Design and evaluation of meningococcal vaccines through structure-based modification of host and pathogen molecules.

Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against the meningococcus and recruits the host complement regulator, fH. As the high affinity interaction between fHbp and fH could impair immune responses, we sought to identify non-functional fHbps that could act as effective immunogens. This was achieved by alanine substitution of fHbps from all three variant groups (V1, V2 and V3 fHbp) of the protein; while some residues affected fH binding in each variant group, the distribution of key amino underlying the interaction with fH differed between the V1, V2 and V3 proteins. The atomic structure of V3 fHbp in complex with fH and of the C-terminal barrel of V2 fHbp provide explanations to the differences in the precise nature of their interactions with fH, and the instability of the V2 protein. To develop transgenic models to assess the efficacy of non-functional fHbps, we determined the structural basis of the low level of interaction between fHbp and murine fH; in addition to changes in amino acids in the fHbp binding site, murine fH has a distinct conformation compared with the human protein that would sterically inhibit binding to fHbp. Non-functional V1 fHbps were further characterised by binding and structural studies, and shown in non-transgenic and transgenic mice (expressing chimeric fH that binds fHbp and precisely regulates complement system) to retain their immunogenicity. Our findings provide a catalogue of non-functional fHbps from all variant groups that can be included in new generation meningococcal vaccines, and establish proof-in-principle for clinical studies to compare their efficacy with wild-type fHbps.

Safer fluid prescribing at North Bristol Trust: Bringing practice in line with NICE Guidance with a redesign of the fluid prescription chart.

The National Institute of Clinical Excellence (NICE) released new fluid guidelines following data suggesting 20% of patients receiving fluids suffer adversely (2013). This quality improvement group assessed fluid prescribing in a tertiary teaching centre and introduced a new fluid- prescribing chart to align practice with NICE recommendations. Notes and corresponding fluid prescription charts were reviewed for evidence of (1) indication, (2) co-morbidities, and (3) further management as surrogate markers of safe prescribing in accordance with NICE. Overall, the data showed practice fell short and prompted a redesign of the Trust fluid prescription chart. Three different variations of the chart were issued consecutively using a PDSA method (plan, do, study, act) over a 6-month period. They all included indication, co-morbidities and further management plans as constant design features. Suggestions from interested parties were incorporated and an educational programme was implemented to promote awareness. Prior to our intervention, an indication for fluids was documented in 26% of notes, it took an average of 4.6 minutes to find co-morbidities, and further management plans were rarely documented. Following the new prescription chart, an indication was recorded in 72% of cases, co-morbidities noted on 63% of charts with 93.1% accuracy, and further management documented in 100% of cases. The new fluid prescription chart encourages prescribers to incorporate NICE recommendations when prescribing fluids. The new fluid prescription design has since been rolled out Trust wide.

Mechanisms of meningococcal colonisation.

Despite advances against infectious diseases over the past century, Neisseria meningitidis remains a major causative agent of meningitis and septicaemia worldwide. Its adaptation for survival in the human nasopharynx makes the meningococcus a highly successful commensal bacterium. Recent progress has been made in understanding the mechanisms that enable neisserial colonisation, in terms of the role of type IV pili, the impact of other adhesins, biofilm formation, nutrient acquisition and resistance to host immune defences. Refinements in cell-based and in vivo models will lead to improved understanding of the colonisation process, and hopefully to more effective vaccines and therapeutic strategies.