Enhanced specific immune responses by CpG DNA in mice immunized with recombinant hepatitis B surface antigen and HB vaccine

<p>Abstract</p> <p>Background</p> <p>Hepatitis B vaccine adjuvant, alum, is generally used for vaccination although it does not stimulate Th1 immunity and 10% of the population has low or no antibody response. Efforts have been continued to find more efficient vaccine adjuvants for better antibody response as well as stimulation of Th1 immunity.</p> <p>Methods</p> <p>CpG DNA was used as an adjuvant for recombinant HBsAg to immunize 6- to 8-week-old female BALB/c mice with or without alum for different dosages. The production of HBsAb, CD80 and CD86 from dendritic cells, and cytokines IL-10, IL12, etc., were analyzed and compared for the performance of immunization.</p> <p>Results</p> <p>5-20 μg CpG DNA had the best co-stimulation effect of HBsAb serum conversion for mice vaccinated with recombinant expressed HBsAg. The mice vaccinated with recombinant 20 μg CpG DNA and regular vaccine (containing alum adjuvant) had the highest concentration of antibody production. IL-12b, IL-12a and IL10 mRNA reached to the peak level between 3 and 6 hours after the CpG DNA induction in splenocytes. The expression levels of CD80 and CD86 leucocyte surface molecules were increased with 20 μg CpG DNA alone or with 20 μg CpG DNA and 4 μg HBsAg.</p> <p>Conclusions</p> <p>Our results confirmed the adjuvant effect of CpG DNA for HBsAg in the mouse model. The increase of IL10 and IL12 production suggested the involvement of Th1 cell activation. The activation of CD80 and CD86 molecules by CpG-ODN might be part of the mechanism of T/B cells coordination and the enhancement of recombinant HBsAg induced immune response.</p

You Need Multiple Exiting: Dynamic Early Exiting for Accelerating Unified Vision Language Model

Large-scale Transformer models bring significant improvements for various downstream vision language tasks with a unified architecture. The performance improvements come with increasing model size, resulting in slow inference speed and increased cost for severing. While some certain predictions benefit from the full complexity of the large-scale model, not all of inputs need the same amount of computation to conduct, potentially leading to computation resource waste. To handle this challenge, early exiting is proposed to adaptively allocate computational power in term of input complexity to improve inference efficiency. The existing early exiting strategies usually adopt output confidence based on intermediate layers as a proxy of input complexity to incur the decision of skipping following layers. However, such strategies cannot apply to encoder in the widely-used unified architecture with both encoder and decoder due to difficulty of output confidence estimation in the encoder. It is suboptimal in term of saving computation power to ignore the early exiting in encoder component. To handle this challenge, we propose a novel early exiting strategy for unified visual language models, which allows dynamically skip the layers in encoder and decoder simultaneously in term of input layer-wise similarities with multiple times of early exiting, namely \textbf{MuE}. By decomposing the image and text modalities in the encoder, MuE is flexible and can skip different layers in term of modalities, advancing the inference efficiency while minimizing performance drop. Experiments on the SNLI-VE and MS COCO datasets show that the proposed approach MuE can reduce expected inference time by up to 50\% and 40\% while maintaining 99\% and 96\% performance respectively

Establishment of the 1st Chinese national standard for CA6 neutralizing antibody

Coxsackievirus A6 (CA6) is one of the major causative agents of herpangina and hand-foot-mouth disease (HFMD). Since 2008, CA6 has circulated widely around the world. Especially in Asia-Pacific region CA6 had even replaced enterovirus A71 (EV71) and coxsackievirus A16 (CA16) as the main prevalent strain of HFMD. In the recent 10 years, monovalent and multivalent vaccines against CA6 have been researched and developed by manufacturers from China, Korea, and the USA. The neutralizing antibody titer is a key indicator for accurately evaluating immunogenicity of vaccine. However, so far, the World Health Organization international standard for CA6 neutralizing antibody has not been available. In order to meet the needs of evaluating the immunogenicity of vaccines against CA6, the first Chinese national standard for CA6 neutralizing antibody was established, which was conducted to ensure that methods used to measure the neutralizing antibody titers against CA6 are accurate, reliable, and comparable. Three lyophilized candidate standards (29#, 39# and 44#) were produced with 0.40 ml/vial from plasma samples donated by healthy individuals. The collaborative study showed that the 29# candidate standard could effectively minimize the variability in neutralization titers between labs and across challenging viruses of different genotypes (A, D1, and D3). Therefore, the 29# candidate sample was established as the first Chinese national standard for CA6 neutralizing antibody test. This standard has good long-term stability and was assigned a potency of 150 units per milliliter (U/ml) of CA6 neutralizing antibody. It will contribute to ensure uniformity of potency or activity of vaccines and potentially therapeutic antibody preparations

A Cocktail of Lipid Nanoparticle-mRNA Vaccines Broaden Immune Responses against β-Coronaviruses in a Murine Model

Severe acute respiratory syndrome (SARS)-coronavirus (CoV), Middle Eastern respiratory syndrome (MERS)-CoV, and SARS-CoV-2 have seriously threatened human life in the 21st century. Emerging and re-emerging β-coronaviruses after the coronavirus disease 2019 (COVID-19) epidemic remain possible highly pathogenic agents that can endanger human health. Thus, pan-β-coronavirus vaccine strategies to combat the upcoming dangers are urgently needed. In this study, four LNP-mRNA vaccines, named O, D, S, and M, targeting the spike protein of SARS-CoV-2 Omicron, Delta, SARS-CoV, and MERS-CoV, respectively, were synthesized and characterized for purity and integrity. All four LNP-mRNAs induced effective cellular and humoral immune responses against the corresponding spike protein antigens in mice. Furthermore, LNP-mRNA S and D induced neutralizing antibodies against SARS-CoV and SARS-CoV-2, which failed to cross-react with MERS-CoV. Subsequent evaluation of sequential and cocktail immunizations with LNP-mRNA O, D, S, and M effectively elicited broad immunity against SARS-CoV-2 variants, SARS-CoV, and MERS-CoV. A direct comparison of the sequential with cocktail regimens indicated that the cocktail vaccination strategy induced more potent neutralizing antibodies and T-cell responses against heterotypic viruses as well as broader antibody activity against pan-β-coronaviruses. Overall, these results present a potential pan-β-coronavirus vaccine strategy for improved preparedness prior to future coronavirus threats

Research progress on substitution of in vivo method(s) by in vitro method(s) for human vaccine potency assays

Introduction Potency is a critical quality attribute for controlling quality consistency and relevant biological properties of vaccines. Owing to the high demand for animals, lengthy operations and high variability of in vivo methods, in vitro alternatives for human vaccine potency assays are extensively developed. Areas covered Herein, in vivo and in vitro methods for potency assays of previously licensed human vaccines were sorted, followed by a brief description of the background for substituting in vivo methods with in vitro alternatives. Based on the analysis of current research on the substitution of vaccine potency assays, barriers and suggestions for substituting were proposed. Expert opinion Owing to the variability of in vivo methods, the correlation between in vivo and in vitro methods may be low. One or more in vitro method(s) that determine the vaccine antigen content and functions, should be established. Since the substitution involves with the change of critical quality attributes and specifications, the specifications of in vitro methods should be appropriately set to maintain the efficacy of vaccines. For novel vaccines in research and development, in vitro methods for monitoring the consistency and relevant biological properties, should be established based on reflecting the immunogenicity of vaccines

Development of a pseudovirus-based assay for measuring neutralizing antibodies against Coxsackievirus A10

Coxsackievirus A10 (CV-A10) has recently emerged as a major pathogen of hand, foot, and mouth disease in children worldwide. Currently no effective treatments are available; development of anti-CV-A10 vaccine is a most cost-effective way for CV-A10 prevention. Robust assay to measure neutralizing antibody (NtAb) titres elicited by vaccination would greatly prompt anti-CV-A10 vaccine development. Compare to the traditional neutralization assay based on inhibition of cytopathic effects (herein after referred to as cNT) which is time-consuming and labor-intensive, in this study we developed an efficient high-throughput neutralization antibody assay based on CV-A10 pseudoviruses (herein after referred to as pNT). In the pNT, anti-CV-A10 NtAb titre was negatively corresponded with the relative luminescent unit (RLU) produced by luciferase reporter gene incorporated in pseudovirus genome. As described in this study, the NtAb against CV-A10 could be detected within 10–16 h, anti- CV-A10 NtAb in 67 human serum samples were measured in parallel with pNT and cNT assays, a good correlation (r = 0.83,p < .0001) and good agreement(97%) were shown between cNT and pNT, indicating that the pNT provides a rapid and convenient procedure for measuring NtAb production against anti-CV-A10 NtAb measurement

Dynamics of 8G12 competitive antibody in “prime-boost” vaccination of Hepatitis E vaccine

Hepatitis E virus still poses a great threat to public health worldwide. To date, Hecolin® is the only licensed HEV vaccine in China. Total anti-HEV antibody has been used to reflect vaccine induced immune response in clinical trials for the lack of robust HEV neutralizing antibody detection methods. In this study, we applied a broad neutralizing mouse monoclonal antibody 8G12 to develop a competitive ELSIA assay and quantified 8G12 competitive antibody (8G12-like antibody) in serum samples. The presence of 8G12-like antibody was detected both from participants from HEV vaccine clinical trial and mice immunized with HEV vaccine. Furthermore, 8G12-like antibody was found to have a similar dynamic pattern as anti-HEV antibody during “prime-boost” vaccination, and the proportion of 8G12-like antibody in anti-HEV antibody increased along boost vaccination. Together with previously reported finding that 8G12 could block the most binding of HEV vaccine induced serum antibody to vaccine antigen, we proposed that 8G12-like antibody might be a promising surrogate for vaccine induced HEV neutralizing antibody and had potential to be used as a convenient indicator for HEV vaccine potency evaluation