal morbidity with data from the nationally representative Indian Rotavirus Surveillance Network and applies rates of rotavirus related events to UNICEF birth and mortality estimates for India. These estimates, while limited by the lack of data from nationally representative population based studies, use methods consistent with those employed by the World Health Organization Child Health Epidemiology Reference Group. We estimate that 11.37 million episodes of rotavirus gastroenteritis occur each year in India, requiring 3.27 million outpatient visits and 872,000 inpatient admissions when health access is unconstrained, resulting in a need for Rs. 10.37 billion each year in direct costs. An estimated 78,000 rotavirus-associated deaths occur annually of which 59,000 occur in the first 2 years of life. Introduction of a rotavirus vaccine of similar efficacy to the Rotavac in the national immunization program would result in 686,277 fewer outpatient visits, 291,756 fewer hospitalizations and 26,985 fewer deaths each year in India, assuming no indirect effects for the vaccine.

Accelerating next-generation vaccine development for global disease prevention.

Vaccines are among the greatest successes in the history of public health. However, past strategies for vaccine development are unlikely to succeed in the future against major global diseases such as AIDS, tuberculosis, and malaria. For such diseases, the correlates of protection are poorly defined and the pathogens evade immune detection and/or exhibit extensive genetic variability. Recent advances have heralded in a new era of vaccine discovery. However, translation of these advances into vaccines remains impeded by lack of understanding of key vaccinology principles in humans. We review these advances toward vaccine discovery and suggest that for accelerating successful vaccine development, new human immunology-based clinical research initiatives be implemented with the goal of elucidating and more effectively generating vaccine-induced protective immune responses.

Improving the performance of enteric vaccines in the developing world.

Vaccines against important enteric pathogens such as rotavirus and poliovirus have shown lower efficacy in some populations. The application of new technologies and diverse scientific disciplines are needed to realize the promise of truly universal and effective solutions to combat those and other enteric diseases.

Convalescent phase sera from children infected with G12 rotavirus cross-neutralize rotavirus strains belonging to the Wa genogroup.

The emergence of G12 rotaviruses raises questions about the ability of candidate vaccines in providing protection against such emerging genotypes. Therefore, we assessed cross-neutralization against four reference rotavirus strains namely Wa (G1P[8]), DS-1 (G2P[4]), 116E (G9P[11]) and RV024 (G12P[6]) using paired sera from 28 children infected with G1P[8], G2P[4], G9P[6/8] or G12P[6] genotypes. Convalescent sera of G12P[6]-infected children demonstrated heterotypic response against 116E and Wa strains (50 and 33.3 %). In contrast, none of the four G2P[4]-infected children seroconverted against Wa or RV024 rotaviruses. The geometric mean neutralizing antibody titre in convalescent sera of G12P[6]-infected children was eightfold higher against strains belonging to the Wa genogroup (i.e. G1, G9 and G12 rotavirus) than against strains belonging to the DS-1 genogroup (G2 rotavirus). In conclusion, this study demonstrates that neutralization in part may be genogroup specific, and thus a monovalent vaccine based on the Wa genogroup is likely to protect against the G12 rotaviruses.

Population-based incidence of intussusception and a case-control study to examine the association of intussusception with natural rotavirus infection among indian children.

BACKGROUND: A rotavirus vaccine previously licensed in the United States was withdrawn because it caused intussusception. Data on background intussusception rates in developing countries are required to plan pre- and postlicensure safety studies for new rotavirus vaccines. Also, it is unclear whether natural rotavirus infection is associated with intussusception. METHODS: Passive surveillance for intussusception in a large, well-defined, poor, urban population in Delhi, India, was conducted in 2 phases. Intussusception was confirmed by ultrasonography or surgery. Fecal samples obtained from patients with intussusception at study hospitals (irrespective of their residence in study areas) and healthy control subjects were tested for rotavirus with use of enzyme immunoassay. If available, resected intestinal tissue samples were tested for rotavirus with use of immunohistochemistical analysis and reverse-transcription polymerase chain reaction. RESULTS: The incidence of intussusception requiring hospitalization was 17.7 cases per 100,000 infant-years of follow-up (95% confidence interval, 5.9-41.4 cases per 100,000 infant-years). Detection rates of rotavirus in stool samples did not differ significantly between case patients and control subjects (4 of 42 case patients vs 6 of 92 control subjects), and no evidence of rotavirus was detected in any of the 22 patients with intussusception for whom intestinal tissue samples were available. CONCLUSIONS: The incidence of intussusception among Indian infants appears to be lower than that reported in other middle- and high-income countries. Natural rotavirus infection does not appear to be a major cause of intussusception in Indian infants.

Genomic characterization of nontypeable rotaviruses and detection of a rare G8 strain in Delhi, India.

In the present investigation we molecularly characterized nontypeable rotavirus strains previously identified during surveillance in New Delhi, India. The majority of strains were demonstrated to belong to genotype G1 (54.5%) or P[8] (77.8%) on the basis of nucleotide sequencing of fragments from their VP7 and VP4 genes. The other genotypes detected included G2, G8, G9, G12, and P[4]. A G8P[6] strain, strain DS108, was detected for the first time in northern India. The VP7 gene of DS108 was most homologous with the VP7 gene of a bovine G8 strain, strain A5 (98.9%), indicating its bovine parentage. In contrast, the VP4 gene had a high degree of nucleotide sequence homology (92.9% to 99.1%) with the VP4 genes of human P[6] strains. The VP6 gene and nonstructural genes (NSP1 to NSP3 and NSP5) were most homologous with the VP6 gene and nonstructural genes of human rotaviruses belonging to the DS1 genogroup. Interestingly, the NSP4 gene of DS108 clustered within genotype E6 that until now had only two representative strains, both with G12P[6] specificity (strains RV176-00 and N26-02). Together, these results indicate that G8 strain DS108 belongs to the DS1 genogroup and could be the result of the acquisition of the VP7, VP4, and NSP4 genes by a human G2P[4] strain from more than one donor, similar to the evolution of G12P[6] strain RV176-00. The present study highlights the importance of characterizing multiple genes of nontypeable rotavirus strains to detect novel strains and get a more complete picture of rotavirus evolution.

Research priorities to reduce global mortality from newborn infections by 2015.

BACKGROUND: Newborn infections are responsible for approximately one-third of the estimated 4.0 million neonatal deaths that occur globally every year. Appropriately targeted research is required to guide investment in effective interventions, especially in low resource settings. Setting global priorities for research to address neonatal infections is essential and urgent. METHODS: The Department of Child and Adolescent Health and Development of the World Health Organization (WHO/CAH) applied the Child Health and Nutrition Research Initiative (CHNRI) priority-setting methodology to identify and stimulate research most likely to reduce global newborn infection-related mortality by 2015. Technical experts were invited by WHO/CAH to systematically list and then use standard methods to score research questions according to their likelihood to (i) be answered in an ethical way, (ii) lead to (or improve) effective interventions, (iii) be deliverable, affordable, and sustainable, (iv) maximize death burden reduction, and (v) have an equitable effect in the population. The scores were then weighted according to the values provided by a wide group of stakeholders from the global research priority-setting network. FINDINGS: On a 100-point scale, the final priority scores for 69 research questions ranged from 39 to 83. Most of the 15 research questions that received the highest scores were in the domain of health systems and policy research to address barriers affecting existing cost-effective interventions. The priority questions focused on promotion of home care practices to prevent newborn infections and approaches to increase coverage and quality of management of newborn infections in health facilities as well as in the community. While community-based intervention research is receiving some current investment, rigorous evaluation and cost analysis is almost entirely lacking for research on facility-based interventions and quality improvement. INTERPRETATION: Given the lack of progress in improving newborn survival despite the existence of effective interventions, it is not surprising that of the top ranked research priorities in this article the majority are in the domain of health systems and policy research. We urge funding agencies and investigators to invest in these research priorities to accelerate reduction of neonatal deaths, particularly those due to infections.

Natural immunity to rotavirus infection in children.

Annual deaths in infants and young children due to rotavirus (RV) infection are around 100,000 in India and about 600,000 globally. Development of a vaccine for this disease is a high priority. The protective mechanisms for RV diarrhea in human are not fully understood, but it is known that children develop natural immunity against RV. Early exposure to RV results in most severe episode of diarrhea and subsequent infections are milder or asymptomatic. Of the immune responses measured during natural infection, RV-specific antibodies have been well documented, whereas data on cellular immunity in humans are sparse. It is generally thought that two outer capsid proteins VP4 and VP7 play a critical role in protective immunity by stimulating production of neutralizing antibodies. While serotype- specific protection mediated by antibodies directed against the outer capsid proteins may be a mechanism of protection, such a correlate for protection has been difficult to demonstrate in humans during clinical trials. Increasing evidences suggest that viral proteins that lack a capacity of eliciting neutralizing antibody response also induce protective immunity. Limited efforts have focused on the role of non-structural proteins in protective immunity. This review describes current understanding of antibody responses in children with focus on responses specific to viral antigens with their possible role in protective immunity. We have also briefly reviewed the responses elicited to non-antibody effectors during RV infection in human subjects.

Evaluation of IFN-gamma response to rotavirus and non-structural protein NSP4 of rotavirus in children following severe rotavirus diarrhea.

BACKGROUND: Rotavirus (RV) is the commonest cause of severe gastroenteritis in young children worldwide. However the natural immune mechanisms controlling and preventing rotavirus disease in humans are not fully understood. OBJECTIVE: To examine cellular immune responses to whole rotavirus (vaccine strain, 116E) and non-structural protein-4 (116E-NSP4) in children during natural rotavirus-infection. STUDY DESIGN: Gamma-interferon (IFN-gamma) responses were evaluated by enzyme-linked immunospot assay in peripheral blood mononuclear cells from children with RV (n=26) or non-RV (n=10) gastroenteritis and from RV-exposed adults (n=10). Additionally, IL-4 responses were assessed in 5 of the 10 adults and 6 of 26 RV-infected children. RESULTS: IFN-gamma secreting cells specific to whole RV were detected in 68% of RV-positive children and to NSP4 in 43% of these children between 4 and 30 days of illness onset. IFN-gamma responses were transient and were found higher in RV-exposed adults than in children (P<0.05). Within the RV-positive group, IFN-gamma responses in children with prior RV-exposure were higher than children without prior exposure (P<0.05). The response to whole RV and NSP4 were positively correlated (P<0.01, r(s)=0.66). CONCLUSIONS: Significant IFN-gamma responses to rotavirus candidate vaccine strain 116E were detected in children during natural RV-infection and in RV-exposed adults. Significant IFN-gamma responses to NSP4 were also observed in these study groups.

Effectiveness of zinc supplementation plus oral rehydration salts compared with oral rehydration salts alone as a treatment for acute diarrhea in a primary care setting: a cluster randomized trial.

OBJECTIVE: The purpose of this work was to evaluate whether education about zinc supplements and provision of zinc supplements to caregivers is effective in the treatment of acute diarrhea and whether this strategy adversely affects the use of oral rehydration salts. PATIENTS AND METHODS: Six clusters of 30,000 people each in Haryana, India, were randomly assigned to intervention and control sites. Government and private providers and village health workers were trained to prescribe zinc and oral rehydration salts for use in diarrheal episodes in 1-month-old to 5-year-old children in intervention communities; in the control sites, oral rehydration salts alone was promoted. In 2 cross-sectional surveys commencing 3 months (survey 2) and 6 months (survey 3) after the start of the intervention, care-seeking behavior, drug therapy, and oral rehydration salts use during diarrhea, diarrheal and respiratory morbidity, and hospitalization rates were measured. RESULTS: In the 2 surveys, zinc was used in 36.5% (n = 1571) and 59.8% (n = 1649) and oral rehydration salts in 34.8% (n = 1571) and 59.2% (n = 1649) of diarrheal episodes occurring in the 4 weeks preceding interviews in the intervention areas. In control areas, oral rehydration salts were used in 7.8% (n = 2209) and 9.8% (n = 2609) of episodes. In the intervention communities, care seeking for diarrhea reduced by 34% (survey 3), as did the prescription of drugs of unknown identity (survey 3) and antibiotics (survey 3) for diarrhea. The 24-hour prevalences of diarrhea and acute lower respiratory infections were lower in the intervention communities (survey 3). All-cause, diarrhea, and pneumonia hospitalizations in the preceding 3 months were reduced in the intervention compared with control areas (survey 3). CONCLUSIONS: Diarrhea is more effectively treated when caregivers receive education on zinc supplementation and have ready access to supplies of oral rehydration salts and zinc, and this approach does not adversely affect the use of oral rehydration salts; in fact, it greatly increases use of the same.

Effect of zinc added to multi-vitamin supplementation containing low-dose vitamin A on plasma retinol level in children--a double-blind randomized, controlled trial.

In a community-based double-blind randomized trial in children aged 6-35 months, both intervention and control groups received a multi-vitamin syrup containing vitamin A, while the intervention group had zinc gluconate (equivalent to 10 mg of elemental zinc) additional in the syrup. There was a significant decrease in diarrhoea and pneumonia in the intervention group. This study was undertaken to investigate if addition of zinc to vitamin A had improved plasma retinol levels, which, in turn, was responsible for the effects observed in the intervention group. In a randomly-selected subsample of 200 children--100 each from the intervention and the control group, plasma retinol levels after 120 days of supplementation were measured. There was no difference in the mean plasma retinol levels [the difference in the mean 0.46 microg/dL (95% confidence interval -1.42-2.36)] between the two groups following supplementation. No difference in plasma retinol levels was observed in the subgroups based on base-line nutritional status and plasma zinc levels. Addition of zinc to low-dose vitamin A in this study did not improve the vitamin A status of children and cannot explain morbidity effects of the intervention.

Folate, but not vitamin B-12 status, predicts respiratory morbidity in north Indian children.

BACKGROUND: Vitamin deficiencies are often part of malnutrition, which predisposes to acute lower respiratory tract infections. OBJECTIVE: The objective was to measure the association between cobalamin and folate status and subsequent respiratory morbidity. DESIGN: A prospective cohort study was conducted in 2482 children aged 6-30 mo nested in a zinc supplementation trial. We measured plasma concentrations of folate, cobalamin, methylmalonic acid, and total homocysteine (tHcy) and followed the children for 4 mo. RESULTS: We observed 1176 episodes of acute lower respiratory tract infections. Children with folate concentrations in the lowest quartile (interquartile range: 6.4-20.0 nmol/L) had a 44% higher incidence [adjusted incidence rate ratio (IRR): 1.44; 95% CI: 1.23, 1.70] of acute lower respiratory tract infections than did children in the other 3 quartiles. For tHcy, the IRR was 1.24 (1.07, 1.40) in a comparison of those in the highest quartile with those in the other quartiles. Breastfeeding was associated with high folate concentrations and protection against subsequent respiratory tract infections. This protection was significantly and substantially reduced after adjustment for plasma folate concentrations at baseline. Compared with the children in the other 3 quartiles, the IRR for being in the lowest quartile of cobalamin was 1.13 (0.76, 1.03) and for being in the highest quartile of methylmalonic acid was 1.12 (0.96, 1.31). CONCLUSIONS: Poor folate status appears to be an independent risk factor for lower respiratory tract infections in young children. This study also suggests that the protective effect of breastfeeding is partly mediated by folate provided through breast milk.

Adding zinc to supplemental iron and folic acid does not affect mortality and severe morbidity in young children.

Studies have found a substantial reduction in diarrhea and respiratory morbidity in young children receiving zinc supplementation. The impact of daily zinc supplementation administered with iron plus folic acid (IFA) in young children on all-cause hospitalizations and mortality in comparison with IFA alone was evaluated. In a double blind cluster-randomized controlled trial, 94,359 subjects aged 1-23 mo were administered a daily dose of zinc plus IFA or IFA alone for a duration of 12 mo after enrollment. The intervention group tablet contained 10 mg of elemental zinc, 12.5 mg of iron, and 50 microg of folic acid. The control group tablets were similar except that they contained a placebo for zinc. Infants aged <6 mo were administered half a tablet, and those older received 1 tablet dissolved in breast milk or water. Hospitalizations were captured by trained study physicians through the surveillance of 8 hospitals. Deaths and hospitalizations were ascertained through visits to households by study supervisors once every 2 mo. The overall death rates did not differ significantly between the 2 groups when adjusted for cluster randomization (hazard ratio = 1.02, 95% CI 0.87, 1.19). Zinc and IFA supplementation compared with IFA alone did not affect adjusted hospitalization rates (overall rate ratio = 1.08, 95% CI 0.98, 1.19; diarrhea-specific rate ratio = 1.15, 95% CI 0.99, 1.34; or pneumonia-specific rate ratio = 1.09, 95% CI 0.94, 1.25). The lack of impact of zinc on mortality and hospitalization rates in this study may have been due to the use of lower daily zinc dosing than used in some of the morbidity prevention trials or from an interaction between zinc and iron, where the addition of iron may have adversely affected potential effects of zinc on immune function and morbidity. Future research should address iron and zinc interaction effects on important functional outcomes.