具有高安全性和有效性的Ⅱ期两阶段临床试验

Ⅱ期临床试验的主要目的是对药物治疗的安全性和有效性进行评估.针对具有高安全性的Ⅱ期两阶段临床试验,给出小样本量下关于安全性和有效性的精确检验方法,并证明最大Ⅰ类错误概率与Ⅱ类错误概率分别在原假设和备择假设的边界处达到.在期望样本量最小原则下,给出最优两阶段设计的构造方法和常用设计表,供实际应用选用.     

Precise Epitope Organization with Self-adjuvant Framework Nucleic Acid for Efficient COVID-19 Peptide Vaccine Construction

Peptide vaccines have advantages in easy fabrication and high safety, but their effectiveness is hampered by the poor immunogenicity of the epitopes themselves. Herein, we constructed a series of framework nucleic acids (FNAs) with regulated rigidity and size to precisely organize epitopes in order to reveal the influence of epitope spacing and carrier rigidity on the efficiency of peptide vaccines. We found that assembling epitopes on rigid tetrahedral FNAs (tFNAs) with the appropriate size could efficiently enhance their immunogenicity. Further, by integrating epitopes from SARS-CoV-2 on preferred tFNAs, we constructed a COVID-19 peptide vaccine which could induce high titers of IgG against the receptor binding domain (RBD) of SARS-CoV-2 spike protein and increase the ratio of memory B and T cells in mice. Considering the good biocompatibility of tFNAs, our research provides a new idea for developing efficient peptide vaccines against viruses and possibly other diseases.     

Vegetable Extracts and Nutrients Useful in the Recovery from Helicobacter pylori Infection: A Systematic Review on Clinical Trials

Helicobacter pylori (H. pylori) infections affect almost half of the world’s population, with gradually increasing incidence in developed countries. Eradication of H. pylori may provide significant benefits to the affected individual by healing a number of gastrointestinal and extra-digestive disorders. But due to increased microbial resistance and lack of patient adherence to the therapy, the eradication rate of H. pylori is below 80% with current pharmacological therapies. The usage of botanicals for their therapeutic purposes and medicinal properties have been increased in last decades. They can be use as alternative H. pylori treatments, especially against drug-resistant strains. Epidemiological studies have revealed that people with lower vegetable and micronutrient intake may be at increased risk of H. pylori infection. We have undertaken a review of clinical trials to evaluate the efficacy of vegetable extracts and micronutrients in patients with H. pylori. Various databases, such as Google Scholar, PubMed, Scopus, Web of Science, and the Cochrane Library, were searched for the articles published in English. A total of 24 clinical studies (15 for vegetable extracts and 9 for micronutrients) were selected to be reviewed and summarized in this article. Vegetable extracts (Broccoli sprouts, curcumin, Burdock complex, and Nigella sativa) and micronutrients (vitamin C and E) were not found to be as effective as single agents in H. pylori eradication, rather their efficacy synergized with conventional pharmacological therapies. Conversely, GutGard was found to be significantly effective as a single agent when compared to placebo control.     

Structural and immunogenicity analysis of reconstructed ancestral and consensus P48/45 for cross-species anti malaria transmission-blocking vaccine

The development of the anti-malaria vaccine holds a promising future in malaria control. One of the anti-malaria vaccine strategies known as the transmission-blocking vaccine (TBV) is to inhibit the parasite transmission between humans and mosquitoes by targeting the parasite gametocyte. Previously, we found that P48/45 included in the 6-Cysteine protein family shared by Plasmodium sp. We also detected vaccine properties possessed by all human-infecting Plasmodium and could be used as a cross-species anti-malaria vaccine. In this study, we investigated the efficacy of P48/45 through the ancestral and consensus reconstruction approach. P48/45 phylogenetic and time tree analysis was done by RAXML and BEAST2. GRASP server and Ugene software were used to reconstruct ancestral and consensus sequences, respectively. The protein structural prediction was made by using a psipred and Rosetta program. Each protein characteristic of P48/45 was analyzed by assessing hydrophobicity and Post-Translational Modification sites. Meanwhile, the Epitope sequence for B-cell, T-cell, and HLA was determined using an immunoinformatics approach. Lastly, molecular docking simulation was done to determine native binding interactions of P48/45-P230. The result showed a distinct protein characteristic of ancestral and consensus sequences. The immunogenicity analysis revealed the number of epitopes in the ancestral sequence is greater than the consensus sequence. The study also found a conserved epitope located in the binding site and consists of specific Post-Translational Modification sites. Hence, our research provides detailed insight into ancestral and consensus P48/45 efficacy for the cross-species anti-malaria vaccine.     

Parametric identification of nonlinear systems using multiple trials

It is observed that the harmonic balance (HB) method of parametric identification of nonlinear system may not give right identification results for a single test data. A multiple-trial HB scheme is suggested to obtain improved results in the identification, compared with a single sample test. Several independent tests are conducted by subjecting the system to a range of harmonic excitations. The individual data sets are combined to obtain the matrix for inversion. This leads to the mean square error minimization of the entire set of periodic orbits. It is shown that the combination of independent test data gives correct results even in the case where the individual data sets give wrong results.     

Gas and Particle Dynamics of a Contoured Shock Tube for Pre-clinical Microparticle Drug Delivery

We investigate the gas-particle dynamics of a device designed for biological pre-clinical experiments. The device uses transonic/supersonic gas flow to accelerate microparticles such that they penetrate the outer skin layers. By using a shock tube coupled to a correctly expanded nozzle, a quasi-one-dimensional, quasi-steady flow (QSF) is produced to uniformly accelerate the microparticles. The system utilises a microparticle “cassette” (a diaphragm sealed container) that incorporates a jet mixing mechanism to stir the particles prior to diaphragm rupture. Pressure measurements reveal that a QSF exit period – suitable for uniformly accelerating microparticles – exists between 155 and 220 mus after diaphragm rupture. Immediately preceding the QSF period, a starting process secondary shock was shown to form with its (x,t) trajectory comparing well to theoretical estimates. To characterise the microparticle, flow particle image velocimetry experiments were conducted at the nozzle exit, using particle payloads with varying diameter (2.7–48 μm), density (600–16,800 kg/m³) and mass (0.25–10 mg). The resultant microparticle velocities were temporally uniform. The experiments also show that the starting process does not significantly influence the microparticle nozzle exit velocities. The velocity distribution across the nozzle exit was also uniform for the majority of microparticle types tested. For payload masses typically used in pre-clinical drug and vaccine applications (≤ 1 mg), it was demonstrated that payload scaling does not affect the microparticle exit velocities. These characteristics show that the microparticle exit conditions are well controlled and are in agreement with ideal theory. These features combined with an attention to the practical requirements of a pre-clinical system make the device suitable for investigating microparticle penetration into the skin for drug delivery.     

Operational issues and network effects in vaccine markets

One of the most important concerns for managing public health is the prevention of infectious diseases. Although vaccines provide the most effective means for preventing infectious diseases, there are two main reasons why it is often difficult to reach a socially optimal level of vaccine coverage: (i) the emergence of operational issues (such as yield uncertainty) on the supply side, and (ii) the existence of negative network effects on the consumption side. In particular, uncertainties about production yield and vaccine imperfections often make manufacturing some vaccines a risky process and may lead the manufacturer to produce below the socially optimal level. At the same time, negative network effects provide incentives to potential consumers to free ride off the immunity of the vaccinated population. In this research, we consider how a central policy-maker can induce a socially optimal vaccine coverage through the use of incentives to both consumers and the vaccine manufacturer. We consider a monopoly market for an imperfect vaccine; we show that a fixed two-part subsidy is unable to coordinate the market, but derive a two-part menu of subsidies that leads to a socially efficient level of coverage.     

Designing a potent L1 protein-based HPV peptide vaccine: A bioinformatics approach

BackgroundOncogenic human papilloma viruses (HPV) are the cause of various types of cancer, specifically cervical cancer. L1 protein is the main protein of HPV capsid which targeted in many vaccine-producing attempts. However, they have not enough coverage on the various high risk HPV types. Therefore, having a low cost potent HPV vaccine to protect against all members of the α-papillomaviridea family will be promising. In this study, L1 protein-based peptide vaccine was designed using immunoinformatics methods which provides physicochemical properties such as stability in room temperature, potential of antigenicity, non-allergic properties and no requirement with eukaryotic host system.ResultsThe designed vaccine has two HPV conserved epitopes with lengths 18 and 27 amino acids in all members of α-papillomaviridea. These peptides promote humoral and cellular immunity and INF-γ responses. In order to ensure strong induction of immune responses, Flagellin, a Toll like receptor 5(TLR-5) agonist, and a short synthetic toll like receptor 4 (TLR-4) agonist were also joined to the epitopes. Structure of the designed- vaccine was validated using Rampage and ERRAT and a high quality 3D structure of the vaccine protein was provided. Docking studies demonstrated an appropriate and stable interaction between the vaccine and TLR-5.ConclusionsThe vaccine is expected to have a high quality structure and suitable properties including high stability, solubility and a high potential to be expressed in E.coli. High potentiality of the vaccine in inducing humoral and cellular immune responses, may be considered as an anti-tumor vaccine.     

Physicochemical properties of SARS-CoV-2 for drug targeting,virus inactivation and attenuation,vaccine formulation and quality control

The material properties of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its proteins are discussed. We review the viral structure, size, rigidity, lipophilicity, isoelectric point, buoyant density and centrifugation conditions, stability against pH, temperature, UV light, gamma radiation, and susceptibility to various chemical agents including solvents and detergents. Possible inactivation, downstream, and formulation conditions are given including suitable buffers and some first ideas for quality-control methods. This information supports vaccine development and discussion with competent authorities during vaccine approval and is certainly related to drug-targeting strategies and hygienics. Several instructive tables are given, including the pI and grand average of hydropathicity (GRAVY) of SARS-CoV-1 and -2 proteins in comparison. SARS-CoV-1 and SARS-CoV-2 are similar in many regards, so information can often be derived. Both are unusually stable, but sensitive at their lipophilic membranes. However, since seemingly small differences can have strong effects, for example, on immunologically relevant epitope settings, unevaluated knowledge transfer from SARS-CoV-1 to SARS-CoV-2 cannot be advised. Published knowledge regarding downstream processes, formulations and quality assuring methods is, as yet, limited. However, standard approaches employed for other viruses and vaccines seem to be feasible including virus inactivation, centrifugation conditions, and the use of adjuvants.     

The potential use of mesenchymal stem cells in hematopoietic stem cell transplantation

In the last 10 years, mesenchymal stem cells (MSCs) have emerged as a therapeutic approach to regenerative medicine, cancer, autoimmune diseases, and many more due to their potential to differentiate into various tissues, to repair damaged tissues and organs, and also for their immunomodulatory properties. Findings in vitro and in vivo have demonstrated immune regulatory function of MSCs and have facilitated their application in clinical trials, such as those of autoimmune diseases and chronic inflammatory diseases. There has been an increasing interest in the role of MSCs in allogeneic hematopoietic stem cell transplantation (HSCT), including hematopoietic stem cell engraftment and the prevention and treatment of graft-versus-host disease (GVHD), and their therapeutic potential has been reported in numerous clinical trials. Although the safety of clinical application of MSCs is established, further modifications to improve their efficacy are required. In this review, we summarize advances in the potential use of MSCs in HSCT. In addition, we discuss their use in clinical trials of the treatment of GVHD following HSCT, the immunomodulatory capacity of MSCs, and their regenerative and therapeutic potential in the field of HSCT.