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bioRxiv2021

Subtle immunological differences in mRNA-1273 and BNT162b2 COVID-19 vaccine induced Fc-functional profiles

The successful development of several COVID-19 vaccines has substantially reduced morbidity and mortality in regions of the world where the vaccines have been deployed. However, in the wake of the emergence of viral variants, able to evade vaccine induced neutralizing antibodies, real world vaccine efficacy has begun to show differences across the mRNA platforms, suggesting that subtle variation in immune responses induced by the BNT162b2 and mRNA1273 vaccines may provide differential protection. Given our emerging appreciation for the importance of additional antibody functions, beyond neutralization, here we profiled the postboost binding and functional capacity of the humoral response induced by the BNT162b2 and mRNA-1273 in a cohort of hospital staff. Both vaccines induced robust humoral immune responses to WT SARS-CoV-2 and VOCs. However, differences emerged across epitopespecific responses, with higher RBD- and NTD-specific IgA, as well as functional antibodies (ADNP and ADNK) in mRNA-1273 vaccine recipients. Additionally, RBD-specific antibody depletion highlighted the different roles of non-RBD-specific antibody effector function induced across the mRNA vaccines, providing novel insights into potential differences in protective immunity generated across these vaccines in the setting of newly emerging VOCs.

immunology↗

bioRxiv2021

SARS-CoV-2 vaccination induces immunological memory able to cross-recognize variants from Alpha to Omicron

We address whether T cell responses induced by different vaccine platforms (mRNA-1273, BNT162b2, Ad26.COV2.S, NVX-CoV2373) cross-recognize SARS-CoV-2 variants. Preservation of at least 83% and 85% for CD4+ and CD8+ T cell responses was found, respectively, regardless of vaccine platform or variants analyzed. By contrast, highly significant decreases were observed for memory B cell and neutralizing antibody recognition of variants. Bioinformatic analyses showed full conservation of 91% and 94% of class II and class I spike epitopes. For Omicron, 72% of class II and 86% of class I epitopes were fully conserved, and 84% and 85% of CD4+ and CD8+ T cell responses were preserved. In-depth epitope repertoire analysis showed a median of 11 and 10 spike epitopes recognized by CD4+ and CD8+ T cells from vaccinees. Functional preservation of the majority of the T cell responses may play an important role as a second-level defense against diverse variants.

immunology↗

bioRxiv2022

Immunological memory to Common Cold Coronaviruses assessed longitudinally over a three-year period

Understanding immune memory to Common Cold Coronaviruses (CCCs) is relevant for assessing its potential impact on the outcomes of SARS-CoV-2 infection, and for the prospects of pan-corona vaccines development. We performed a longitudinal analysis, of pre-pandemic samples collected from 2016-2019. CD4+ T cells and antibody responses specific for CCC and to other respiratory viruses, and chronic or ubiquitous pathogens were assessed. CCC-specific memory CD4+ T cells were detected in most subjects, and their frequencies were comparable to those for other common antigens. Notably, responses to CCC and other antigens such as influenza and Tetanus Toxoid (TT) were sustained over time. CCC-specific CD4+ T cell responses were also associated with low numbers of HLA-DR+CD38+ cells and their magnitude did not correlate with yearly changes in the prevalence of CCC infections. Similarly, spike RBD-specific IgG responses for CCC were stable throughout the sampling period. Finally, high CD4+ T cell reactivity to CCC, but not antibody responses, was associated with high pre-existing SARS-CoV-2 immunity. Overall, these results suggest that the steady and sustained CCC responses observed in the study cohort are likely due to a relatively stable pool of CCC-specific memory CD4+ T cells instead of fast decaying responses and frequent reinfections.

immunology↗

bioRxiv2022

Aedes aegypti Malpighian tubules are immunologically activated following systemic Toll activation

BackgroundCanine heartworm is a widespread and potentially fatal mosquito-borne disease caused by infections with the parasitic nematode, Dirofilaria immitis. We have previously shown that systemic activation of the Toll immune pathway via silencing of the negative regulator Cactus in Aedes aegypti blocks parasite development in the Malpighian tubules, the mosquito renal organ. However, it was not established whether the Malpighian tubules were directly responding to Toll activation or were alternatively responding to upregulated proteins or other changes to the hemolymph driven by other tissues. Distinguishing these possibilities is crucial for developing more precise strategies to block D. immitis while potentially avoiding the fitness cost to the mosquito associated with Cactus silencing. MethodsThis study defines the transcriptional response Malpighian tubules and changes to the hemolymph proteome of Ae. aegypti after systemic Toll activation via intra-thoracic injection of dsCactus. ResultsWe found Malpighian tubules significantly increase expression of Toll pathway target genes that significantly overlapped expression changes occurring in whole mosquitoes. Additionally, we identified a significant overlap between the transcriptional response of the Malpighian tubules and proteins upregulated in the hemolymph. ConclusionsOur data show that Malpighian tubules are capable of RNAi-mediated gene silencing and directly respond to dsCactus treatment by upregulating canonical Toll pathway targets. Though not definitive, the strong correspondence between the Malpighian tubule transcriptional and the hemolymph proteomic responses provides evidence that the tubules may contribute to mosquito humoral immunity.

immunology↗

bioRxiv2022

Polyethylene glycol (PEG)-associated immunological effects triggered by clinically relevant lipid nanoparticles

With the large-scale vaccination of lipid nanoparticles (LNP)-based COVID-19 mRNA vaccines, elucidating the potential polyethylene glycol (PEG)-associated immune responses triggered by clinically relevant LNP has become imminent. However, inconsistent findings were observed across very limited population-based studies. Herein we initiated a study using LNP carrier of Comirnaty(R) as a representative, and simulated real-world clinical practice covering a series of time points and various doses correlated with approved LNP-delivered drugs in a rat model. We demonstrated the time- and dose-dependency of LNP-induced anti-PEG antibodies in rats. As a thymus-independent antigen, LNP unexpectedly induced isotype switch and immune memory, leading to rapid enhancement and longer lasting time of anti-PEG IgM and IgG upon re-injection in rats. Importantly, initial LNP injection accelerated the blood clearance of subsequent dosing in rats. These findings refine our understandings on LNP and possibly other PEG derivatives, and may promote optimization of related premarket guidelines and clinical protocols.

immunology↗

bioRxiv2023

Impact of aging on the immunological and microbial landscape of the lung during non-tuberculous mycobacterial infection

Nontuberculous mycobacteria (NTM) are environmentally ubiquitous and predominately cause pulmonary disease (NTMPD). The incidence of NTMPD has steadily increased and is now more prevalent than that of Mycobacterium tuberculosis (M. tb) in the US. Moreover, the prevalence of NTMPD increases with age; therefore, it is likely that the burden of NTMPD will continue to increase in the coming decades as the number of those over the age of 65 increased in the U.S population. However, the mechanisms leading to higher susceptibility and severity of NTMPD with aging are poorly defined. Here, we used a rhesus macaque model of intrabronchial infection with M. avium complex in young and aged animals to address this knowledge gap. Unilateral infection resulted in a robust inflammatory response predominantly in the inoculated lung, however, immune cell infiltration and antigen-specific T cell responses were detected in both lungs. Nasal, oral, and fecal swabs, and BAL samples were profiled using 16S amplicon sequencing. These data suggested that decompartmentalization of the lower respiratory microbiome was occurring, evidenced by detection of bacterial DNA typically found in the gut and oral-pharyngeal cavity in bronchoalveolar samples following infection. Radiographic studies, gross pathology, and histopathology examination revealed increased disease severity in aged compared to young animals with pulmonary consolidation, edema, and lesions. Finally, single cell RNA sequencing indicated that aged animals generated a dysregulated macrophage and CD8 T cell response to MAC infection.

immunology↗

bioRxiv2023

Addition of adjuvant to DTaP modulates vaccine-induced immunological responses but is insufficient to improve protection in CD-1 mice

3.1Pertussis is a vaccine-preventable respiratory disease caused by the Gram-negative bacterium Bordetella pertussis. While vaccination rates remain high in developed countries, incidence of pertussis has increased following the transition from wP vaccines to aP vaccines. The reemergence of pertussis is attributed, in part, to waning immunity induced by aP vaccination. Therefore, the objective of this work was to determine if addition of adjuvant to DTaP can modulate the immune response and improve protection compared to DTaP alone. In this study we immunized outbred, female CD-1 mice with 1/320th the human dose of vehicle control, DTaP, and DTaP supplemented with adjuvant. Markers of early vaccine-induced memory were measured using a chemokine assay or by flow cytometry. Protection was assessed by measuring serological responses and quantifying bacterial burden in the respiratory tract at day 3 post-challenge. From this work we identified a partially protective aP vaccine dose to use for vaccination and challenge studies. We observed that MPLA and SWE promote robust anti-B. pertussis antibody responses and stimulate significant increases in early markers of vaccine-induced memory such as CXCL13, FDCs, and TFH cells. Quil-A induced Th1 responses compared to DTaP alone, but none of the adjuvants improved protection against challenge with B. pertussis. Overall, the data suggests that addition of adjuvant modulates the protective immune responses induced by aPs. Further studies are needed to evaluate the B cell compartment and longevity of protection.

immunology↗

bioRxiv2023

Multi-omic Profiling Reveals Early Immunological Indicators for Identifying COVID-19 Progressors

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a rapid response by the scientific community to further understand and combat its associated pathologic etiology. A focal point has been on the immune responses mounted during the acute and post-acute phases of infection, but the immediate post-diagnosis phase remains relatively understudied. We sought to better understand the immediate post-diagnosis phase by collecting blood from study participants soon after a positive test and identifying molecular associations with longitudinal disease outcomes. Multi-omic analyses identified differences in immune cell composition, cytokine levels, and cell subset-specific transcriptomic and epigenomic signatures between individuals on a more serious disease trajectory (Progressors) as compared to those on a milder course (Non-progressors). Higher levels of multiple cytokines were observed in Progressors, with IL-6 showing the largest difference. Blood monocyte cell subsets were also skewed, showing a comparative decrease in non-classical CD14-CD16+ and intermediate CD14+CD16+ monocytes. Additionally, in the lymphocyte compartment, CD8+ T effector memory cells displayed a gene expression signature consistent with stronger T cell activation in Progressors. Importantly, the identification of these cellular and molecular immune changes occurred at the early stages of COVID-19 disease. These observations could serve as the basis for the development of prognostic biomarkers of disease risk and interventional strategies to improve the management of severe COVID-19. One Sentence SummaryImmunological changes associated with COVID-19 progression can be detected during the early stages of infection.

immunology↗

bioRxiv2023

Systems immunology of transcriptional responses to viral infection identifies conserved antiviral pathways across macaques and humans

Viral pandemics and epidemics pose a significant global threat, with emerging and re-emerging viruses responsible for four pandemics in the 21st century alone. While macaques have been utilized as a model for understanding viral disease in a controlled setting, it remains unclear how conserved the antiviral responses to diverse viruses are between macaques and humans. To address this critical knowledge gap, we conducted a comprehensive cross-species analysis of transcriptomic data from over 6000 blood samples from macaques and humans infected with one of 31 viruses, including Lassa, Ebola, Marburg, Zika, and dengue. Our findings demonstrate that irrespective of primate or viral species, there are conserved antiviral responses which are consistent regardless of infection phase (acute, chronic, or latent) and viral genome type (DNA or RNA viruses). Moreover, by leveraging longitudinal data from experimental challenges, we identified virus-specific response dynamics such as host responses to Coronaviridae and Orthomyxoviridae infections peaking 1-3 days earlier than responses to Filoviridae and Arenaviridae viral infections. Additionally, through comparative analysis of immune responses across viruses, we identified a unique enrichment of lymphoid cellular response modules in macaque Flaviviridae infection that persists in human responses to dengue. Our results underscore macaque studies as a powerful tool for gaining new insights into viral pathogenesis and immune responses that translate to humans, which can inform viral therapeutic development and enable pandemic preparedness. One sentence summaryUsing longitudinal macaque viral challenge studies, we identified shared and virus-specific responses to infection that replicate in human viral disease - thereby demonstrating the utility of macaque models of viral infection to understand antiviral biology and for pandemic preparedness.

immunology↗

bioRxiv2023

ZEB1 shapes AML immunological niches suppressing CD8 T-cell activity while fostering Th17 cell expansion.

Acute myeloid leukemia (AML) development and progression is favored by immune suppression directly triggered by leukemia cells. ZEB1 is a key transcription factor in epithelial-to-mesenchymal transition which, we show here, is capable immune regulation in AML. Leukemic cells which had ZEB1 knocked down have reduced engraftment and extramedullary disease when transplanted into immune competent mice due to concomitant activation of CD8 T lymphocytes and reduced expansion of Th17 cells. Differently, in ZEB1 competent AML, IL-17 sustains the development of a pro-invasive and self-maintaining loop inducing MMPs and SOCS2. In humans, AML patients show, in situ on bone marrow biopsies, a direct correlation between ZEB1 and Th17 and, in gene expression profile when divided according to the median value of ZEB1 expression, a different overall survival and relapse along with the expression of MMPs, SOCS2 and Th17 cells enrichment. Overall, our data shed new light into the role of ZEB1 in AML that entwines both pro-tumoral and immune regulatory capacity in AML blasts.

immunology↗

bioRxiv2023

Immunologic changes are detectable in the peripheral blood transcriptome of clinically asymptomatic Chagas cardiomyopathy patients

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a neglected parasitic disease that affects approximately 6 million individuals worldwide. Of those infected, 20-30% will go on to develop chronic Chagas cardiomyopathy (CCC), and ultimately many of these individuals will progress to advanced heart failure. The mechanism by which this progression occurs is poorly understood, as few studies have focused on early CCC. In this study, we sought to understand the physiologic changes associated with T. cruzi infection and the development of CCC. We analyzed gene expression in the peripheral blood of asymptomatic Chagas patients with early structural heart disease, Chagas patients without any signs or symptoms of disease, and Chagas-negative patients with and without early structural heart disease. Our analysis shows that early CCC was associated with a downregulation of various peripheral immune response genes, with gene expression changes suggestive of reduced antigen presentation and T cell activation. Notably, these genes and processes were distinct from those of early cardiomyopathy in Chagas-negative patients, suggesting that the processes mediating CCC may be unique from those mediating progression to other cardiomyopathies. This work highlights the importance of the immune response in early CCC, providing insight into the early pathogenesis of this disease. The changes we have identified may serve as biomarkers of progression and could inform strategies for the treatment of CCC in its early stages, before significant cardiac damage has occurred.

immunology↗

bioRxiv2023

Tick bite-induced Alpha-Gal Syndrome and Immunologic Responses in an Alpha-Gal Deficient Murine Model

IntroductionAlpha-Gal Syndrome (AGS) is a delayed allergic reaction due to specific IgE antibodies targeting galactose--1,3-galactose (-gal), a carbohydrate found in red meat. This condition has gained significant attention globally due to its increasing prevalence, with more than 450,000 cases estimated in the United States alone. Previous research has established a connection between AGS and tick bites, which sensitize individuals to -gal antigens and elevate the levels of -gal specific IgE. However, the precise mechanism by which tick bites influence the hosts immune system and contribute to the development of AGS remains poorly understood. This study investigates various factors related to ticks and the host associated with the development of AGS following a tick bite, using mice with a targeted disruption of alpha-1,3-galactosyltransferase (AGKO) as a model organism. MethodsLone-star tick (Amblyomma americanum) and gulf-coast tick (Amblyomma maculatum) nymphs were used to sensitize AGKO mice, followed by pork meat challenge. Tick bite site biopsies from sensitized and non-sensitized mice were subjected to mRNA gene expression analysis to assess the host immune response. Antibody responses in sensitized mice were also determined. ResultsOur results showed a significant increase in the titer of total IgE, IgG1, and -gal IgG1 antibodies in the lone-star tick-sensitized AGKO mice compared to the gulf-coast tick-sensitized mice. Pork challenge in Am. americanum -sensitized mice led to a decline in body temperature after the meat challenge. Gene expression analysis revealed that Am. americanum bites direct mouse immunity toward Th2 and facilitate host sensitization to the -gal antigen, while Am. maculatum did not. ConclusionThis study supports the hypothesis that specific tick species may increase the risk of developing -gal-specific IgE and hypersensitivity reactions or AGS, thereby providing opportunities for future research on the mechanistic role of tick and host-related factors in AGS development.

immunology↗

bioRxiv2024

Novel 3-D macrophage spheroid model reveals reciprocal regulation of immunomechanical stress and mechano-immunological response

PurposeIn many diseases, an overabundance of macrophages contributes to adverse outcomes. While numerous studies have compared macrophage phenotype after mechanical stimulation or with varying local stiffness, it is unclear if and how macrophages themselves contribute to mechanical forces in their microenvironment. MethodsRaw 264.7 murine macrophages were embedded in a confining agarose gel, where they proliferated to form spheroids over time. Gels were synthesized at various concentrations to tune the stiffness and treated with various growth supplements to promote macrophage polarization. The spheroids were then analyzed by immunofluorescent staining and qPCR for markers of proliferation, mechanosensory channels, and polarization. Finally, spheroid geometries were used to computationally model the strain generated in the agarose by macrophage spheroid growth. ResultsMacrophages form spheroids and generate growth-induced mechanical forces (i.e., solid stress) within confining agarose gels, which can be maintained for at least 16 days in culture. Increasing agarose concentration restricts spheroid expansion, promotes discoid geometries, limits gel deformation, and induces an increase in iNOS expression. LPS stimulation increases spheroid growth, though this effect is reversed with the addition of IFN-{gamma}. Ki67 expression decreases with increasing agarose concentration, in line with the growth measurements. ConclusionsMacrophages alone both respond to and generate solid stress. Understanding how macrophage generation of growth-induced solid stress responds to different environmental conditions will help to inform treatment strategies for the plethora of diseases that involve macrophage accumulation.

immunology↗

bioRxiv2024

Spatiotemporal transcriptomic profiling reveals the dynamic immunological landscape of alveolar echinococcosis

Alveolar echinococcosis (AE) is caused by the invasive growth of the metacestodes of Echinococcus multilocularis (E. multilocularis). The early diagnosis, management, and treatment of AE remains challenging. Herein, we integrated bulk RNA-seq, scRNA-seq, and ST technologies to reveal the immune characteristics both spatially and chronologically in E. multilocularis infected mouse liver. An unprecedented high-resolution spatial atlas of the E. multilocularis infection foci was obtained, revealing the pivotal role of neutrophils, Spp1+ monocyte-derived macrophages (MoMFs), and fibroblasts in AE progression. We observed continuous recruitment of neutrophils and macrophages into the infected tissues, indicating prolonged immune stimulation by the growing metacestodes. However, their spatial distribution patterns and functions changed during the infection cause. At the early infection stage, Il1bhi neutrophils aggregated in the lesion displayed the highest pattern-recognition receptor activity and may kill the metacestodes through NETosis, but their death in the infection foci might also trigger immune suppression. Meanwhile, Spp1+ MoMFs attached to the protoscoleces to clear the infection. At the late infection stage, the neutrophils failed to infiltrate into the lesion although their continuous recruitment into the infected liver. Even though the Spp1+ MoMFs enclosing the microcysts of E. multilocularis may retain their pathogen-killing ability, they may also promote fibrosis and angiogenesis through interaction with fibroblasts. The pro- and anti-inflammatory phenotype balance of these immune cells may be associated with the transition of parasite control strategy from "active killing" to "negative segregation" by the host. Our findings identify key molecular traits involved in AE development, which may benefit the treatment of echinococcosis.

immunology↗

bioRxiv2024

The reparative immunologic consequences of stem cell transplantation as a cellular therapy for refractory Crohn's disease

BackgroundTreatment strategies for Crohns disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) has emerged as a therapy for medically refractory CD. SCT was developed to rescue cancer patients from myelosuppressive chemotherapy but its use for CD and other immune diseases necessitates reimagining SCT as a cellular therapy that restores appropriately responsive immune cell populations from hematopoietic progenitors in the stem cell autograft (i.e. immune "reset"). Here we present a paradigm to understand SCT as a cellular therapy for immune diseases and reveal how SCT re-establishes cellular immunity utilizing high-dimensional cellular phenotyping and functional studies of the stem cell grafts. MethodsImmunophenotyping using CyTOF, single cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing was performed on peripheral blood and intestinal tissue samples from refractory CD patients who underwent SCT. The stem cell graft from these patients was analyzed using flow cytometry and functionally interrogated using a murine model for engraftment. ResultsOur study revealed a remodeling of intestinal macrophages capable of supporting mucosal healing that was independently validated using multimodal studies of immune reconstitution events including CyTOF and scRNA-seq. Functional interrogation of hematopoietic stem cells (HSCs) using a xenograft model demonstrated that HSCs shape the timing of immune reconstitution, the selected reconstitution of specific cell lineages and potentially the clinical efficacy of SCT. ConclusionsThese studies indicate that SCT serves as a myeloid-directed cellular therapy re-establishing homeostatic intestinal macrophages that support intestinal healing and suggest refractory CD evolves from impairment of restorative functions in myeloid cells. Furthermore, we report heterogeneity among HSCs from CD patients which may drive SCT outcomes and suggests an unrecognized impact of CD pathophysiology on HSC in the marrow niche.

immunology↗

bioRxiv2024

The differential immunological impact of photon vs proton radiation therapy in high grade lymphopenia

Radiation therapy has long been a cornerstone of cancer treatment. More recently, immune checkpoint blockade has also been applied across a variety of cancers, often leading to remarkable response rates. However, photon-based radiotherapy - which accounts for the vast majority - is also known to frequently induce profound lymphopenia, which might limit the efficacy of immune system based combinations. Proton beam therapy is known to produce a less drastic lymphopenia, which raises the possibility of greater synergy with immunotherapy. In this study we aimed to explore the exact nature of the differential impact of the two radiation modalities upon the immune system. We used multiparametric flow cytometry and deep sequencing of rearranged TCRb loci to investigate a cohort of 20 patients with gastrointestinal tumors who received either therapy. Proton-treated patients remained relatively stable throughout treatment for most metrics considered, whereas those who received photons saw a profound depletion in naive T cells, increase in effector/memory populations, and loss of TCR diversity. The repertoires of photon-treated patients underwent oligoclonal expansion after their lymphocyte count nadirs, particularly of CD8+ Temra cells, driving this reduction in diversity. Across the entire cohort, this reduction in post-nadir diversity inversely correlated with the overall survival time of those patients who died. This raises the possibility that increased adoption of proton-based or other lymphocyte sparing radiotherapy regimes may lead to better survival in cancer patients.

immunology↗

bioRxiv2024

Unraveling the immunological roles of serum amyloid A3 in aortic immune cell subsets during atherosclerosis progression

Atherosclerosis is a growing concern in developed nations, necessitating the identification of therapeutic targets for advancing personalized medicine. Serum amyloid A3 (Saa3) has been linked to accelerated plaque progression by affecting cholesterol metabolism and modulation of inflammation. We hypothesize that knocking out Saa3 (Saa3-/-) could mitigate plaque development by regulating aortic immune cell compositions during atherosclerosis progression. Using a murine model, we induced atherosclerosis via a gain-of-function mutant PCSK9-encoding adeno-associated viral vector (AAVmPCSK9) in female wild-type (WT) and Saa3-/- mice. Saa3-/- mice developed smaller plaques than WT mice, and single-cell RNA sequencing revealed significant differences in aortic immune cell populations, particularly among aortic macrophages. Aortic macrophages in atherosclerotic Saa3-/-mice represent an anti-inflammatory and tissue-repairing phenotype and the Trem2hi macrophages, characterized by high Gpnmb, Lpl, and Spp1 expressions, predominated over the typical foamy macrophages in Saa3-/- compared to WT mice. Notably, SAA3 regulates cholesterol metabolism and inflammatory responses in foamy macrophages. Our study highlights Saa3 as a key modulator of aortic immune cells that impact atherosclerosis progression.

immunology↗

bioRxiv2024

Immunological response against bovine viral diarrhoea virus (BVDV) types 1 and 2 after vaccination with DIVENCE (R), measured by ELISA and serum neutralisation on serum and milk samples

BackgroundA novel subunit vaccine, DIVENCE(R), comprises different bovine respiratory and reproductive antigens, including BVDV-1 E2 recombinant glycoprotein and BVDV-2 E2 recombinant glycoprotein. This study evaluated the immune response against BVDV-1 and 2 generated by DIVENCE(R) over the long term in different strains. MethodsTwo different studies were conducted to assess the immune response induced by DIVENCE(R). In the first study, 20 seronegative young calves (55-104 days of age) were randomly distributed into the vaccinated or control group. All animals were given four intramuscular doses (D0, D21, D204 and D570) of 2 mL DIVENCE(R) or phosphate-buffered saline (PBS). Blood samples were collected to assess BVDV serum antibodies (ELISA) and neutralising antibodies (SN) against BVDV-1 and BVDV-2. In the second trial, heifers (from 10 months of age until calving) and cows (between first and seventh calving) were included and assigned to the vaccinated and control groups. Three different farms were enrolled in the study. The administration regimen was the same as described in the first study. Blood samples were collected from 32 random animals on each farm (16 vaccinated and 16 control animals). Additionally, bulk tank milk samples from each farm were obtained at different time-points and individual milk samples were obtained from vaccinated and control animals. The immune response against BVDV was analysed in serum and milk samples using different ELISA kits. Neutralising antibodies induced by DIVENCE(R) against different BVDV isolates from Europe and the Americas were also assessed in this trial. ResultsOverall, DIVENCE(R) induced high levels of total antibodies (ELISA) and neutralising antibodies against BVDV-1 and BVDV-2. These values were significantly (p<0.05) greater than the control group from 21 days after the second dose (D42) until the end of the study (D591). The high antibody levels, particularly after the third dose, were similar to those that described efficacy against experimental challenges of BVDV-1 and 2 in pregnant animals. In the field trial, similar results were observed in terms of total antibodies (ELISA) against BVDV, and no induction of anti-p80 antibodies was observed in vaccinated animals at any time. Additionally, analyses on individual and bulk tank milk samples also confirmed that no anti-p80 antibodies were induced in vaccinated animals. Furthermore, high levels of neutralising antibodies were observed against different BVDV isolates from Europe and the Americas. ConclusionThe DIVENCE(R) vaccine induced a strong immune response against BVDV-1 and BVDV-2, and this response allows infected and vaccinated animals to be differentiated (DIVA vaccine).

immunology↗