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The coronavirus 2019 (COVID-19) pandemic, as well as the resulting public health measures, impacted many aspects of society. The conduct of important pediatric vaccine trials was among these. Analyzing data from six ongoing non-COVID-19 pediatric vaccine trials we aimed to assess the operational impact of the COVID-19 pandemic using descriptive analyses. We identified multiple operational disruptions in trial conduct. Additionally, we identified higher percentages of missed routine vaccinations than investigational vaccines throughout the observation period. Overall, the impact of the COVID-19 pandemic was most apparent early in the pandemic period while adaptations to the pandemic were developed; however, some disruptions persisted throughout the observation period. Pediatric vaccine clinical trials are critical to developing new and/or improved vaccines for the pediatric population. Continued evaluation of the impacts of COVID-19 on pediatric vaccine clinical trials is warranted.

Background: The immunogenicity and safety of a booster dose of tetanus toxoid-conjugate quadrivalent meningococcal vaccine (MenACYW-TT), alone or co-administered with MenB vaccine, were assessed in healthy 13-25-year olds who received MenACYW-TT or a CRM-conjugate vaccine (MCV4-CRM) 3-6 years earlier., Methods: This phase IIIb open-label trial (NCT04084769) evaluated MenACYW-TT-primed participants, randomized to receive MenACYW-TT alone or with a MenB vaccine, and MCV4-CRM-primed participants who received MenACYW-TT alone. Functional antibodies against serogroups A, C, W and Y were measured using human complement serum bactericidal antibody assay (hSBA). The primary endpoint was vaccine seroresponse (post-vaccination titers ≥1:16 if pre-vaccination titers <1:8; or a ≥4-fold increase if pre-vaccination titers ≥1:8) 30 days post booster. Safety was evaluated throughout the study., Results: The persistence of the immune response following primary vaccination with MenACYW-TT was demonstrated. Seroresponse after MenACYW-TT booster was high regardless of priming vaccine (serogroup A: 94.8% vs 93.2%; C: 97.1% vs 98.9%; W: 97.7% vs 98.9%; and Y; 98.9% vs 100% for MenACWY-TT-primed and MCV4-CRM-primed groups, respectively). Co-administration with MenB vaccines did not affect MenACWY-TT immunogenicity. No vaccine-related serious adverse events were reported., Conclusions: MenACYW-TT booster induced robust immunogenicity against all serogroups, regardless of the primary vaccine received, and had an acceptable safety profile., Impact: A booster dose of MenACYW-TT induces robust immune responses in children and adolescents primed with MenACYW-TT or another MCV4 (MCV4-DT or MCV4-CRM), respectively. Here, we demonstrate that MenACYW-TT booster 3-6 years after primary vaccination induced robust immunogenicity against all serogroups, regardless of the priming vaccine (MenACWY-TT or MCV4-CRM), and was well tolerated. Persistence of the immune response following previous primary vaccination with MenACYW-TT was demonstrated. MenACYW-TT booster with MenB vaccine co-administration did not affect MenACWY-TT immunogenicity and was well tolerated. These findings will facilitate the provision of broader protection against IMD particularly in higher-risk groups such as adolescents., (© 2023. The Author(s).)

MenACYW-TT is a quadrivalent meningococcal tetanus toxoid-conjugate vaccine designed to prevent invasive meningococcal disease. The primary objective of this study was to demonstrate non-inferiority of the vaccine seroresponse to a single dose of MenACYW-TT compared with MCV4-DT, a licensed meningococcal quadrivalent diphtheria-conjugate vaccine. This Phase III double-blind, multicenter trial was conducted in meningococcal vaccine-naïve individuals aged 2-55 years in Japan (NCT04368429; jRCT2080225192). Participants were randomized 1:1 to receive either MenACYW-TT (n = 180) or MCV4-DT (n = 180). Functional antibodies against meningococcal serogroups A, C, W, and Y were measured using a serum bactericidal antibody assay with human complement (hSBA) at baseline (D0) and 30 days after vaccination (D30). Seroresponse was defined as a post-vaccination titer ≥1:16 in participants with a baseline titer <1:8; or a ≥4-fold increase in titer in participants with a baseline titer ≥1:8. Safety data were collected for 30 days. Non-inferiority of the seroresponse to MenACYW-TT vs. MCV4-DT was demonstrated on D30 for each serogroup tested (A: 85.6% vs. 65.4%; C: 96.6% vs. 62.6%; W: 87.4% vs. 49.2%; Y: 97.7% vs. 63.5%). MenACYW-TT was well tolerated with no safety concerns identified. A single dose of MenACYW-TT was well tolerated, with a non-inferior seroresponse compared with MCV4-DT. MenACYW-TT could thus be used as an alternative vaccine in meningococcal vaccine-naïve individuals.

Booster doses of meningococcal conjugate vaccines induce long-term protection against invasive meningococcal disease. We evaluated the immunogenicity and safety of a booster dose of MenACYW-TT in pre-school children who were primed 3 years earlier with MenACYW-TT or MCV4-TT (Nimenrix®). In this Phase III, open-label, multi-center study (NCT03476135), children (4-5 years old), who received a primary dose of MenACYW-TT or MCV4-TT as toddlers in a previous study, received a booster dose of MenACYW-TT. Titers of antibody against meningococcal serogroups A, C, W and Y were measured by serum bactericidal assay using human (hSBA) and baby rabbit (rSBA) complement in samples collected before (D0) and 30 days after (D30) booster vaccination. Safety was assessed over the 30-day study period. Ninety-one participants received the booster dose. In both study groups, hSBA titers increased from D0 to D30; serogroup C titers [95% confidence interval] were higher in the MenACYW-TT-primed vs MCV4-TT-primed group at D0 (106 [73.2, 153] vs 11.7 [7.03, 19.4], respectively) and D30 (5894 [4325, 8031] vs 1592 [1165, 2174], respectively); rSBA results were similar. Nearly all participants achieved ≥1:8 hSBA and rSBA titers at D30, which were higher or comparable to those observed post-primary dose, suggesting rapid booster responses. At D0, all hSBA and rSBA titers were higher than those observed pre-primary dose, suggesting persistence of immunogenicity. The MenACYW-TT booster dose was well-tolerated and had similar safety outcomes across study groups. These findings suggest that MenACYW-TT elicits robust booster responses in children primed 3 years earlier with MenACYW-TT or MCV4-TT.

Background: The MenACYW-TT conjugate vaccine is approved for prevention of invasive meningococcal disease (IMD) as a single dose in individuals ≥2 years of age in the United States and ≥12 months in EU and some other countries. This Phase II study evaluated the safety and immunogenicity of this vaccine and of concomitant pediatric vaccines in infants/toddlers (6 weeks-15 months of age)., Methods: Five schedules of the MenACYW-TT conjugate vaccine were evaluated in the United States: 2, 4, 6, and 12 months; 2, 4, 6, and 15 months; 2, 4, and 12 months; 6 and 12 months; and 12 months alone. Routine pediatric vaccines (DTaP-IPV/Hib, PCV7/PCV13, MMR, and varicella) were administered per approved schedules. Proportions of participants with serum bactericidal antibodyassay with human complement (hSBA) titers ≥1:4 and ≥1:8, SBA with baby rabbit complement (rSBA) titers ≥1:8 and ≥1:128, and immune responses against concomitant vaccines were determined., Results: Tenderness and irritability were the most frequent solicited injection site and systemic reactions. Similar proportions of participants achieved an hSBA titer ≥1:8 for all four serogroups regardless of whether 2 or 3 doses were administered in the first year of life. Following a second-year dose, 91-100% of participants achieved the threshold for all 4 serogroups in all schedules regardless of the number of doses in the first year of life. Similar responses were seen with rSBA. Immunogenicity and safety profile of concomitant vaccines was similar whether the MenACYW-TT conjugate vaccine was administered or not., Conclusion: MenACYW-TT conjugate vaccine administered with pediatric vaccines is safe and immunogenic regardless of the schedule and does not affect the immunogenicity or safety of the concomitant vaccines., Clinical Trial Registry: NCT01049035., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CR, JP, DN, EJ, and MSD currently are, and LMP and XDC were employees of Sanofi Pasteur at the time the study was conducted and hold stock options in Sanofi Pasteur., Inc. MC, JH, AG, and AJ received a grant to carry out the research at their respective study sites., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Growth in the livestock sector is associated with heightened risk for epidemic diseases. The increasing spillover of new diseases from wildlife is being driven by wide-scale anthropogenic changes allowing for more frequent and closer wildlife-human and wildlife-livestock contacts. An increasing number of epidemics in livestock are associated with rapid transition of livestock systems from extensive to intensive, and local to global movement of livestock and their products through value chain networks with weak biosecurity. Major livestock epidemics in the past two decades have had substantial economic impacts, and the COVID-19 pandemic highlights the devastating socio-economic consequences that spillovers can have when not identified and controlled early in the process of emergence. This highlights the importance of Veterinary Services to integrated, whole-of-society efforts to control infectious diseases in animals. Emphasis within Veterinary Services must be placed on prevention and preparedness. The authors suggest four areas for continued improvement in Veterinary Services to meet this challenge. These are a) continued development of staff capacity for risk assessment and value chain analysis, together with improved policies and communication, b) appropriate adaptation of approaches to prevention and control in resource-poor settings, c) improved multi-sectoral and transboundary cooperation, which enables the sharing of resources and expertise, and d) systematic approaches that enable Veterinary Services to influence decisionmaking for trade, markets, business, public health, and livelihood development at the national and regional levels.

Invasive meningococcal disease has high morbidity and mortality, with infants and young children among those at greatest risk. This phase III, open-label, randomised study in toddlers aged 12-23 months evaluated the immunogenicity and safety of meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT), a tetanus toxoid conjugated vaccine against meningococcal serogroups A, C, W and Y, when coadministered with paediatric vaccines (measles, mumps and rubella [MMR]; varicella [V]; 6-in-1 combination vaccine against diphtheria, tetanus, pertussis, polio, hepatitis B and Haemophilus influenzae type b [DTaP-IPV-HepB-Hib] and pneumococcal conjugate vaccine [PCV13])(NCT03205371). Immunogenicity to each meningococcal serogroup was assessed by serum bactericidal antibody assay using human complement (hSBA). Vaccine safety profiles were described up to 30 days post-vaccination. A total of 1183 participants were enrolled. The proportion with seroprotection (hSBA ≥1:8) to each meningococcal serogroup at Day 30 was comparable between the MenACYW-TT and MenACYW-TT + MMR + V groups (≥92 and ≥96%, respectively), between the MenACYW-TT and MenACYW-TT + DTaP-IPV-HepB-Hib groups (≥90% for both) and between the MenACYW-TT and MenACYW-TT + PCV13 groups (≥91 and ≥84%, respectively). The safety profiles of MenACYW-TT, and MMR + V, DTaP-IPV-HepB-Hib, and PCV13, with or without MenACYW-TT, were generally comparable. Coadministration of MenACYW-TT with paediatric vaccines in toddlers had no clinically relevant effect on the immunogenicity and safety of any of the vaccines.

Vaccination remains the best strategy to reduce invasive meningococcal disease. This study evaluated an investigational tetanus toxoid-conjugate quadrivalent meningococcal vaccine (MenACYW-TT) vs. a licensed tetanus toxoid-conjugate quadrivalent meningococcal vaccine (MCV4-TT) (NCT02955797). Healthy toddlers aged 12-23 months were included if they were either meningococcal vaccine-naïve or MenC conjugate (MCC) vaccine-primed (≥1 dose of MCC prior to 12 months of age). Vaccine-naïve participants were randomised 1:1 to either MenACYW-TT (n = 306) or MCV4-TT (n = 306). MCC-primed participants were randomised 2:1 to MenACYW-TT (n = 203) or MCV4-TT (n = 103). Antibody titres against each of the four meningococcal serogroups were measured by serum bactericidal antibody assay using the human complement. The co-primary objectives of this study were to demonstrate the non-inferiority of MenACYW-TT to MCV4-TT in terms of seroprotection (titres ≥1:8) at Day 30 in both vaccine-naïve and all participants (vaccine-naïve and MCC-primed groups pooled). The immune response for all four serogroups to MenACYW-TT was non-inferior to MCV4-TT in vaccine-naïve participants (seroprotection: range 83.6-99.3% and 81.4-91.6%, respectively) and all participants (seroprotection: range 83.6-99.3% and 81.4-98.0%, respectively). The safety profiles of both vaccines were comparable. MenACYW-TT was well-tolerated and demonstrated non-inferior immunogenicity when administered to MCC vaccine-primed and vaccine-naïve toddlers.

Significant global efforts have been directed towards understanding the epidemiology of highly pathogenic avian influenza (HPAI) across poultry production systems and in wild-bird reservoirs, yet understanding of disease dynamics in the village poultry setting remains limited. This article provides a detailed account of the first laboratory-confirmed outbreak of HPAI in the south-eastern provinces of Lao PDR, which occurred in a village in Sekong Province in October 2018. Perspectives from an anthropologist conducting fieldwork at the time of the outbreak, clinical and epidemiological observations by an Australian veterinarian are combined with laboratory characterization and sequencing of the virus to provide insights about disease dynamics, biosecurity, outbreak response and impediments to disease surveillance. Market-purchased chickens were considered the likely source of the outbreak. Observations highlighted the significance of a-lack-of pathognomonic clinical signs and commonness of high-mortality poultry disease with consequent importance of laboratory diagnosis. Sample submission and testing was found to be efficient, despite the village being far from the national veterinary diagnostic laboratory. Extensively raised poultry play key roles in ritual, livelihoods and nutrition of rural Lao PDR people. Unfortunately, mass mortality of chickens due to diseases such as HPAI and Newcastle disease (ND) imposes a significant burden on smallholders in Lao PDR, as in most other SE Asian countries. We observed that high mortality of chickens is perceived by locals as a new 'normal' in raising poultry; this sense of it being 'normal' is a disincentive to reporting of mortality events. Establishing effective people-centred disease-surveillance approaches with local benefit, improving market-biosecurity and veterinary-service support to control vaccine-preventable poultry diseases could all reduce mass-mortality event frequency, improve veterinary-producer relationships and increase the likelihood that mortality events are reported. Priority in each of these aspects should be on working with smallholders and local traders, appreciating and respecting their perspectives and local knowledge., (© 2020 Blackwell Verlag GmbH.)

Background: Invasive meningococcal disease is a major cause of meningitis in children. An investigational meningococcal (serogroups A, C, Y, and W) tetanus toxoid conjugate vaccine (MenACYW-TT) could offer protection against invasive meningococcal disease in this population. This phase III study assessed the immunogenicity and safety of MenACYW-TT in children compared with a licensed quadrivalent meningococcal vaccine conjugated with diphtheria protein CRM197 (MenACWY-CRM)., Methods: Healthy children 2-9 years of age in the United States, including Puerto Rico, were randomized (1:1) to receive MenACYW-TT (n = 499) or MenACWY-CRM (n = 501) (NCT03077438). Meningococcal antibody titers to the 4 vaccine serogroups were measured using a serum bactericidal antibody assay with human complement (hSBA) before and at day 30 after vaccination. Noninferiority between the vaccine groups was assessed by comparing seroresponse rates (postvaccination titers ≥1:16 when prevaccination titers were <1:8, or ≥4-fold increase if prevaccination titers were ≥1:8) to the 4 serogroups at day 30. Safety was monitored., Results: The proportion of participants achieving seroresponse at day 30 in the MenACYW-TT group was noninferior to the MenACWY-CRM group (A: 55.4% vs. 47.8%; C: 95.2% vs. 47.8%; W: 78.8% vs. 64.1%; Y: 91.5% vs. 79.3%, respectively). Geometric mean titers for serogroups C, W, and Y were higher with MenACYW-TT than for MenACWY-CRM. Both vaccines were well-tolerated and had similar safety profiles., Conclusions: MenACYW-TT was well-tolerated in children and achieved noninferior immune responses to MenACWY-CRM against each of the 4 vaccine serogroups.

Background: MenACYW-TT is an investigational quadrivalent (serogroups A, C, W and Y) meningococcal conjugate vaccine that is being developed for protection against invasive meningococcal disease., Methods: In this Phase 3, blinded, randomized study, 3344 meningococcal vaccine-naïve 10-55-year-olds were randomized (3:3:3:2) to receive one of three lots of MenACYW-TT or licensed quadrivalent meningococcal conjugate vaccine, MCV4-DT (NCT02842853). Antibody titers were assessed by human and rabbit complement serum bactericidal antibody assays. The co-primary objectives were to demonstrate lot-to-lot consistency of MenACYW-TT by the between-lot geometric mean titer ratios (GMTR) at Day 30, and non-inferiority of Day 30 vaccine seroresponses (titers ≥ 1:16 if pre-vaccination titers < 1:8, or ≥ 4-fold increase if pre-vaccination titers ≥ 1:8) with MenACYW-TT vs MCV4-DT. Further objectives included safety and immunogenicity., Results: Lot consistency was demonstrated for all three lots, with GMTRs ranging from 0.87 to 1.1. The proportion of participants achieving seroresponse in the MenACYW-TT group (data pooled from the 3 lots) was non-inferior to MCV4-DT (A: 74% vs 55%; C: 89% vs 48%; W: 80% vs 61%; Y: 91% vs 73%, respectively). MenACYW-TT and MCV4-DT had similar safety profiles; no safety concerns were identified., Conclusions: The study met both co-primary endpoints, demonstrating lot-to-lot consistency and non-inferiority of MenACYW-TT vs MCV4-DT in adolescents and adults., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MSD, JP, DN, and EJ are employees of Sanofi Pasteur. JP reports personal fees from Sanofi Pasteur, during the conduct of the study. JH has nothing to disclose., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The quadrivalent meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT) was assessed as a booster in this Phase III trial (NCT02752906). Quadrivalent meningococcal conjugate vaccine (MCV4)-primed individuals aged ≥15 y (n = 810) were randomized 1:1 to receive a single booster dose of MenACYW-TT (n = 403) or a licensed MCV4 (Menactra®; MCV4-DT [n = 407]). Serum bactericidal antibody assay with human complement (hSBA) was used to measure functional antibodies against serogroups A, C, W, and Y at baseline and Day 30 post-vaccination. Proportions of participants achieving seroresponse (post-vaccination titer ≥1:16 for those with baseline titer <1:8 or ≥4-fold increase in post-vaccination titer for those with baseline titer ≥1:8) were determined. Safety data were collected for 180 d post-vaccination. Non-inferiority of the immune response was demonstrated for MenACYW-TT compared with MCV4-DT based on the proportion of participants achieving hSBA vaccine seroresponse for each of the meningococcal serogroups at Day 30. Moreover, ≥99% of participants in both study groups had hSBA titers ≥1:8 for the four meningococcal serogroups at Day 30. Reactogenicity profiles were comparable between groups. These Phase III data in adolescents and adults show that MenACYW-TT boosts the immune response in those primed with MCV4 vaccines 4-10 y previously, irrespective of whether MCV4-DT or MCV4-CRM was used for priming.

Neisseria Meningitidis: can lead to invasive meningococcal disease to which young children are particularly vulnerable. We assessed the immunogenicity and safety of Sanofi Pasteur's investigational quadrivalent (serogroups A, C, Y, and W) meningococcal tetanus-toxoid conjugate vaccine, MenACYW-TT, as a single dose, in healthy meningococcal vaccine-naïve toddlers versus a licensed conjugate vaccine MCV4-TT (NCT03205358). In this Phase II study conducted in Finland, 188 toddlers aged 12-24 months were randomized 1:1 to MenACYW-TT or MCV4-TT. Serum bactericidal antibody assays using human complement (hSBA) and baby rabbit complement (rSBA) measured antibodies against each serogroup before and 30 days after vaccination. Participants were monitored for immediate adverse events (AEs) and post-vaccination AEs for 30 days. All analyses were descriptive. All 188 participants completed the study. The Day 30 hSBA seroresponses (hSBA titer <8 at baseline and post-vaccination titer ≥8, or ≥8 at baseline and ≥4-fold increase post-vaccination) were comparable between participants receiving MenACYW-TT (96.7-100%), and MCV4-TT (86.0-100.0%) for each serogroup. Most unsolicited AEs were of Grade 1 or Grade 2 intensity. There were no immediate hypersensitivity reactions, and no AEs or serious AEs leading to discontinuation from the study. In this exploratory study, MenACYW-TT vaccine was well tolerated and immunogenic. If confirmed in Phase III, a single dose of the MenACYW-TT vaccine may show promise as an alternative vaccine option for toddlers receiving meningococcal vaccination for the first time.

MenACYW-TT is an investigational quadrivalent meningococcal conjugate vaccine intended for the prevention of invasive meningococcal disease (IMD) caused by serogroups A, C, W, and Y in individuals aged 6 weeks and above. This Phase II, randomized, open-label, multicenter, exploratory study assessed the safety and immunogenicity of MenACYW-TT compared with a quadrivalent meningococcal polysaccharide vaccine (MPSV4) in 301 healthy adults aged ≥56 y in the US (NCT01732627). Participants were randomized 2:1 to receive MenACYW-TT or MPSV4. Serum bactericidal assays using human (hSBA) or baby rabbit (rSBA) complement were used to measure functional antibodies against meningococcal serogroups A, C, W, and Y at baseline and 30 d post-vaccination. Safety data were collected up to 30 d post-vaccination. Proportions of study participants with hSBA titers ≥1:8 against serogroups A, C, W, and Y were increased at Day 30 compared with baseline in both vaccine groups. The proportions of participants with hSBA titers ≥1:8 after MenACYW-TT vaccination were comparable to those after MPSV4 vaccination for serogroups A and C (A: 93.8% vs. 85.1%; C: 74.9% vs. 62.8%) and distinctly higher than after MPSV4 for serogroups W and Y (W: 79.5% vs. 60.6%; Y: 80.5% vs. 59.6%). Proportions of participants with rSBA titers ≥1:8 were comparable between vaccine groups for all four serogroups. The reactogenicity profiles of both vaccines were similar. Most unsolicited adverse events (AEs) were of Grade 1 or Grade 2 intensity, and no serious AEs were reported. The MenACYW-TT conjugate vaccine was well tolerated and immunogenic in adults aged ≥56 y.

Background: MenACYW-TT is an investigational quadrivalent meningococcal conjugate vaccine intended for use in individuals ≥6 weeks of age. We evaluated the safety and immunogenicity of MenACYW-TT when compared to a licensed quadrivalent conjugate meningococcal vaccine (Menveo®; MCV4-CRM; GlaxoSmithKline, Italy), and when co-administered with tetanus, diphtheria, acellular pertussis (Tdap) and human papilloma virus (HPV4) vaccines in healthy meningococcal vaccine-naïve adolescents (10-17 years old) in the United States of America., Methods: In this pivotal Phase II, open-label, multicenter study, 1715 participants were randomized to receive MenACYW-TT, MCV4-CRM, MenACYW-TT co-administered with Tdap and HPV4, or Tdap and HPV4 vaccines alone (NCT02199691). The primary objective was to evaluate whether antibody responses to MenACYW-TT antigens were non-inferior to antibody responses after MCV4-CRM administration. Meningococcal antibody titers were determined using human complement serum bactericidal assay (hSBA) with titers measured at baseline, and 30 days post vaccination (D30). A vaccine seroresponse was defined as baseline titers <1:8 with post-vaccination titers ≥1:8 or baseline titers ≥1:8 with a ≥4-fold increase at post-vaccination. Safety data were collected up to six months post-vaccination., Results: Non-inferiority was demonstrated for MenACYW-TT vs MCV4-CRM (primary endpoint), and for MenACYW-TT co-administered with Tdap and HPV4 vs MenACYW-TT alone (secondary endpoint). The vaccine seroresponse rate was higher with MenACYW-TT than with MCV4-CRM, for each serogroup: A: 75.6% vs 66.4%; C: 97.2% vs 72.6%; W: 86.2% vs 66.6%; Y: 97.0% vs 80.8%. The safety profiles of MenACYW-TT, MCV4-CRM, and Tdap and HPV4 vaccines, administered with or without MenACYW-TT, were comparable. There were no vaccine-related serious adverse events., Conclusions: The MenACYW-TT vaccine was well tolerated and generated an immune response that was non-inferior to the licensed MCV4-CRM vaccine. Immunogenicity and safety profiles were comparable when MenACYW-TT was administered with or without Tdap and HPV4 vaccines in meningococcal vaccine-naïve adolescents., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LJC, JP, EJ, & MSD are employees of Sanofi Pasteur. JH and SC received a grant to carry out the research at their respective study sites., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This open-label study assessed the safety and immunogenicity of two doses (14 days apart) of an indigenously manufactured, killed, bivalent (Vibrio cholerae O1 and O139), whole-cell oral cholera vaccine (SHANCHOL; Shantha Biotechnics) in healthy adults (n = 100) and children (n = 100) in a cholera endemic area (Vellore, South India) to fulfill post-licensure regulatory requirements and post-World Health Organization (WHO) prequalification commitments. Safety and reactogenicity were assessed, and seroconversion rates (i.e. proportion of participants with a ≥ 4-fold rise from baseline in serum vibriocidal antibody titers against V. cholerae O1 Inaba, O1 Ogawa and O139, respectively) were determined 14 days after each vaccine dose. No serious adverse events were reported during the study. Commonly reported solicited adverse events were headache and general ill feeling. Seroconversion rates after the first and second dose in adults were 67.7% and 55.2%, respectively, against O1 Inaba; 47.9% and 45.8% against O1 Ogawa; and 19.8% and 20.8% against O139. In children, seroconversion rates after the first and second dose were 80.2% and 68.8%, respectively, against O1 Inaba; 72.9% and 67.7% against O1 Ogawa; and 26.0% and 18.8% against O139. The geometric mean titers against O1 Inaba, O1 Ogawa, and O139 in both adults and children were significantly higher after each vaccine dose compared to baseline titers (P < 0.001; for both age groups after each dose versus baseline). The seroconversion rates for O1 Inaba, O1 Ogawa, and O139 in both age groups were similar to those in previous studies with the vaccine. In conclusion, the killed, bivalent, whole-cell oral cholera vaccine has a good safety and reactogenicity profile, and is immunogenic in healthy adults and children. Trial Registration: ClinicalTrials.gov NCT00760825; CTRI/2012/01/002354., Competing Interests: Venkata Raghava Mohan, Santosh Raj, Ajit Pal Singh, Deok Ryun Kim, Yanghee Kim, Binod Sah and Mohammad Ali have no relevant conflict of interest to declare. Naveena Aloysia D’Cor, Venkat Jayanth Midde, Sridhar Vemula and Santhosh Kumar Narla are employed by Shantha Biotechnics Pvt. Ltd, a Sanofi Company. Tarun Saluja was employed by Shantha Biotechnics Pvt. Ltd at the time of study but is currently an employee of the International Vaccine Institute, Seoul. Mandeep Singh Dhingra was an employee of Shantha Biotechnics Pvt. Ltd at the time of the study but is currently an employee of Sanofi Pasteur, USA (part of the parent company of Shantha Biotechnics Pvt. Ltd). Mandeep Singh Dhingra and Naveena Aloysia D’Cor also own stock interests in Sanofi. The International Vaccine Institute, Seoul received funding from the Bill and Melinda Gates Foundation to study the oral cholera vaccine (Shanchol), but has no commercial interest in the vaccine. The vaccine was provided by Shantha Biotechnics Pvt. Ltd (a Sanofi Company). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

In Bangladesh, the poultry industry is an economically and socially important sector, but it is persistently threatened by the effects of H5N1 highly pathogenic avian influenza. Thus, identifying the optimal control policy in response to an emerging disease outbreak is a key challenge for policy-makers. To inform this aim, a common approach is to carry out simulation studies comparing plausible strategies, while accounting for known capacity restrictions. In this study we perform simulations of a previously developed H5N1 influenza transmission model framework, fitted to two separate historical outbreaks, to assess specific control objectives related to the burden or duration of H5N1 outbreaks among poultry farms in the Dhaka division of Bangladesh. In particular, we explore the optimal implementation of ring culling, ring vaccination and active surveillance measures when presuming disease transmission predominately occurs from premises-to-premises, versus a setting requiring the inclusion of external factors. Additionally, we determine the sensitivity of the management actions under consideration to differing levels of capacity constraints and outbreaks with disparate transmission dynamics. While we find that reactive culling and vaccination policies should pay close attention to these factors to ensure intervention targeting is optimised, across multiple settings the top performing control action amongst those under consideration were targeted proactive surveillance schemes. Our findings may advise the type of control measure, plus its intensity, that could potentially be applied in the event of a developing outbreak of H5N1 amongst originally H5N1 virus-free commercially-reared poultry in the Dhaka division of Bangladesh., Competing Interests: The authors have declared that no competing interests exist.

Schizophrenia is one of the psychotic mental disorders characterized by symptoms of thought, behavior, and social problems. Newer biomedicine and pharmacotherapy has been investigated for the treatment of various neuropsychiatric disorders in the past few decades. Spinacia oleracea is one of these, reported to have beneficial effect against several neurodegenerative disorders. The present study was carried to explore the protective effects of Spinacia oleracea seed extract (SOEE) in an experimental model of ketamine-induced schizophrenia in mice. Ketamine (50 mg/kg, i.p.) was used to induce stereotyped psychotic behavioural symptoms in mice. Behavioral studies (locomotor activity, stereotype behaviors, immobility duration and memory retention) were carried out to investigate the protective of SOEE on ketamine-induced psychotic symptoms, followed by biochemical, neurochemical and cellular alterations in the brain. Treatment with SOEE for 15 consecutive days significantly attenuated stereotyped behavioral symptoms in mice. Biochemical estimations revealed that SOEE reduced lipid peroxidation and restored total brain proteins. Furthermore, SOEE remarkably reduced dopamine levels, AChE activity & inflammatory surge (serum TNF-α) and increased the levels of GABA and reduced glutathione in mice. The outcomes of the study suggested that SOEE could ameliorate ketamine-induced psychotic symptoms in mice, indicating a protective effect in the treatment of schizophrenia., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: The Avian Influenza A (H5N1) virus is endemic in poultry in Egypt. The winter of 2014/2015 was particularly worrying as new clusters of HPAI A (H5N1) virus emerged, leading to an important number of AI A (H5N1) outbreaks in poultry farms and sporadic human cases. To date, few studies have investigated the distribution of HPAI A (H5N1) outbreaks in Egypt in relation to protective / risk factors at the farm level, a gap we intend to fill. The aim of the study was to analyse passive surveillance data that were based on observation of sudden and high mortality of poultry or drop in duck or chicken egg production, as a basis to better understand and discuss the risk of HPAI A (H5N1) presence at the farm level in large parts of the Nile Delta., Results: The probability of HPAI A (H5N1) presence was associated with several characteristics of the farms. Vaccination status, absence of windows/openings in the farm and the number of birds per cycle of production were found to be protective factors, whereas the presence of a duck farm with significant mortality or drop in egg production in the village was found to be a risk factor., Conclusions: Results demonstrate the key role of several prevention and biosecurity measures to reduce HPAI A (H5N1) virus circulation, which could promote better poultry farm biosecurity in Egypt.

Over the years, the emergence of novel H5 and H7 highly pathogenic avian influenza viruses (HPAI) has been taking place through two main mechanisms: first, the conversion of a low pathogenic into a highly pathogenic virus, and second, the reassortment between different genetic segments of low and highly pathogenic viruses already in circulation. We investigated and summarized the literature on emerging HPAI H5 and H7 viruses with the aim of building a spatio-temporal database of all these recorded conversions and reassortments events. We subsequently mapped the spatio-temporal distribution of known emergence events, as well as the species and production systems that they were associated with, the aim being to establish their main characteristics. From 1959 onwards, we identified a total of 39 independent H7 and H5 LPAI to HPAI conversion events. All but two of these events were reported in commercial poultry production systems, and a majority of these events took place in high-income countries. In contrast, a total of 127 reassortments have been reported from 1983 to 2015, which predominantly took place in countries with poultry production systems transitioning from backyard to intensive production systems. Those systems are characterized by several co-circulating viruses, multiple host species, regular contact points in live bird markets, limited biosecurity within value chains, and frequent vaccination campaigns that impose selection pressures for emergence of novel reassortants. We conclude that novel HPAI emergences by these two mechanisms occur in different ecological niches, with different viral, environmental and host associated factors, which has implications in early detection and management and mitigation of the risk of emergence of novel HPAI viruses.

Gallic acid has been reported to possess a number of psychopharmacological activities. These activities are attributed to the antioxidant potential due to the presence of phenolic moeity. The present study was carried out to investigate the protective effects of gallic acid in an experimental model of ketamine-induced psychosis in mice. Ketamine (50 mg/kg, i.p.) was used to induce stereotyped psychotic behavioural symptoms in mice. Behavioural studies (locomotor activity, stereotype behaviour, immobility duration and memory retention) were carried out to investigate the protective of gallic acid on ketamine-induced psychotic symptoms, followed by biochemical and neurochemical changes and cellular alterations in the brain. Chronic treatment with gallic acid for 15 consecutive days significantly attenuated stereotyped behavioural symptoms in mice. Biochemical estimations revealed that gallic acid reduced the lipid peroxidation and restored the total brain proteins. Furthermore, gallic acid remarkably reduced the dopamine levels, AChE activity and inflammatory surge (serum TNF-α), and increased the levels of GABA and increased glutathione in mice. The study revealed that gallic acid could ameliorate psychotic symptoms and biochemical changes in mice, indicating protective effects in psychosis.

The fifth epidemic wave of avian influenza A(H7N9) virus in China during 2016-2017 demonstrated a geographic range expansion and caused more human cases than any previous wave. The factors that may explain the recent range expansion and surge in incidence remain unknown. We investigated the effect of anthropogenic, poultry, and wetland variables on all epidemic waves. Poultry predictor variables became much more important in the last 2 epidemic waves than they were previously, supporting the assumption of much wider H7N9 transmission in the chicken reservoir. We show that the future range expansion of H7N9 to northern China may increase the risk of H7N9 epidemic peaks coinciding in time and space with those of seasonal influenza, leading to a higher risk of reassortments than before, although the risk is still low so far.

In the last few years, several reassortant subtypes of highly pathogenic avian influenza viruses (HPAI H5Nx) have emerged in East Asia. These new viruses, mostly of subtype H5N1, H5N2, H5N6, and H5N8 belonging to clade 2.3.4.4, have been found in several Asian countries and have caused outbreaks in poultry in China, South Korea, and Vietnam. HPAI H5Nx also have spread over considerable distances with the introduction of viruses belonging to the same 2.3.4.4 clade in the U.S. (2014-2015) and in Europe (2014-2015 and 2016-2017). In this paper, we examine the emergence and spread of these new viruses in Asia in relation to published datasets on HPAI H5Nx distribution, movement of migratory waterfowl, avian influenza risk models, and land-use change analyses. More specifically, we show that between 2000 and 2015, vast areas of northeast China have been newly planted with rice paddy fields (3.21 million ha in Heilongjiang, Jilin, and Liaoning) in areas connected to other parts of Asia through migratory pathways of wild waterfowl. We hypothesize that recent land use changes in northeast China have affected the spatial distribution of wild waterfowl, their stopover areas, and the wild-domestic interface, thereby altering transmission dynamics of avian influenza viruses across flyways. Detailed studies of the habitat use by wild migratory birds, of the extent of the wild-domestic interface, and of the circulation of avian influenza viruses in those new planted areas may help to shed more light on this hypothesis, and on the possible impact of those changes on the long-distance patterns of avian influenza transmission.

The killed bivalent (O1 and O139) whole cell oral cholera vaccine (OCV) (Shanchol™) was first licensed in India in 2009 and World Health Organization pre-qualified in 2011. We assessed the safety and immunogenicity of this OCV in the Philippines. This was a phase IV, single-arm, descriptive, open-label study. We recruited 336 participants from 2 centers: 112 participants in each age group (1-4, 5-14 and ≥ 15 years). Participants received 2 OCV doses 14 d apart. Safety was monitored throughout the trial. Blood samples were collected at baseline (pre-vaccination) and 14 d after each dose. Serum vibriocidal antibody titers to V. cholerae O1 (El Tor Inaba and El Tor Ogawa) and O139 strains were assessed, with seroconversion defined as ≥ 4-fold increase from baseline in titers. No immediate unsolicited systemic adverse events/reactions were observed. Unsolicited systemic adverse events were mostly grade 1 intensity. One serious adverse event occurred after the first dose, but was unrelated to vaccination. High seroconversion rates (range 69-92%) were achieved against the O1 serotypes with a trend toward higher rates in the 1-4 y (86-92%) and 5-14 y (86-88%) age groups than the ≥ 15 y age group (69-83%). Lower seroconversion rates were achieved against the O139 serotype (35-70%), particularly in those aged ≥ 15 y (35-42%). The 2-dose regimen of the killed bivalent whole cell OCV was well-tolerated in this study conducted in the Philippines, a cholera-endemic country. Robust immune responses were observed even after a single-dose.

Highly pathogenic avian influenza H5N1 remains a persistent public health threat, capable of causing infection in humans with a high mortality rate while simultaneously negatively impacting the livestock industry. A central question is to determine regions that are likely sources of newly emerging influenza strains with pandemic causing potential. A suitable candidate is Bangladesh, being one of the most densely populated countries in the world and having an intensifying farming system. It is therefore vital to establish the key factors, specific to Bangladesh, that enable both continued transmission within poultry and spillover across the human-animal interface. We apply a modelling framework to H5N1 epidemics in the Dhaka region of Bangladesh, occurring from 2007 onwards, that resulted in large outbreaks in the poultry sector and a limited number of confirmed human cases. This model consisted of separate poultry transmission and zoonotic transmission components. Utilising poultry farm spatial and population information a set of competing nested models of varying complexity were fitted to the observed case data, with parameter inference carried out using Bayesian methodology and goodness-of-fit verified by stochastic simulations. For the poultry transmission component, successfully identifying a model of minimal complexity, which enabled the accurate prediction of the size and spatial distribution of cases in H5N1 outbreaks, was found to be dependent on the administration level being analysed. A consistent outcome of non-optimal reporting of infected premises materialised in each poultry epidemic of interest, though across the outbreaks analysed there were substantial differences in the estimated transmission parameters. The zoonotic transmission component found the main contributor to spillover transmission of H5N1 in Bangladesh was found to differ from one poultry epidemic to another. We conclude by discussing possible explanations for these discrepancies in transmission behaviour between epidemics, such as changes in surveillance sensitivity and biosecurity practices., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Rotavirus remains the leading cause of diarrhoea among children <5years. We assessed immunogenic non-inferiority of a tetravalent bovine-human reassortant rotavirus vaccine (BRV-TV) over the licensed human-bovine pentavalent rotavirus vaccine RV5., Methods: Phase III single-blind study (parents blinded) in healthy infants randomized (1:1) to receive three doses of BRV-TV or RV5 at 6-8, 10-12, and 14-16weeks of age. All concomitantly received a licensed diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b conjugate vaccine (DTwP-HepB-Hib) and oral polio vaccine (OPV). Immunogenic non-inferiority was evaluated in terms of the inter-group difference in anti-rotavirus serum IgA seroresponse (primary endpoint), and seroprotection/seroresponse rates to DTwP-HepB-Hib and OPV vaccines. Seroresponse was defined as a ≥4-fold increase in titers from baseline to D28 post-dose 3. Non-inferiority was declared if the difference between groups (based on the lower limit of the 95% confidence interval [CI]) was above -10%. Each subject was evaluated for solicited adverse events 7days and unsolicited & serious adverse events 28days following each dose of vaccination., Results: Of 1195 infants screened, 1182 were randomized (590 to BRV-TV; 592 to RV5). Non-inferiority for rotavirus serum IgA seroresponse was not established: BRV-TV, 47.1% (95%CI: 42.8; 51.5) versus RV5, 61.2% (95%CI: 56.8; 65.5); difference between groups, -14.08% (95%CI: -20.4; -7.98). Serum IgA geometric mean concentrations at D28 post-dose 3 were 28.4 and 50.1U/ml in BRV-TV and RV5 groups, respectively. For all DTwP-HepB-Hib and OPV antigens, seroprotection/seroresponse was elicited in both groups and the -10% non-inferiority criterion between groups was met. There were 16 serious adverse events, 10 in BRV-TV group and 6 in RV5 group; none were classified as vaccine related. Both groups had similar vaccine safety profiles., Conclusion: BRV-TV was immunogenic but did not meet immunogenic non-inferiority criteria to RV5 when administered concomitantly with routine pediatric antigens in infants., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Vaccination is considered as the most cost effective method for preventing infectious diseases. Low grade fever is a known adverse effect of vaccination. In India, it is a common clinical practice to prescribe paracetamol either prophylactically or therapeutically to manage fever. Some studies have shown that paracetamol interferes with antibody responses following immunization. This manuscript reports the outcome of a post hoc analysis of data from a clinical trial of a pentavalent vaccine in Indian infants where paracetamol was not used or was used either as prophylaxis or for treatment of fever., Methods: Pre and post vaccine antibody levels against Diphtheria, Tetanus, Pertussis, Hepatitis B, Haemophilus influenzae type B were assessed in no paracetamol and paracetamol groups. The paracetamol group was further divided into prophylactic and treatment groups., Results: Similar rates of seroprotection/seroresponse for anti-D, anti-T, anti-wP, anti-PT, anti-HBs and anti-PRP were observed in all the groups. There was no clear tendency for difference in percentage seroprotection/seroresponse and geometric mean (GM) titers in any of the groups., Conclusion: The study found no evidence that paracetamol usage either as prophylactic or for treatment impact immunological responses to DTwP-HepB-Hib combination vaccine. [Clinical trial registry of India (study registration number CTRI/2012/08/002872)]., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rotavirus is the leading cause of severe and dehydrating diarrhea in children aged under 5 years. We undertook this hospital-based surveillance study to examine the possible relationship between the severity of diarrhea and the various G-group rotaviruses circulating in India. Stool samples (n = 2,051) were systematically collected from 4,711 children aged <5 years admitted with severe acute gastroenteritis to 12 medical school centers from April 2011 to July 2012. Rotavirus testing was undertaken using a commercially available enzyme immunoassay kit for the rotavirus VP6 antigen (Premier Rotaclone Qualitative ELISA). Rotavirus positive samples were genotyped for VP7 and VP4 antigens by reverse-transcription polymerase chain reaction at a central laboratory. Of the stool samples tested for rotavirus antigen, 541 (26.4%) were positive for VP6 antigen. Single serotype infections from 377 stool samples were compared in terms of gastroenteritis severity. Among those with G1 rotavirus infection, very severe diarrhea (Vesikari score ≥ 16) was reported in 59 (33.9%) children, severe diarrhea (Vesikari score 11-15) in 104 (59.8%), moderate (Vesikari score 6-10) and mild diarrhea (Vesikari score 0-5) in 11 (6.3%). Among those with G2 infection, very severe diarrhea was reported in 26 (27.4%) children, severe diarrhea in 46 (48.4%), and moderate and mild diarrhea in 23 (24.2 %). Among those with G9 infection, very severe diarrhea was reported in 47 (54.5%) children, severe diarrhea in 29 (33.6%), and moderate and mild diarrhea in 10 (11.9%). Among those with G12 infection, very severe diarrhea was reported in 9 (40.9%) children and severe diarrhea in 13 (59.1%). The results of this study indicate some association between rotavirus serotypes and severity of gastroenteritis.

In the last two decades, two important avian influenza viruses infecting humans emerged in China, the highly pathogenic avian influenza (HPAI) H5N1 virus in the late nineties, and the low pathogenic avian influenza (LPAI) H7N9 virus in 2013. China is home to the largest population of chickens (4.83 billion) and ducks (0.694 billion), representing, respectively 23.1 and 58.6% of the 2013 world stock, with a significant part of poultry sold through live-poultry markets potentially contributing to the spread of avian influenza viruses. Previous models have looked at factors associated with HPAI H5N1 in poultry and LPAI H7N9 in markets. However, these have not been studied and compared with a consistent set of predictor variables. Significant progress was recently made in the collection of poultry census and live-poultry market data, which are key potential factors in the distribution of both diseases. Here we compiled and reprocessed a new set of poultry census data and used these to analyse HPAI H5N1 and LPAI H7N9 distributions with boosted regression trees models. We found a limited impact of the improved poultry layers compared to models based on previous poultry census data, and a positive and previously unreported association between HPAI H5N1 outbreaks and the density of live-poultry markets. In addition, the models fitted for the HPAI H5N1 and LPAI H7N9 viruses predict a high risk of disease presence for the area around Shanghai and Hong Kong. The main difference in prediction between the two viruses concerned the suitability of HPAI H5N1 in north-China around the Yellow sea (outlined with Tianjin, Beijing, and Shenyang city) where LPAI H7N9 has not spread intensely.

Global disease suitability models are essential tools to inform surveillance systems and enable early detection. We present the first global suitability model of highly pathogenic avian influenza (HPAI) H5N1 and demonstrate that reliable predictions can be obtained at global scale. Best predictions are obtained using spatial predictor variables describing host distributions, rather than land use or eco-climatic spatial predictor variables, with a strong association with domestic duck and extensively raised chicken densities. Our results also support a more systematic use of spatial cross-validation in large-scale disease suitability modelling compared to standard random cross-validation that can lead to unreliable measure of extrapolation accuracy. A global suitability model of the H5 clade 2.3.4.4 viruses, a group of viruses that recently spread extensively in Asia and the US, shows in comparison a lower spatial extrapolation capacity than the HPAI H5N1 models, with a stronger association with intensively raised chicken densities and anthropogenic factors., Competing Interests: The authors declare that no competing interests exist.

Ethnopharmacological Relevance: Benign prostatic hyperplasia (BPH) is a common urological disorder of men. The ethnomedicinal use of an African plant Prunus africana (Hook.f.) Kalkman (Pygeum) in treating men's problems made it a popular remedy all over the globe for the treatment of BPH and related disorders. However, rampant collections made from the wild in Africa have pushed the plant to Appendix II of CITES demanding conservation of the species., Aim of the Study: In the present study, the aim was to unearth the protective effect of bark of different species of Prunus against BPH. The five selected Indian plants of family Rosaceae viz. Prunus amygdalus Stokes, Prunus armeniaca L., Prunus cerasoides Buch.-Ham. ex D. Don, Prunus domestica L. and Prunus persica (L.) Batsch were evaluated against P. africana (Hook.f.) Kalkman for a suitable comparison of efficacy as antiBPH agents., Materials and Methods: The antiBPH activity was evaluated in testosterone (2mg/kg/day, s.c, 21 days) induced BPH in Wistar rats. The parameters studied were body weights; histopathological examination, immunohistochemistry (PCNA) and biochemical estimations of the prostate; supported by prostatic index, testicular index, creatinine, testosterone levels; antioxidant and anti-inflammatory evaluation. The study also included chemical profiling using three markers (β-sitosterol, docosyl ferulate and ursolic acid) and estimation of β-sitosterol content through GC., Results: The Prunus species showed the presence of all the three markers in their TLC fingerprint profile and maximum amount of β-sitosterol by GC was observed in P. domestica. Interestingly, all the species exhibited significant amelioration in testosterone induced parameters with P. domestica showing the most encouraging effect as indicated from histopathological examination, immunohistochemistry and biochemical studies. The Prunus species further showed remarkable anti-inflammatory and antioxidant activity signifying their role in interfering with various possible factors involved in BPH., Conclusions: These findings are suggestive of a meaningful inhibitory effect of testosterone induced BPH by the bark of different species of Prunus in the order of P. domestica, P. persica, P. amygdalus, P. cerasoides and P. armeniaca with an efficacy of P. domestica comparable to P. africana and can be used as the potential backup of Pygeum for the management of BPH., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The highly pathogenic avian influenza (HPAI) H5N1 virus has been circulating in Asia since 2003 and diversified into several genetic lineages, or clades. Although the spatial distribution of its outbreaks was extensively studied, differences in clades were never previously taken into account. We developed models to quantify associations over time and space between different HPAI H5N1 viruses from clade 1, 2.3.4 and 2.3.2 and agro-ecological factors. We found that the distribution of clades in the Mekong region from 2004 to 2013 was strongly regionalised, defining specific epidemiological zones, or epizones. Clade 1 became entrenched in the Mekong Delta and was not supplanted by newer clades, in association with a relatively higher presence of domestic ducks. In contrast, two new clades were introduced (2.3.4 and 2.3.2) in northern Viet Nam and were associated with higher chicken density and more intensive chicken production systems. We suggest that differences in poultry production systems in these different epizones may explain these associations, along with differences in introduction pressure from neighbouring countries. The different distribution patterns found at the clade level would not be otherwise apparent through analysis treating all outbreaks equally, which requires improved linking of disease outbreak records and genetic sequence data.

Pentavalent combination vaccines are important tools to strengthen the immunization programs in numerous countries throughout the world. A large number of countries have recognized the value of combination vaccines and have introduced whole cell pentavalent vaccines into their immunization programs. A phase III, multi-center, randomized, single blinded study of a fully liquid pentavalent DTwP-HepB-Hib investigational vaccine (Shan5™) was conducted across India in 2 cohorts: 15 toddlers were evaluated for safety and immunogenicity following a single booster dose (Cohort 1) followed by 1085 infants (Cohort 2) evaluated for immunogenicity and safety following 3-dose primary immunization of the investigational vaccine or a locally licensed comparator vaccine (Pentavac SD). Immune consistency analysis among 3 lots of the investigational vaccine, and immune non-inferiority analysis of pooled (3 lots) data of investigational vaccine vs. comparator vaccine were carried out in cohort 2. The vaccines demonstrated comparable safety and immune responses in cohort 1. In cohort 2, equivalent immune consistency among 3 lots was observed for all antigens except whole cell pertussis antigens, where a marginal variation was observed which was linked to the low power of the test and concluded to not have any clinical significance. Immune non-inferiority against the comparator vaccine was demonstrated for all 5 antigens. Safety results were comparable between vaccine groups. This investigational, fully-liquid, whole-cell pertussis (wP) containing new pentavalent vaccine was found to be safe and immunologically non-inferior to the licensed comparator vaccine.

Background: A bivalent killed whole cell oral cholera vaccine has been found to be safe and efficacious for five years in the cholera endemic setting of Kolkata, India, when given in a two dose schedule, two weeks apart. A randomized controlled trial revealed that the immune response was not significantly increased following the second dose compared to that after the first dose. We aimed to evaluate the impact of an extended four week dosing schedule on vibriocidal response., Methodology/principal Findings: In this double blind randomized controlled non-inferiority trial, 356 Indian, non-pregnant residents aged 1 year or older were randomized to receive two doses of oral cholera vaccine at 14 and 28 day intervals. We compared vibriocidal immune responses between these schedules. Among adults, no significant differences were noted when comparing the rates of seroconversion for V. cholerae O1 Inaba following two dose regimens administered at a 14 day interval (55%) vs the 28 day interval (58%). Similarly, no differences in seroconversion were demonstrated in children comparing the 14 (80%) and 28 day intervals (77%). Following 14 and 28 day dosing intervals, vibriocidal response rates against V. cholerae O1 Ogawa were 45% and 49% in adults and 73% and 72% in children respectively. Responses were lower for V. cholerae O139, but similar between dosing schedules for adults (20%, 20%) and children (28%, 20%)., Conclusions/significance: Comparable immune responses and safety profiles between the two dosing schedules support the option for increased flexibility of current OCV dosing. Further operational research using a longer dosing regimen will provide answers to improve implementation and delivery of cholera vaccination in endemic and epidemic outbreak scenarios.

In India, majority outbreaks of highly pathogenic avian influenza (HPAI) H5N1 have occurred in eastern states of West Bengal, Assam and Tripura. This study aimed to identify disease clusters and risk factors of HPAI H5N1 in these states, for targeted surveillance and disease control. A spatial scan statistic identified two significant disease clusters in West Bengal and Assam, occurring during January and November-December 2008, respectively. Key risk factors were identified at sub-district level using bootstrapped logistic regression and boosted regression trees model. With both methods, HPAI H5N1 outbreaks in backyard poultry were associated with accessibility in terms of time taken to access a city with >50,000 persons, human population density and duck density (P<0.005). In addition, areas at lower elevation were also identified as high risk by BRT model. It is recommended that risk-based surveillance should be implemented in high duck density areas and all live-bird markets in high-throughput locations., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: A rotavirus vaccine could soon become part of India's national immunization program. However the occurrence of intussusception due to rotavirus vaccine is a potential safety concern. This surveillance aimed at the collection of baseline data on childhood intussusception which would facilitate the monitoring of intussusception cases after the introduction of rotavirus vaccines., Methods: We retrospectively reviewed medical records of confirmed intussusception cases in children under the age of five, treated during 2007-2012 at two tertiary care hospitals attached to medical schools in India. Demographic, clinical, diagnostic and treatment practices data were obtained from hospital records., Results: Over a five to six year observation period, we identified 187 confirmed cases of intussusception, of which 75% were males. The median age of intussusception was 8 months, and we observed a possible trend in the distribution of cases with the highest number of cases being reported in the month of April and lowest in the month of October. The most common diagnostic methods used were ultrasonography and abdominal radiography with most cases being treated surgically (71%). The median length of hospital stay was 8 days (range 1-40) and mean was 10.2 days. Records of any fatality due to intussusception were not found during the review of the records., Conclusions: This analysis provides an estimate of the baseline data of childhood intussusception prior to the introduction of the rotavirus vaccination as a part of routine immunization in India. A prospective surveillance system using a standardized case definition is needed in order to better examine the incidence of intussusception in developing countries., (Copyright © 2014. Published by Elsevier Ltd.)

Background: Rotavirus is the leading cause of severe, dehydrating diarrhea in children aged <5 years globally, with an estimated 25 million outpatient visits and 2 million hospitalizations attributable to rotavirus infections each year. The aim of this hospital-based surveillance was to summarize the local epidemiological and virological features of rotavirus and to estimate the disease burden in the population under surveillance in India., Methods: During the 16 months surveillance period from April 2011 through July 2012, a total of 4711 children under the age of 5 years were admitted with acute diarrhea at 12 medical centers attached to medical schools throughout India. Stool samples were randomly collected from 2051 (43.5%) subjects and were analyzed for rotavirus positivity using commercial enzyme immunoassay kit (Premier Rotaclone Qualitative Elisa) at the respective study centers. Rotavirus positive samples were genotyped for VP7 and VP4 by reverse-transcription polymerase chain reaction (RT-PCR) at a central laboratory., Results: During the study period, maximum number of rotavirus related hospitalizations were reported from December 2011 through February 2012. Out of the 2051 stool samples tested for rotavirus, overall 541 (26.4%) samples were positive for rotavirus VP6 antigen in stool. The highest positivity was observed in the month of December, 2011 (52.5%) and lowest in the month of May, 2011 (10.3%). We found that majority of the rotavirus positive cases (69.7%) were in children <24 months of age. The most common genotypes reported were G1 (38%), G2 (18%), G9 (18%), G12 (9%) and mixed strains (17%)., Conclusions: The results of this study confirm the significant burden of acute rotavirus gastroenteritis as a cause of hospitalizations in under five children in India., (Copyright © 2014. Published by Elsevier Ltd.)

Background: Rotavirus infections, prevalent in human populations worldwide are mostly caused by Group A viruses. Live attenuated rotavirus vaccines are highly effective in preventing severe rotavirus gastroenteritis. However, the cost of these vaccines and local availability can be a barrier for widespread adoption in public health programs in developing countries where infants suffer a heavy burden of rotavirus related morbidity and mortality. A phase I/II study was carried out with the long term aim to produce a locally licensed vaccine which is equally safe and immunogenic as compared to available licensed vaccines., Methods: This study was conducted in two cohorts. In the first cohort, 20 healthy adults were administered a single dose of the rotavirus vaccine (highest antigen concentration planned for infants) or placebo and were followed up for 10 days for safety. Following demonstration of safety in adult volunteers, 100 healthy infants were recruited (cohort 2) and randomly divided into five equal study groups. They were administered three doses of either the investigational rotavirus vaccine (BRV-TV) at one of the three antigen concentrations or Rotateq or Placebo at 6-8, 10-12 and 14-16 weeks of age. All infants were followed up for safety till 28 days after the third dose. Immune response to the vaccine, in terms of seroresponse and geometric mean concentrations, was compared across the five study groups., Results: Increase in anti-rotavirus serum IgA antibodies from baseline, demonstrated higher immune response for all the three antigen concentrations of BRV-TV vaccine and RotaTeq in comparison with the placebo. Sero-response rates for placebo, BRV-TV dose-levels 10(5.0) FFU, 10(5.8) FFU, 10(6.4) FFU, and Rotateq at 28 days post third dose were 11.1%, 27.8%, 41.2%, 83.3%, and 63.2% respectively using the four-fold or more criteria. The BRV-TV vaccine arm corresponding to the highest antigen concentration of 10(6.4) FFU had a higher sero-response rate compared to the active comparator arm (RotaTeq), 28 days post each vaccine dose. The safety profile was comparable across the treatment groups., Conclusions: Overall, the results showed that all three doses of BRV-TV vaccine were safe, well tolerated and displayed good immunogenicity (dose-response) in healthy Indian infants., (Copyright © 2014. Published by Elsevier Ltd.)

Background: Many studies have shown that the levels of oxidative stress (increased lipid peroxidation, decreased glutathione levels and endogenous antioxidant enzyme activities) and proinflammatory cytokines (e.g., TNF-α) are increased in patients with chronic fatigue syndrome. Gallic acid and other phenolic compounds are potent antioxidants and inhibitor of cytokine production. The present study was designed to investigate the effect of newly synthesized conjugated esters of trimethylgallic acid in an experimental model of chronic stress., Methods: The animals were forced to swim individually for a period of 6min every day for 15 days to induce chronic stress. The locomotor activity, anxiety-like behavior, and memory retention were evaluated in chronically stressed animals, followed by biochemical estimations and neuroinflammatory surge in the brain., Results: Chronic treatment with trimethylgallic acid esters for 15 days significantly reversed the chronic stress-induced behavioral (impaired locomotor activity, anxiety-like behavior, and decreased percentage of memory retention), biochemical (increased lipid peroxidation and nitrite levels; decreased glutathione levels, superoxide dismutase and catalase activities), and inflammation surge (serum TNF-α) in stressed mice., Conclusions: The study revealed that trimethylgallic acid esters could ameliorate chronic stress-induced various behavioral and biochemical alterations in mice, showing protective effects against chronic stress., (Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

A single dose of live attenuated tetravalent (G1-G4) bovine human reassortant rotavirus vaccine (BRV-TV) was administered to healthy Indian adult volunteers, who were assessed for safety and immunogenicity of the vaccine with 3:1 randomization to vaccine or placebo. All 20 adult male volunteers in the study had rotavirus specific serum IgA at baseline. There were no side effects or adverse events reported. Administration of BRV-TV was not associated with fever, diarrhea, or altered liver transaminases. Rotavirus IgA seroconversion post single dose administration was 27%. This study shows that BRV-TV is non-reactogenic, safe and immunogenic in adults. The IgA units estimated for the same sample using human G1P[8] rotavirus strain as the antigen were consistently higher than with the bovine G6P[5] WC3 strain and the human G2P[4] DS-1 strain antigen. The use of different human and bovine rotavirus strains as antigens in a quantitative rotavirus specific serum IgA assay resulted in different estimations of IgA antibody in the same sample., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: During the development of a vaccine, identification of the correlates of protection is of paramount importance for establishing an objective criterion for the protective performance of the vaccine. However, the ascertainment of correlates of immunity conferred by any vaccine is a difficult task., Methods: While conducting a phase three double-blind, cluster-randomized, placebo-controlled trial of a bivalent killed whole-cell oral cholera vaccine in Kolkata, we evaluated the immunogenicity of the vaccine in a subset of participants. Randomly chosen participants (recipients of vaccine or placebo) were invited to provide blood samples at baseline, 14 days after the second dose and one year after the first dose. At these time points, serum geometric mean titers (GMT) of vibriocidal antibodies and seroconversion rates for vaccine and placebo arms were calculated and compared across the age strata (1 to 5 years, 5 to 15 years and more than 15 years) as well as for all age groups., Results: Out of 137 subjects included in analysis, 69 were vaccinees and 68 received placebo. There were 5•7 and 5•8 geometric mean fold (GMF) rises in titers to Vibrio cholerae Inaba and Ogawa, respectively at 14 days after the second dose, with 57% and 61% of vaccinees showing a four-fold or greater titer rise, respectively. After one year, the titers to Inaba and Ogawa remained 1•7 and 2•8 fold higher, respectively, compared to baseline. Serum vibriocidal antibody response to V. cholerae O139 was much lower than that to Inaba or Ogawa. No significant differences in the GMF-rises were observed among the age groups., Conclusions: The reformulated oral cholera vaccine induced a statistically significant anti-O1 Inaba and O1 Ogawa vibriocidal antibody response 14 days after vaccination, which although declined after one year remained significantly higher than baseline. Despite this decline, the vaccine remained protective five years after vaccination.

Background: Efficacy and safety of a two-dose regimen of bivalent killed whole-cell oral cholera vaccine (Shantha Biotechnics, Hyderabad, India) to 3 years is established, but long-term efficacy is not. We aimed to assess protective efficacy up to 5 years in a slum area of Kolkata, India., Methods: In our double-blind, cluster-randomised, placebo-controlled trial, we assessed incidence of cholera in non-pregnant individuals older than 1 year residing in 3933 dwellings (clusters) in Kolkata, India. We randomly allocated participants, by dwelling, to receive two oral doses of modified killed bivalent whole-cell cholera vaccine or heat-killed Escherichia coli K12 placebo, 14 days apart. Randomisation was done by use of a computer-generated sequence in blocks of four. The primary endpoint was prevention of episodes of culture-confirmed Vibrio cholerae O1 diarrhoea severe enough for patients to seek treatment in a health-care facility. We identified culture-confirmed cholera cases among participants seeking treatment for diarrhoea at a study clinic or government hospital between 14 days and 1825 days after receipt of the second dose. We assessed vaccine protection in a per-protocol population of participants who had completely ingested two doses of assigned study treatment., Findings: 69 of 31 932 recipients of vaccine and 219 of 34 968 recipients of placebo developed cholera during 5 year follow-up (incidence 2·2 per 1000 in the vaccine group and 6·3 per 1000 in the placebo group). Cumulative protective efficacy of the vaccine at 5 years was 65% (95% CI 52-74; p<0·0001), and point estimates by year of follow-up suggested no evidence of decline in protective efficacy., Interpretation: Sustained protection for 5 years at the level we reported has not been noted previously with other oral cholera vaccines. Established long-term efficacy of this vaccine could assist policy makers formulate rational vaccination strategies to reduce overall cholera burden in endemic settings., Funding: Bill & Melinda Gates Foundation and the governments of South Korea and Sweden., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: We evaluated the herd protection conferred by an oral cholera vaccine using 2 approaches: cluster design and geographic information system (GIS) design., Methods: Residents living in 3933 dwellings (clusters) in Kolkata, India, were cluster-randomized to receive either cholera vaccine or oral placebo. Nonpregnant residents aged≥1 year were invited to participate in the trial. Only the first episode of cholera detected for a subject between 14 and 1095 days after a second dose was considered. In the cluster design, indirect protection was assessed by comparing the incidence of cholera among nonparticipants in vaccine clusters vs those in placebo clusters. In the GIS analysis, herd protection was assessed by evaluating association between vaccine coverage among the population residing within 250 m of the household and the occurrence of cholera in that population., Results: Among 107 347 eligible residents, 66 990 received 2 doses of either cholera vaccine or placebo. In the cluster design, the 3-year data showed significant total protection (66% protection, 95% confidence interval [CI], 50%-78%, P<.01) but no evidence of indirect protection. With the GIS approach, the risk of cholera among placebo recipients was inversely related to neighborhood-level vaccine coverage, and the trend was highly significant (P<.01). This relationship held in multivariable models that also controlled for potentially confounding demographic variables (hazard ratio, 0.94 [95% CI, .90-.98]; P<.01)., Conclusions: Indirect protection was evident in analyses using the GIS approach but not the cluster design approach, likely owing to considerable transmission of cholera between clusters, which would vitiate herd protection in the cluster analyses., Clinical Trials Registration: NCT00289224.

The study was planned to assess and compare immunogenicity and safety of an indigenous DTPw-Hib combination vaccine (Shan 4) with EasyFour, the available DTwP-Hib vaccine in India. Overall 210 healthy infants, six to eight weeks of age, were randomized to receive three doses of either Shan 4 or EasyFour at 6, 10 and 14 weeks of age. Antibodies were analyzed prior to and four to six weeks post third vaccine dose. Solicited and unsolicited local and systemic events in the follow up period after each dose were recorded. Post vaccination 100% of the infants in Shan 4 and EasyFour groups had seroprotective concentrations of Anti PRP-T IgG antibodies, IgG anti-diphtheria toxoid antibodies and IgG anti-tetanus toxoid antibodies. Following third dose of vaccination 86.99% subjects in the Shan 4 group and 73.85% subjects in the EasyFour group seroconverted for anti-pertussis antibody titres. Two Serious Adverse Events (SAE s) were reported during the course of the study, all unrelated to the respective vaccine administered. Most commonly reported adverse events in both the groups were pain at injection site, mild fever (<103°F) and minor swelling at injection site. The study proved that Shan 4 was safe and immunogenic compared to the available licensed vaccine.

The study was planned to assess and compare the immune response and safety of an indigenous DTPwHB-Hib pentavalent liquid combination vaccine (Shan 5) with Easyfive and TritanrixHB+ Hiberix, the two available pentavalent combination vaccines. Four hundred infants were randomized to receive three doses of either Shan 5 or one of the two comparators. Antibody analysis was performed prior to and four to six weeks post third vaccine dose. Solicited local and systemic events upto three days and unsolicited adverse events in the 30 days follow up period after each dose were recorded. A total of 365 subjects completed the study. Four to six weeks after third dose, 98.32% of the subjects in Shan 5 group had seroprotective Anti PRP-T IgG antibody concentrations (> or =0.15 microg/mL) as compared to 100% and 98.94% subjects in TritanrixHB + Hiberix and Easyfive groups respectively. Seroprotective levels for Anti-HBs (> or =10 mIU/mL) were observed in 97.77%, 97.83% and 98.94% subjects in Shan 5, TritanrixHB + Hiberix and Easyfive groups respectively. Comparable immune responses were observed for the three other components (D, T and P) in all the groups. Four Serious Adverse Events (SAEs) were reported (three with Shan 5 and one with Easyfive), all unrelated to the respective vaccines. Most commonly reported adverse events in all the groups were pain at injection site, mild fever (<103 degrees F) and minor swelling at injection site. The study proved that Shan 5 was safe and immunogenic compared to the two other licensed vaccines.

A case of rarely encountered Salmonella Typhi septic arthritis of the hip in a child with no preexisting disease is reported. Salmonella etiology was not suspected in this case, and the diagnosis was made only after bacterial isolation. Arthrotomy was done as an initial mode of management, followed by intravenous ciprofloxacin therapy to which the child responded favorably.

We have examined the epididymal (caput, corpus and cauda) and ejaculated spermatozoa of bufallo-bull (Bubalus bubalis) employing microscopic and spectroscopic techniques. Fluorescein isothiocyanate conjugated lectins namely concanavalin A (Con A), Dolichos biflorus (DBA), Maclura pomifera (MPA), peanut agglutinin (PNA), soybean agglutinin (SBA) and wheat germ agglutinin (WGA) were used to study the changes in the sperm surface carbohydrate make up as the spermatozoa mature. Quantitative analysis of the lectin binding was made flow cytometrically. 31P-NMR (nuclear magnetic resonance) spectra of the sperms obtained from different regions (head, body and tail) of the epididymis and of the ejaculate were analyzed to assess their metabolic activity. And the kinetics of spin label reduction of these samples was monitored with ESR (electron spin resonance) spectroscopy. These observations are supplemented with the electron microscopic (SEM and TEM) examination of the epididymal and ejaculated spermatozoa.