Vaccine Targets Research Articles

Out of focus but still relevant? Influenza-related resource utilization and vaccination coverage gaps in adults below 60 years of age with underlying conditions: an analysis of 2016–2024 real-world data in Germany

Background In 2003, the WHO aimed for a 75% or higher influenza vaccination rate among at-risk populations. However, this target was achieved in a few groups during selected seasons in some European countries, and never in Germany. Adults with underlying conditions (UCs) are a critical negleted group for influenza vaccination. This study aimed to identify data gaps in influenza burden and vaccination coverage among adults under 60 with UCs in Germany and bridge these gaps using real-world data. Material and methods We conducted systematic research and analyses using German administrative and claims databases from June 2016 to April 2024. We report on epidemiology, direct care costs, indirect costs from work incapacity, vaccination coverage rates, and describe data gaps. Results Influenza data for high-risk populations are limited. Comprehensive data on influenza epidemiology and vaccination coverage rates (VCR) is available, though with a delay in data availability. Before and after the pandemic, individuals aged 50-59 had the highest rates of influenza-related hospitalization and ICU admission compared to younger age groups. Across all age groups and seasons, individuals with UC experienced higher rates of medically attended influenza cases, hospitalizations, and healthcare costs, with those aged 35–59 being particularly vulnerable. Vaccine coverage was higher in adults aged 35–59 compared to those aged 18–24, and in females compared to males. Limitations Discrepancies of vaccination status, limited data availability, and variations among the extent of UCs. Conclusion In Germany, recent policy measures have mainly targeted those aged 60 and above. While this elderly population experiences the highest disease-related impact, influenza can also lead to substantial healthcare resource utilization (HCRU) and costs in younger populations with chronic UCs; Facilitating vaccination access for this group, such as through pharmacies, is essential. Definition of quantifiable vaccination targets and measures to increase vaccination rates based on these targets are required.

Enhanced anti-tumor efficacy of electroporation (EP)-mediated DNA vaccine boosted by allogeneic lymphocytes in pre-established tumor models

BackgroundTumor-reactive T cells play a crucial role in anti-tumor responses, but T cells induced by DNA vaccination are time-consuming processes and exhibit limited anti-tumor efficacy. Therefore, we evaluated the anti-tumor effectiveness of reactive T cells elicited by electroporation (EP)-mediated DNA vaccine targeting epidermal growth factor receptor variant III (pEGFRvIII plasmid), in conjunction with adoptive cell therapy (ACT), involving the transfer of lymphocytes from a pEGFRvIII EP-vaccinated healthy donor.MethodsThe validation of the established pEGFRvIII plasmid and EGFRvIII-positive cell model was confirmed through immunofluorescence and western blot analysis. Flow cytometry and cytotoxicity assays were performed to evaluate the functionality of antigen-specific reactive T cells induced by EP-mediated pEGFRvIII vaccines, ACT, or their combination. The anti-tumor effectiveness of EP-mediated pEGFRvIII vaccines alone or combined with ACT was evaluated in the B16F10-EGFRvIII tumor model.ResultsEP-mediated pEGFRvIII vaccines elicited serum antibodies and a robust cellular immune response in both healthy and tumor-bearing mice. However, this response only marginally inhibited early-stage tumor growth in established tumor models. EP-mediated pEGFRvIII vaccination followed by adoptive transfer of lymphocytes from vaccinated healthy donors led to notable anti-tumor efficacy, attributed to the synergistic action of antigen-specific CD4+ Th1 cells supplemented by ACT and antigen-specific CD8+ T cells elicited by the EP-mediated DNA vaccination.ConclusionsOur preclinical studies results demonstrate an enhanced anti-tumor efficacy of EP-mediated DNA vaccination boosted with adoptively transferred, vaccinated healthy donor-derived allogeneic lymphocytes.

IPVS STATEMENT on HPV vaccination: No longer supply constraints: Towards achieving WHO vaccine targets

The global supply of human papillomavirus (HPV) prophylactic vaccines has been constrained since 2020.Vaccine manufacturers have increased capacity and new HPV vaccines are now available. Vaccine supply is now able to meet the full HPV vaccine demand which has been achieved earlier than predicted.

Eimeria tenella rhoptry neck protein 2 plays a key role in the process of invading the host intestinal epithelium

The Apicomplexa parasitic phylum rhoptry neck protein 2 (RON2) plays a key role in the process of invading host cells. Eimeria tenella, an intracellular protozoan shares a similar conserved invasion pattern. However, whether E. tenella RON2 participates in the process of invading the host intestinal epithelium is poorly understood. In this study, the sequence of EtRON2 was analyzed and expressed. The expression of the truncated extracellular N-terminal fragment of EtRON2 (403–700 aa, designated EtRON2403–700) with a molecular mass of 38.3 kDa. EtRON2 in the sporozoite protein was detected at 151.4 kDa by rabbit anti-rEtRON2403–700 antibody. Immunofluorescence results showed that EtRON2 was mainly localized to the nucleus and apex of the E. tenella sporozoite. qPCR results showed that the highest expression level of EtRON2 was detected in sporulated oocysts compared with other developmental stages of E. tenella. In vitro invasion inhibition assays showed that the capacity of sporozoites to invade DF-1 cells was significantly inhibited after pretreatment with the rabbit anti-rEtRON2403–700 antibody. Silencing the EtRON2 gene by RNA interference (RNAi) significantly inhibited EtRON2 expression and significantly reduced the invasion of DF-1 cells by sporozoites. In vivo experiments revealed a significant decrease parasite burden and oocyst outputs in chicks after infection with EtRON2 gene-silenced sporozoites by cloacal inoculation. Recombinant EtRON2403–700 (rEtRON2403–700) immunizes chicks effectively against E. tenella infection by inducing humoral immunity and upregulating IFN-γ and CD8+ T lymphocytes. Furthermore, chicks exhibited increased relative weight gain rates, lower cecum lesion scores, and reduced oocyst outputs during the E. tenella challenge. H&E staining showed that the cecum tissue of chicks immunized with rEtRON2403–700 showed relatively mild histopathological changes. In conclusion, the results of this study demonstrated that EtRON2 plays a key role in E. tenella invasion of the host intestinal epithelium and provides a potential target for vaccines against E. tenella infection.

Mtb-Specific HLA-E-Restricted T Cells Are Induced during Mtb Infection but Not after BCG Administration in Non-Human Primates and Humans.

Background: Novel vaccines targeting the world's deadliest pathogen Mycobacterium tuberculosis (Mtb) are urgently needed as the efficacy of the Bacillus Calmette-Guérin (BCG) vaccine in its current use is limited. HLA-E is a virtually monomorphic unconventional antigen presentation molecule, and HLA-E-restricted Mtb-specific CD8+ T cells can control intracellular Mtb growth, making HLA-E a promising vaccine target for Mtb. Methods: In this study, we evaluated the frequency and phenotype of HLA-E-restricted Mtb-specific CD4+/CD8+ T cells in the circulation and bronchoalveolar lavage fluid of two independent non-human primate (NHP) studies and from humans receiving BCG either intradermally or mucosally. Results: BCG vaccination followed by Mtb challenge in NHPs did not affect the frequency of circulating and local HLA-E-Mtb CD4+ and CD8+ T cells, and we saw the same in humans receiving BCG. HLA-E-Mtb T cell frequencies were significantly increased after Mtb challenge in unvaccinated NHPs, which was correlated with higher TB pathology. Conclusions: Together, HLA-E-Mtb-restricted T cells are minimally induced by BCG in humans and rhesus macaques (RMs) but can be elicited after Mtb infection in unvaccinated RMs. These results give new insights into targeting HLA-E as a potential immune mechanism against TB.

Evaluation of PLGA, lipid-PLGA hybrid nanoparticles, and cationic pH-sensitive liposomes as tuberculosis vaccine delivery systems in a Mycobacterium tuberculosis challenge mouse model – A comparison

Tuberculosis (TB) continues to pose a global threat for millennia, currently affecting over 2 billion people and causing 10.6 million new cases and 1.3 million deaths annually. The only existing vaccine, Mycobacterium Bovis Bacillus Calmette-Guérin (BCG), provides highly variable and inadequate protection in adults and adolescents. This study explores newly developed subunit tuberculosis vaccines that use a multistage protein fusion antigen Ag85b-ESAT6-Rv2034 (AER). The protection efficacy, as well as in vivo induced immune responses, were compared for five vaccines: BCG; AER-CpG/MPLA mix; poly(D,L-lactic-co-glycolic acid) (PLGA); lipid-PLGA hybrid nanoparticles (NPs); and cationic pH-sensitive liposomes (the latter three delivering AER together with CpG and MPLA). All vaccines, except the AER-adjuvant mix, induced protection in Mycobacterium tuberculosis (Mtb)-challenged C57/Bl6 mice as indicated by a significant reduction in bacterial burden in lungs and spleens of the animals. Four AER-based vaccines significantly increased the number of circulating multifunctional CD4+ and CD8+ T-cells producing IL-2, IFNγ, and TNFα, exhibiting a central memory phenotype. Furthermore, AER-based vaccines induced an increase in CD69+ B-cell counts as well as high antigen-specific antibody titers. Unexpectedly, none of the observed immune responses were associated with the bacterial burden outcome, such that the mechanism responsible for the observed vaccine-induced protection of these vaccines remains unclear. These findings suggest the existence of non-classical protective mechanisms for Mtb infection, which could, once identified, provide interesting targets for novel vaccines.

Membrane Permeability and Drug Targeting Potential of Phospholipid‐Based Nanocarriers in Lung Cancer Therapy

AbstractLung cancer has become the leading cause of cancer‐related deaths, surpassing all other forms of cancer. Among lung cancers, non‐small cell lung cancer (NSCLC) accounts for approximately 85% of cases. The use of tobacco, genetic traits, and radiation exposure are amongst the major reasons of lung cancer. The ongoing research in the medical field has considered the efficacy of nanocarriers in targeting various cancer cells. Among several biomaterials, lipid‐based nanocarriers have gained special attention due to their excellent compatibility, improved targeting efficacy, and encapsulation ability of diverse therapeutic agents. Phospholipids are naturally occurring amphiphilic moieties found in all living creatures. The presence of phospholipids in biomembrane aids the permeability of phospholipid‐based drug carrier. It can also facilitate targeting of therapeutic agents to cancer microenvironment without degrading the encapsulated drug. Phospholipids can be employed to develop conjugated nanocarriers and vesicular nanoformulation that can result in prolonged circulatory half‐life and controlled release of drugs. Phospholipids are also suitable biomaterials to attach a ligand for tissue‐specific targeting. Recent researches have reported effective targeting of chemotherapeutic agents, genes, and vaccines through phospholipid‐based nanocarriers to lung cancer cells. This review focuses on the rationality and applications of phospholipid‐based nanocarriers in lung cancer therapy.

Sublingual immune cell clusters and dendritic cell distribution in the oral cavity.

The oral mucosa is the first line of defense against pathogenic bacteria and plays a vital role in maintaining tolerance to food antigens and commensal bacteria. We used CD11c reporter mice to visualize dendritic cells (DCs), a key immune cell population, in the oral cavity. We identified differences in DC density in each oral tissue region. Sublingual immune cell clusters (SLICs) extended from the lamina propria to the epithelium, where DCs and T cells resided in close contact with each other and innate lymphoid cells (ILCs). Targeted in situ photolabeling revealed that the SLICs comprised mostly of CD11c+CD11b+ DCs and were enriched for cDC1s and Langerhans cells. Although the frequency of T cell subsets was similar within and outside the SLICs, tissue resident memory T cells were significantly enriched within the clusters and cluster size increased in response to inflammation. Collectively, we found that SLICs form a unique microenvironment that facilitates T cell-DC interactions in the steady state and during inflammation. Since the oral mucosa is an important target for needle-free vaccination and sublingual immunotherapy to induce tolerogenic responses, the novel insight into the localized immunoregulation provided in this study may accelerate the development of these approaches.

Biogenesis and Function of circRNAs in Pulmonary Fibrosis.

Pulmonary fibrosis is a class of fibrosing interstitial lung diseases caused by many pathogenic factors inside and outside the lung, with unknown mechanisms and without effective treatment. Therefore, a comprehensive understanding of the molecular mechanism implicated in pulmonary fibrosis pathogenesis is urgently needed to develop new and effective measures. Although circRNAs have been widely acknowledged as new contributors to the occurrence and development of diseases, only a small number of circRNAs have been functionally characterized in pulmonary fibrosis. Here, we systematically review the biogenesis and functions of circRNAs and focus on how circRNAs participate in pulmonary fibrogenesis by influencing various cell fates. Meanwhile, we analyze the current exploration of circRNAs as a diagnostic biomarker, vaccine, and therapeutic target in pulmonary fibrosis and objectively discuss the challenges of circRNA- based therapy for pulmonary fibrosis. We hope that the review of the implication of circRNAs will provide new insights into the development circRNA-based approaches to treat pulmonary fibrosis.

Reaching national Covid-19 vaccination targets whilst decreasing inequalities in vaccine uptake: Public health teams' challenges in supporting disadvantaged populations

BackgroundUK local authority public health teams (LAPHT) supported delivery of the Covid-19 vaccination programme, particularly to disadvantaged populations. We explored the challenges encountered and lessons learnt by LAPHTs in tackling low Covid-19 vaccine uptake. The aim of this study was to understand what works, and how, in addressing local inequalities in relation to uptake of the Covid-19 vaccination with a view to generalising insights to building back fairer after the pandemic and into the future. Study designQualitative. MethodWe conducted in-depth on-line interviews with Directors of Public Health or their representatives from 21 English local authorities covering a total population of over 8 million people. Data were analysed thematically. ResultsAccessing the requisite (and accurate) data, engaging with communities, and working with National Health Service (NHS) organisations presented challenges in delivering initiatives to improve vaccine uptake, particularly for disadvantaged groups. LAPHT’s assets beneficial to the programme - in-depth knowledge and experience of their communities and locality - were not considered in the national vaccination programme. Community engagement and relationships with local NHS featured heavily in the majority of LAPHTs responses to improving vaccine uptake rates. ConclusionsIncorporating local public health infrastructure, expertise and existing relationships into national vaccination planning during epidemics or pandemics is crucial. Community engagement and good relationships with NHS staff help to reach and serve disadvantaged populations. How these can be developed and maintained in the longer term without future investment was a concern. Future research should explore the design and implementation of PH and NHS joint service delivery models to tackle health inequalities, informed by experiences of the Covid-19 vaccination programme and with input from community partners.

Lnc-H19-derived protein shapes the immunosuppressive microenvironment of glioblastoma.

The immunosuppressive tumor microenvironment (TME) is a prominent feature of glioblastoma (GBM), the most lethal primary brain cancer resistant to current immunotherapies. The mechanisms underlying GBM-TME remain to be explored. We report that long non-coding RNA (LncRNA) H19 encodes an immune-related protein called H19-IRP. Functionally separated from H19 RNA, H19-IRP promotes GBM immunosuppression by binding to the CCL2 and Galectin-9 promoters and activating their transcription, thereby recruiting myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), leading to Tcell exhaustion and an immunosuppressive GBM-TME. H19-IRP, overexpressed in clinical GBM samples, acts as a tumor-associated antigen (TAA) presented by major histocompatibility complex class I (MHC-I). A circular RNA vaccine targeting H19-IRP (circH19-vac) triggers a potent cytotoxic Tcell response against GBM and inhibits GBM growth. Our results highlight the unrevealed function of H19-IRP in creating immunosuppressive GBM-TME by recruiting MDSCs and TAMs, supporting the idea of targeting H19-IRP with cancer vaccine for GBM treatment.

RipE expression correlates with high ATP levels in Ehrlichia, which confers resistance during the extracellular stage to facilitate a new cycle of infection.

Ehrlichiosis is a potentially life-threatening disease caused by infection with the obligatory intracellular bacteria Ehrlichia species. Ehrlichia japonica infection of mice provides an animal model of ehrlichiosis as it recapitulates full-spectrum and lethal ehrlichiosis in humans. The E. japonica transposon mutant of EHF0962, which encodes a previously uncharacterized hypothetical protein, is attenuated in both infection and virulence in mice. EHF0962 was hence named here as resistance-inducing protein of Ehrlichia (RipE). Using this ΔripE mutant, we studied how RipE protein contributes to Ehrlichia pathogenesis. Ehrlichia species have an intracellular developmental cycle and a brief extracellular stage to initiate a new cycle of infection. Majority of RipE proteins were expressed on the surface of the smaller infectious dense-core stage of bacteria. Extracellular ΔripE E. japonica contained significantly less adenosine triphosphate (ATP) and lost infectivity more rapidly in culture compared with wild-type (WT) E. japonica. Genetic complementation in the ΔripE mutant or overexpression of ripE in WT E. japonica significantly increased bacterial ATP levels, and RipE-overexpressing E. japonica was more virulent in mice than WT E. japonica. RipE is conserved among Ehrlichia species. Immunization of mice with recombinant RipE induced an in vitro infection-neutralizing antibody, significantly prolonged survival time after a lethal dose of E. japonica challenge, and cross-protected mice from infection by Ehrlichia chaffeensis, the agent of human monocytic ehrlichiosis. Our findings shed light on the extracellular stage of Ehrlichia, highlighting the importance of RipE and ATP levels in Ehrlichia for extracellular resistance and the next cycle of infection. Thus, RipE is a critical Ehrlichia protein for infection as such can be a potential vaccine target for ehrlichiosis.

Surface protein distribution in Group B Streptococcus isolates from South Africa and identifying vaccine targets through in silico analysis.

Group B Streptococcus (GBS) is a major cause of pneumonia, sepsis, and meningitis in infants younger than 3 months of age. Furthermore, GBS infection in pregnant women is associated with stillbirths and pre-term delivery. It also causes disease in immunocompromised adults and the elderly, but the highest incidence of the disease occurs in neonates and young infants. At this time, there are no licensed vaccines against GBS. Complete GBS genome sequencing has helped identify genetically conserved and immunogenic proteins, which could serve as vaccine immunogens. In this study, in silico reverse vaccinology method were used to evaluate the prevalence and conservation of GBS proteins in invasive and colonizing isolates from South African infants and women, respectively. Furthermore, this study aimed to predict potential GBS vaccine targets by evaluating metrics such as antigenicity, physico-chemical properties, subcellular localization, secondary and tertiary structures, and epitope prediction and conservation. A total of 648 invasive and 603 colonizing GBS isolate sequences were screened against a panel of 89 candidate GBS proteins. Ten of the 89 proteins were highly genetically conserved in invasive and colonizing GBS isolates, nine of which were computationally inferred proteins (gbs2106, SAN_1577, SAN_0356, SAN_1808, SAN_1685, SAN_0413, SAN_0990, SAN_1040, SAN_0226) and one was the surface Immunogenic Protein (SIP). Additionally, the nine proteins were predicted to be more antigenic than the SIP protein (antigenicity score of > 0.6498), highlighting their potential as GBS vaccine antigen targets.

In silico elucidation of protein-protein interaction network in fish pathogen Flavobacterium Columnare

Flavobacterium columnare is a virulent intracellular bacterial pathogen that causes an infection known as columnaris in many species of fish. Some economically important fish species are strongly affected by columnaris, leading to a high mortality rate and significant economic losses. Previous in silico studies have provided various biological insights into F. columnare, including its interaction with MHC class I alleles and the epitopic region within outer membrane proteins. However, the protein-protein interaction networks underlying the growth, defense, and pathogenesis of F. columnare remain largely unknown. This study was conducted to identify the protein-protein interaction (PPI) networks and hub proteins of F. columnare that can be used as drug or vaccine targets. A total of 500 protein sequences were retrieved from UniprotKB in FASTA format and analyzed using VaxiJen, PSORTb, STRING, Cytoscape, and BLASTp programs. The results demonstrated that 60% of F. columnare proteins were predicted as antigenic proteins, most of which were associated with catalytic activity and metabolic processes, identified as cytoplasmic proteins. Ten hub proteins with the highest number of functional interactions were identified, which were also antigenic and non-host homologous. In conclusion, F. columnare hub proteins represent potential therapeutic targets in drug and vaccine development against columnaris infection.

Trichinellaspiralis C-type lectin mediates larva invasion of gut mucosa via binding to syndecan-1 and damaging epithelial integrity in mice

C-type lectin (CTL) plays a vital role in parasite adhesion, invading host's cells and immune escape. The objective of this research was to explore whether recombinant T. spiralis CTL (rTsCTL) binding with syndecan-1 damages intestine epithelial integrity and mediates T. spiralis intrusion in mice. The results showed that rTsCTL interacted with syndecan-1 and activated STAT3 pathway in gut epithelium, decreased tight junctions (TJs) expressions and damaged gut epithelium integrity, promoted T. spiralis intrusion, and increased expression level of inflammatory cytokine and mucin. The syndecan-1 inhibitor (β-xyloside) and STAT3 phosphorylation inhibitor (Stattic) significantly suppressed syndecan-1 expression and STAT3 pathway activation, reduced the expression levels of TJs, pro-inflammatory cytokines (TNF-α and IL-1β), Muc2 and Muc5ac, and declined intestinal permeability in T. spiralis-infected mice. These results revealed that the inhibitors suppressed T. spiralis invasion and development in gut mucosa, decreased intestinal adult burdens and relieved gut inflammation. These findings further testified that the in vivo binding of TsCTL with syndecan-1 destroyed enteral mucosal epithelial integrity and promoted T. spiralis intrusion of gut mucosa via activating STAT3 pathway and decreasing TJs expression. TsCTL could be deemed as a promising vaccine target to interrupt T. spiralis infection.

Allosteric mechanism of membrane fusion activation in a herpesvirus.

Herpesviridae infect nearly all humans for life, causing diseases that range from painful to life-threatening1. These viruses penetrate cells by employing a complex apparatus composed of separate receptor-binding, signal-transmitting, and membrane-fusing components2. But how these components coordinate their functions is unknown. Here, we determined the 4.19-angstrom cryoEM reconstruction of the central signal-transmitting component from herpes simplex virus 2, the gH/gL complex, in its elusive pre-activation state. Analysis of the continuum of conformational ensembles observed in cryoEM data revealed a series of structural rearrangements in gH/gL that allosterically transmit the fusion-triggering signal from the receptor-binding glycoprotein gD to the membrane fusogen gB. Furthermore, we identified a structural "switch" element in gH/gL that refolds and flips 180 degrees during the transition from pre-activation to activated form. Conservation of this "switch" in gH/gL homologs suggests that the proposed fusion triggering mechanism may apply to all Herpesviridae and points to a new target for subunit-based vaccines and treatment efforts.

High prevalence of HPV-56 and HPV-39 in Sari, Iran: an analysis of genotype distribution

BackgroundHuman papillomavirus (HPV) is responsible for the most common sexually transmitted infection, particularly among sexually active individuals. Understanding the geographical distribution and epidemiology of the most prevalent HPV genotypes is essential for developing effective prevention strategies. Consequently, this study aimed to examine the distribution of HPV genotypes among HPV-positive women and men in Sari, the capital city of Mazandaran province in northern Iran.Materials and methodsHPV DNA was extracted (PZP Company, Molecular IVD, Iran) from genital and cervical samples of the study participants. Genotyping was conducted for 90 cases utilizing the High + Low Papilloma Strip test (Operon Company, Spain). Demographic data were statistically analyzed in correlation with the virological data (STATA version 17).ResultsOverall, 67.7% (61 out of 90) of the cases tested positive for HPV, with 75% of those being classified as high-risk. The participant group consisted of 92% females (83) and 8% males (7). The highest HPV prevalence, 75% (36), was observed in females and males aged under 31, with the majority of positive cases belonging to high-risk genotypes. The most frequently identified genotypes were HPV-11 (23%), HPV-6 (21%), HPV-56 (18%), HPV-39 (16%), HPV-16, HPV-91, and HPV-66 each comprising (14%). HPV-56 was the most common high-risk genotype, accounting for 11 cases (18%), followed by HPV-39, which was present in 10 cases (16%).ConclusionThe prevalence of HPV infection was particularly high among individuals under the age of 31 for both genders, with men exhibiting a 100% infection rate. These findings emphasize the urgent need for targeted education aimed at the younger population and the implementation of infection control measures. Specifically, widespread HPV vaccination targeting HPV-6, HPV-11, HPV-39, and HPV-56 should be prioritized for the general population.

Pneumolysin-responsive liposomal platform for selective treatment of Streptococcus pneumoniae.

The bacterium Streptococcus pneumoniae has become a leading cause of meningitis, sepsis, and bacterial pneumonia worldwide, with increased prevalence of antibiotic-resistant serotypes serving to exacerbate the issue. The main factor responsible for colonization and immune response escape in pneumococcal infections is the secreted molecule pneumolysin, which is a subset within a family of related toxins that form transmembrane pores in biological membranes through cholesterol recognition and binding. The conserved activity and structure of pneumolysin between all observed S. pneumoniae serotypes, along with its requirement for pathogenicity, has made this molecule an attractive target for vaccination, diagnostic, and sequestration platforms, but not yet as a facilitative agent for therapeutic treatment. Consequently, the present work aimed to examine the impact of liposomal cholesterol content for pneumolysin-induced release of the encapsulated antimicrobial peptide nisin. It was determined that a cholesterol content above 45mol% was necessary to facilitate interactions with both purified pneumolysin toxin and S. pneumoniae culture, demonstrated through enhanced nisin release and a reduction in hemolytic rates upon exposure of the toxin with cholesterol-rich vesicles. Antibacterial testing highlighted the ability of the developed platform to elicit a potent and specific bactericidal response in vitro against cultured S. pneumoniae when compared to a control strain, Staphylococcus epidermidis. It further improved viability of a fibroblast cell line upon S. pneumoniae challenge, outperforming free nisin via the synergistic impact of simultaneous bacterial clearance and pneumolysin neutralization. These findings collectively indicate that cholesterol-rich liposomes hold promise as a selective treatment platform against pneumococcal infections.

Research Progress of Cryptosporidium Adhesion and Gliding Motility Related Proteins

This review focuses on the complex molecular mechanisms involved in the adhesion and gliding motility of Cryptosporidium, emphasizing the importance of these processes in Cryptosporidium infection and summarizing the virulence factors involved. Subsequently, The manuscript meticulously examines the functional profiles and the chronicled research trajectories of adhesion-associated virulence factors, namely CSL, gp40/15, and gp900. In parallel, it explores the repertoire of factors implicated in gliding motility, including TRAP-C1, Cptsp4, and CpROM. Each factor is contextualized within the broader framework of the parasite's engagement with host defenses and its evasion strategies. Moreover, the review prognosticates the prospective research avenues that these factors are poised to influence, offering a measured appraisal of their viability as targets for vaccine and therapeutic development. The discourse encapsulates the current state of knowledge while venturing into the uncharted territories of potential, thereby establishing a robust foundation for future investigative endeavors aimed at demystifying the biological intricacies and pathogenic mechanisms of Cryptosporidium.

Phase II Trial of HER-Vaxx, a B-cell Peptide-Based Vaccine, in HER2-Overexpressing Advanced Gastric Cancer Patients Under Platinum-Based Chemotherapy (HERIZON).

A multicenter, randomized, open-label, phase II study (HERIZON; NCT02795988) was conducted to evaluate the clinical and immunologic efficacy of HER-Vaxx (IMU-131), a B-cell, peptide-based vaccine targeting HER2 overexpressed in 6% to 30% of gastroesophageal adenocarcinomas (GEA). Patients (n = 36) with GEA were treated with standard-of-care chemotherapy (n = 17) or HER-Vaxx plus chemotherapy (n = 19), using the recommended phase 2 dose for the vaccine. Overall survival (OS; primary endpoint), safety, progression-free survival (PFS), clinical response (secondary endpoints), and vaccine-induced HER2-specific antibody levels in serum and correlation with tumor response rates (exploratory endpoints) were investigated. A 40% OS benefit [HR, 0.60; median OS, 13.9 months; 80% confidence interval (CI), 7.52-14.32] for patients treated with HER-Vaxx plus chemotherapy compared with OS of 8.31 months (80% CI, 6.01-9.59) in patients that received chemotherapy alone. A 20% PFS difference was obtained for the vaccination arm (HR, 0.80; 80% CI, 0.47, 1.38). No additional toxicity due to HER-Vaxx was observed. The vaccine-induced high levels of HER2-specific total IgG and IgG1 antibodies (P < 0.001 vs. controls) that significantly correlated with tumor reduction (IgG, P = 0.001; IgG1, P = 0.016), had a significant capacity in inhibiting phosphorylation of the intracellular HER2-signaling pathways, mediated antibody-dependent cellular cytotoxicity, and decreased immunosuppressive FOXP3+ regulatory T cells. HER-Vaxx plus standard chemotherapy exhibits an excellent safety profile and improves OS. Furthermore, vaccine-induced immune response was significantly associated with reduced tumor size compared with standard-of-care chemotherapy. The presented vaccination approach may substitute for treatment with trastuzumab, upon unavailability or toxicity, based on further evidence of equivalent treatment efficacy.