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Vaccines Jun 2024Human papillomavirus (HPV) is a prevalent cause of mucosal and cutaneous infections and underlying conditions ranging from benign warts to anogenital and oropharyngeal...
Human papillomavirus (HPV) is a prevalent cause of mucosal and cutaneous infections and underlying conditions ranging from benign warts to anogenital and oropharyngeal cancers affecting both males and females, notably cervical cancer. Cervical cancer is the fourth leading cause of cancer deaths among women globally and is the most impactful in low- and middle-income countries (LMICs), where the costs of screening and licensed L1-based HPV vaccines pose significant barriers to comprehensive administration. Additionally, the licensed L1-based HPV vaccines fail to protect against all oncogenic HPV types. This study generated three independent lots of an L2-based target antigen (LBTA), which was engineered from conserved linear L2-protective epitopes (aa11-88) from five human alphapapillomavirus genotypes in under cGMP conditions and adjuvanted with aluminum phosphate. Vaccination of rabbits with LBTA generated high neutralizing antibody titers against all 17 HPV types tested, surpassing the nine types covered by Gardasil9. Passive transfer of naïve mice with LBTA antiserum revealed its capacity to confer protection against vaginal challenge with all 17 αHPV types tested. LBTA shows stability at room temperature over >1 month. Standard and toxicology studies suggest a promising safety profile. These findings suggest LBTA's promise as a next-generation vaccine with comprehensive coverage aimed at reducing the economic and healthcare burden of cervical and other HPV+ cancers in LMICs, and it has received regulatory approval for a first-in-human clinical study (NCT05672966).
PubMed: 38932417
DOI: 10.3390/vaccines12060689 -
Vaccines Jun 2024Approved COVID-19 vaccines primarily induce neutralizing antibodies targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein. However, the...
Approved COVID-19 vaccines primarily induce neutralizing antibodies targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein. However, the emergence of variants of concern with RBD mutations poses challenges to vaccine efficacy. This study aimed to design a next-generation vaccine that provides broader protection against diverse coronaviruses, focusing on glycan-free S2 peptides as vaccine candidates to overcome the low immunogenicity of the S2 domain due to the N-linked glycans on the S antigen stalk, which can mask S2 antibody responses. Glycan-free S2 peptides were synthesized and attached to SARS-CoV-2 virus-like particles (VLPs) lacking the S antigen. Humoral and cellular immune responses were analyzed after the second booster immunization in BALB/c mice. Enzyme-linked immunosorbent assay revealed the reactivity of sera against SARS-CoV-2 variants, and pseudovirus neutralization assay confirmed neutralizing activities. Among the S2 peptide-conjugated VLPs, the S2.3 (N1135-K1157) and S2.5 (A1174-L1193) peptide-VLP conjugates effectively induced S2-specific serum immunoglobulins. These antisera showed high reactivity against SARS-CoV-2 variant S proteins and effectively inhibited pseudoviral infections. S2 peptide-conjugated VLPs activated SARS-CoV-2 VLP-specific T-cells. The SARS-CoV-2 vaccine incorporating conserved S2 peptides and CoV-2 VLPs shows promise as a universal vaccine capable of generating neutralizing antibodies and T-cell responses against SARS-CoV-2 variants.
PubMed: 38932406
DOI: 10.3390/vaccines12060676 -
Vaccines Jun 2024T help (Th), stimulation of toll-like receptors (pathogen-associated molecular patterns, PAMPs), and antigen organization and repetitiveness (pathogen-associated...
Identifying Key Drivers of Efficient B Cell Responses: On the Role of T Help, Antigen-Organization, and Toll-like Receptor Stimulation for Generating a Neutralizing Anti-Dengue Virus Response.
T help (Th), stimulation of toll-like receptors (pathogen-associated molecular patterns, PAMPs), and antigen organization and repetitiveness (pathogen-associated structural patterns, PASPs) were shown numerous times to be important in driving B-cell and antibody responses. In this study, we dissected the individual contributions of these parameters using newly developed "Immune-tag" technology. As model antigens, we used eGFP and the third domain of the dengue virus 1 envelope protein (DV1 EDIII), the major target of virus-neutralizing antibodies. The respective proteins were expressed alone or genetically fused to the N-terminal fragment of the cucumber mosaic virus (CMV) capsid protein-nCMV, rendering the antigens oligomeric. In a step-by-step manner, RNA was attached as a PAMP, and/or a universal Th-cell epitope was genetically added for additional Th. Finally, a PASP was added to the constructs by displaying the antigens highly organized and repetitively on the surface of CMV-derived virus-like particles (CuMV VLPs). Sera from immunized mice demonstrated that each component contributed stepwise to the immunogenicity of both proteins. All components combined in the CuMV VLP platform induced by far the highest antibody responses. In addition, the DV1 EDIII induced high levels of DENV-1-neutralizing antibodies only if displayed on VLPs. Thus, combining multiple cues typically associated with viruses results in optimal antibody responses.
PubMed: 38932390
DOI: 10.3390/vaccines12060661 -
Vaccines May 2024The potency of inactivated seasonal influenza vaccine is harmonised by establishing the haemagglutinin (HA) content using the compendial single radial diffusion (SRD)...
The potency of inactivated seasonal influenza vaccine is harmonised by establishing the haemagglutinin (HA) content using the compendial single radial diffusion (SRD) method. SRD reagents (antigens and antisera) are prepared, calibrated and distributed by regulatory agencies as standards for potency testing, following the biannual World Health Organization (WHO) announcements of the virus strains suitable for inclusion in the vaccine. The generation of a homologous hyperimmune sheep antiserum constrains the time to vaccine release. This study tests the application of heterologous antisera to determine the potency of influenza vaccine compared to that of a standard homologous antiserum. The results indicate that the selected heterologous sheep antisera directed to seasonal H1N1, H3N2 or B Victoria virus strains can be used to determine the accurate potency of inactivated seasonal influenza vaccines. Individually selected antisera could be useful for two to fourteen seasons. A limitation to the heterologous antiserum approach is the diversity of each individual serum, indicating that the empirical determination of a specific serum is required. This application has the potential to enable the earlier availability of a seasonal vaccine and reduce animal usage.
PubMed: 38932325
DOI: 10.3390/vaccines12060596 -
Microorganisms Jun 2024Serine protease inhibitors are a superfamily of proteins that regulate various physiological processes including fibrinolysis, inflammation and immune responses. In...
Serine protease inhibitors are a superfamily of proteins that regulate various physiological processes including fibrinolysis, inflammation and immune responses. In parasite systems, serpins are believed to play important roles in parasite colonization, inhibition of host immune serine proteases and penetration of defensive barriers. However, serpins are less well characterized in schistosomes. In this study, a serpin (Smserpin-p46) containing a 1360 base pair open reading frame, was cloned, expressed and functionally characterized. Bioinformatics analysis revealed that Smserpin-p46 contains the key residues, structural domains and motifs characteristic of inhibitory serpins. Gene expression profiling demonstrated stage-specific expression of with the highest expression in adult male worms. Recombinant Smserpin-p46 (rSmserpin-p46) inhibited both human neutrophil cathepsin G and elastase, key serine proteases involved in NETosis, a program for the formation of neutrophil extracellular traps. Using specific rabbit antiserum, Smserpin-p46 was detected in soluble worm antigen preparation and was localized to the adult worm tegument. Cumulatively, the expression of Smserpin-p46 on the parasite tegument and its ability to inhibit proteases involved in NETosis highlights the importance of this serpin in parasite-host interactions and encourages its further investigation as a candidate vaccine antigen for the control of schistosomiasis.
PubMed: 38930546
DOI: 10.3390/microorganisms12061164 -
International Journal of Molecular... Jun 2024Ruthenium chloride (RuCl) is widely utilized for synthesis and catalysis of numerous compounds in academia and industry and is utilized as a key molecule in a variety of...
Ruthenium chloride (RuCl) is widely utilized for synthesis and catalysis of numerous compounds in academia and industry and is utilized as a key molecule in a variety of compounds with medical applications. Interestingly, RuCl has been demonstrated to modulate human plasmatic coagulation and serves as a constituent of a compounded inorganic antivenom that neutralizes the coagulopathic effects of snake venom in vitro and in vivo. Using thrombelastography, this investigation sought to determine if RuCl inhibition of the fibrinogenolytic effects of venom could be modulated by vehicle composition in human plasma. Venom was exposed to RuCl in 0.9% NaCl, phosphate-buffered saline (PBS), or 0.9% NaCl containing 1% dimethyl sulfoxide (DMSO). RuCl inhibited venom-mediated delay in the onset of thrombus formation, decreased clot growth velocity, and decreased clot strength. PBS and DMSO enhanced the effects of RuCl. It is concluded that while a Ru-based cation is responsible for significant inhibition of venom activity, a combination of Ru-based ions containing phosphate and DMSO enhances RuCl-mediated venom inhibition. Additional investigation is indicated to determine what specific Ru-containing molecules cause venom inhibition and what other combinations of inorganic/organic compounds may enhance the antivenom effects of RuCl.
Topics: Humans; Dimethyl Sulfoxide; Antivenins; Crotalid Venoms; Animals; Blood Coagulation; Crotalus; Ruthenium Compounds; Sodium Chloride; Thrombelastography; Venomous Snakes
PubMed: 38928132
DOI: 10.3390/ijms25126426 -
International Journal of Molecular... Jun 2024Eastern Diamondback Rattlesnake () envenomation is a medical emergency encountered in the Southeastern United States. The venom contains a snake venom thrombin-like...
Eastern Diamondback Rattlesnake () envenomation is a medical emergency encountered in the Southeastern United States. The venom contains a snake venom thrombin-like enzyme (SVTLE) that is defibrinogenating, causing coagulopathy without effects on platelets in humans. This investigation utilized thrombelastographic methods to document this coagulopathy kinetically on the molecular level in a rabbit model of envenomation via the analyses of whole blood samples without and with platelet inhibition. Subsequently, the administration of a novel ruthenium compound containing site-directed antivenom abrogated the coagulopathic effects of envenomation in whole blood without platelet inhibition and significantly diminished loss of coagulation in platelet-inhibited samples. This investigation provides coagulation kinetic insights into the molecular interactions and results of SVTLE on fibrinogen-dependent coagulation and confirmation of the efficacy of a ruthenium antivenom. These results serve as a rationale to investigate the coagulopathic effects of other venoms with this model and assess the efficacy of this site-directed antivenom.
Topics: Animals; Rabbits; Antivenins; Crotalus; Crotalid Venoms; Blood Coagulation; Thrombelastography; Ruthenium; Snake Bites; Male; Venomous Snakes
PubMed: 38928044
DOI: 10.3390/ijms25126334 -
Genes Jun 2024Galectins are innate immune system regulators associated with disease progression in cancer. This paper aims to investigate the correlation between mutated...
Galectins are innate immune system regulators associated with disease progression in cancer. This paper aims to investigate the correlation between mutated cancer-critical genes and galectin levels in breast cancer patients to determine whether galectins and genetic profiles can be used as biomarkers for disease and potential therapy targets. Prisma Health Cancer Institute's Biorepository provided seventy-one breast cancer samples, including all four stages spanning the major molecular subtypes and histologies. Hotspot mutation statuses of cancer-critical genes were determined using multiplex PCR in tumor samples from the same patients by Precision Genetics and the University of South Carolina Functional Genomics Core Facility. The galectin-1, -3, and -9 levels in patients' sera were analyzed using Enzyme-linked Immunosorbent Assay (ELISA). An analysis was performed using JMP software to compare mean and median serum galectin levels between samples with and without specific cancer-critical genes, including pooled -test, Wilcoxon Rank Sum Test, ANOVA, and Steel Dwass Test (α=0.05). Our analysis indicates that mutations correlate with elevated serum levels of galectin-9 in patients with breast cancer. In patients with Luminal A subtype, mutation correlates with lower serum galectin-1 and -9 levels and mutations correlate with higher serum galectin-3 levels. Patients with invasive ductal carcinoma had significantly higher serum galectin-3 levels than patients with ductal carcinoma in situ. Patients with both and mutations exhibit elevated serum galectin-3 levels, while patients with one or neither mutation show no significant difference in serum galectin-3 levels. In addition, metastatic breast cancer samples were more likely to have a or mutation compared to primary breast cancer samples. The relationship between genetic mutations and galectin levels has the potential to identify appropriate candidates for combined therapy, targeting genetic mutations and galectins. Further understanding of the effect of genetic mutations and galectin levels on cancer progression and metastasis could aid in the search for biomarkers for breast cancer diagnosis, disease progression, and prognosis.
Topics: Humans; Breast Neoplasms; Female; Galectins; Mutation; Biomarkers, Tumor; Galectin 1; Middle Aged; Galectin 3; Adult; Blood Proteins
PubMed: 38927753
DOI: 10.3390/genes15060818 -
BMC Public Health Jun 2024To analyze the vulnerability factors of snakebite patients in China.
OBJECTIVE
To analyze the vulnerability factors of snakebite patients in China.
METHODS
Multi-stage random sampling was used as the main sampling method and snowball sampling as the auxiliary sampling method. The knowledge, attitude and behavior of snakebite among Chinese residents were investigated. Non-parametric test was used to compare the percentage differences in residents' knowledge, attitude and behavior of snakebite, and generalized linear regression analysis was used to analyze the influencing factors, and the vulnerability factors of snakebite patients were comprehensively analyzed.
RESULTS
A total of 6338 subjects were included in this study, of which 68.4% were males, and 58.6% were farmers, workers and service personnel. The median total score of knowledge, attitude, and behavior was 26 (22,36). The patients who were improperly treated after injury were ligation proximal to the affected area (23.43%), squeezing (21.82%), and oral and suction wounds (8.74%). Did not go to hospital due to poverty (1351 cases) and did not receive antivenom (2068 cases). There were 21.32% and 32.63%, respectively. Among 4270 patients injected with antivenom 30.7% were vaccinated within 2 h. Among the patients who went to the hospital for treatment (4987), 75.0% arrived at the hospital within 6 h; Among the 4,761 patients who made emergency calls, 37.4% were treated within 0.5 h.
CONCLUSIONS
Snakebite patients in China have weak knowledge about snakebite, low awareness of medical treatment, lack of correct prevention and emergency treatment measures, dependence on folk remedies, poor housing and so on. In addition, there are low availability of antivenoms and unreasonable distribution of medical resources in some areas of China. Multisectoral and multidisciplinary cooperation should be developed to prevent and control snakebites in order to reduce the burden caused by snakebites.
Topics: Snake Bites; Humans; China; Male; Female; Adult; Health Knowledge, Attitudes, Practice; Middle Aged; Young Adult; Adolescent; Antivenins; Risk Factors; Surveys and Questionnaires; Aged
PubMed: 38926898
DOI: 10.1186/s12889-024-19169-3 -
Emergency Medicine Clinics of North... Aug 2024Envenomations are the 23rd most common reason for calls to US poison control centers, with over 35,000 incidents reported annually. Snake bites account for over 20% of... (Review)
Review
Envenomations are the 23rd most common reason for calls to US poison control centers, with over 35,000 incidents reported annually. Snake bites account for over 20% of those calls, while marine envenomations are likely underreported at 3% to 4%. While these types of envenomations may not be encountered on a daily basis for many physicians, the different types of envenomations warrant unique management strategies based on the offending creature and symptom presentation. This text serves as a review of the epidemiology, clinical presentations, and management of endemic North American species of snakes and marine vertebrate and invertebrate envenomations.
Topics: Humans; Snake Bites; Animals; Antivenins; Bites and Stings; North America; Snakes
PubMed: 38925780
DOI: 10.1016/j.emc.2024.02.020