Update on CVD 103-HgR single-dose, live oral cholera vaccine.

Cholera remains endemic in >50 countries, putting millions at risk, especially young children for whom killed vaccines offer limited protection. An oral, live attenuated vaccine - CVD 103-HgR (Vaxchora vaccine) - was licensed by the US FDA in 2016 for adults aged 18-64 years traveling to endemic regions, based on clinical trials in human volunteers showing the vaccine was well tolerated and conferred 90% efficacy within 10 days. The evidence base for Vaxchora vaccine has expanded with additional clinical trial data, in older adults (aged 46-64 years) and children (aged 2-17 years), demonstrating that the vaccine produces a strong vibriocidal antibody response.

Anti-O-specific polysaccharide (OSP) immune responses following vaccination with oral cholera vaccine CVD 103-HgR correlate with protection against cholera after infection with wild-type Vibrio cholerae O1 El Tor Inaba in North American volunteers.

Background: Cholera is an acute voluminous dehydrating diarrheal disease caused by toxigenic strains of Vibrio cholerae O1 and occasionally O139. A growing body of evidence indicates that immune responses targeting the O-specific polysaccharide (OSP) of V. cholerae are involved in mediating protection against cholera.

Antibody-Based Correlates of Protection Against Cholera Analysis of a Challenge Study in a Cholera-Naïve Population.

Immunologic correlates of protection can be used to infer vaccine efficacy for populations in which challenge trials or field studies are infeasible. In a recent cholera challenge trial (WH Cohen et al, Clinical Infectious Disease 62: 1329-1335, 2016), 134 North American cholera-naïve volunteers were randomized to receive either the live, attenuated single-dose cholera vaccine CVD 103-HgR or placebo, and titers of vibriocidal antibodies against classical Inaba were assessed 10 days after treatment. Subsequent to the immunologic evaluation, each subject ingested a fixed quantity of virulent O1 El Tor Inaba.

The Live Attenuated Cholera Vaccine CVD 103-HgR Primes Responses to the Toxin-Coregulated Pilus Antigen TcpA in Subjects Challenged with Wild-Type Vibrio cholerae.

One potential advantage of live attenuated bacterial vaccines is the ability to stimulate responses to antigens which are only expressed during the course of infection. To determine whether the live attenuated cholera vaccine CVD 103-HgR (Vaxchora) results in antibody responses to the in vivo-induced toxin-coregulated pilus antigen TcpA, we measured IgA and IgG responses to Vibrio cholerae O1 El Tor TcpA in a subset of participants in a recently reported experimental challenge study. Participants were challenged with V.

Single-dose Live Oral Cholera Vaccine CVD 103-HgR Protects Against Human Experimental Infection With Vibrio cholerae O1 El Tor.

Background: No licensed cholera vaccine is presently available in the United States. Cholera vaccines available in other countries require 2 spaced doses. A single-dose cholera vaccine that can rapidly protect short-notice travelers to high-risk areas and help control explosive outbreaks where logistics render 2-dose immunization regimens impractical would be a major advance.

Development of a multi-biomarker disease activity test for rheumatoid arthritis.

Background: Disease activity measurement is a key component of rheumatoid arthritis (RA) management. Biomarkers that capture the complex and heterogeneous biology of RA have the potential to complement clinical disease activity assessment.

Objectives: To develop a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis.

An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression.

Objectives: To determine whether molecular remission defined by a multi-biomarker disease activity (MBDA) score predicts a reduced risk of joint damage progression, and whether the MBDA score can augment existing classifications of remission.

Methods: The study examined 271 visits for 163 RA patients in the Leiden Early Arthritis Cohort. The MBDA score and other variables from each visit were evaluated for prediction of progression [change in Sharp-van der Heijde Score (ΔSHS) >3] over the ensuing 12 months.

Characterization of a multiplex, 12-biomarker test for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that primarily involves the joints. Accurate and frequent assessment of RA disease activity is critical to optimal treatment planning. A novel algorithm has been developed to determine a multi-biomarker disease activity (MBDA) score based upon measurement of the concentrations of 12 serum biomarkers in multiplex format.

Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity.

Objective: Quantitative assessment of disease activity in rheumatoid arthritis (RA) is important for patient management, and additional objective information may aid rheumatologists in clinical decision making. We validated a recently developed multibiomarker disease activity (MBDA) test relative to clinical disease activity in diverse RA cohorts.

Methods: Serum samples were obtained from the Index for Rheumatoid Arthritis Measurement, Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study, and Leiden Early Arthritis Clinic cohorts.

Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study.

Objectives: To evaluate the performance of individual biomarkers and a multi-biomarker disease activity (MBDA) score in the early rheumatoid arthritis (RA) patient population from the computer assisted management in early rheumatoid arthritis (CAMERA) study.

Methods: Twenty biomarkers were measured in the CAMERA cohort, in which patients were treated with either intensive or conventional methotrexate-based treatment strategies. The MBDA score was calculated using the concentrations of 12 biomarkers (SAA, IL-6, TNF-RI, VEGF-A, MMP-1, YKL-40, MMP-3, EGF, VCAM-1, leptin, resistin and CRP) according to a previously trained algorithm.

Severe protein C deficiency is associated with organ dysfunction in patients with severe sepsis.

Purpose: The aim of this study was to assess the relationship between protein C levels and temporal changes in organ dysfunction.

Materials And Methods: Using data from the placebo arm of Recombinant Human Activated PROtein C Worldwide Evaluation in Severe Sepsis trial (N = 775), we compared the development of organ dysfunction over time, in adult severe sepsis patients with and without severe protein C deficiency.

Results: At study enrollment (baseline), patients with and without severe protein C deficiency were similar in age and likelihood of comorbidities.

Diabetes does not alter mortality or hemostatic and inflammatory responses in patients with severe sepsis.

Objective: Diabetes patients have an increased risk of sepsis. Several inflammatory and coagulant pathways that are activated during sepsis are also up-regulated in diabetes patients. We tested our a priori hypothesis that the presence of diabetes adversely affects the outcome of sepsis.

Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease.

Background: A pilot study showed that ruboxistaurin (RBX), a protein kinase C beta inhibitor, significantly decreased albuminuria and stabilized kidney function over 1 yr in patients who had diabetic nephropathy and persistent macroalbuminuria despite receiving the current standard of care, including renin-angiotensin system inhibition. In contrast, in a trial of patients with diabetic retinopathy, investigators reported the adverse event "diabetic nephropathy" more frequently in patients who received RBX.

Design, Setting, Participants, And Measurements: The purpose of this study was to evaluate long-term effects of RBX on kidney outcomes among patients with diabetic eye disease in three diabetic retinopathy trials (n = 1157).

ENHANCE: results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis.

Objective: To gather additional 28-day all-cause mortality data and safety information for pediatric patients with severe sepsis who received drotrecogin alfa (activated) (DrotAA).

Design And Setting: Single-arm, open-label, multicentered study conducted in 59 study sites in 15 countries.

Patients: One-hundred eighty-eight children (term newborn to <18 yrs old) with severe sepsis were consecutively enrolled in the study.

Dynamics of CD4 and CD8 T cell responses to cytomegalovirus in healthy human donors.

To study the dynamics of cytomegalovirus (CMV) immunity in healthy immunocompetent hosts, interferon-gamma-producing CD4 and CD8 T cell responses in the presence or absence of CMV antigens were measured from 15 CMV-seropositive donors and 13 CMV-seronegative donors. Cytokine responses in the absence of antigen were significantly higher in CMV-seropositive donors. Also, a disproportionate number of CD69(+) cells isolated ex vivo from CMV-seropositive donors were specific for CMV, suggesting recent reactivation in vivo.