Search Results (3,946)

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important pathogens affecting the global swine industry. This review summarizes current knowledge of PRRSV-induced suppression of adaptive immune responses, with particular emphasis on impaired T cell activity, dysregulated B cell responses, delayed and insufficient neutralizing antibody production, and viral strategies that limit effective immune clearance. In addition, recent advances and limitations in vaccine development and antiviral strategies are presented. By integrating insights from viral pathogenesis and host immune responses, this review provides a comprehensive perspective on current challenges and emerging strategies for effective PRRSV control. Full article

Oncolytic viruses (OVs) can selectively lyse tumor cells and remodel the immunosuppressive tumor microenvironment. However, monotherapy is limited by low response rates, systemic delivery barriers and antiviral-mediated viral clearance. Combinatorial strategies with immune-checkpoint inhibitors, CAR-T cells, cancer vaccines, microbiota intervention, chemotherapy and radiotherapy produce potent synergistic antitumor effects. Herein, we review the spatiotemporal-dependent synergistic mechanisms by which OVs convert “cold” tumors into immunologically “hot” lesions, alongside recent pre-clinical and clinical progress of various combination regimens. We further discuss major bottlenecks including unstable efficacy, cumulative toxicity and translational obstacles. Several promising biomarkers, such as baseline TME immunophenotypes, dynamic neutralizing-antibody kinetics, STING-IFN signaling and gut microbiota, support individualized OV-based therapy. Finally, we outline near-term sequential-optimization strategies and long-term directions centered on intelligently engineered OVs and multi-modal combinatorial platforms, offering guidance for future rational design of oncolytic viro-immunotherapy. Full article

Background/Objectives: Lyssaviruses pose a persistent global public health threat, underscoring the need for broad-spectrum neutralizing antibodies to improve rabies post-exposure prophylaxis (PEP). The humanized monoclonal antibody cocktail SYN023 is approved for PEP in China and under active global regulatory review. This study aimed to validate pseudovirus-based neutralization assays, verify SYN023 epitope prediction accuracy, and systematically characterize its pan-lyssavirus neutralizing activity. Methods: Assay validation was performed by directly comparing neutralization titers obtained with authentic rabies virus (RABV) and pseudotyped virus. Epitope analysis was performed, followed by in vivo evaluation in a canine PEP challenge model. The pseudovirus-based neutralization assay was used to assess SYN023 broad-spectrum activity across diverse lyssaviruses. Results: Neutralization titers from authentic and pseudotyped viruses showed high concordance (R² = 0.8341, p < 0.0001), supporting the pseudovirus system as a reliable surrogate assay. Epitope analysis confirmed that SYN023’s epitope is fully conserved in the highly virulent New York City (NYC) RABV strain. In canine PEP challenge studies using the NYC strain, SYN023 conferred strong protection at 0.1–0.5 mg/kg. SYN023 exhibited potent neutralizing activity against phylogenetically diverse non-rabies lyssaviruses, including Mokola virus (MOKV; EC₅₀ = 14.74 µg/mL), whereas three clinically validated reference antibodies failed to neutralize MOKV even at concentrations up to 1000 µg/mL. Conclusions: This study demonstrates that the pseudovirus-based neutralization assay is a reliable surrogate assay. It also confirms the functional accuracy of the epitope mapping strategy and demonstrates the broad neutralization spectrum of SYN023 against a diverse panel of lyssaviruses. Full article

Peste des Petits Ruminants (PPR) is an economically devastating transboundary viral disease of small ruminants across Africa, Asia, and the Middle East. Despite effective live attenuated vaccines and the FAO/WOAH global eradication campaign targeting 2030, recurrent outbreaks persist, particularly among young goats. A major underrecognized obstacle is maternal antibody (MA) interference in goat kids, which compromises early-life vaccination and creates hidden immunity gaps within vaccinated herds. Maternal antibodies, acquired exclusively via colostrum, provide temporary passive protection but can neutralize vaccine virus and reduce effective seroconversion. This creates a critical “window of susceptibility” (typically 2–5 months of age) during which goat kids are neither protected against field infection nor responsive to vaccination. Reported estimates vary from approximately 70–100 days to detectability for up to 6 months, depending on the endpoint, assay, and study population. Conventional serosurveillance overestimates herd immunity because seropositive goat kids with residual MAs are falsely classified as protected. Fixed-age mass vaccination campaigns thus fail to achieve effective immunity in the most vulnerable age group. Strategies to overcome MA interference include delayed primary vaccination, booster schedules, targeted immunization, intranasal vaccination, and recombinant vaccines. Major barriers include poor farmer awareness, inadequate cold-chain infrastructure, and transboundary animal movement. Rapid farm turnover represents a separate operational barrier that further complicates vaccination timing. Achieving PPR eradication by 2030 requires a paradigm shift toward age-specific immunity in goat kids. Age-stratified protocols, farmer education, standardized diagnostic thresholds, rapid pen-side MA tests, and longitudinal studies in underrepresented regions including Pakistan are urgently needed. Full article

This study evaluated the serological profile, vaccine-induced antibody response, reproductive performance, and associated reproductive factors in Nellore heifers vaccinated against bovine alphaherpesvirus 1 (BoAHV-1), bovine viral diarrhea virus (BVDV), and Leptospira spp. in a commercial herd in Central Brazil. Heifers (n = 1925) were allocated to four groups: non-vaccinated control (n = 485), Leptospira-vaccinated (n = 478), viral-vaccinated (n = 484), and combined viral–leptospiral-vaccinated (n = 478); a 400-heifer subset was bled before vaccination and 50 and 120 days later. Antibodies were measured by virus neutralization (BoAHV-1, BVDV) and by microscopic agglutination test (Leptospira spp.). Data were analyzed by generalized linear mixed models. Baseline seroprevalence was 49.8% (199/400) for BVDV, 11.2% (45/400) for BoAHV-1, and 1.2% (5/400) for the Leptospira serovars included in the vaccine formulation. Viral-containing vaccines induced marked seroconversion against BoAHV-1 and BVDV in seronegative heifers, sustained to 120 days. The Leptospira spp. response was transient, peaking at 50 days. Pregnancy per artificial insemination after the first fixed-time artificial insemination (FTAI) was 51.4% (990/1925) at 30 and 48.4% (931/1925) at 60 days, with 6.0% pregnancy loss. Cumulative pregnancy over two FTAI did not differ among groups (70.0%; 1317/1881; p = 0.18). Corpus luteum presence (p = 0.0002) and inseminator (p = 0.01) were associated with pregnancy outcome. Direct pathogen detection was not performed, so active infection or viral reactivation could not be ruled out. Pre-breeding vaccination induced pathogen-specific humoral responses, particularly against the viral agents, but was not associated with improved pregnancy outcome under the conditions evaluated. Full article

The progression of chronic kidney disease (CKD) entails the development of complications, such as anemia and disturbances in mineral homeostasis, among others, and both of them have been shown to be closely related. In fact, high phosphorus (P) and excessive production of fibroblast growth factor 23 (FGF23) are hallmarks of the mineral alterations found in CKD, both of which have been associated with the development of anemia. The objective of this study was to evaluate whether the modulation of P load may impact the severity of CKD-related anemia as well as to separate the effects of FGF23 from those of P by the administration of an AntiFGF23 antibody while also investigating the involvement of hypoxia-inducible factor (HIF) signaling in these actions. To address this objective, we used a CKD model based on 5/6 nephrectomy (Nx). In a first experiment, CKD rats received diets with 0.2, 0.6, or 1.2% of P for 4 weeks. In a second study, Nx rats fed a 1.2% P diet were treated with an AntiFGF23 antibody for the same period. In an additional experiment, the effect of the exogenous administration of FGF23 and AntiFGF23 was evaluated. In all the experiments, we analyzed the hematological status, parameters of renal function and mineral metabolism, and HIF signaling. In CKD, the increase in P load was associated with an expected progressive elevation in FGF23 and an aggravation of anemia. In a situation of uremia with high P load, the neutralization of FGF23 restored hematological alterations while producing a significant inhibition in renal HIF1Alpha. In the absence of renal damage, the administration of recombinant FGF23 produced a decrease in serum iron and reticulocytes without changes in HIF signaling. In conclusion, progressive and concomitant increases in P and FGF23 produce an aggravation of anemia of renal origin. In this setting, the normalization of hematological parameters induced by FGF23 blockade is associated with the inhibition of renal HIF signaling. Thus, the implementation of FGF23-targeting therapies might constitute an additional strategy for the clinical management of CKD-related anemia. Full article

Hyperinflammatory disorders are severe clinical syndromes characterized by uncontrolled immune activation, sustained release of inflammatory mediators, and multiorgan injury. Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are two representative hyperinflammatory syndromes. Growing evidence has identified interferon gamma (IFN-γ) as an important mediator, contributing to persistent immune activation and amplification of inflammatory responses. Emapalumab is a fully human, high-affinity monoclonal antibody targeting IFN-γ that exerts its therapeutic effects by selectively neutralizing IFN-γ and suppressing its downstream inflammatory activity. Clinical studies have established the therapeutic utility of emapalumab in primary HLH, while its potential applications are increasingly being explored in Still’s disease-associated MAS, secondary HLH, chimeric antigen receptor (CAR) T-cell therapy-associated hyperinflammatory states, and hematopoietic stem cell transplantation-related settings. This review summarizes the biological basis of IFN-γ-driven hyperinflammation, the molecular mechanism of action of emapalumab, and current clinical evidence for its use in HLH, MAS, and other hyperinflammatory conditions, while discussing the limitations of existing evidence and priorities for future research. Full article

Metabotropic glutamate receptor 2 (mGluR2) is a critical endocytic receptor for influenza A virus (IAV) entry, making it an attractive target for host-directed antiviral interventions. A recombinant truncated fragment of mGluR2 was expressed and purified from HEK293F cells in the present investigation. Immunization of BALB/c mice followed by splenocyte fusion yielded three stable hybridoma clones: 1G3B2, 2D5A9, and 4E1C6. All three monoclonal antibodies (mAbs) exhibited strong binding affinity to both denatured and native forms of mGluR2 in Western blot and immunofluorescence assays. In vitro neutralization assays revealed that clone 1G3B2 reduced H9 subtype IAV titers by approximately 7.7 folds and suppressed intracellular viral antigen expression in a dose-dependent manner. Clones 2D5A9 and 4E1C6, while showing no viral blocking efficacy, are valuable as research tools for Western blot and IFA applications. Genetic sequencing of 1G3B2 resolved its heavy and light chain variable regions, identifying a unique, prolonged heavy-chain CDR3 loop (TRHPVNNWAWFAY). This work reports three mAbs against mGluR2 and 1G3B2 could serve as a candidate agent for developing host-directed anti-influenza therapeutics. Full article

Background: Zika virus (ZIKV) and dengue virus (DENV) co-circulate in tropical regions and elicit cross-reactive immunity. However, differential neutralization of closely related ZIKV strains remains unclear. This study characterizes the neutralization profiles of dengue-immune sera against DENV and two Asian-lineage ZIKV strains, P6-740 and PRVABC59. Methods: Sera from suspected dengue infections and from healthy donors were screened for anti-DENV IgM and IgG antibodies and anti-ZIKV IgM and IgG antibodies by ELISA and grouped. Neutralization against DENV serotypes and two ZIKV strains was quantified using the foci reduction neutralization test (FRNT). Complete genome sequences of ZIKV P6-740 and PRVABC59 were compared to identify amino acid differences. Results: Sera containing anti-DENV IgG showed higher neutralizing activity against both DENV and ZIKV than IgG-negative sera. Neutralization was also detected in some ELISA-seronegative samples. Across all immunological groups, neutralization titers were higher against ZIKV P6-740 than ZIKV PRVABC59. Among healthy donors with evidence of previous dengue exposure, 58% exhibited a ≥4-fold difference between the two ZIKV strains, of which 80% favored ZIKV P6-740. Among seronegative healthy blood donors, 45% exhibited a 4-fold difference, of which 89% favored P6-740. Four amino acid substitutions were identified in the envelope (E) protein. Conclusions: Dengue-induced immunity differentially neutralizes closely related ZIKV strains, with generally stronger activity against P6-740, suggesting that viral genetic variation may influence cross-neutralization outcomes. Full article

Background/Objectives: During the 2025–26 influenza season, the antigenically distinct A(H3N2) subclade K emerged and spread globally, raising significant concerns regarding seasonal vaccine effectiveness. This study aimed to map antigenic and structural divergence of this novel strain compared to the 2025/26 A(H3N2) vaccine component. Furthermore, we investigated how this vaccine mismatch impacts functional humoral immunity by directly comparing antibody neutralization profiles between individuals with vaccine-induced protection and those with infection-acquired immunity. Methods: Phylogenetic and structural modeling analyses were performed on 2025–26 Israeli influenza samples to identify genetic distances and mutations in the hemagglutinin protein compared to the 2025/26 A(H3N2) vaccine component. Hemagglutination inhibition (HI) and microneutralization assays were conducted using 2025–26 winter serum samples from a cohort of vaccinated healthcare workers and vaccinated convalescents to quantify antibody responses against both vaccine-like and subclade K strains. Results: Phylogenetic analysis revealed a clear dominance of the subclade K strain in Israel during the winter of 2025–26. Significant vaccine mismatch was defined by eight newly identified hemagglutinin mutations in the circulating subclade K strains. Serological testing demonstrated that while vaccination alone produced a modest two-to-three-fold increase in antibody titers, baseline protection against subclade K remained critically low. Conversely, natural infection in vaccinated convalescents elicited a significantly stronger, broader immune response, demonstrating a 6-fold and 13-fold increase in neutralizing antibodies against the vaccine-like and subclade K strains, respectively. Conclusions: Natural infection provides a more pronounced increase in both binding and neutralizing antibodies compared to vaccination alone, which might contribute to broader cross-protection against antigenically drifted variants. These findings highlight the primary limitations of current influenza strain prediction and emphasize the urgent need for faster, more adaptable vaccine manufacturing platforms to better match actual circulating strains. Full article

Background/Objectives: Conjugation of polyethylene glycol (PEG) to L-asparaginase (ASP) reduces immunogenicity and prolongs the half-life of this biological drug used to treat acute lymphoblastic leukemia (ALL). However, some patients develop anti-drug antibodies (anti-ASP and anti-PEG), which may impair efficacy through neutralization or faster elimination and may cause hypersensitivity reactions. Their clinical impact remains debated, partly due to variability in analytical methods and cut-points often defined by statistical rather than clinical outcomes. Methods: To address this issue, we used two assays to measure anti-PEG antibodies in 27 sera from 25 children with ALL who showed reactions to PEG-ASP—either clinical allergy with reduced ASP activity (n = 18) or allergic-like reactions without major activity loss (n = 9)—and in 25 sera from 19 children with ALL but without clinically relevant reactions. Sera from 16 healthy children were used as controls. This design enabled assessment of sensitivity and specificity using clinically relevant cut-points. Results: Anti-PEG IgG (but not IgM), measured by ELISA, correlated with reduced drug activity, showing 83% sensitivity and 91% specificity. We also developed a surface plasmon resonance (SPR) assay, capable of detecting simultaneously both anti-PEG and anti-ASP antibodies and analyzing binding kinetics. ROC analysis of SPR data showed 78% sensitivity and 94% specificity. Conclusions: Overall, these findings highlight the importance of clinically defined cut-points, support a key role of anti-PEG antibodies in hypersensitivity with reduced drug activity, and suggest that measuring anti-PEG antibodies may help guide therapeutic decisions. Full article

Background/Objectives: Despite the gradual waning of global interest in SARS-CoV-2, the continued evolution and emergence of viral variants underscore the need for broadly protective vaccines. Vaccines targeting the highly mutable S1 subunit of the spike protein have shown limited breadth of protection, whereas conserved regions within the S2 fusion machinery remain critical targets for the development of vaccines effective against future variants. This study evaluated two mRNA-lipid nanoparticle (mRNA-LNP) vaccines encoding HR121, a conserved HR1-HR2-HR1 fusion-intermediate immunogen, in comparison with a recombinant HR121 protein vaccine. Methods: Two mRNA vaccine candidates, TM-HR121 and Fc-HR121, were designed to present HR121 through distinct antigen presentation strategies by incorporating a transmembrane anchor or an IgG Fc domain, respectively. Immunogenicity and protective efficacy were assessed in New Zealand White rabbits, BALB/c mice, and Golden Syrian hamsters. Results: Both mRNA vaccines elicited robust HR121-specific binding antibody responses and broad neutralizing activity against seven SARS-CoV-2 pseudoviruses in rabbits. In mice, the mRNA vaccines induced higher peak IgG titers, a more balanced IgG1/IgG2a profile, stronger antigen-specific IFN-γ responses, and enhanced T-cell responses compared with the recombinant protein vaccine, while maintaining detectable IL-4 responses. In hamsters, immunization with the HR121 mRNA vaccines significantly reduced lung viral RNA levels and attenuated pulmonary pathology and nucleocapsid antigen expression following authentic SARS-CoV-2 challenge. Conclusions: HR121-based mRNA-LNP vaccines successfully elicited cross-variant humoral and cellular immune responses and conferred protective efficacy in small-animal models. These findings support HR121 mRNA-LNP vaccines as a promising strategy for the development of broadly protective coronavirus vaccines targeting conserved S2 fusion epitopes. Full article

Background/Objectives: Bovine ephemeral fever virus (BEFV) causes an economically important arthropod-borne cattle disease. In 2023, a lineage I “Mayotte-like” (ML) strain emerged in Israel during an outbreak in vaccinated herds, raising concerns about its antigenic match with the live-attenuated vaccine based on Australian strain 919. We compared G-protein neutralizing sites and cross-neutralization among the vaccine strain, Israeli lineage IIIa strains from 2000 and 2021, and ML. Methods: G1–G3 neutralizing-site sequences were compared. Serum-neutralization assays tested all four viruses using sera from 87 cattle across five vaccination/exposure groups. Log₂-transformed titers were compared within animals. Results: ML differed from the vaccine strain at eight amino acid positions within G1–G3, whereas the lineage IIIa strains differed from the vaccine strain at three or four positions. In vaccinated, unexposed calves, neutralizing titers against the vaccine and 2021 strains were 4.0- and 2.7-fold higher, respectively, than against ML (both p < 0.01). In unvaccinated 2021-exposed cattle, titers against the 2021 strain were 6.5-fold higher than against ML (p < 0.01). In unvaccinated 2023-exposed cattle, titers against ML were 4.76-fold higher than against the vaccine strain (p < 0.01). Between-strain differences were smaller in vaccinated 2023-exposed cattle. Conclusions: Sequence divergence and cross-neutralization indicate a markedly reduced antigenic match between the Australian 919 vaccine strain and the ML strain. Given the continued circulation and emergence of antigenically divergent BEFV strains and their potential for geographic spread, challenge and field-effectiveness studies are urgently needed to determine the clinical protection afforded by the current vaccine. Lineage-matched or multivalent vaccines should therefore be prioritized to broaden protection against circulating and newly emerging strains. Full article

Background/Objectives: Adults eligible for respiratory syncytial virus (RSV) vaccination may also receive influenza, COVID-19, pneumococcal, or herpes zoster vaccines. We compared immunogenicity and safety between coadministration and sequential schedules. Methods: We searched PubMed, Embase, Web of Science, Scopus, and CENTRAL from inception to 3 August 2026 for randomized trials in adults aged 50 years or older. Eligible trials compared RSVPreF3 OA coadministration with sequential administration of the partner vaccine followed by RSVPreF3 OA. Random-effects models pooled neutralizing-antibody geometric mean ratios (GMRs; coadministration/sequential) separately for RSV-A and RSV-B and risk ratios for safety outcomes. Risk of bias and certainty were assessed using RoB 2 and GRADE, respectively. Results: Six trials randomized 5455 participants. Pooled RSV-A and RSV-B GMRs were 0.895 (95% CI 0.816–0.983) and 0.922 (95% CI 0.837–1.016), respectively. In trial-specific per-protocol analyses, non-inferiority criteria were met for recombinant zoster vaccine (RZV) and 20-valent pneumococcal conjugate vaccine (PCV20) antibody endpoints, but non-inferiority was not demonstrated for SARS-CoV-2 XBB.1.5 neutralizing antibodies (GMR 0.763, 95% CI 0.662–0.885) or the adjuvanted quadrivalent influenza vaccine A/H3N2 response. The pooled risk ratio for serious adverse events was 0.831 (95% CI 0.530–1.303), with limited precision. Certainty was low for RSV-A and very low for RSV-B, mainly reflecting risk of bias and inconsistency. Conclusions: In adults aged 50 years or older, same-day RSVPreF3 OA coadministration was associated with lower RSV-neutralizing antibody responses than sequential administration, while partner-vaccine immunogenicity varied by product and antigen. Non-inferiority was not demonstrated for the SARS-CoV-2 XBB.1.5 and adjuvanted-QIV A/H3N2 antibody endpoints. No clear safety difference between schedules was identified, and the clinical significance of the antibody differences remains uncertain. Registration: PROSPERO CRD420261470812. Full article

Objectives: The VaCoMRI study tracked a cohort of healthcare workers from 2020 through June 2024 to characterize the long-term sustainability of hybrid and vaccine-induced SARS-CoV-2 immunity. Methods: An initial anti-nucleocapsid (N) IgG screening of 4554 health-care workers in early 2020 identified participants who had been infected during the first wave. Anti-N-positive and anti-N-negative individuals then received BNT162b2 through the institutional vaccination program, yielding groups with hybrid and vaccine-induced immunity. Both groups were monitored regularly for nearly four years for breakthrough infections (BTI). Serum collected regularly after vaccination and after BTI was analyzed for anti-N, quantitative anti-spike (anti-S) IgG, and surrogate viral neutralizing antibody (sVNT) titers. Results: Over a median follow-up of 1180 days, 142 healthcare workers contributed longitudinal samples; 66.2% experienced one BTI and 14.1% a second. In initially seronegative individuals, anti-N titers decreased 2.3-fold between 3 and 6 months after the first BTI, with seropositivity dropping from 82% to 40.4% (median time to seronegativity: 179 days). Prior anti-N seropositivity was associated with 4.5-fold higher anti-N IgG levels after BTI, with elevated levels persisting through 9 months. In both groups, the third vaccine dose significantly enhanced anti-S antibody persistence after 9 months compared to the second dose. In infection-naïve individuals, anti-S IgG titers remained 4.2-fold and sVNT titers 7.2-fold higher. Hybrid immunity was similarly durable: two vaccine doses after prior anti-N seropositivity yielded anti-S IgG and sVNT levels comparable to three-dose vaccination. Conclusions: This study demonstrates a rapid waning of anti-N IgG that severely limits its reliability for retrospective serosurveillance of SARS-CoV-2 exposure in occupational settings. The combination of vaccination and infection induced robust and durable spike-directed antibody responses. However, these were determined using assays based on the ancestral spike protein. This may limit the prediction of protection from SARS-CoV-2 variants, which usually cause BTIs. Full article