Immune Response Persistence and Safety of a Booster Dose of the Tetravalent Dengue Vaccine in Adolescents and Adults Who Previously Completed the 3-dose Schedule 4-5 Years Earlier in Latin America: A Randomized Placebo-controlled Trial.

BACKGROUND: We previously described an increased immune response 28 days after a booster dose of the live, attenuated, tetravalent dengue vaccine (CYD-TDV) in healthy adolescents and adults in Latin America (CYD64, NCT02623725). This follow-up study evaluated immune response persistence and safety of a CYD-TDV booster dose up to Month (M) 24 post-booster. METHODS: This study included 250 participants who previously received 3 primary doses of CYD-TDV in the CYD13 (NCT00993447) and CYD30 (NCT01187433) studies, and who were randomized 4-5 years later to receive a CYD-TDV booster or placebo (3:1). Dengue neutralizing antibodies against the parental dengue virus strains were assessed using the plaque reduction neutralization test (PRNT50) at M6, M12, and M24 post-booster. Post-booster memory B-cell responses were assessed in a subset of participants using the FluoroSpot assay up to M12 post-booster. RESULTS: In the CYD-TDV group (n = 187), dengue neutralizing antibody geometric mean titers (GMTs) declined from the peak at day 28 through to M24 for all serotypes. GMTs at M24 were similar to those at pre-booster among baseline dengue seropositives. A similar trend was observed for baseline dengue seronegatives, albeit at a lower magnitude. Previous vaccination-induced detectable B-cell memory responses in seropositives and seronegatives that decreased to pre-booster levels at M12 post-booster. The CYD-TDV booster dose was well-tolerated. CONCLUSIONS: In baseline dengue seropositives, following a CYD-TDV booster dose administered 4-5 years after primary immunization, dengue neutralizing antibody GMTs and B-cell memory responses peaked in the short-term before gradually decreasing over time. A CYD-TDV booster dose could improve protection against dengue during outbreak periods.

Dengue Vaccine Booster in Healthy Adolescents and Adults in Latin America: Evaluation 4-5 Years After a Primary 3-Dose Schedule.

BACKGROUND: The tetravalent dengue vaccine (CYD-TDV, Dengvaxia, Sanofi Pasteur) demonstrated efficacy in 2 previous phase III trials conducted in endemic countries. Neutralizing antibodies (NAbs) elicited by 3 doses of this vaccine have been associated with efficacy. Long-term follow-up data has shown that NAb immune responses tend to wane over time, after the third dose. This study compared the immune response elicited by a booster (4th) dose of CYD-TDV with the immune responses from the same participants obtained post-dose 3 of the primary series administered 4-5 years earlier. METHODS: This multicenter, observer-blind, randomized, placebo-controlled, phase II noninferiority trial was conducted in healthy adolescents and adults in dengue endemic countries of Latin America (Colombia, Honduras, Brazil, Mexico and Puerto Rico). All participants had been immunized with 3 doses of CYD-TDV in phase II studies conducted 4-5 years earlier. NAb levels against each dengue virus serotype 28 days postbooster or placebo injection were reported. RESULTS: A total of 187 participants received CYD-TDV and 64 received placebo. Prospectively defined noninferiority criteria for dengue NAbs after the booster dose compared with postdose 3 were met for all 4 serotypes. Prospectively defined superiority criteria were met for 3 of the 4 serotypes. CONCLUSIONS: Antidengue NAb levels can be boosted to levels at least as high as, or higher than those observed after completion of the primary 3-dose series, with an additional dose of CYD-TDV 4-5 years after the standard 3-dose vaccination schedule.

Cytokine gene expression in Walker 256: a comparison of variants A (aggressive) and AR (regressive).

Two variants of this Walker 256 tumor have been previously reported as Walker 256 A and variant AR. The variant A has more aggressive property than variant AR and can induce systemic effects such as anorexia, sodium and water retention, followed by weight loss and death. The mechanisms involved in enhancing tumor regression and progression in this model are still incompletely understood. In the present study, serum and spleen mononuclear cells and tumor cells from animals inoculated with variants A and AR, were isolated to investigate the TGF-beta, IL-12, IFN-gamma and TNF-alpha and relationship with anemia, weight of animals, weight of spleen, volume of tumor and osmotic fragility compared with controls inoculated with Ringer Lactate. Results demonstrate that the group inoculated with variant A, compared to variant AR, shows high levels of TGF-beta gene expression in both tumor tissue and spleen cells, no expression of IFN-gamma and a progressive and higher levels of IL-12 in tumor tissue without inflammatory infiltrate visualized by optical microscopy. These results suggest that the aggressively of variant A is relate to cytokine modulation, facilitating the growth and escape of tumor cells. Furthermore, IL-12 seems to be constitutively expressed in both tumor lineage A and AR.

Severe hypoleptinaemia associated with insulin resistance in patients with common variable immunodeficiency.

OBJECTIVE: Common variable immunodeficiency (CVI) is a primary immunodeficiency syndrome characterized by impaired production of antibodies and recurrent infections. Delay in diagnosis leads to metabolic wastage and low body weight. Leptin, a hormone produced by white adipose tissue, modulates insulin action by signal transduction cross-talk and by direct action on pancreatic beta-cells. We hypothesized that patients with CVI might present a defective regulation of leptin production and insulin resistance. PATIENTS: Thirteen CVI patients (39 +/- 11 years) under gammaglobulin replacement were evaluated in parallel with 13 gender-, age-, body weight- and body mass index (BMI)-matched healthy voluntaries, and with data from two large population series, the Bruneck and the Hoorn Studies. MEASUREMENTS: Serum leptin and insulin levels, homeostasis model assessment - insulin resistance (HOMA-IR), body composition, haematological, biochemical and immunoglobulin measurements were obtained. Data were analysed by a one-way analysis of variance (anova) and by Pearson's rank analysis. The institutional ethics committee approved the study, and informed consent was obtained from patients and controls. RESULTS: No differences were found between CVI and the control group when comparing gender distribution, age, body weight, BMI, waist/hip ratio, relative body fat and fasting glucose levels. Leptin levels were lower (P < 0.05) in CVI patients than in controls and lower than fasting leptin levels detected in a large population study. CVI patients' serum leptin levels did not correlate with BMI (r = 0.074, P = 0.8) and their high HOMA-IR indicated insulin resistance. CONCLUSIONS: CVI patients are relatively hypoleptinaemic and insulin resistant, and their serum leptin levels are not correlated to their BMI.