A combined approach to assess the potential coverage of a multicomponent protein-based vaccine

Meningococcal disease caused by Neisseria meningitidis sero- group B is a public health concern even in developed countries. Despite glycoconjugate vaccines against the other invasive sero- groups (A, C, W135, Y) are already available and successfully introduced in many countries, no vaccine is currently in use for prevention of serogroup B meningitis. A protein based, multicomponent vaccine (4CMenB) has been developed and proposed for prevention of invasive serogroup B meningococcal disease (MenB). This novel vaccine has been tested in clinical trials and shown to be well tolerated and immunogenic, inducing bactericidal antibodies in infants, adolescents and adults. The high level of genetic and antigenic variability observed in MenB clinical isolates, requires a suitable method to assess the ability of the 4CMenB vaccine to cover genetically diverse menig- ococcal strains and to estimate the potential public health impact. To this purpose the Meningococcal Antigen Typing System (MATS) has been developed and recently described. This method provides a quick and reproducible tool to estimate the level of expression and immunoreactivity of each of the vaccine antigens, in any meningococcal isolate, and it is related to the likelihood that the isolate will be killed by sera from immunized subjects. A multi-laboratory study involving several European countries, demonstrates that the 4CMenB has the potential to protect against a significant proportion of menB strains circulating in Europe. The full article is free available on www.jpmh.or

Uncertainty quantification applied to hemodynamic simulations of thoracic aorta aneurysms: Sensitivity to inlet conditions

In this work, the numerical simulation of the blood flow inside a patient specific aorta in presence of an aneurysm is considered. A systematic sensitivity analysis of numerical predictions to the shape of the inlet flow rate waveform is carried out. In particular, two parameters are selected to describe the inlet waveform: the stroke volume and the period of the cardiac cycle. In order to limit the number of hemodynamic simulations required, we used a stochastic method based on the generalized polynomial chaos (gPC) approach, in which the selected parameters are considered as random variables with a given probability distribution. The uncertainty is propagated through the numerical model and a continuous response surface of the output quantities of interest in the parameter space can be recovered through a “surrogate” model. For both selected uncertain parameters, we first assumed uniform Probability Density Functions (PDFs) on a given variation range, and then we used clinical data to construct more accurate beta PDFs. In all cases, the two input parameters appeared to have a significant influence on wall shear stresses, confirming the need of using patient-specific inlet conditions

MOLECULAR AND SEROLOGICAL DIVERSITY OF NEISSERIA MENINGITIDIS CARRIER STRAINS ISOLATED FROM ITALIAN STUDENTS AGED 14-22 YEARS.

Neisseria meningitidis is an obligate human commensal that commonly colonizes the oropharyngeal mucosa. Carriage is age dependent and very common in young adults. The relationships between carriage and invasive disease are not completely understood. In this work, we performed a longitudinal carrier study in adolescents and young adults (173 subjects). Overall, 32 subjects (18.5%) had results that were positive for meningococcal carriage in at least one visit (average monthly carriage rate, 12.1%). Only five subjects tested positive at all four visits. All meningococcal isolates were characterized by molecular and serological techniques. Multilocus sequence typing, PorA typing, and sequencing of the 4CMenB vaccine antigens were used to assess strain diversity. The majority of positive subjects were colonized by capsule null (34.4%) and capsular group B strains (28.1%), accounting for 23.5% and 29.4% of the total number of isolates, respectively. The fHbp and nhba genes were present in all isolates, while the nadA gene was present in 5% of the isolates. The genetic variability of the 4CMenB vaccine antigens in this collection was relatively high compared with that of other disease-causing strain panels. Indications about the persistence of the carriage state were limited to the time span of the study. All strains isolated from the same subject were identical or cumulated minor changes over time. The expression levels and antigenicities of the 4CMenB vaccine antigens in each strain were analyzed by the meningococcal antigen typing system (MATS), which revealed that expression can change over time in the same individual. Future analysis of antigen variability and expression in carrier strains after the introduction of the MenB vaccine will allow for a definition of its impact on nasopharyngeal/oropharyngeal carriage

Predicted Strain Coverage of a New Meningococcal Multicomponent Vaccine (4CMenB) in Spain: Analysis of the Differences with Other European Countries

BACKGROUND: A novel meningococcal multicomponent vaccine, 4CMenB (Bexsero®), has been approved in Europe, Canada, Australia and US. The potential impact of 4CMenB on strain coverage is being estimated by using Meningococcal Antigen Typing System (MATS), an ELISA assay which measures vaccine antigen expression and diversity in each strain. Here we show the genetic characterization and the 4CMenB potential coverage of Spanish invasive strains (collected during one epidemiological year) compared to other European countries and discuss the potential reasons for the lower estimate of coverage in Spain. MATERIAL AND METHODS: A panel of 300 strains, a representative sample of all serogroup B Neisseria meningitidis notified cases in Spain from 2009 to 2010, was characterized by multilocus sequence typing (MLST) and FetA variable region determination. 4CMenB vaccine antigens, PorA, factor H binding protein (fHbp), Neisseria Heparin Binding Antigen (NHBA) and Neisserial adhesin A (NadA) were molecularly typed by sequencing. PorA coverage was assigned to strain with VR2 = 4. The levels of expression and cross-reactivity of fHbp, NHBA and NadA were analyzed using MATS ELISA. FINDINGS: Global estimated strain coverage by MATS was 68.67% (95% CI: 47.77-84.59%), with 51.33%, 15.33% and 2% of strains covered by one, two and three vaccine antigens, respectively. The predicted strain coverage by individual antigens was: 42% NHBA, 36.33% fHbp, 8.33% PorA and 1.33% NadA. Coverage within the most prevalent clonal complexes (cc) was 70.37% for cc 269, 30.19% for cc 213 and 95.83% for cc 32. CONCLUSIONS: Clonal complexes (cc) distribution accounts for variations in strain coverage, so that country-by-country investigations of strain coverage and cc prevalence are important. Because the cc distribution could also vary over time, which in turn could lead to changes in strain coverage, continuous detailed surveillance and monitoring of vaccine antigens expression is needed in those countries where the multicomponent vaccine is introduced. This is really important in countries like Spain where most of the strains are predicted to be covered by only one vaccine antigen and the chance for escape mutants to emerge with vaccine use is higher. Based on the observed data, cc213 should receive special attention as it is associated with low predicted strain coverage, and has recently emerged in Spain.This work was partially supported by Novartis Vaccines & Diagnostics.S

Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study.

This multicenter, open-label phase 2 trial determined the safety and efficacy of carfilzomib, a novel and irreversible proteasome inhibitor, in combination with cyclophosphamide and dexamethasone (CCyd) in patients with newly diagnosed multiple myeloma (NDMM) aged 6565 years or who were ineligible for autologous stem cell transplantation. Patients (N=58) received CCyd for up to nine 28-day cycles, followed by maintenance with carfilzomib until progression or intolerance. After a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response. After a median follow-up of 18 months, the 2-year PFS and OS rates were 76% and 87%, respectively. The most frequent grade 3-5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grade 1-2 (9%). Fourteen percent of patients discontinued treatment owing to adverse events, and 21% of patients required carfilzomib dose reductions. This is the first study of carfilzomib in combination with an alkylating agent in elderly patients with NDMM; results showed high complete response rates and a good safety profile. This study was registered at clinicaltrials.gov, identifier: NCT01346787

Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study.

This multicenter, open-label phase 2 trial determined the safety and efficacy of carfilzomib, a novel and irreversible proteasome inhibitor, in combination with cyclophosphamide and dexamethasone (CCyd) in patients with newly diagnosed multiple myeloma (NDMM) 6565 years of age or who were ineligible for autologous stem cell transplantation. Patients (N 5 58) received CCyd for up to 9 28-day cycles, followed by maintenance with carfilzomib until progression or intolerance. After a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 76% and 87%, respectively. The most frequent grade 3 to 5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grades 1 and 2 (9%). Fourteen percent of patients discontinued treatment because of adverse events, and 21% of patients required carfilzomib dose reductions. In summary, results showed high complete response rates and a good safety profile. This trial was registered at clinicaltrials.gov as #NCT01346787. \ua9 2014 by The American Society of Hematology

Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma

Purpose: Continuous therapy (CT) prolongs progression-free survival 1 (PFS1; time from random assignment until the first progression or death), but chemotherapy-resistant relapse may negatively impact overall survival (OS). Progression-free survival 2 (PFS2; time from random assignment until the second progression or death) may represent an additional tool to estimate outcome. This study evaluates the benefit of novel agent-based CT versus fixed duration of therapy (FDT) in patients with newly diagnosed myeloma. Methods: We included patients enrolled onto three phase III trials that randomly assigned patients to novel agent-based CT versus FDT. Primary analyses were restricted to the intent-to-treat population eligible for CT (patients progression free and alive at 1 year after random assignment). Primary end points were PFS1, PFS2, and OS. All hazard ratios (HRs) and 95% CIs were adjusted for several potential confounders using Cox models. Results: In the pooled analysis of the three trials, 604 patients were randomly assigned to CT and 614 were assigned to FDT. Median follow-up was 52 months. In the intent-to-treat CT population, CT (n = 417), compared with FDT (n = 410), significantly improved PFS1 (median, 32 v 16 months, respectively; HR, 0.47; 95% CI, 0.40 to 0.56; P < .001), PFS2 (median, 55 v 40 months, respectively; HR, 0.61; 95% CI, 0.50 to 0.75; P < .001), and OS (4-year OS, 69% v 60%, respectively; HR, 0.69; 95% CI, 0.54 to 0.88; P = .003). Conclusion: In this pooled analysis, CT significantly improved PFS1, PFS2, and OS. The improvement in PFS2 suggests that the benefit reported during first remission is not cancelled by a shorter second remission. PFS2 is a valuable end point to estimate long-term clinical benefit and should be included in future trials. Copyright © 2015 American Society of Clinical Oncology. All rights reserved