We build on auto-encoding sequential Monte Carlo (AESMC): a method for model and proposal learning based on maximizing the lower bound to the log marginal likelihood in a broad family of structured probabilistic models. Our approach relies on the efficiency of sequential Monte Carlo (SMC) for performing inference in structured probabilistic models and the flexibility of deep neural networks to model complex conditional probability distributions. We develop additional theoretical insights and introduce a new training procedure which improves both model and proposal learning. We demonstrate that our approach provides a fast, easy-to-implement and scalable means for simultaneous model learning and proposal adaptation in deep generative models.

We outline the idiosyncrasies of neural information processing and machine learning in quantitative finance. We also present some of the approaches we take towards solving the fundamental challenges we face.

After enormous efforts to fight for a successful HIV vaccine, movement ended with frustration. While people are celebrating victories of disease prophylaxis and healthy improvement, millions of them are still struggling numerous unsettled dreadful illnesses, i.e., HIV, malaria, TB, cancer and autoimmune disorders. A theory of Intact Protected Complement (IPC) immunity proposed in this review is to focus on hijacked complement system, the powerful leverage weapon restrained by many pathogens or cancer cells. The theory is to stimulate more investigations to discover key block in continuous achievement in successful vaccine development and immune therapy.

Bacillus Calmette-Guérin (BCG) and recombinant BCG (rBCG) vaccines can be genetically traced back to a live attenuated strain of Mycobacterium bovis.As organism viability is essential for the stimulation of a protective immune response, monitoring the count of viable organisms is an integral part of vaccine quality control.The colonyforming unit (CFU) test has been the conventional assay for determining BCG viability, and is a widely accepted surrogate for BCG potency.CFU analysis, however, is problematic and time consuming.The slowness and high variability of CFU test results are the main driving forces for manufacturers and control laboratories to look for a rapid, more reproducible alternative viable count assay.A modified adenosine triphosphate (ATP) luminescence assay was developed by Statens Serum Institut and was promoted by the WHO as an alternative viable count assay.However, certain conditions during the processes of sample preparation and ATP extraction have to be established before the ATP assay can meet the requirements of robustness and reproducibility.This study is focused on identifying the conditions necessary for a reliable process of ATP analysis for BCG/rBCG preparations.Using our improved ATP assay protocol, we demonstrated that the correlation coefficient between CFU count and ATP concentration of BCG/rBCG vaccines was high (R 2 =0.83 for accelerated stability samples and R 2 >0.97 for all other preparations).The ATP luminescence assay is a rapid, sensitive, reliable, strain-non-specific method in quantification of the viability of live attenuated mycobacterial vaccine preparations.

Background: Although BCG is the most widely administered vaccine in the world, there have never been as many cases of TB as there are now.Globally, more than 8.8 million people developed active TB and 1.4 million-many of them-died in 2010.It is estimated that half of pulmonary TB cases arise from latent Mtb infection, making the study of latency and reactivation of utmost importance.Methods: Widely administered BCG vaccines and a gene modified recombinant BCG (rBCG) strain, AERAS-422, were used as models to investigate the growth promoting function of resuscitation-promoting factors (Rpfs) in different bacilli culture phases.Different supernatant fractions were prepared by ultrafiltration, and the promoting function of each fraction containing secreted Rpf(s) was evaluated by growth curve monitoring and colony counting on 7H10 agar plates.Results: The promoting effect of culture supernatants was mainly associated with the high molecular weight fraction (>30 kDa), which stimulated bacterial growth, but did not extend the exponential phase of stimulated culture.Anti-RpfB antibody showed significant growth restriction of the tested cultures.When comparing rBCG cultures containing 7H9 medium, the 10 -30 kDa fraction, or the >30 kDa fraction, only the >30 kDa fraction was displayed with down-regulation of the secretion of RpfC, D and E. In colony counting tests, the plates containing the >30 kDa fraction had total countable colony numbers 2 to 3 fold higher than the plates with the 10 -30 kDa fraction, and colonies appeared one to two weeks earlier than on the regular plates.The potential applications of the prepared supernatant fractions containing RpfA and RpfB are discussed, which may include accelerating diagnosis of Mtb infection and future TB vaccine development.

To improve the conventional BCG vaccine in cake appearance and integrity, a new formulation with corresponding freeze drying cycle was developed for a recombinant BCG vaccine. The new formulation contains mannitol as a bulking agent, and trehalose, sucrose and sodium glutamate as stabilizers. The formulation and freeze drying cycle were tested with different super cooling rates and secondary drying temperatures, with or without an annealing process. Thermodynamic behavior was characterized using differential scanning calorimetry (DSC). Varying the secondary drying temperature and presence/absence of an annealing step caused marked differences in cake thermodynamic profiles irrespective of different cooling rates. The annealing process allowed efficient crystallization of the mannitol. Failure to crystallize the bulking agent had the potential to depress the Tg′ and compromise storage stability in the final lyophile by crystallizing from the solid during storage, even when the secondary drying temperature was as high as 40°C. The improved formulation and freeze drying cycle resulted in good recovery of 53.2% during lyophilization and a higher survival rate of 61.7% in an accelerated stability study than the conventional BCG formulation and cycle. In summary, full crystallization was necessary for the mannitol bulking formulation. The freeze dried rBCG vials obtained using the formulation and drying cycle developed here met the requirements of BCG vaccine in good cake appearance, high viability post freeze drying and heat stability during storage.

A powder vaccine intended for aerosol delivery was formulated by spray drying the Ad35-vectored tuberculosis (TB) AERAS-402 vaccine with mannitol-based stabilizers. Thermodynamic properties, water absorption, particle size distribution and morphology of the powders were evaluated. Virus survival during spray drying and storage was determined by medium Tissue Culture Infectious Dose (TCID50). A mannitol-based powder (mannitol–cyclodextrin–trehalose–dextran, MCTD) had a narrow size distribution with a median volume diameter around 3.2–3.5μm (suitable for pulmonary vaccination of humans) and good aerosolization characteristics. The spray dry powders generated from mannitol-based formulations were hydrophobic, which benefits virus survival during both production and storage at 4°C, 25°C and 37°C as compared to the hygroscopic formulations (trehalose, sucrose, dextran, PVP, leucine). In conclusion, this study demonstrates that it is possible to produce in a one-step spray drying process a stable dry powder formulation of a TB vaccine suitable for mass vaccination.