A randomized phase 3 trial of the immunogenicity and safety of coadministration of a live-attenuated tetravalent dengue vaccine (TAK-003) and an inactivated hepatitis a (HAV) virus vaccine in a dengue non-endemic country.

BACKGROUND: Vaccination against hepatitis A virus (HAV) is largely recommended for travelers worldwide. Concurrent dengue and HAV vaccination may be desired in parallel for travelers to countries where both diseases are endemic. This randomized, observer-blind, phase 3 trial evaluated coadministration of HAV vaccine with tetravalent dengue vaccine (TAK-003) in healthy adults aged 18-60 years living in the UK. METHODS: Participants were randomized (1:1:1) to receive HAV vaccine and placebo on Day 1, and placebo on Day 90 (Group 1), TAK-003 and placebo on Day 1, and TAK-003 on Day 90 (Group 2), or TAK-003 and HAV vaccine on Day 1, and TAK-003 on Day 90 (Group 3). The primary objective was non-inferiority of HAV seroprotection rate (anti-HAV ≥ 12.5 mIU/mL) in Group 3 versus Group 1, one month post-first vaccination (Day 30) in HAV-naïve and dengue-naïve participants. Sensitivity analyses were performed on combinations of baseline HAV and dengue serostatus. Secondary objectives included dengue seropositivity one month post-second vaccination (Day 120), HAV geometric mean concentrations (GMCs), and safety. RESULTS: 900 participants were randomized. On Day 30, HAV seroprotection rates were non-inferior following coadministration of HAV and TAK-003 (Group 3: 98.7 %) to HAV administration alone (Group 1: 97.1 %; difference: -1.68, 95 % CI: -8.91 to 4.28). Sensitivity analyses including participants who were neither HAV-naïve nor DENV-naïve at baseline supported this finding. Anti-HAV GMCs on Day 30 were 82.1 (95 % CI: 62.9-107.1) mIU/mL in Group 1 and 93.0 (76.1-113.6) mIU/mL in Group 3. By Day 120, 90.9-96.8 % of TAK-003 recipients were seropositive (neutralizing antibody titer > 10) to all four dengue serotypes. Coadministration of HAV vaccine and TAK-003 was well tolerated, with no important safety risks identified. CONCLUSION: Immune responses following coadministration of HAV vaccine and TAK-003 were non-inferior to administration of HAV vaccine alone. The results support the coadministration of HAV vaccine and TAK-003 with no adverse impact on immunogenicity, safety, and reactogenicity of either vaccine. CLINICALTRIALS: gov registration: NCT03525119.

Cardiac function is not associated with glucose control in older women.

The present study evaluated the effect of age on glucose tolerance and cardiac function and assessed the relationship between metabolic control and cardiac function and performance. Thirty-four healthy women aged 40 to 81 years were divided into two age groups: younger (≤50 years of age, N = 19) and older (≥60 years of age, N = 15). Participants performed an oral glucose tolerance test and a graded cardiopulmonary exercise test with non-invasive haemodynamic measurements. Compared to younger, older women demonstrated significantly higher 2-hour glucose (4.67 ±â€¯1.01 vs 6.08 ±â€¯1.54 mmol/l, P < 0.01), but lower peak exercise O2 consumption (1.96 ±â€¯0.44 vs 1.38 ±â€¯0.26 l/min, P < 0.01) and cardiac power output (4.06 ±â€¯0.76 vs 3.35 ±â€¯0.73 W, P = 0.01). When data from all study participants were combined, there was a significant negative relationship between 2-hour glucose and peak cardiac power (r = -0.39, P = 0.02), and peak O2 consumption (r = -0.40, P = 0.02). The strength of these relationships was affected by age, with moderate negative relationship identified between 2-hour glucose and peak cardiac power output in younger compared to older participants (r = -0.38, P = 0.11 vs. r = -0.09, P = 0.75). Metabolic control and cardiac function decline with age. The lack of relationship between glucose control and cardiac power may suggest that metabolic control does not influence cardiac function and performance in older women.

Water workout application effects on the body composition and motor abilities of 13-year-old female adolescents / Efectos de la aplicación de entrenamiento acuático sobre la composición corporal y las habilidades motoras de adolescentes mujeres de 13 años de edad

The aim of this research was to determine the water workout application effects on anthropometric characteristics, body composition and motor abilities of 13-year-old female adolescents. The research was conducted on the sample of 154 female adolescents from south-eastern Serbia, divided into experimental group (n= 82) and control group (n= 72). In the area of anthropometry, the following components were measured: body height, body mass, body mass index (BMI) and five skinfolds. In the area of body composition, the percentage of body fat and total muscle mass was measured. According to the Eurofit Manual, the standard tests recommended for testing school children were conducted, measuring the following variables in the motor area: plate tapping, sit-andreach, standing broad jump, sit-ups in 30 seconds, bent-arm hang test, agility run 10 x 5 m, and 20 m shuttle-run. The three-times-a-week water training programme lasting for eight weeks was the experimental factor. ANOVA results indicate the statistically significant differences between the experimental and control groups in body mass, BMI, skin biceps brachi, skin suprailiaca, skin medicalf, skin triceps brachi and body composition variables (p<0.01). There were statistically significant differences between the experimental and control groups (p< 0.01) in variables pertaining to the plate tapping, standing broad jump, sit-ups in 30 seconds, 20 m shuttle-run, and sitand- reach and agility run 10 x 5 m (p< 0.05). Based on the obtained results, we can conclude that the water training programme affected the reduction of body composition, improvement of cardiorespiratory endurance, muscular force, muscular endurance and mobility in 13-year-old female adolescents. The given water training programme would be the means for obesity prevention in adolescents, which can be useful for the improvement of youth health and quality of life.

El objetivo de esta investigación fue determinar los efectos de la aplicación de entrenamiento acuático en las características antropométricas, la composición corporal y las habilidades motoras de mujeres de 13 años. La investigación se realizó en una muestra de 154 mujeres adolescentes del sudeste de Serbia, divididas en dos grupos, experimental (n = 82) y control (n = 72). En el área de la antropometría, se midieron los siguientes componentes: Altura corporal, masa corporal, índice de masa corporal (IMC) y cinco pliegues cutáneos. En el área de composición corporal, se midió el porcentaje de grasa corporal y la masa muscular total. Según el Manual de Eurofit, se llevaron a cabo las pruebas estándar recomendadas para evaluar a escolares, midiendo las siguientes variables en el área motora: golpear las placas, sentado y alcance, salto de pie, sentadillas en 30 segundos, prueba de colgar el brazo doblado, agilidad de 10 x 5 m, y 20 m de carrera de lanzadera. El programa experimental de entrenamiento en agua tres veces por semana durante ocho semanas fue el factor experimental. Los resultados de ANOVA indican las diferencias estadísticamente significativas entre los grupos experimental y de control en masa corporal, IMC, pliegue braquio cutáneo, piel suprailiaca, tríceps y variables de composición corporal (p<0,01). Hubo diferencias estadísticamente significativas entre los grupos experimental y control (p<0,01) en las variables relacionadas con el golpe de placas, el salto de pie, las sentadillas en 30 segundos, la carrera de lanzadera de 20 m y la carrera de sentarse y alcanzar, y agilidad 10 x 5 m (p<0,05). En base a los resultados obtenidos, podemos concluir que el programa de entrenamiento acuático provocó una reducción de la composición corporal, el mejoramiento de la resistencia cardiorrespiratoria, la fuerza muscular, la resistencia muscular y la movilidad en mujeres de 13 años. El programa de entrenamiento realizado en agua, sería el medio para la prevención de la obesidad en adolescentes, que puede ser útil para mejorar la salud y la calidad de vida de los jóvenes.

Relation between body composition and motor abilities of children up to 7 years of age / Relación entre composición corporal y habilidades motoras en niños de hasta 7 años de edad

In a sample of 125 respondents, 62 boys and 63 girls, who attended the first grade of primary schools in Subotica with average age of 7.39 decimal years, a measurement of basic anthropometric characteristics was performed, general motor skills were determined based on seven motor tests, and body composition was determined using the In Body 230 device. Regression analysis showed that the predictor system of variables for assessing body composition (amount of body fat, the total amount of water and the total amount of muscles) was statistically significantly associated with the criterion defined as general motor factor and with it describes 39% of common variability in boys (R=0.63; p<0.05) and 34% in girls (R=0.58; p<0.05). Standardized regression coefficient indicated that both for boys and girls aged 7.39 decimal years, statistically, the total amount of body fat, body weight, negatively affect general motor skills and for the girls, statistically, body height has a positive effect.

Se realizó la medición de las características antropométricas básicas y habilidades motoras generales en una muestra de 62 niños y 63 niñas, con una edad promedio de 7,39 años, de primer año de escuelas primarias en Subotica. Las características se determinaron en base de siete pruebas motoras, además de la composición corporal que se determinó utilizando el dispositivo In Body 230. El análisis de regresión mostró que el sistema predictor de las variables para evaluar composición corporal (cantidad de grasa corporal, cantidad total de agua y cantidad total de músculos) se asoció con el criterio definido como factor motor en general de manera estadísticamente significativa, y con ella se describió un 39% de variabilidad común en los niños (R=0,63, p<0,05) y en el 34% de las niñas (R=0,58, p<0,05). El coeficiente de regresión estandarizado indicó que tanto para niños y niñas de 7,39 años, la cantidad total de grasa y peso corporal afectan negativamente las habilidades motrices generales y para las niñas, la altura del cuerpo tiene un efecto estadísticamente positivo.

CD4 T cell responses in latent and chronic viral infections.

The spectrum of tasks which is fulfilled by CD4 T cells in the setting of viral infections is large, ranging from support of CD8 T cells and humoral immunity to exertion of direct antiviral effector functions. While our knowledge about the differentiation pathways, plasticity, and memory of CD4 T cell responses upon acute infections or immunizations has significantly increased during the past years, much less is still known about CD4 T cell differentiation and their beneficial or pathological functions during persistent viral infections. In this review we summarize current knowledge about the differentiation, direct or indirect antiviral effector functions, and the regulation of virus-specific CD4 T cells in the setting of persistent latent or active chronic viral infections with a particular emphasis on herpes virus infections for the former and chronic lymphocytic choriomeningitis virus infection for the latter.

IL-10 suppression of NK/DC crosstalk leads to poor priming of MCMV-specific CD4 T cells and prolonged MCMV persistence.

IL-10 is an anti-inflammatory cytokine that regulates the extent of host immunity to infection by exerting suppressive effects on different cell types. Herpes viruses induce IL-10 to modulate the virus-host balance towards their own benefit, resulting in prolonged virus persistence. To define the cellular and molecular players involved in IL-10 modulation of herpes virus-specific immunity, we studied mouse cytomegalovirus (MCMV) infection. Here we demonstrate that IL-10 specifically curtails the MCMV-specific CD4 T cell response by suppressing the bidirectional crosstalk between NK cells and myeloid dendritic cells (DCs). In absence of IL-10, NK cells licensed DCs to effectively prime MCMV-specific CD4 T cells and we defined the pro-inflammatory cytokines IL-12, IFN-γ and TNF-α as well as NK cell activating receptors NKG2D and NCR-1 to regulate this bidirectional NK/DC interplay. Consequently, markedly enhanced priming of MCMV-specific CD4 T cells in Il10(-/-) mice led to faster control of lytic viral replication, but this came at the expense of TNF-α mediated immunopathology. Taken together, our data show that early induction of IL-10 during MCMV infection critically regulates the strength of the innate-adaptive immune cell crosstalk, thereby impacting beneficially on the ensuing virus-host balance for both the virus and the host.

Absence of cross-presenting cells in the salivary gland and viral immune evasion confine cytomegalovirus immune control to effector CD4 T cells.

Horizontal transmission of cytomegaloviruses (CMV) occurs via prolonged excretion from mucosal surfaces. We used murine CMV (MCMV) infection to investigate the mechanisms of immune control in secretory organs. CD4 T cells were crucial to cease MCMV replication in the salivary gland (SG) via direct secretion of IFNγ that initiated antiviral signaling on non-hematopoietic cells. In contrast, CD4 T cell helper functions for CD8 T cells or B cells were dispensable. Despite SG-resident MCMV-specific CD8 T cells being able to produce IFNγ, the absence of MHC class I molecules on infected acinar glandular epithelial cells due to viral immune evasion, and the paucity of cross-presenting antigen presenting cells (APCs) prevented their local activation. Thus, local activation of MCMV-specific T cells is confined to the CD4 subset due to exclusive presentation of MCMV-derived antigens by MHC class II molecules on bystander APCs, resulting in IFNγ secretion interfering with viral replication in cells of non-hematopoietic origin.

T-cell help permits memory CD8(+) T-cell inflation during cytomegalovirus latency.

CD4(+) T cells are implied to sustain CD8(+) T-cell responses during persistent infections. As CD4(+) T cells are often themselves antiviral effectors, they might shape CD8(+) T-cell responses via help or via controlling antigen load. We used persistent murine CMV (MCMV) infection to dissect the impact of CD4(+) T cells on virus-specific CD8(+) T cells, distinguishing between increased viral load in the absence of CD4(+) T cells and CD4(+) T-cell-mediated helper mechanisms. Absence of T-helper cells was associated with sustained lytic MCMV replication and led to a slow and gradual reduction of the size and function of the MCMV-specific CD8(+) T-cell pool. However, when virus replication was controlled in the absence of CD4(+) T cells, CD8(+) T-cell function was comparably impaired, but in addition CD8(+) T-cell inflation, a hallmark of CMV infection, was completely abolished. Thus, CD8(+) T-cell inflation during latent CMV infection is strongly dependent on CD4(+) T-cell helper functions, which can partially be compensated by ongoing lytic viral replication in the absence of CD4(+) T cells.

Altered NK cell development and enhanced NK cell-mediated resistance to mouse cytomegalovirus in NKG2D-deficient mice.

NKG2D is a potent activating receptor on natural killer (NK) cells and acts as a molecular sensor for stressed cells expressing NKG2D ligands such as infected or tumor-transformed cells. Although NKG2D is expressed on NK cell precursors, its role in NK cell development is not known. We have generated NKG2D-deficient mice by targeting the Klrk1 locus. Here we provide evidence for an important regulatory role of NKG2D in the development of NK cells. The absence of NKG2D caused faster division of NK cells, perturbation in size of some NK cell subpopulations, and their augmented sensitivity to apoptosis. As expected, Klrk1(-/-) NK cells are less responsive to tumor targets expressing NKG2D ligands. Klrk1(-/-) mice, however, showed an enhanced NK cell-mediated resistance to mouse cytomegalovirus infection as a consequence of NK cell dysregulation. Altogether, these findings provide evidence for regulatory function of NKG2D in NK cell physiology.