Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists

Vaccines are the most effective tool for preventing infectious diseases; however, subunit vaccines, considered the safest type, suffer from poor immunogenicity and require adjuvants to create a strong and sustained immune response. As adjuvants, pathogen-associated molecular patterns (PAMPs) offer potent immunostimulatory properties and defined mechanisms of action through their cognate pattern recognition receptors (PRRs). Their activity can be further enhanced through combining two or more PAMPs, particularly those that activate multiple immune signaling pathways. However, the cytosolic localization of many PRRs requires intracellular delivery of PAMPs for optimal biological activity, which is particularly true of the stimulator of interferon genes (STING) PRR. Using acetalated dextran (Ace-DEX) microparticles (MPs) encapsulating STING agonist 3′3′-cyclic GMP-AMP (cGAMP) combined with soluble PAMPS, we screened the effect of codelivery of adjuvants using primary mouse bone marrow derived dendritic cells (BMDCs). We identified that codelivery of cGAMP MPs and soluble Toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) elicited the broadest cytokine response. cGAMP and R848 were then coencapsulated within Ace-DEX MPs via electrospray. Using the model antigen ovalbumin, we observed that Ace-DEX MPs coencapsulating cGAMP and R848 (cGAMP/R848 Ace-DEX MPs) induced antigen-specific cellular immunity, and a balanced Th1/Th2 humoral response that was greater than cGAMP Ace-DEX MPs alone and PAMPs delivered in separate MPs. These data indicate that polymeric Ace-DEX MPs loaded with STING and TLR7/8 agonists represent a potent cellular and humoral vaccine adjuvant

Predicting acoustic dose associated with marine mammal behavioural responses to sound as detected with fixed acoustic recorders and satellite tags

Funding: US Office of Naval Research, US Strategic Environmental Research and Development Program (SERDP RC-2337), the French Ministry of Defence (DGA), and the Netherlands Ministry of Defence.To understand the consequences of underwater noise exposure for cetaceans, there is a need for assessments of behavioural responses over increased spatial and temporal scales. Bottom-moored acoustic recorders and satellite tags provide such long-term and large spatial coverage of behaviour compared to short-duration acoustic-recording tags. However, these tools result in a decreased resolution of data from which an animal response can be inferred, and no direct recording of the sound received at the animal. This study discusses the consequence of the decreased resolution of data from satellite tags and fixed acoustic recorders on the acoustic dose estimated by propagation modelling and presents a method for estimating the range of sound levels that animals observed with these methods have received. This problem is illustrated using experimental results obtained during controlled exposures of northern bottlenose whales (Hyperoodon ampullatus) exposed to naval sonar, carried out near Jan Mayen, Norway. It is shown that variability and uncertainties in the sound field, resulting from limited sampling of the acoustic environment, as well as decreased resolution in animal locations, can lead to quantifiable uncertainties in the estimated acoustic dose associated with the behavioural response (in this case avoidance and cessation of foraging.PostprintPeer reviewe

A robust microparticle platform for a STING-targeted adjuvant that enhances both humoral and cellular immunity during vaccination

Most FDA-approved adjuvants for infectious agents boost humoral but not cellular immunity, and have poorly-understood mechanisms. Stimulator of interferon genes (STING, also known as MITA, MPYS, or ERIS) is an exciting adjuvant target due to its role in cyclic dinucleotide (CDN)-driven anti-viral immunity; however, a major hindrance is STING's cytosolic localization which requires intracellular delivery of its agonists. As a result, STING agonists administered in a soluble form have elicited suboptimal immune responses. Delivery of STING agonists via particle platforms has proven a more successful strategy, but the opportunity for improved formulations and bioactivity remains. In this study we evaluated the adjuvant activity of the potent STING agonist, CDN 3′3′-cGAMP (cGAMP), encapsulated in acid-sensitive acetalated dextran (Ace-DEX) polymeric microparticles (MPs) which passively target antigen-presenting cells for intracellular release. This formulation was superior to all particle delivery systems evaluated and maintained its bioactivity following a sterilizing dose of gamma irradiation. Compared to soluble cGAMP, the Ace-DEX cGAMP MPs enhanced type-I interferon responses nearly 1000-fold in vitro and 50-fold in vivo, caused up to a 104-fold boost in antibody titers, increased Th1-associated responses, and expanded germinal center B cells and memory T cells. Furthermore, the encapsulated cGAMP elicited no observable toxicity in animals and achieved protective immunity against a lethal influenza challenge seven months post-immunization when using CDN adjuvant doses up to 100-fold lower than previous reports. For these reasons, Ace-DEX MP-encapsulated cGAMP represents a potent vaccine adjuvant of humoral and cellular immunity

The sound pressure field in the ocean due to bottom interacting paths

SIGLEAvailable from British Library Document Supply Centre- DSC:DX172077 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

The sonar equation and the definitions of propagation loss

A rigorous application of the traditional definition of sonar equation terms leads to the appearance of an unexpected factor, not routinely included, equal to the ratio of the characteristic impedance at the receiver to that at the source. An omission of this factor can lead to non-negligible errors for realistic conditions. It is further argued that a gradual change in the de facto definition of propagation loss occurred between 1965 and 1980. Two alternatives to the traditional sonar equation are suggested, each using one of the two propagation loss definitions and both eliminating the unwanted impedance ratio. © 2004 Acoustical Society of America

Effect of Wind on Long Range Propagation in Shallow Water

Long range acoustic propagation in isothermal conditions is considered, involving multiple reflections from the sea surface. If the sea is calm there is almost perfect reflection and hence low loss. The effect of wind is to increase propagation loss due to the interaction with near-surface bubble clouds and rough surface scattering. Both mechanisms are modelled using the FFP program OASES. The model predictions are compared with published measurements for a frequency of 2 kHz and wind speeds up to 10 m/s. It is shown that the effect of each mechanism separately is insufficient to explain the measured reflection losses, but the combined predicted effect of both is consistent with observation

Effect of wind-generated bubbles on fixed range acoustic attenuation in shallow water at 1-4 kHz

Long-range acoustic propagation in isothermal conditions is considered, involving multiple reflections from the sea surface. If the sea is calm there is almost perfect reflection and hence little loss of acoustic energy or coherence. The effect of wind is to increase propagation loss due to rough surface scattering and the interaction with near-surface bubble clouds. Previously published measurements of wind-related attenuation in shallow water, at a fixed range of 23 km, are converted to surface reflection loss by dividing the total attenuation by the expected number of surface interactions. Theoretical predictions of coherent reflection loss are compared with these measurements in the frequency range 0.9-4.0 kHz and wind speeds up to 13 m/s. Apart from an unexplained seasonal dependence, it is shown that the magnitude of the predicted rough surface scattering loss is sufficient to explain the measurements if the effect of bubbles is included, and not otherwise. The bubbles are found to play an important catalytic role, not by scattering or absorbing sound, but by refracting it up towards the sea surface and thus enhancing the scattering loss associated with the rough air-sea boundary. Possible explanations for the apparent seasonal variations in the measurements are explored. © 2005 Acoustical Society of America