Whole-cell vaccine candidates induce a protective response against virulent Acinetobacter baumannii.

Acinetobacter baumannii causes multi-system diseases in both nosocomial settings and a pre-disposed general population. The bacterium is not only desiccation-resistant but also notoriously resistant to multiple antibiotics and drugs of last resort including carbapenem, colistin, and sulbactam. The World Health Organization has categorized carbapenem-resistant A. baumannii at the top of its critical pathogen list in a bid to direct urgent countermeasure development. Several early-stage vaccines have shown a range of efficacies in healthy mice, but no vaccine candidates have advanced into clinical trials. Herein, we report our findings that both an ionizing γ-radiation-inactivated and a non-ionizing ultraviolet C-inactivated whole-cell vaccine candidate protects neutropenic mice from pulmonary challenge with virulent AB5075, a particularly pathogenic isolate. In addition, we demonstrate that a humoral response is sufficient for this protection via the passive immunization of neutropenic mice.

Select Whole-Cell Biofilm-Based Immunogens Protect against a Virulent Staphylococcus Isolate in a Stringent Implant Model of Infection.

Many microbes of concern to human health remain without vaccines. We have developed a whole-microbe inactivation technology that enables us to rapidly inactivate large quantities of a pathogen while retaining epitopes that were destroyed by previous inactivation methods. The method that we call UVC-MDP inactivation can be used to make whole-cell vaccines with increased potency. We and others are exploring the possibility of using improved irradiation-inactivation technologies to develop whole-cell vaccines for numerous antibiotic-resistant microbes. Here, we apply UVC-MDP to produce candidate MRSA vaccines which we test in a stringent tibia implant model of infection challenged with a virulent MSRA strain. We report high levels of clearance in the model and observe a pattern of protection that correlates with the immunogen protein profile used for vaccination.

Radiation-Inactivated Acinetobacter baumannii Vaccine Candidates.

Acinetobacter baumannii is a bacterial pathogen that is often multidrug-resistant (MDR) and causes a range of life-threatening illnesses, including pneumonia, septicemia, and wound infections. Some antibiotic treatments can reduce mortality if dosed early enough before an infection progresses, but there are few other treatment options when it comes to MDR-infection. Although several prophylactic strategies have been assessed, no vaccine candidates have advanced to clinical trials or have been approved. Herein, we rapidly produced protective whole-cell immunogens from planktonic and biofilm-like cultures of A. baumannii, strain AB5075 grown using a variety of methods. After selecting a panel of five cultures based on distinct protein profiles, replicative activity was extinguished by exposure to 10 kGy gamma radiation in the presence of a Deinococcus antioxidant complex composed of manganous (Mn2+) ions, a decapeptide, and orthophosphate. Mn2+ antioxidants prevent hydroxylation and carbonylation of irradiated proteins, but do not protect nucleic acids, yielding replication-deficient immunogenic A. baumannii vaccine candidates. Mice were immunized and boosted twice with 1.0 × 107 irradiated bacterial cells and then challenged intranasally with AB5075 using two mouse models. Planktonic cultures grown for 16 h in rich media and biofilm cultures grown in static cultures underneath minimal (M9) media stimulated immunity that led to 80-100% protection.

Atmospheric seasonal forecasts of the twentieth century: multi-decadal variability in predictive skill of the winter North Atlantic Oscillation (NAO) and their potential value for extreme event attribution.

Based on skill estimates from hindcasts made over the last couple of decades, recent studies have suggested that considerable success has been achieved in forecasting winter climate anomalies over the Euro-Atlantic area using current-generation dynamical forecast models. However, previous-generation models had shown that forecasts of winter climate anomalies in the 1960s and 1970s were less successful than forecasts of the 1980s and 1990s. Given that the more recent decades have been dominated by the North Atlantic Oscillation (NAO) in its positive phase, it is important to know whether the performance of current models would be similarly skilful when tested over periods of a predominantly negative NAO. To this end, a new ensemble of atmospheric seasonal hindcasts covering the period 1900-2009 has been created, providing a unique tool to explore many aspects of atmospheric seasonal climate prediction. In this study we focus on two of these: multi-decadal variability in predicting the winter NAO, and the potential value of the long seasonal hindcast datasets for the emerging science of probabilistic event attribution. The existence of relatively low skill levels during the period 1950s-1970s has been confirmed in the new dataset. The skill of the NAO forecasts is larger, however, in earlier and later periods. Whilst these inter-decadal differences in skill are, by themselves, only marginally statistically significant, the variations in skill strongly co-vary with statistics of the general circulation itself suggesting that such differences are indeed physically based. The mid-century period of low forecast skill coincides with a negative NAO phase but the relationship between the NAO phase/amplitude and forecast skill is more complex than linear. Finally, we show how seasonal forecast reliability can be of importance for increasing confidence in statements of causes of extreme weather and climate events, including effects of anthropogenic climate change.

Towards seasonal forecasting of malaria in India.

BACKGROUND: Malaria presents public health challenge despite extensive intervention campaigns. A 30-year hindcast of the climatic suitability for malaria transmission in India is presented, using meteorological variables from a state of the art seasonal forecast model to drive a process-based, dynamic disease model. METHODS: The spatial distribution and seasonal cycles of temperature and precipitation from the forecast model are compared to three observationally-based meteorological datasets. These time series are then used to drive the disease model, producing a simulated forecast of malaria and three synthetic malaria time series that are qualitatively compared to contemporary and pre-intervention malaria estimates. The area under the Relative Operator Characteristic (ROC) curve is calculated as a quantitative metric of forecast skill, comparing the forecast to the meteorologically-driven synthetic malaria time series. RESULTS AND DISCUSSION: The forecast shows probabilistic skill in predicting the spatial distribution of Plasmodium falciparum incidence when compared to the simulated meteorologically-driven malaria time series, particularly where modelled incidence shows high seasonal and interannual variability such as in Orissa, West Bengal, and Jharkhand (North-east India), and Gujarat, Rajastan, Madhya Pradesh and Maharashtra (North-west India). Focusing on these two regions, the malaria forecast is able to distinguish between years of "high", "above average" and "low" malaria incidence in the peak malaria transmission seasons, with more than 70% sensitivity and a statistically significant area under the ROC curve. These results are encouraging given that the three month forecast lead time used is well in excess of the target for early warning systems adopted by the World Health Organization. This approach could form the basis of an operational system to identify the probability of regional malaria epidemics, allowing advanced and targeted allocation of resources for combatting malaria in India.

RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.

Recent genome-wide association studies have linked common variants in the human genome to Parkinson's disease (PD) risk. Here we show that the consequences of variants at 2 such loci, PARK16 and LRRK2, are highly interrelated, both in terms of their broad impacts on human brain transcriptomes of unaffected carriers, and in terms of their associations with PD risk. Deficiency of the PARK16 locus gene RAB7L1 in primary rodent neurons, or of a RAB7L1 ortholog in Drosophila dopamine neurons, recapitulated degeneration observed with expression of a familial PD mutant form of LRRK2, whereas RAB7L1 overexpression rescued the LRRK2 mutant phenotypes. PD-associated defects in RAB7L1 or LRRK2 led to endolysosomal and Golgi apparatus sorting defects and deficiency of the VPS35 component of the retromer complex. Expression of wild-type VPS35, but not a familial PD-associated mutant form, rescued these defects. Taken together, these studies implicate retromer and lysosomal pathway alterations in PD risk.