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Background Serum IgG anti-Vi titers attained by 327 children 6–23 months of age immunized with Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar TCV®), of whom 193/327 received a booster dose 2 years post-primary vaccination, were previously reported. Methods Anti-Vi IgG in boosted and unboosted children 3, 5, and 7 years post-primary immunization were monitored using three different enzyme-linked immunosorbent assays (ELISAs): Vacczyme™ kit ELISA (all specimens); “Szu” ELISA (all specimens), and National Institute of Biological Standards NIBSC ELISA (subset). Endpoints analyzed included: persisting seroconversion (titer remaining ≥ 4-fold above baseline), geometric mean titer (GMT), geometric mean-fold rise post-vaccination, and percent exhibiting putative protective anti-Vi level (≥2 µgSzu/ml) using Szu method and National Institutes of Health IgG reference standard. In assessing the persistence of elevated anti-Vi titers stimulated by Typbar-TCV®, four subgroups were compared based on whether or not the initially enrolled children were boosted on day 720 and whether they provided serum on all key timepoints, or if they missed one or more timepoints: i) Among boosted participants, an “All Specimens Cohort” (ASC) comprised 86 children who provided sera on days 42, 720 (booster), 762 (42 days post-booster), 1095, 1825 and 2555, to define kinetics of the Vi antibody response in a fully compliant cohort of boosted children monitored over seven years; ii) Among non-boosted subjects, a compliant All Specimens Cohort of 25 children provided sera on days 0, 42, 720, 1095, 1825, and 2555; iii) Among boosted children, an “Any Available Specimen” (AAS) subgroup consisted of boosted children who provided sera on days 0, 42, and 720 days and also on one or more of days 762, 1095, 1825, or 2555 but not on all those time points; iv) Among the non-boosted subjects, there was also an Any Available Specimen subgroup of 47 children who provided sera on days 0 and 42, of whom 41 subsequently contributed sera on one or more of days 1095, 1825 and 2555. Results Vacczyme™ GMTs among boosted ASC children (N = 86) increased significantly on day 762, and remained 32-fold, 14-fold, and 10-fold over baseline at 3, 5 and 7 years; among unboosted ASC children (N = 25), GMTs remained 21-fold, 8-fold and 5-fold over baseline, respectively. Post-primary vaccination, 72% and 44% of unboosted ASC subjects (N = 25) exhibited persisting seroconversion by Vacczyme™ at 5 and 7 years, respectively; the corresponding numbers for ASC boosted subjects were 84% and 71%. Amongst the four sub-groups, boosted subjects showed higher prevalence of persisting seroconversion at most time points with the gap widening by 7th year, though not statistically significant (except 3rd year). Tested by Szu and also NIBSC ELISAs, 92–100% of unboosted ASC children showed persisting seroconversion at 7 years with 100% also exceeding the Szu protective threshold. Conclusion To extend protection, administering a booster of Typbar TCV® to children ∼5 years after their primary dose, i.e., coinciding with school entry, may be advisable. Typbar TCV® is presently the only WHO pre-qualified Vi conjugate vaccine with reported efficacy, effectiveness, and long-term immunogenicity findings.

Summary Background BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 μg or 6 μg) formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel). We previously reported findings from a double-blind, multicentre, randomised, controlled phase 1 trial on the safety and immunogenicity of three different formulations of BBV152 (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) and one Algel-only control (no antigen), with the first dose administered on day 0 and the second dose on day 14. The 3 μg and 6 μg with Algel-IMDG formulations were selected for this phase 2 study. Herein, we report interim findings of the phase 2 trial on the immunogenicity and safety of BBV152, with the first dose administered on day 0 and the second dose on day 28. Methods We did a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152 in healthy adults and adolescents (aged 12–65 years) at nine hospitals in India. Participants with positive SARS-CoV-2 nucleic acid and serology tests were excluded. Participants were randomly assigned (1:1) to receive either 3 μg with Algel-IMDG or 6 μg with Algel-IMDG. Block randomisation was done by use of an interactive web response system. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to treatment group allocation. Two intramuscular doses of vaccine were administered on day 0 and day 28. The primary outcome was SARS-CoV-2 wild-type neutralising antibody titres and seroconversion rates (defined as a post-vaccination titre that was at least four-fold higher than the baseline titre) at 4 weeks after the second dose (day 56), measured by use of the plaque-reduction neutralisation test (PRNT50) and the microneutralisation test (MNT50). The primary outcome was assessed in all participants who had received both doses of the vaccine. Cell-mediated responses were a secondary outcome and were assessed by T-helper-1 (Th1)/Th2 profiling at 2 weeks after the second dose (day 42). Safety was assessed in all participants who received at least one dose of the vaccine. In addition, we report immunogenicity results from a follow-up blood draw collected from phase 1 trial participants at 3 months after they received the second dose (day 104). This trial is registered at ClinicalTrials.gov , NCT04471519 . Findings Between Sept 5 and 12, 2020, 921 participants were screened, of whom 380 were enrolled and randomly assigned to the 3 μg with Algel-IMDG group (n=190) or 6 μg with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT50) at day 56 were significantly higher in the 6 μg with Algel-IMDG group (197·0 [95% CI 155·6–249·4]) than the 3 μg with Algel-IMDG group (100·9 [74·1–137·4]; p=0·0041). Seroconversion based on PRNT50 at day 56 was reported in 171 (92·9% [95% CI 88·2–96·2] of 184 participants in the 3 μg with Algel-IMDG group and 174 (98·3% [95·1–99·6]) of 177 participants in the 6 μg with Algel-IMDG group. GMTs (MNT50) at day 56 were 92·5 (95% CI 77·7–110·2) in the 3 μg with Algel-IMDG group and 160·1 (135·8–188·8) in the 6 μg with Algel-IMDG group. Seroconversion based on MNT50 at day 56 was reported in 162 (88·0% [95% CI 82·4–92·3]) of 184 participants in the 3 μg with Algel-IMDG group and 171 (96·6% [92·8–98·8]) of 177 participants in the 6 μg with Algel-IMDG group. The 3 μg with Algel-IMDG and 6 μg with Algel-IMDG formulations elicited T-cell responses that were biased to a Th1 phenotype at day 42. No significant difference in the proportion of participants who had a solicited local or systemic adverse reaction in the 3 μg with Algel-IMDG group (38 [20·0%; 95% CI 14·7–26·5] of 190) and the 6 μg with Algel-IMDG group (40 [21·1%; 15·5–27·5] of 190) was observed on days 0–7 and days 28–35; no serious adverse events were reported in the study. From the phase 1 trial, 3-month post-second-dose GMTs (MNT50) were 39·9 (95% CI 32·0–49·9) in the 3μg with Algel-IMDG group, 69·5 (53·7–89·9) in the 6 μg with Algel-IMDG group, 53·3 (40·1–71·0) in the 6 μg with Algel group, and 20·7 (14·5–29·5) in the Algel alone group. Interpretation In the phase 1 trial, BBV152 induced high neutralising antibody responses that remained elevated in all participants at 3 months after the second vaccination. In the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses compared with the phase 1 trial. The 6 μg with Algel-IMDG formulation has been selected for the phase 3 efficacy trial. Funding Bharat Biotech International. Translation For the Hindi translation of the abstract see Supplementary Materials section.

This is a comprehensive report on immunogenicity of COVAXIN® booster dose against ancestral and Variants of Concern (VOCs) up to 12 months. It is well known that neutralizing antibodies induced by COVID-19 vaccines wane within 6 months of vaccination leading to questions on the effectiveness of two-dose vaccination against breakthrough infections. Therefore, we assessed the persistence of immunogenicity up to 6 months after a two or three-dose with BBV152 and the safety of a booster dose in an ongoing phase 2, double-blind, randomized controlled trial (ClinicalTrials.gov: NCT04471519). We report persistence of humoral and cell mediated immunity up to 12 months of vaccination, despite decline in the magnitude of antibody titers. Administration of a third dose of BBV152 increased neutralization titers against both homologous (D614G) and heterologous strains (Alpha, Beta, Delta, Delta Plus and Omicron) with a slight increase in B cell memory responses. Thus, seronversion rate remain high in boosted recipients compared to non-booster, even after 6 months, post third dose against variants. No serious adverse events observed, except pain at the injection site, itching and redness. Hence, these results indicate that a booster dose of BBV152 is safe and necessary to ensure persistent immunity to minimize breakthrough infections of COVID-19, due to newly emerging variants.Trial registration: Registered with the Clinical Trials Registry (India) No. CTRI/2021/04/032942, dated 19/04/2021 and on Clinicaltrials.gov: NCT04471519.

A typhoid Vi capsular-polysaccharide tetanus toxoid conjugate vaccine (Typbar-TCV®) was recommended by the World Health Organization for use in children >6 months of age. The present post-marketing surveillance study was intended to assess the clinical safety of approximately 11 million doses of TCV sold till 2019 in a diverse age range Indian population. Both active and passive post-marketing surveillance studies were conducted at multiple centers. Active surveillance was performed in two periods, Period-I: February to October 2016, Period-II: April 2017 to October 2018. In Period-II, the Brighton Collaboration Criteria adverse event case definitions were used. Passive surveillance was performed from February 2016 to December 2019 through voluntary reporting by pediatricians across India. During the active surveillance, 1147 adverse events were reported among 4,991 (23.0%) subjects in Period-I, and 596 adverse events among 3898 (21.3%) subjects in Period-II. The most frequent adverse events were fever (9.2% and 12.02%in Periods I and II, respectively), pain at the injection site (8.3% and 7.33%), and swelling (4.0% and 1.93%). No serious adverse events (SAEs) were reported during either Period. Passive surveillance revealed 235 adverse events, including 25 SAEs requiring hospitalization, of which two were due to typhoid fever. All the events mentioned above occurred within one week of vaccination, and all the subjects have recovered from AEs with medications. All reported adverse events resolved with no clinical sequelae. Observations in this study are consistent with the pre-licensure studies with no additional safety signals detected, confirming that Typbar-TCV® is safe.Abbreviations: AE: Adverse event; LMIC: low- and middle-income countries; PMS: Post-marketing surveillance; SAE: Serious adverse event; TCV: Vi-polysaccharide tetanus -toxoid conjugate vaccine (Typbar-TCV®).

Purpose: To evaluate the clinico-radiological outcome of complex tibial plateau fractures treated with Ilizarov external fixation with or without minimal internal fixation. Methods: This retrospective review was conducted on all the cases of Schatzker types V and VI tibial plateau fractures treated by Ilizarov external fixation between July 2006 and December 2015 with the minimum follow-up duration of one year. There were 30 patients: 24 males and 6 females, mean age 43.33 years, and mean follow-up 3.6 years. Three of them were open fractures; 15 cases were Schatzkertype V fractures and the other 15 type VI. According to AO/OTA classification, there were 11 type C1, 12 C2 and 7 type C3 fractures. Outcome assessment was made with American Knee Society Score (AKSS) and Rasmussen's Radiological Score (RRS) at final follow-up. Results: Out of the 30 cases, mini-open reduction was performed in 7, bone graft in 4, minimal internal fixation in 10 and knee temporary immobilisation in 11 patients. Mean duration of external fixation was 11.8 weeks. All fractures united. Pin tract infections in 7 and common peroneal neuropathy in 2 patients were self-limiting. Two patients had axial misalignment of less than 10°. At final follow-up, the mean knee range of motion was 114.7, mean AKSS 81.5 and mean RRS 16.7. On statistical analysis, Schatzker type of fractures, use of minimal internal fixation and knee-spanning did not influence the final outcome. Conclusion: Ilizarov external fixator with or without minimal internal fixation provides acceptable outcome for complex tibial plateau fractures. Care must be taken to look for minor loss of alignment, especially in Type VI Schatzker fractures after removal of the fixator. However small sample size precludes firm conclusions. Key words: Tibial plateau fractures; Schatzker's classification; Ilizarov techniques; Ring fixator

Background: A functional newborn care corner (NBCC) is critical to provide immediate care to newborns including resuscitation, warmth, and initial care to sick newborns. NBCC provides an acceptable environment for all infants at birth, and it is mandatory for all delivery points at all levels in the health system including operation theaters. Objective: The objective of this study was to find the status of availability of NBCCs and service provision in selected public health facilities of Bihar. Methods: A total of 57 NBCCs, having high delivery load (>100 deliveries/month), across 25 high-priority districts in Bihar, were selected purposively in consultation with the State Health Society, Bihar, for the assessment. These facilities were assessed for the availability and/or functioning of infrastructure, equipment maintenance, human resource, supply of drugs and consumables, adherence to protocols, and record keeping. Results: Only 22.8% of the NBCCs were found to be fully functional, majority (68.4%) were partially functional, and 9% were nonfunctional. Thirty-seven (64.9%) NBCCs were located inside the labor room premises. Approximately, one-third of the neonates delivered were kept in NBCCs. Equipment though available lacked the provision of annual maintenance contract. Essential drugs such as adrenaline (24.6%) and Vitamin K injection (42.1%) were not available in many facilities. Only 6.2% of the newborns had low birth weight, indicating underreporting. Majority of the health-care staff available were trained but possessed poor skills. Data recording and reporting was also suboptimal. Conclusion: The network of NBCCs needs to be strengthened across the state and linked with higher facilities to achieve the desired reduction in neonatal morbidity and mortality.

Background: Several programmatic and logistic issues affect the overall performance of Accredited Social Health Activists (ASHAs). Bihar Government provided bicycles to ASHAs in West Champaran district for increasing coverage of services by improving their mobility. Objective: To assess the use of bicycles by ASHAs and it's effect on service delivery. It also captures the perspectives of ASHAs in terms of its utilization for performing tasks. Methods: A community-based quasi-experimental study was undertaken during March-May 2016. Proportion of newborn babies visited within 24 h of birth was the primary outcome. Data were collected from two intervention blocks (West Champaran district) and a control block from the neighboring East Champaran district. A total of 323 (177 from intervention blocks and 146 from control block) mothers having children

Background: Quality of care at the facilities during childbirth remains a major concern. Improved quality could have the greatest dividend in saving maternal and newborn lives. Objective: The objective of this study was to implement quality assurance measures in the labor rooms of select public health facilities in two districts of Bihar. Methods: The labor room quality assurance intervention was implemented in two districts, Gaya and Purnea in Bihar. Health facilities having >200 deliveries/month were assessed using labor room quality assurance checklist developed by the Ministry of Health and Family Welfare. The critical gaps affecting service delivery were identified, and a list of priority actions for quality improvement was developed. An intervention model was rolled out in consultation with the district authorities focusing on the building blocks of the health system. The interventions were implemented from August 2014 to March 2016 in selected facilities after which an assessment was conducted. Results: Initial assessment of labor room was conducted in 24 facilities. After 2 years of intervention, there was a definite improvement in quality assurance scores in most facilities. The infection control scores increased by 20 points in Gaya (from 40 to 59.9) and 10 points in Purnea (from 57.6 to 67.1). The highest gain in scores was observed in quality management component in Gaya (from 6.2 to 58.2). The model attempted to incorporate all the elements of the health system to ensure scalability and sustainability. Conclusion: It is possible to have an implementable quality assurance mechanism within public health system with sustained efforts and commitment.

Background The stillbirth rate is an indicator of quality of care during pregnancy and delivery. Good quality care is supported by a functional heath system. The objective of this study was to explore the risk factors for stillbirths, particularly those related to a health system. Methods This case-control study was conducted in two districts of Bihar, India. Information on cases (stillbirths) were obtained from facilities as reported by Health Management Information System; controls were consecutive live births from the same population as cases. Data were collected from 400 cases and 800 controls. The risk factors were compared using a hierarchical approach and expressed as odds ratio, attributable fractions and population attributable fractions. Results Of all the factors studied, 22 risk factors were independently associated with stillbirths. Health system-related factors were: administration of two or more doses of oxytocics to augment labour before reaching the facilities (OR 1.6; 95% CI 1.2–2.1), any complications during labour (OR 2.3;1.7–3.1), >30 min to reach a facility from home (OR 1.4;1.05–1.8), >10 min to attend to the pregnant woman after reaching the facility (OR 2.8;1.7–4.5). In the final regression model, modifiable health system-related risk factors included: >10 min taken to attend to women after they reach the facilities (AOR 3.6; 95% CI 2.5–5.1), untreated hypertension during pregnancy (AOR 2.9; 95% CI 1.5–5.6) and presence of any complication during labour, warranting treatment (AOR 1.7; 95% CI 1.2–2.4). Among mothers who reported complications during labour, time taken to reach the facility was significantly different between stillbirths and live births (2nd delay; 33.5 min v/s 25 min; p 30 min to reach the facility 0.48 (95% CI 0.31–0.60) and institution of management 10 min after reaching the facility 0.68 (95% CI 0.58–0.75). Reaching a facility within 30 min, initiation of management within 10 min of reaching the facility and timely management of complications during labour could have prevented 17%, 37% and 20% of stillbirths respectively. Conclusion A pro-active health system with accessible, timely and quality obstetric services can prevent a considerable proportion of stillbirths in low and middle income countries. Electronic supplementary material The online version of this article (10.1186/s12884-018-1660-1) contains supplementary material, which is available to authorized users.

Background— Although various studies revealed the beneficial effects of statins in post–cardiac transplant patients, these were relatively small and low-powered studies. We performed a meta-analysis of published studies to evaluate the role of statins in post–cardiac transplant patients, specifically examining the effects on hemodynamically significant/fatal graft rejection, coronary vasculopathy, terminal cancer, and overall survival. Methods and Results— We searched PubMed, Cochran CENTRAL, and Web of Science databases using the search terms “cardiac transplant” or “heart transplant,” and “statin” for a literature search. A random-effects model with Mantel–Haenszel method was used to pool the data. We identified 10 studies, 4 randomized controlled trials, and 6 nonrandomized studies, which compared outcomes in heart transplant recipients undergoing statin therapy to statin-naive patients. A pooled analysis of 9 studies reporting mortality revealed that the use of statins was associated with significant reduction in all-cause mortality (odds ratio, 0.26; 95% confidence interval, 0.20–0.35; P P =0.0005), incidence of coronary vasculopathy (odds ratio, 0.33; 95% confidence interval, 0.16–0.68; P =0.003), and terminal cancer (odds ratio, 0.30; 95% confidence interval, 0.15–0.63; P =0.002). Conclusions— The evidence from a pooled analysis suggests that statins improve survival in heart transplant recipients. Statins may prevent fatal rejection episodes, decrease terminal cancer risk, and reduce the incidence of coronary vasculopathy. Additional prospective studies are needed to further investigate and explain this association.