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Respiratory syncytial virus (RSV) is the second most common pathogen causing infant mortality. Additionally, RSV is a major cause of morbidity and mortality in older adults (age ≥60 years) similar to influenza. A protein-based maternal vaccine and monoclonal antibody (mAb) are now market-approved to protect infants, while an mRNA and two protein-based vaccines are approved for older adults. First-year experience protecting infants with nirsevimab in high-income countries shows a major public health benefit. It is expected that the RSV vaccine landscape will continue to develop in the coming years to protect all people globally. The vaccine and mAb landscape remain active with 30 candidates in clinical development using four approaches: protein-based, live-attenuated and chimeric vector, mRNA, and mAbs. Candidates in late-phase trials aim to protect young infants using mAbs, older infants and toddlers with live-attenuated vaccines, and children and adults using protein-based and mRNA vaccines. This Review provides an overview of RSV vaccines highlighting different target populations, antigens, and trial results. As RSV vaccines have not yet reached low-income and middle-income countries, we outline urgent next steps to minimise the vaccine delay., Competing Interests: Declaration of interests JT and NIM received support for attending meetings or travel from the ResViNET Foundation. UMC Utrecht (LJB and NIM) received grants from AbbVie, AstraZeneca, The Bill & Melinda Gates Foundation, the Dutch Lung Foundation, The Gates Medical Research Institute, GlaxoSmithKline (GSK), Janssen, MedImmune, MeMed, Merck, Novavax, Pfizer, and Sanofi; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Ablynx, AstraZeneca, Bavaria Nordic, GSK, Janssen, MabXience, MedImmune, MEDtalks, Merck, Moderna, Novavax, Pfizer, Sanofi, and Virology Education. LJB is founding chairman of the ReSViNET Foundation. UJB was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); and is named as an inventor on patents for live-attenuated RSV, with royalties paid to the National Institutes of Health by Sanofi Pasteur. ADC received grants from The Bill & Melinda Gates Foundation and WHO. CC received grants from Sanofi Pasteur, the Centers for Disease Control and Prevention, The Bill & Melinda Gates Foundation, and the Task Force for Global Health. RD received grants from Pfizer, Merck, MedImmune, and AstraZeneca; consulting fees from Pfizer, Merck and GSK; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Merck, Sanofi Pasteur, GSK, MedImmune, and AstraZeneca; and participated on a data safety monitoring boards or advisory boards for Pfizer, Merck, and GSK. BSG is named as an inventor on patents for RSV vaccines and mABS; received royalties from the NIH; and consulting fees from GSK, Pfizer, AstraZeneca, Sanofi Pasteur, and Exevir. RAK received grants from the NIH and Sanofi Pasteur. YL received grants from GSK, Merck, and WHO; consulting fees from Pfizer and WHO; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer; and support for attending meetings or travel from Pfizer. AJP received grants from The Bill & Melinda Gates Foundation, Wellcome, Cepi, the Medical Research Council, the NIH and Care Research, AstraZeneca, the European Commission, and the Serum Institute of India; royalties from AstraZeneca for the development of COVID-19 vaccines; consulting fees from Shionogi; is chair of the Joint Committee on Vaccination and Immunization of the Department of Health and Social Care; and has been member of the Strategic Advisory Group of Experts on Immunization for WHO. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Severely underweight (SUW) children contribute significantly to under-five mortality and morbidity. There are WHO guidelines for the management of severe acute malnutrition but no specific guidelines for SUW management., Objective: The objectives were to achieve a recovery rate of 30% at 90 days of treatment for severe underweight (SUW) children aged 6-60 months, compare changes in weight-for-age Z (WAZ) scores, growth patterns, and case fatality rates between intervention and reference arms (RA), and reduce the prevalence of SUW in the intervention arm (IA). The target of a 30% recovery rate was achievable and significant based on our past research conducted in similar settings., Methods: Design: A prospective controlled community-based, longitudinal, two arms (IA, RA), intervention study with long follow-up was conducted between January 2011 and October 2023., Setting: Primary care for participants from 14 villages in rural Melghat, India., Participants: The study participants included SUW children aged 6-60 months and age-matched (±2 weeks) normal controls. The SAMMAN (Acronym for SAM-Management) intervention was comprised of local therapeutic food-micronutrient (LTF-MN) therapy for 90 days, intensive behavior change communication, infection treatment, and quarterly anthropometric records. SUW recovery, growth patterns, case fatality rate, prevalence at 90 days of therapy and at 60 months of age, and survival until early adolescence were assessed. ANCOVA analysis was used to obtain changes in Z-scores., Results: In the IA, the recovery rate was 36.8% at 90 days and 78.2% at 60 months of age. The mean difference in change in WAZ scores between the intervention arm and the reference arm was statistically significant ( p < 0.0001). Growth patterns were similar between the two arms up to early adolescence. The SUW case fatality rate was significantly lower in the IA (0.9%) as compared to 4.62% in the RA at 60 months ( p = 0.022). The reduction in SUW prevalence in intervention villages was higher than in the control villages ( p < 0.001). The cost of management per SUW child was 3888 INR (47 USD) less than RUTF., Conclusion: The SAMMAN intervention is safe and cost-effective for significantly improving WAZ scores, sustainable, and hence replicable in resource-limited areas.

Background Objectives: Most of the ocular morbidities among school children are preventable or treatable. Melghat, a difficult to access, hilly, forest, tribal area with poorly developed infrastructure in the Amravati district of Maharashtra. Scarcity of ophthalmologists and low health-seeking behaviour of tribal people contributes to the high burden of ocular morbidity. Given the lack of published studies on the ocular morbidity among children in Melghat, outreach programmes are essential to diagnose and treat visual impairments promptly. The objective was to determine the prevalence of ocular morbidity among children in the tribal area of Melghat., Methods: A community-based observational study was carried out in the Chikhaldara and Dharni blocks of Melghat. Children from 15 tribal villages were screened for eye disorders by trained paramedics. Most of the children were examined by an ophthalmologist. We used Chi-square test for categorical variables., Results: A total of 4357 children aged between 6 and 18 yr were examined. Of these 2336 (53.6%) were females and 2021 (46.4%) were males. Out of 4357 children, 507 (11.63%) had an ocular morbidity. The prevalence of ocular morbidity and refractive error increased in the age group of 8-10 yr (P<0.05 and <0.001, respectively). Refractive error was the most common ocular morbidity (n=339; 7.8%), followed by vitamin A deficiency (VAD) (n=120; 2.8%)., Interpretation Conclusions: The prevalence of refractive error and VAD in this study was significantly higher than the rest of India and the world. For the prevention of childhood blindness, immediate intervention programme, including eye screening by trained paramedics, treatment by an ophthalmologist and prophylaxis, is crucial., (Copyright © 2023 Copyright: © 2023 Indian Journal of Medical Research.)

Background & Objectives: Verbal autopsy (VA) is the systematic and retrospective inquiry (from relatives) about the symptoms of an illness prior to death. In tribal India, 67-75 per cent of deaths occur at home with an unknown cause of death (CoD). Hence, the aim of this study was to determine the CoD in the 16-60 yr age group utilizing VA., Methods: A prospective, community based longitudinal study was conducted in 32 tribal villages in the Melghat region of Maharashtra, between 2004 and 2020. Number of deaths and VAs in 16-60 yr age group were collected by village health workers (VHWs) and supervisors, verified by five different persons (internal-external) and cross-checked by three VA interpretation trained physicians. A modified version of WHO VA was used. Cause-specific mortality fractions were calculated., Results: Of the 1011 deaths recorded, mortality in males was significantly higher than females (P<0.001). A total of 763 VAs were conducted which revealed that tuberculosis was the leading CoD, followed by jaundice, heart diseases, diarrhoea, central nervous system infections and suicide. Suicides were significantly more common among males than in females (P=0.046). Significantly, more deaths occurred during the monsoon (P=0.002), especially diarrhoeal deaths (P=0.024)., Interpretation & Conclusions: The findings of this study suggest that, in Indian tribal areas, infectious diseases are the leading causes of morbidity and one of the major causes of deaths in economically productive age group. Intensified VHW-mediated interventions are required to reduce the premature deaths.

Background: Melghat, an impoverished rural area in Maharashtra state, India; has scarce hospital services and low health-seeking behaviour. At baseline (2004) the under-five mortality rate (U5MR) (number of deaths in children aged 0-5 years/1000 live births) was 147.21 and infant mortality rate (IMR) (number of deaths of infants aged under 1 year/1000 live births) was 106.6 per 1000 live births. We aimed at reducing mortality rates through home-based child care (HBCC) using village health workers (VHWs)., Methods: A cluster-randomised control trial was conducted in 34 randomly assigned clusters/villages of Melghat, Maharashtra state, between 2004 and 2009. Participants included all under-five children and their parents. Interventions delivered through VHWs were patient-public involvement, newborn care, disease management and behaviour change communications. Primary outcome indicators were U5MR and IMR. Secondary outcome indicators were neonatal mortality rate (NMR) (number of neonatal deaths aged 0-28 days/1000 live births) and perinatal mortality rate (PMR) (number of stillbirths and early neonatal deaths/1000 total births). Analysis was by intention-to-treat at the individual level. This trial was extended to a service phase (2010-2015) in both arms and a government replication phase (2016-2019) only for the intervention clusters/areas (IA)., Findings: There were 18 control areas/clusters (CA) allocated and analysed with 4426 individuals, and 16 of 18 allocated IA, analysed with 3230 individuals. The IMR and U5MR in IA were reduced from 106.60 and 147.21 to 32.75 and 50.38 (reduction by 69.28% and 65.78%, respectively) compared with increases in CA from 67.67 and 105.3 to 86.83 and 122.8, respectively, from baseline to end of intervention. NMR and PMR in IA showed reductions from 50.76 to 22.67 (by 55.34%) and from 75.06 to 24.94 (by 66.77%) respectively. These gains extended to villages in the service and replication phases., Interpretation: This socio-culturally contextualised model for HBCC through VHWs backed up with institutional support is effective for significant reduction of U5MR, IMR and NMR in impoverished rural areas. This reduction was maintained in the study area during the service phase, indicating feasibility of implementation in large-scale public health programmes. Replicability of the model was demonstrated by a linear decline in all the mortality rates in 20 new villages during the government phase., Trial Registration Number: NCT02473796., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To study socioeconomic status (SES) and living conditions (LC) as risk factors for latent tuberculosis infection (LTBI) and their impact on QuantiFERON-TB gold (QFT-G) and tuberculin skin test (TST) outcome for determining a better diagnostic test for LTBI in the malnourished tribal population of Melghat., Settings and Design: Six hundred sixty nine participants matching the inclusion criteria were recruited from 10 tribal villages of Melghat region, India., Subjects and Methods: Complete information related to various risk factors and test outcome was obtained on 398 participants, which was analyzed as per predefined conceptual framework. Factors were classified based on their relevance either at individual or household level, and subsequently based on the possibility of intervention. Data were partitioned into concordant and discordant sets depending on test agreement., Results: In concordant set, the two tests revealed that LTBI was significantly associated with smoking (adjusted odds ratio [aOR]: 2.64 [95% confidence interval [CI]: 1.03-6.79]), tobacco usage (aOR: 2.74 [95% CI: 1.50-4.99]), and malnourishment (aOR: 1.97 [95% CI: 1.12-3.48]) after basic adjustment. Inclusion of latent variable SES and LC in the model has mediating effect on the association of above factors with LTBI. Further, the association of SES and LC with LTBI in concordant set was unaltered in presence of other cofactors. From discordant set, results of QFT-G corroborated with that of concordant set., Conclusions: Poor SES and LC can be considered as strong risk factors linked with LTBI as compared to malnourishment, which is often targeted in such communities. Further, our study showed QFT-G test as a reliable tool in screening of LTBI in the tribal population of Melghat, India.

Lack of diagnostic capacity has been a crucial barrier preventing an effective response to the challenges of malnutrition and tuberculosis (TB). Point-of-care diagnostic tests for TB in immuno-incompetent, malnourished population are thus needed to ensure rapid and accurate detection. The aim of the study was to identify potential biomarkers specific for TB infection and progression to overt disease in the malnourished population of Melghat. A prospective cohort study was conducted in the year 2009 through 2011 in six villages of the Melghat region. 275 participants consisting of malnourished cases with a) active TB (n = 32), b) latent TB infection (n = 90), c) with no clinical or bacteriological signs of active or latent TB (n = 130) and healthy control subjects (n = 23) were recruited for the study. The proteome changes of the host serum in response to Mycobacterium tuberculosis (M.tb) infection were investigated using one dimensional electrophoresis in combination with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Three most differentially expressed proteins; alpha-2-macroglobulin (A-2-M), sero-transferrin and haptoglobin were identified by MALDI-TOF MS analysis, which were up-regulated in the malnourished patients with active TB and down-regulated in the malnourished patients compared with the healthy controls. Additionally, follow-up studies indicated that the expression of these proteins increased to nearly two folds in patients who developed active disease from latent state. Our preliminary results suggest that A-2-M, sero-transferrin and haptoglobin may be clinically relevant host biomarkers for TB diagnosis and disease progression in the malnourished population. This study provides preliminary framework for an in-depth analysis of the biomarkers in larger well-characterized cohorts. Evaluation of these biomarkers in follow-up cases may further aid in improving TB diagnosis.

The tuberculin skin test (TST) and interferon-gamma release assays (IGRA), namely, the QuantiFERON-TB Gold test (QFT), remain the standard immunological diagnostic tools for latent tuberculosis (TB) infection (LTBI). However, the sub-optimal detection rates of both of these tests are major impediments in recognizing the population at risk. This study was aimed at evaluating additional cytokines besides interferon-gamma (IFN-γ) as biomarkers for improving LTBI diagnosis in the tribal population of Melghat, India. Seventy-four close TB contacts were stratified by QFT and TST results into: (i) QFT+/TST+ (n = 26), (ii) QFT+/TST- (n = 12), (iii) QFT-/TST- (n = 35) and (iv) QFT-/TST+ (n = 1) groups. A panel of cytokines (IL-6, IL-10, TNF-α and IL-2R) was then evaluated in antigen-stimulated QFT cell-free culture supernatants using IMMULITE-1000, an automated immunoassay analyzer. Cytokine estimation showed significantly higher levels of IL-6 in the QFT+/TST+ group, while significantly higher levels of IL-10 were found in the QFT-/TST- group. Correlation analysis identified a positive correlation between IL-6 and the QFT response (r = 0.6723, P < 0.0001), while a negative correlation was seen between QFT and IL-10 expression (r = -0.3271, P = 0.0044). Similarly, IL-6 was positively correlated with TST levels (r = 0.6631, P <0 .0001), and conversely, a negative correlation was found between TST and IL-10 expression (r = -0.5698, P < 0.0001). The positive and negative predictive values of IL-6 were found to be 92.59 and 93.33%, respectively, and the positive and negative predictive values of IL-10 were 96.55 and 91.18%, respectively. No significant impact of the demographic characteristics on cytokine positivity was observed. Our preliminary results suggest that the evaluation of additional cytokines in QFT cell-free culture supernatants may be valuable for the identification of LTBI. Combining IL-6 and IL-10 with QFT and/or TST could markedly improve the detection accuracy of LTBI. Our observations require investigation in larger well-characterized cohorts along with follow-up studies to further confirm the study outcome., (Copyright © 2015 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.)

Background: Malnutrition is a major risk factor for the development of tuberculosis (TB). In India, Melghat is among the tribal regions which consist of highest number of malnutrition cases. Because of the paucity of TB data from these malnourished areas there is an urgent need for the development and evaluation of improved TB diagnostic tests. In the present study, three in house developed diagnostic tests namely TB-Ag(antigen) ELISA, Adenosine deaminase (ADA) estimation and IS6110 polymerase chain reaction (PCR) assay were investigated for the detection of Mycobacterium tuberculosis (M. tb.) infection., Methods: For investigation, blood samples were collected from 128 study subjects from six villages of Melghat tribal area and evaluated using three in house developed assays, namely TB-Ag ELISA, ADA estimation and IS6110 PCR., Results: The TB-Ag ELISA method yielded 83% sensitivity and 94% specificity. The ADA and PCR assay gave a sensitivity of 61% and 49% and specificity of 62% and 98% respectively. A considerable good agreement of 82.81% (k=0.472) between TB-Ag ELISA and PCR was observed. The overall sensitivity of TB-Ag ELISA was significantly higher (p<0.05) than the ADA and PCR while PCR yielded highest specificity among all the three evaluated tests., Conclusions: We concluded that the routine use of TB-Ag ELISA can be useful for screening of suspected TB patients in the malnourished population where sophisticated laboratory set up is difficult.