Structural basis for cooperativity of human monoclonal antibodies to meningococcal factor H-binding protein

Monoclonal antibody (mAb) cooperativity is a phenomenon triggered when mAbs couples promote increased bactericidal killing compared to individual partners. Cooperativity has been deeply investigated among mAbs elicited by factor H-binding protein (fHbp), a Neisseria meningitidis surface-exposed lipoprotein and one of the key antigens included in both serogroup B meningococcus vaccine Bexsero and Trumenba. Here we report the structural and functional characterization of two cooperative mAbs pairs isolated from Bexsero vaccines. The 3D electron microscopy structures of the human mAb-fHbp-mAb cooperative complexes indicate that the angle formed between the antigen binding fragments (fAbs) assume regular angle and that fHbp is able to bind simultaneously and stably the cooperative mAbs pairs and human factor H (fH) in vitro. These findings shed light on molecular basis of the antibody-based mechanism of protection driven by simultaneous recognition of the different epitopes of the fHbp and underline that cooperativity is crucial in vaccine efficacy

Human protective response induced by meningococcus B vaccine is mediated by the synergy of multiple bactericidal epitopes

Abstract 4CMenB is the first broad coverage vaccine for the prevention of invasive meningococcal disease caused by serogroup B strains. To gain a comprehensive picture of the antibody response induced upon 4CMenB vaccination and to obtain relevant translational information directly from human studies, we have isolated a panel of human monoclonal antibodies from adult vaccinees. Based on the Ig-gene sequence of the variable region, 37 antigen-specific monoclonal antibodies were identified and produced as recombinant Fab fragments, and a subset also produced as full length recombinant IgG1 and functionally characterized. We found that the monoclonal antibodies were cross-reactive against different antigen variants and recognized multiple epitopes on each of the antigens. Interestingly, synergy between antibodies targeting different epitopes enhanced the potency of the bactericidal response. This work represents the first extensive characterization of monoclonal antibodies generated in humans upon 4CMenB immunization and contributes to further unraveling the immunological and functional properties of the vaccine antigens. Moreover, understanding the mechanistic nature of protection induced by vaccination paves the way to more rational vaccine design and implementation

The influence of design and everyday practices on individual heating and cooling behaviour in residential homes

Emerging results from practice-based research demonstrate that energy efficient houses often do not meet theoretical energy use based on the current standards of residential buildings. A factor influencing this inconsistency is related to user behaviour and everyday practices. The objective of this research is to uncover some of the complexities associated with the practices of heating and cooling in the home, which are influenced by motivations, knowledge and technologies, including the use of photovoltaic panels. For this purpose, ten Australian houses were established as embedded Living Labs and monitored for over a year. The results confirm the variation of energy use in houses; in this case, similar designs vary by up to 33%. The type of heating and cooling systems that houses rely on through the year was found to be a major determinant in energy use. However, energy variation between houses is also linked to intra-home practices and behaviours. This research found that individuals living in the same house may have different motivations and/or heating and cooling practices, affecting the overall energy use. For instance, one individual who is motivated to save on energy bills might turn on appliances during the day to make the most of solar panels or use the heater for brief periods of time, whilst another inhabitant of the same house might turn on the heater for extended periods out of habit or to achieve a hedonic experience. The adoption of an explanatory design mixed-method approach to study everyday practices in the home showed that the routines, household configuration, technology and varied occupant motivations impact on the practice of ambient heating and cooling, impacting its regularity, duration, time of the day and intensity

Promoting energy-saving behaviour : formal social groups as promising middle actors for municipal interventions

Erworben im Rahmen der Schweizer Nationallizenzen (http://www.nationallizenzen.ch)City governments worldwide are trying to motivate their citizens to reduce their energy use – a particular challenge as they try to reach individual households. A promising strategy to engage the public broadly entails collaborating with middle actors to multiply the effects of municipal interventions. Some of these middle actors are formal social groups (e.g. sports clubs and neighbourhood associations). We conducted an online experiment (N = 136) to determine whether such interventions were more effective when they are communicated through formal social groups than when communicated through city governments. Participants received letters containing advice for saving energy in the household. Willingness to participate was higher when the letters came from formal social groups than when they came from a city agency. Furthermore, actual members of formal social groups generally were more willing to participate. Our evidence suggests that formal social groups are promising middle actors for energy conservation campaigns and that city governments should engage more often with these groups to communicate with residents

Impact of mitral regurgitation on the outcome of patients treated with CRT-D: data from the InSync ICD Italian Registry.

Background: We assessed the influence of clinically significant mitral regurgitation (MR) on clinical-echocardiographic response and outcome in heart failure (HF) patients treated with a biventricular defibrillator (cardiac resynchronization therapy defibrillator [CRT-D]). Methods and Results: A total of 659 HF patients underwent successful implantation of CRT-D and were enrolled in a multicenter prospective registry (median follow-up of 15 months). Following baseline echocardiographic evaluation, patients were stratified into two groups according to the severity of MR: 232 patients with more than mild MR (Group MR+: grade 2, 3, and 4 MR) versus 427 patients with mild (grade 1) or no functional MR (Group MR−). On 6- and 12-month echocardiographic evaluation, MR was seen to have improved in the vast majority of MR+ patients, while it remained unchanged in most MR− patients. On 12-month follow-up evaluation, a comparable response to CRT was observed in the two groups, in terms of the extent of left ventricular reverse remodeling and combined clinical and echocardiographic response. During long-term follow-up, event-free survival did not differ between MR+ and MR− patients, even when subpopulations of patients with ischemic heart disease and with dilated cardiomyopathy were analyzed separately. On multivariate analysis, the only independent predictor of death from any cause was the lack of β-blocker use. Conclusions: This observational analysis supports the use of CRT-D in HF patients with clinically significant MR; MR had no major influence on patient outcom