Immunogenicity and Induction of Functional Antibodies in Rabbits Immunized with a Trivalent Typhoid-Invasive Nontyphoidal Salmonella Glycoconjugate Formulation.

Typhoid fever due to Salmonella Typhi and invasive nontyphoidal Salmonella (iNTS) infections caused by serovars Enteritidis (SE) and Typhimurium (STm) are major pediatric health problems in sub-Saharan Africa. Typhoid has high complication rates, and iNTS infections have high case fatality rates; moreover, emerging antimicrobial resistance is diminishing treatment options. Vi capsule-based typhoid conjugate vaccine (Typbar-TCV™), licensed in India and pre-qualified by the World Health Organization, elicits durable immunity when administered to infants, but no iNTS vaccines are licensed or imminent. We have developed monovalent SE and STm glycoconjugate vaccines based on coupling lipopolysaccharide-derived core-O polysaccharide (COPS) to phase 1 flagellin protein (FliC) from the homologous serovar. Herein, we report the immunogenicity of multivalent formulations of iNTS COPS:FliC conjugates with Typbar-TCV™. Rabbits immunized with the trivalent typhoid-iNTS glycoconjugate vaccine generated high titers of serum IgG antibody to all three polysaccharide antigens for which anti-COPS IgG antibodies were directed primarily against serogroup-specific OPS epitopes. Responses to SE and STm FliC were lower relative to anti-COPS titers. Post-vaccination rabbit sera mediated bactericidal activity in-vitro, and protected mice after passive transfer against challenge with virulent SE or STm Malian blood isolates. These results support accelerated progression to clinical trials.

Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study.

BACKGROUND: Enteric fever caused by Salmonella Typhi remains a major public health problem in developing countries. Typbar-TCV is a single-dose typhoid Vi polysaccharide-tetanus toxoid conjugate vaccine for persons ≥6 months of age. METHODS: Six hundred fifty-four healthy subjects aged 2-45 years enrolled in a double-blind, randomized controlled trial (RCT) received a single dose of Typbar-TCV or comparator "Vi polysaccharide" (Typbar), and 327 healthy subjects aged 6-23 months received a single dose of Typbar-TCV in an open-label trial (OLT); both received single- or multidose presentations from different lots. After 2 years, subsets in each group received a booster dose. The primary objective included analysis of geometric mean titer (GMTs) and 4-fold rise of anti-Vi serum immunoglobulin G (IgG) enzyme-linked immunosorbent assay titers over baseline (seroconversion [SCN]) 42 days after immunization. RESULTS: Typbar-TCV recipients in the RCT attained higher anti-Vi IgG GMTs 42 days after immunization (SCN, 97%; GMT, 1293 [95% confidence interval {CI}, 1153-1449]) than recipients of Typbar (SCN, 93%; GMT, 411 [95% CI, 359-471]) (P < .001). Typbar-TCV was highly immunogenic in the OLT (SCN, 98%; GMT, 1937 [95% CI, 1785-2103]). Two years after vaccination, anti-Vi titers remained higher in Typbar-TCV subjects (GMT, 82 [95% CI, 73-92]); and exhibited higher avidity (geometric mean avidity index [GMAI], 60%) than in Typbar recipients (GMT, 46 [95% CI, 40-53]; GMAI 46%) in the RCT (P < .001). OLT Typbar-TCV recipients achieved GMT of 48 (95% CI, 42-55) and GMAI of 57%. Typbar-TCV induced multiple IgG subclasses and strong booster responses in all ages. No serious vaccine-attributable adverse events were observed. CONCLUSIONS: Single-dose Typbar-TCV is well tolerated and induces robust and long-lasting serum anti-Vi IgG across age groups. CLINICAL TRIALS REGISTRATION: CTRI/2011/08/001957, CTRI/2014/01/004341.

Influence of environmental factors on macrofoulant assemblages on moored buoys in the eastern Arabian Sea.

Factors governing the distribution of organisms in the pelagic ocean are understudied. In this paper we describe environmental parameters and macrofouling assemblages on 11 buoys deployed in the Arabian Sea for an average duration of 322 days. Macrofoulants on all the mooring components extending from the sea-surface to a depth of 1800-4300 m were documented. Role of temperature, salinity, dissolved oxygen, biological productivity and zooplankton community in governing the macrofoulant distribution are described. Species composition, vertical zonation and wet biomass exhibited significant spatial variations. Lepas anatifera constituted more than 90% of foulant wet biomass on all moorings. Assemblages in the southeastern (SEAS), east-central (ECAS) and northeast (NEAS) regions were distinct. Density of L. anatifera on surface buoys were low in SEAS (0.2±0.09 no./cm2), high in ECAS (0.32±0.11 no./cm2) and moderate in NEAS (0.23±0.04no./cm2). Macrofoulants were observed up to a depth of 75 m in SEAS, 130 m in ECAS and 120 m in NEAS. The depth profile of macrofoulant assemblages on moorings could be related to the prevalent hypoxic condition. Vertical profiles of wet biomass on all moorings exhibited subsurface maxima at depth ranging from 10 to 20 m, consequent to the abundance of L. anatifera in a thermally stable depth of water column, wherein diurnal and semidiurnal temperature variability was minimal. We attribute the observed variation in fouling assemblages to dissolved oxygen levels, salinity and diurnal variability in temperature and salinity.

Macaca radiata (bonnet monkey): a spontaneous model of nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a well-recognized condition that includes a spectrum of clinicopathology conditions ranging from steatotosis to cirrhosis and liver failure. Available animal models are not ideal as they show only a partial resemblance to characteristic human NAFLD. OBJECTIVE: This study was aimed at identifying a nonhuman primate model of NAFLD resembling features of human NAFLD, which will be useful in understanding the mechanism of the onset of this disease and for developing novel therapeutic modalities. METHODS: The histological status of the liver and serum levels of triglycerides (TG), cholesterol, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of aged bonnet monkeys were compared with that of the aged rhesus and adult bonnet monkeys. Histopathology and immunostaining of liver sections and oil red 'O' confirmed NAFLD in aged bonnet monkeys. RESULTS: Aged bonnet monkeys showed a significant (P<0.01) increase in serum TG, AST and ALT compared with aged rhesus and adult bonnet monkeys. Histopathology of the liver of aged bonnet macaques showed diffused microvesicular and macrovesicular fatty changes, perivenular and portal and perisinusoidal fibrosis with fatty degeneration of hepatocytes, and immunostaining of liver sections was suggestive of NAFLD. CONCLUSION: The spontaneous occurrence of NAFLD in normal animals is rare, but aged bonnet monkeys may serve as a unique animal model for studies related to NAFLD because they mimic pathophysiological features of human NAFLD.

Genetically modified mouse models for the study of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and type 2 diabetes. NAFLD represents a large spectrum of diseases ranging from (1) fatty liver (hepatic steatosis); (2) steatosis with inflammation and necrosis; to (3) cirrhosis. The animal models to study NAFLD/nonalcoholic steatohepatitis (NASH) are extremely useful, as there are still many events to be elucidated in the pathology of NASH. The study of the established animal models has provided many clues in the pathogenesis of steatosis and steatohepatitis, but these remain incompletely understood. The different mouse models can be classified in two large groups. The first one includes genetically modified (transgenic or knockout) mice that spontaneously develop liver disease, and the second one includes mice that acquire the disease after dietary or pharmacological manipulation. Although the molecular mechanism leading to the development of hepatic steatosis in the pathogenesis of NAFLD is complex, genetically modified animal models may be a key for the treatment of NAFLD. Ideal animal models for NASH should closely resemble the pathological characteristics observed in humans. To date, no single animal model has encompassed the full spectrum of human disease progression, but they can imitate particular characteristics of human disease. Therefore, it is important that the researchers choose the appropriate animal model. This review discusses various genetically modified animal models developed and used in research on NAFLD.

Pathology of the male baboon (Papio spp.) urogenital system.

BACKGROUND: Comprehensive reports on male baboon urogenital pathology are not available. METHODS: We performed a retrospective study of 2246 male baboon necropsy records over 19 years. RESULTS: A total of 289 urogenital lesions were diagnosed in 197 (8.8%) baboons. The most frequently affected organs in decreasing order were kidney, testicle, urinary bladder, penis and prepuce, seminal vesicle, ureter, and prostate. Lesions were rare in the urethra, scrotum, and epididymis. The most common diagnoses in decreasing order were nephritis, urinary bladder cystitis, nephrocalcinosis, pyelonephritis, renal cysts, renal amyloidosis, testicular atrophy, penile/preputial dermatitis, hydronephrosis, orchitis/testicular abscess, glomerulonephritis, renal hemorrhage, hypospadia, nephrosis, renal infarct, hypospermia/aspermia, seminal vesicle mineralization, and hydroureter. We also report six cases of hypospadia, the first report in the baboon. CONCLUSIONS: The male baboon has a low incidence of urogenital disease and renal disease is the most common malady. The role of herpesvirus papio 2 needs further study.

Hematologic and serum biochemical values in aged female bonnet macaques (Macaca radiata) anesthetized with ketamine hydrochloride.

We investigated the effect of ketamine hydrochloride anesthesia on hematologic and serum biochemical values in 10 aged female bonnet macaques (Macaca radiata) before and 120 min after intramuscular administration of ketamine hydrochloride (15 mg/kg body weight). Ketamine anesthesia caused significant reduction in the total leukocyte count, lymphocyte count, red blood cell count, hemoglobin concentration, packed cell volume, and serum concentrations of glucose, total protein, alkaline phosphatase, calcium, sodium, and potassium. Although the effects of ketamine hydrochloride on hematologic and serum biochemical values have been reported for most of the nonhuman primates, no literature on bonnet macaques is available. These findings will be useful in designing experiments assessing pathologic and toxicologic changes in blood and serum parameters and interpreting data obtained from aged bonnet monkeys.