Optimization of the Process for Preparing Bivalent Polysaccharide Conjugates to Develop Multivalent Conjugate Vaccines against Streptococcus pneumoniae or Neisseria meningitidis and Comparison with the Corresponding Licensed Vaccines in Animal Models

Objective:This study aimed to describe,optimize and evaluate a method for preparing multivalent conjugate vaccines by simultaneous conjugation of two different bacterial capsular polysaccharides(CPs)with tetanus toxoid(TT)as bivalent conjugates.Methods:Different molecular weights(MWs)of polysaccharides,activating agents and capsular polysaccharide/protein(CP/Pro)ratio that may influence conjugation and immunogenicity were investigated and optimized to prepare the bivalent conjugate bulk.Using the described method and optimized parameters,a 20-valent pneumococcal conjugate vaccine and a bivalent meningococcal vaccine were developed and their effectiveness was compared to that of corresponding licensed vaccines in rabbit or mouse models.Results:The immunogenicity test revealed that polysaccharides with lower MWs were better for Pn1-TT-Pn3 and MenA-TT-MenC,while higher MWs were superior for Pn4-TT-Pn14,Pn6A-TT-Pn6B,Pn7F-TT-Pn23F and Pn8-TT-Pn11A.For activating polysaccharides,1-cyano-4-dimethylaminopyridinium tetrafluoroborate(CDAP)was superior to cyanogen bromide(CNBr),but for Pn1,Pn3 and MenC,N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride(EDAC)was the most suitable option.For Pn6A-TT-Pn6B and Pn8-TT-Pn11A,rabbits immunized with bivalent conjugates with lower CP/Pro ratios showed significantly stronger CP-specific antibody responses,while for Pn4-TT-Pn14,higher CP/Pro ratio was better.Instead of interfering with the respective immunological activity,our bivalent conjugates usually induced higher IgG titers than their monovalent counterparts.Conclusion:The result indicated that the described conjugation technique was feasible and efficacious to prepare glycoconjugate vaccines,laying a solid foundation for developing extended-valent multivalent or combined conjugate vaccines without potentially decreased immune function.

Safety Observation Study on Haemophilus Influenza Type B Conjugate Vaccines Injected at Different Sites in Chinese Infants

In the present study, the safety of Hoemophilus influenza type b conjugate vaccines inoculated in the upper arm deltoid and vastus lateralis muscle was evaluated. 680 infants aged 2-5 months and 6-12 months were selected to be the research subjects in whom the Hib conjugate vaccines were inoculated by injection in the upper arm deltoid and vastus lateralis muscle, respectively. The safety analysis indicated that there were no statistic differences in the incidence rates of adverse reactions when the Hib conjugate vaccines were inoculated at different sites. So we concluded that the safety of inoculation injection of Hib conjugate vaccines in vastus lateralis muscle was the same as that inoculated in the upper arm deltoid.

Effect of 7 and 13-Valent Pneumococcal Conjugate Vaccines Different Number of Doses for Pneumonia Control in 2008 and 2010 Birth Cohort Children

The 7-valent pneumococcal conjugate vaccine (PCV) was introduced in Uruguay in March 2008. In April 2010, it was replaced by PCV13. Surveillance of both vaccines was performed on hospitalized children with consolidated pneumonia. The effect of different number of vaccine doses was evaluated in 2008 and 2010 birth cohorts vaccinated with PCV7 and PCV13 respectively. The study aims to estimate the effects of PCV7 and PCV13 different number of doses on consolidated pneumonia, through the study of hospitalized children from 2008 and 2010 birth cohorts. Vaccination records of every child were available providing precise vaccination data;therefore a new approach was used to estimate PCVs effect. Incidence rate was calculated for each year of the study and for the different number of vaccine doses used each year. Exposure was calculated as person per year and rate ratio values determined the decrease of consolidated pneumonias. This decrease in percentage was estimated as the difference between the incidence with no vaccine and the incidence of every one of the doses. Incidence rate ratio revealed significant values for the three vaccine doses of PCVs for both cohorts. Upon comparing incidences, significant reduction percentages of consolidated pneumonia admissions were found. The reduction percentage of consolidated pneumonia for fully vaccinated (3 doses) patients was 69.3% and 84.6 % for PCV7 and PCV13, respectively. These results confirm that PCV7 and PCV13 are highly effective for reducing pediatric hospitalizations due to consolidated pneumonia, as reported by other national publications and demonstrated by international researchers.

Synthesis, Characterization, and Immunological Properties of LPS-Based Vaccines Composed of O-Polysaccharides Conjugated with Recombinant Exoprotein A from Pseudomonas aeruginosa

Pseudomonas aeruginosa remains one of the major pathogens affecting immunocompromised patients. LPS-based monovalent (MV) and polyvalent (PV) conjugate vaccines were prepared from the most prevalent strains of P. aeruginosa International Antigenic Typing Scheme (IATS) 6, 10, 11 and 20 to evaluate their immunogenicity and protective capacities from infection by the pathogens. Conjugation of the O-polysaccharide (O-PS) antigens of P. aeruginosa strains to the common immunogenic recombinant Exotoxin A (rEPA) supports the multi-antigenic approach for the development of a vaccine that provides cross protection against various strains of the pathogen. The O-PSs were indirectly conjugated through adipic acid dihydrazide (ADH) to rEPA by carbodiimidemediated condensation reaction. Mice were immunized with the conjugates emulsified with monophosphoryl lipid A (MPL) or Freund's adjuvant compared with conjugates without adjuvant, unconjugated mixture of rEPA and O-PS emulsified with MPL, and sterile saline. The MV and PV vaccines emulsified with MPL adjuvant elicited the highest anti-O-PS IgM and IgG antibodies. Immunization of mice with MV vaccines derived from IATS 10, 11, and 20, emulsified with MPL adjuvant provided a high level of protection against the homologous bacterial strain. Similarly, high protection was obtained when mice were immunized using PV and challenged separately with bacterial strains 10, 11, and 20, but lower protection against the IATS 6 strain. Also, high cross protection of MV vaccine derived from O-PS of IATS 10 and 20 was obtained against P. aeruginosa IATS 11 strain. The in vivo protection correlated with the level of anti-O-PS IgG in the mice serum.

Plant-based vaccines against viral hepatitis: A panoptic review

The traditional vaccines against hepatitis have been instrumental in reducing the incidence of some types of viral hepatitis;however,the need for cost-effective,easily distributable,and needle-free vaccine alternatives has led to the exploration of plant-based vaccines.Plant-based techniques offer a promising avenue for producing viral hepatitis vaccines due to their low-cost cultivation,scalability,and the potential for oral administration.This review highlights the successful expression of hepatitis B surface antigens in plants and the subsequent formation of virus-like particles,which have shown immunogenicity in preclinical and clinical trials.The challenges such as achieving sufficient antigen expression levels,ensuring consistent dosing,and navigating regulatory frameworks,are addressed.The review considers the potential of plant-based vaccines to meet the demands of rapid vaccine deployment in response to outbreaks and their role in global immunization strategies,particularly in resource-limited settings.This review underscores the significant strides made in plant molecular farming and the potential of plant-based vaccines to complement existing immunization methods against viral hepatitis.

Advances in Zika virus vaccines and therapeutics:A systematic review

Zika virus(ZIKV)is the causative agent of a viral infection that causes neurological complications in newborns and adults worldwide.Its wide transmission route and alarming spread rates are of great concern to the scientific community.Numerous trials have been conducted to develop treatment options for ZIKV infection.This review highlights the latest developments in the fields of vaccinology and pharmaceuticals developments for ZIKV infection.A systematic and comprehensive approach was used to gather relevant and up-to-date data so that inferences could be made about the gaps in therapeutic development.The results indicate that several therapeutic interventions are being tested against ZIKV infection,such as DNA vaccines,subunit vaccines,live-attenuated vaccines,virus-vector-based vaccines,inactivated vaccines,virus-like particles,and mRNA-based vaccines.In addition,approved anti-ZIKV drugs that can reduce the global burden are discussed.Although many vaccine candidates for ZIKV are at different stages of development,none of them have received Food and Drug Authority approval for use up to now.The issue of side effects associated with these drugs in vulnerable newborns and pregnant women is a major obstacle in the therapeutic pathway.

Recent advances on vaccines against malaria: A review

This review aims to summarize the currently viable vaccine strategies including the approved vaccines and the those in trials for next-generation malaria vaccines.Data on malaria vaccine development was collected through a comprehensive review.The literature search was performed using databases including Google Scholar,PubMed,NIH,and Web of Science.Various novel approaches of vaccination are being developed,including those based on radiation-attenuated strategies,monoclonal antibodies,targeted immunogenic peptides,RNA and DNA vaccines,nanoparticle-based vaccines,protein-based vaccination protocols,and whole organism-based vaccination strategies.Trials on RTS,S have entered phase Ⅲtesting,and those based on blood-stage vaccines and vaccines to interrupt malarial transmission have advanced to higher stages of trials.Mathematical modeling,combined drug and vaccine strategies,mass drug administration,polyvalent vaccine formulations,and targeted vaccination campaigns is playing an important role in malarial prevention.Furthermore,assessing coverage,accessibility,acceptability,deployment,compilation,and adherence to specific vaccination strategies in endemic regions is essential for vaccination drives against malaria.

Rotavirus, Norovirus and Astrovirus in Children Aged 0 - 5 Years: Evolution of Prevalence over 10 Years (2013-2023) Following the Introduction of Rotavirus Vaccines in Burkina Faso

Rotaviruses, noroviruses, and astroviruses are responsible for gastroenteritis in children under 5 years old. The objective of our study was to estimate the evolution of prevalence of rotavirus, norovirus and astrovirus infections in children aged 0 to 5 years with gastroenteritis, after the introduction of rotavirus vaccines in Burkina Faso. This cross-sectional study was conducted between January and December 2023, collecting 100 stool samples from children with gastroenteritis at Saint Camille Hospital in Ouagadougou and the Charles De Gaulle University Paediatric Hospital. Noroviruses and astroviruses were detected using multiplex real-time PCR with a Sacace biotechnology detection kit. Data analysis was performed with Stata statistical software, version 16.0. The prevalence of norovirus infections was 14% and astrovirus infections were 9%. Rotavirus infections were found at prevalence of 15%. The age group most affected by norovirus and astrovirus infections was 0 - 12 months, with respective prevalence rates of 73.34% and 55.56%. The most frequently observed clinical signs in children infected with astrovirus were fever (77.78%), diarrhea (55.56%), and vomiting (44.44%). The introduction of rotavirus vaccines has reduced rotavirus-related infections. However, this has not significantly impacted the prevalence of norovirus and astrovirus infections in Burkina Faso.

Design of pH-responsive antimicrobial peptide melittin analog-camptothecin conjugates for tumor therapy

Melittin,a classical antimicrobial peptide,is a highly potent antitumor agent.However,its significant toxicity seriously hampers its application in tumor therapy.In this study,we developed novel melittin analogs with pH-responsive,cell-penetrating and membranelytic activities by replacing arginine and lysine with histidine.After conjugation with camptothecin(CPT),CPT-AAM-1 and CPT-AAM-2 were capable of killing tumor cells by releasing CPT at low concentrations and disrupting cell membranes at high concentrations under acidic conditions.Notably,we found that the C-terminus of the melittin analogs was more suitable for drug conjugation than the N-terminus.CPT-AAM-1 significantly suppressed melanoma growth in vivo with relatively low toxicity.Collectively,the present study demonstrates that the development of antitumor drugs based on pH-responsive antimicrobial peptide-drug conjugates is a promising strategy.

Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

An Adaptive Spectral Conjugate Gradient Method with Restart Strategy

As a generalization of the two-term conjugate gradient method(CGM),the spectral CGM is one of the effective methods for solving unconstrained optimization.In this paper,we enhance the JJSL conjugate parameter,initially proposed by Jiang et al.(Computational and Applied Mathematics,2021,40:174),through the utilization of a convex combination technique.And this improvement allows for an adaptive search direction by integrating a newly constructed spectral gradient-type restart strategy.Then,we develop a new spectral CGM by employing an inexact line search to determine the step size.With the application of the weak Wolfe line search,we establish the sufficient descent property of the proposed search direction.Moreover,under general assumptions,including the employment of the strong Wolfe line search for step size calculation,we demonstrate the global convergence of our new algorithm.Finally,the given unconstrained optimization test results show that the new algorithm is effective.

Recent advances and innovations in the design and fabrication of wearable flexible biosensors and human health monitoring systems based on conjugated polymers

Wearable biosensors have received great interest as patient-friendly diagnostic technologies because of their high flexibility and conformability.The growing research and utilization of novel materials in designing wearable biosensors have accelerated the development of point-of-care sensing platforms and implantable biomedical devices in human health care.Among numerous potential materials,conjugated polymers(CPs)are emerging as ideal choices for constructing high-performance wearable biosensors because of their outstanding conductive and mechanical properties.Recently,CPs have been extensively incorporated into various wearable biosensors to monitor a range of target biomolecules.However,fabricating highly reliable CP-based wearable biosensors for practical applications remains a significant challenge,necessitating novel developmental strategies for enhancing the viability of such biosensors.Accordingly,this review aims to provide consolidated scientific evidence by summarizing and evaluating recent studies focused on designing and fabricating CP-based wearable biosensors,thereby facilitating future research.Emphasizing the superior properties and benefits of CPs,this review aims to clarify their potential applicability within this field.Furthermore,the fundamentals and main components of CP-based wearable biosensors and their sensing mechanisms are discussed in detail.The recent advancements in CP nanostructures and hybridizations for improved sensing performance,along with recent innovations in next-generation wearable biosensors are highlighted.CPbased wearable biosensors have been—and will continue to be—an ideal platform for developing effective and user-friendly diagnostic technologies for human health monitoring.

Effect of electron-electron interaction on polarization process of exciton and biexciton in conjugated polymer

By using one-dimensional tight-binding model modified to include electron-electric field interaction and electron-electron interaction,we theoretically explore the polarization process of exciton and biexciton in cis-polyacetylene.The dynamical simulation is performed by adopting the non-adiabatic evolution approach.The results show that under the effect of moderate electric field,when the strength of electron-electron interaction is weak,the singlet exciton is stable but its polarization presents obvious oscillation.With the enhancement of interaction,it is dissociated into polaron pairs,the spin-flip of which can be observed through modulating the interaction strength.For the triplet exciton,the strong electron-electron interaction restrains its normal polarization,but it is still stable.In the case of biexciton,the strong electron-electron interaction not only dissociate it,but also flip its charge distribution.The yield of the possible states formed after the dissociation of exciton and biexciton is also calculated.

A Stable Open-Shell Conjugated Diradical Polymer with Ultra-High Photothermal Conversion Efficiency for NIR-Ⅱ Photo-Immunotherapy of Metastatic Tumor

Massive efforts have been concentrated on the advance of eminent near-infrared(NIR) photothermal materials(PTMs) in the NIR-Ⅱ window(1000–1700 nm), especially organic PTMs because of their intrinsic biological safety compared with inorganic PTMs. However, so far, only a few NIR-Ⅱresponsive organic PTMs was explored, and their photothermal conversion efficiencies(PCEs) still remain relatively low. Herein, donor–acceptor conjugated diradical polymers with open-shell characteristics are explored for synergistically photothermal immunotherapy of metastatic tumors in the NIR-Ⅱ window. By employing side-chain regulation, the conjugated diradical polymer TTB-2 with obvious NIR-Ⅱ absorption was developed, and its nanoparticles realize a record-breaking PCE of 87.7% upon NIR-Ⅱ light illustration. In vitro and in vivo experiments demonstrate that TTB-2 nanoparticles show good tumor photoablation with navigation of photoacoustic imaging in the NIR-Ⅱ window, without any side-effect. Moreover, by combining with PD-1 antibody,the pulmonary metastasis of breast cancer is high-effectively prevented by the efficient photo-immunity effect. Thus, this study explores superior PTMs for cancer metastasis theranostics in the NIR-Ⅱ window, offering a new horizon in developing radical-characteristic NIR-Ⅱ photothermal materials.

Neoantigen cancer vaccines:a new star on the horizon

Immunotherapy represents a promising strategy for cancer treatment that utilizes immune cells or drugs to activate the patient's own immune system and eliminate cancer cells.One of the most exciting advances within this field is the targeting of neoantigens,which are peptides derived from non-synonymous somatic mutations that are found exclusively within cancer cells and absent in normal cells.Although neoantigen-based therapeutic vaccines have not received approval for standard cancer treatment,early clinical trials have yielded encouraging outcomes as standalone monotherapy or when combined with checkpoint inhibitors.Progress made in high-throughput sequencing and bioinformatics have greatly facilitated the precise and efficient identification of neoantigens.Consequently,personalized neoantigen-based vaccines tailored to each patient have been developed that are capable of eliciting a robust and long-lasting immune response which effectively eliminates tumors and prevents recurrences.This review provides a concise overview consolidating the latest clinical advances in neoantigen-based therapeutic vaccines,and also discusses challenges and future perspectives for this innovative approach,particularly emphasizing the potential of neoantigen-based therapeutic vaccines to enhance clinical efficacy against advanced solid tumors.

Overcoming neutrophil-induced immunosuppression in postoperative cancer therapy: Combined sialic acid-modified liposomes with scaffold-based vaccines

Immunotherapy is a promising approach for preventing postoperative tumor recurrence and metastasis. However, inflammatory neutrophils, recruited to the postoperative tumor site, have been shown to exacerbate tumor regeneration and limit the efficacy of cancer vaccines. Consequently, addressing postoperative immunosuppression caused by neutrophils is crucial for improving treatment outcomes. This study presents a combined chemoimmunotherapeutic strategy that employs a biocompatible macroporous scaffold-based cancer vaccine (S-CV) and a sialic acid (SA)-modified, doxorubicin (DOX)-loaded liposomal platform (DOX@SAL). The S-CV contains whole tumor lysates as antigens and imiquimod (R837, Toll-like receptor 7 activator)-loaded PLGA nanoparticles as immune adjuvants for cancer, which enhance dendritic cell activation and cytotoxic T cell proliferation upon localized implantation. When administered intravenously, DOX@SAL specifically targets and delivers drugs to activated neutrophils in vivo, mitigating neutrophil infiltration and suppressing postoperative inflammatory responses. In vivo and vitro experiments have demonstrated that S-CV plus DOX@SAL, a combined chemo-immunotherapeutic strategy, has a remarkable potential to inhibit postoperative local tumor recurrence and distant tumor progression, with minimal systemic toxicity, providing a new concept for postoperative treatment of tumors.

Co and postseismic fault slip models of the 2022 M_(W)6.7 Menyuan earthquake reveal conjugated faulting tectonics at the central section of the Lenglongling fault

The 2022 M_(W)6.7 Menyuan earthquake ruptured the western end of the Tianzhu seismic gap,providing an opportunity to study the regional seismogenic characteristics and seismic hazards.Here we use interferometric synthetic aperture radar(InSAR)and seismic data to study the mainshock rupture,early afterslip and the second largest aftershock of the 2022 Menyuan earthquake sequences.Our modeling results show that the mainshock ruptured the Lenglongling fault and the Tuolaishan fault with a maximum slip of~3 m.Rapid postseismic transient deformation occurred at the center of the Lenglongling fault.Our afterslip modeling reveals that the majority of afterslip occurred in the deeper part of the Lenglongling fault.A high-angle conjugated faulting event is found at the middle section of the Lenglongling fault.We use the stress inversion to investigate the possible triggering mechanism of the conjugated rupture event.The results indicate the maximum principal stress direction is in~222°,forming a~22°angle between the conjugated fault of second largest aftershock and the mainshock.The calculated normal stress changes indicate the region is within a pull-apart stress field,which favors such a conjugated rupturing event.Our study will help understand the rupture behavior of such kind of conjugated fault in other regions.

Toward innovative veterinary nanoparticle vaccines

Nanoparticles are significant for veterinary vaccine development because they are safer and more effective than conventional formulations.One promising area of research involves self-assembled protein nanoparticles(SAPNs),which have shown potential for enhancing antigen-presenting cell uptake,B-cell activation,and lymph node trafficking.Numerous nanovaccines have been utilized in veterinary medicine,including natural self-assembled protein nanoparticles,rationally designed self-assembled protein nanoparticles,animal virus-derived nanoparticles,bacteriophagederived nanoparticles,and plant-derived nanoparticles,which will be discussed in this review.SAPN vaccines can produce robust cellular and humoral immune responses and have been shown to protect against various animal infectious diseases.This article attempts to summarize these diverse nanovaccine types and their recent research progress in the field of veterinary medicine.Furthermore,this paper highlights their disadvantages and methods for improving their immunogenicity.

Analysis of Public Sentiment regarding COVID-19 Vaccines on the Social Media Platform Reddit

This study undertakes a thorough analysis of the sentiment within the r/Corona-virus subreddit community regarding COVID-19 vaccines on Reddit. We meticulously collected and processed 34,768 comments, spanning from November 20, 2020, to January 17, 2021, using sentiment calculation methods such as TextBlob and Twitter-RoBERTa-Base-sentiment to categorize comments into positive, negative, or neutral sentiments. The methodology involved the use of Count Vectorizer as a vectorization technique and the implementation of advanced ensemble algorithms like XGBoost and Random Forest, achieving an accuracy of approximately 80%. Furthermore, through the Dirichlet latent allocation, we identified 23 distinct reasons for vaccine distrust among negative comments. These findings are crucial for understanding the community’s attitudes towards vaccination and can guide targeted public health messaging. Our study not only provides insights into public opinion during a critical health crisis, but also demonstrates the effectiveness of combining natural language processing tools and ensemble algorithms in sentiment analysis.

Magnetohydrodynamic Conjugate Free Convective Heat Transfer Analysis of an Isothermal Horizontal Circular Cylinder with Temperature Dependent Viscosity

Heat transfers due to MHD-conjugate free convection from the isothermal horizontal circular cylinder while viscosity is a function of temperature is investigated. The governing equations of the flow and connected boundary conditions are made dimensionless using a set of non-dimensional parameters. The governing equations are solved numerically using the finite difference method. Numerical results are obtained for various values of viscosity variation parameter, Prandtl number, magnetic parameter, and conjugate conduction parameter for the velocity and the temperature within the boundary layer as well as the skin friction coefficients and heat transfer rate along the surface.