Immune-Complex Mimics as a Molecular Platform for Adjuvant-Free Vaccine Delivery

Protein-based vaccine development faces the difficult challenge of finding robust yet non-toxic adjuvants suitable for humans. Here, using a molecular engineering approach, we have developed a molecular platform for generating self-adjuvanting immunogens that do not depend on exogenous adjuvants for induction of immune responses. These are based on the concept of Immune Complex Mimics (ICM), structures that are formed between an oligomeric antigen and a monoclonal antibody (mAb) to that antigen. In this way, the roles of antigens and antibodies within the structure of immune complexes are reversed, so that a single monoclonal antibody, rather than polyclonal sera or expensive mAb cocktails can be used. We tested this approach in the context of Mycobacterium tuberculosis (MTB) infection by linking the highly immunogenic and potentially protective Ag85B with the oligomeric Acr (alpha crystallin, HspX) antigen. When combined with an anti-Acr monoclonal antibody, the fusion protein formed ICM which bound to C1q component of the complement system and were readily taken up by antigen-presenting cells in vitro. ICM induced a strong Th1/Th2 mixed type antibody response, which was comparable to cholera toxin adjuvanted antigen, but only moderate levels of T cell proliferation and IFN-γ secretion. Unfortunately, the systemic administration of ICM did not confer statistically significant protection against intranasal MTB challenge, although a small BCG-boosting effect was observed. We conclude that ICM are capable of inducing strong humoral responses to incorporated antigens and may be a suitable vaccination approach for pathogens other than MTB, where antibody-based immunity may play a more protective role

On the flow through Bering Strait: a synthesis of model results and observations

The article of record as published may be found at https://link.springer.com/chapter/10.1007/978-94-017-8863-2_7Bering Strait is the only ocean connection between the Pacific and the Arctic. The flow through this narrow and shallow strait links the Pacific and Arctic oceans and impacts oceanic conditions downstream in the Chukchi Sea and the Western Arctic. We present a model synthesis of exchanges through Bering Strait at monthly to decadal time scales, including results from coupled ice-ocean models and observations. Significant quantities of heat and freshwater are delivered annually into the southern Chukchi Sea via Bering Strait. We quantify seasonal signals, along with interannual variability, over the course of 26 years of multiple model integrations. Volume transport and property fluxes are evaluated among several high- resolution model runs and compared with available moored observations. High-resolution models represent the bathymetry better, and may have a more realistic representation of the flow through the strait, although in terms of fluxes and mean properties, this is not always the case. We conclude that, (i) while some of the models used for Arctic studies achieve the correct order of magnitude for fluxes of volume, heat and freshwater, and have significant correlations with observational results, there is still a need for improvement and (ii) higher spatial resolution is needed to resolve features such as the Alaska Coastal Current (ACC). At the same time, additional measurements with better spatial coverage are needed to minimize uncertainties in observed estimates and to constrain models. Bering Strait is the only ocean connection between the Pacific and the Arctic. The flow through this narrow and shallow strait links the Pacific and Arctic oceans and impacts oceanic conditions downstream in the Chukchi Sea and the Western Arctic. We present a model synthesis of exchanges through Bering Strait at monthly to decadal time scales, including results from coupled ice-ocean models and observations. Significant quantities of heat and freshwater are delivered annually into the southern Chukchi Sea via Bering Strait. We quantify seasonal signals, along with interannual variability, over the course of 26 years of multiple model integrations. Volume transport and property fluxes are evaluated among several high- resolution model runs and compared with available moored observations. High-resolution models represent the bathymetry better, and may have a more realistic representation of the flow through the strait, although in terms of fluxes and mean properties, this is not always the case. We conclude that, (i) while some of the models used for Arctic studies achieve the correct order of magnitude for fluxes of volume, heat and freshwater, and have significant correlations with observational results, there is still a need for improvement and (ii) higher spatial resolution is needed to resolve features such as the Alaska Coastal Current (ACC). At the same time, additional measurements with better spatial coverage are needed to minimize uncertainties in observed estimates and to constrain models.Department of Energy Earth System Modeling program (J. C. K and W. M.), National Science Foundation Office of Polar Programs (J. C. K, W. M., M. S., and J. Z.), and the Office of Naval Research (J. C. K and W. M.) for support of this research. We also thank the Arctic Ocean Model Intercomparison Project (J. C. K. and W. M.). At the National Oceanography Centre Southampton (Y.A. and B. d C.) the study was supported by the UK Natural Environment Research Council as a contribution to the Marine Centres’ Strategic Research Programme Oceans 2025.Support for this work was provided (in part) by NSF grants ARC-0632154, ARC-0855748, and the NOAA-RUSALCA program (R. W.). The mooring data used in this study was collected under funding from ONR, NSF, MMS, AOOS and NOAA-RUSALCA (R. W)

Biological and epidemiological consequences of MTBC diversity

Tuberculosis is caused by different groups of bacteria belonging to the Mycobacterium tuberculosis complex (MTBC). The combined action of human factors, environmental conditions and bacterial virulence determine the extent and form of human disease. MTBC virulence is a composite of different clinical phenotypes such as transmission rate and disease severity among others. Clinical phenotypes are also influenced by cellular and immunological phenotypes. MTBC phenotypes are determined by the genotype, therefore finding genotypes responsible for clinical phenotypes would allow discovering MTBC virulence factors. Different MTBC strains display different cellular and clinical phenotypes. Strains from Lineage 5 and Lineage 6 are metabolically different, grow slower, and are less virulent. Also, at least certain groups of Lineage 2 and Lineage 4 strains are more virulent in terms of disease severity and human-to-human transmission. Because phenotypic differences are ultimately caused by genotypic differences, different genomic loci have been related to various cellular and clinical phenotypes. However, defining the impact of specific bacterial genomic loci on virulence when other bacterial determinants, human and environmental factors are also impacting the phenotype would contribute to a better knowledge of tuberculosis virulence and ultimately benefit tuberculosis control