Effect of parachute delivery on red blood cell (RBC) and plasma quality measures of blood for transfusion.

BACKGROUND: Parachute airdrop offers a rapid transfusion supply option for humanitarian aid and military support. However, its impact on longer-term RBC survival is undocumented. This study aimed to determine post-drop quality of RBCs in concentrates (RCC), and both RBCs and plasma in whole blood (WB) during subsequent storage. STUDY DESIGN AND METHODS: Twenty-two units of leucodepleted RCC in saline, adenine, glucose, mannitol (SAGM) and 22 units of nonclinical issue WB were randomly allocated for air transportation, parachute drop, and subsequent storage (parachute), or simply storage under identical conventional conditions (4 ± 2°C) (control). All blood products were 6-8 days post-donation. Parachute units were packed into Credo Cubes, (Series 4, 16 L) inside a PeliCase (Peli 0350) and rigged as parachute delivery packs. Packs underwent a 4-h tactical flight (C130 aircraft), then parachuted from 250 to 400 ft before ground recovery. The units were sampled aseptically before and after airdrop at weekly intervals. A range of assays quantified the RBC storage lesion and coagulation parameters. RESULTS: Blood units were maintained at 2-6°C and recovered intact after recorded ground impacts of 341-1038 m s-2 . All units showed a classical RBC storage lesion and increased RBC microparticles during 42 days of storage. Fibrinogen and clotting factors decreased in WB during storage. Nevertheless, no significant difference was observed between Control and Parachute groups. Air transportation and parachute delivery onto land did not adversely affect, or shorten, the shelf life of fresh RBCs or WB. DISCUSSION: Appropriately packaged aerial delivery by parachute can be successfully used for blood supply.

Preclinical models for studying immune responses to traumatic injury.

Traumatic injury initiates a large and complex immune response in the minutes after the initial insult, comprising of simultaneous pro- and anti-inflammatory responses. In patients that survive the initial injury, these immune responses are believed to contribute towards complications such as the development of sepsis and multiple organ dysfunction syndrome. These post-traumatic complications affect a significant proportion of patients and are a major contributing factor for poor outcomes and an increased burden on healthcare systems. Therefore, understanding the immune responses to trauma is crucial for improving patient outcomes through the development of novel therapeutics and refining resuscitation strategies. In order to do this, preclinical animal models must mimic human immune responses as much as possible, and as such, we need to understand the constraints of each species in the context of trauma. A number of species have been used in this field; however, these models are limited by their genetic background and their capacity for recapitulating human immune function. This review provides a brief overview of the immune response in critically injured human patients and discusses the most commonly used species for modelling trauma, focusing on how their immune response to serious injury and haemorrhage compares to that of humans.

Distinct Cytokine Profiles Correlate with Disease Severity and Outcome in Longitudinal Studies of Acute Hepatitis B Virus and Hepatitis D Virus Infection in Chimpanzees.

Historical studies conducted in chimpanzees gave us the opportunity to investigate the basis for the different severities of liver damage and disease outcome associated with infection with wild-type hepatitis B virus (HBV) versus a precore HBV mutant, HBV/hepatitis D virus (HDV) coinfection, and HDV superinfection. Weekly samples from 9 chimpanzees were studied for immune responses by measuring plasma levels of 29 cytokines in parallel with alanine aminotransferase (ALT) levels and viral kinetics. Comparison of classic acute hepatitis B (AHB) with severe or progressive AHB and HBV/HDV coinfection or superinfection identified distinct cytokine profiles. Classic AHB (mean ALT peak, 362 IU/liter) correlated with an early and significant induction of interferon alpha-2 (IFN-α2), IFN-γ, interleukin-12 p70 (IL-12 p70), and IL-17A. In contrast, these cytokines were virtually undetectable in severe AHB (mean ALT peak, 1,335 IU/liter), characterized by significant elevations of IL-10, tumor necrosis factor alpha (TNF-α), and MIP-1ß. In progressive AHB (mean ALT peak, 166 IU/liter), there was a delayed and lower-magnitude induction of cytokines. The ALT peak was also delayed (mean, 23.5 weeks) compared to those of classic (13.5 weeks) and severe AHB (7.5 weeks). HBV/HDV coinfection correlated with significantly lower levels of IFN-α2, IFN-γ, and IL-17A, associated with the presence of multiple proinflammatory cytokines, including IL-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-15. Conversely, HDV superinfection induced the highest ALT peak (1,910 IU/liter) and was associated with a general suppression of cytokines. Our data demonstrate that the most severe liver damage, caused by an HBV precore mutant and HDV, correlated with restricted cytokine expression and lack of Th1 response, raising the question of whether these viruses are directly cytopathic.IMPORTANCE Studies performed in chimpanzees at the National Institutes of Health (NIH) demonstrated a significant difference in ALT levels during acute hepatitis of different viral etiologies, with a hierarchy in the extent of liver damage according to the infecting virus: the highest level was in HDV superinfection, followed by infection with a precore HBV mutant, HBV/HDV coinfection, and, lastly, wild-type HBV infection. Our study demonstrates that both the virus and host are important in disease pathogenesis and offers new insights into their roles. We found that distinct cytokine profiles were associated with disease severity and clinical outcome. In particular, resolution of classic acute hepatitis B (AHB) correlated with a predominant Th1 response, whereas HBV/HDV coinfection showed a predominant proinflammatory response. Severe AHB and HDV superinfection showed a restricted cytokine profile and no evidence of Th1 response. The lack of cytokines associated with adaptive T-cell responses toward the precore HBV mutant and HDV superinfection argues in favor of a direct cytopathic effect of these viruses.

Distinct disease features in chimpanzees infected with a precore HBV mutant associated with acute liver failure in humans.

Transmission to chimpanzees of a precore hepatitis B virus (HBV) mutant implicated in acute liver failure (ALF) in humans did not cause ALF nor the classic form of acute hepatitis B (AHB) seen upon infection with the wild-type HBV strain, but rather a severe AHB with distinct disease features. Here, we investigated the viral and host immunity factors responsible for the unusual severity of AHB associated with the precore HBV mutant in chimpanzees. Archived serial serum and liver specimens from two chimpanzees inoculated with a precore HBV mutant implicated in ALF and two chimpanzees inoculated with wild-type HBV were studied. We used phage-display library and next-generation sequencing (NGS) technologies to characterize the liver antibody response. The results obtained in severe AHB were compared with those in classic AHB and HBV-associated ALF in humans. Severe AHB was characterized by: (i) the highest alanine aminotransferase (ALT) peaks ever seen in HBV transmission studies with a significantly shorter incubation period, compared to classic AHB; (ii) earlier HBsAg clearance and anti-HBs seroconversion with transient or undetectable hepatitis B e antigen (HBeAg); (iii) limited inflammatory reaction relative to hepatocellular damage at the ALT peak with B-cell infiltration, albeit less extensive than in ALF; (iv) detection of intrahepatic germline antibodies against hepatitis B core antigen (HBcAg) by phage-display libraries in the earliest disease phase, as seen in ALF; (v) lack of intrahepatic IgM anti-HBcAg Fab, as seen in classic AHB, but at variance with ALF; and (vi) higher proportion of antibodies in germline configuration detected by NGS in the intrahepatic antibody repertoire compared to classic AHB, but lower than in ALF. This study identifies distinct outcome-specific features associated with severe AHB caused by a precore HBV mutant in chimpanzees, which bear closer resemblance to HBV ALF than to classic AHB. Our data suggest that precore HBV mutants carry an inherently higher pathogenicity that, in addition to specific host factors, may play a critical role in determining the severity of acute HBV disease.

Context-dependent regulation of endothelial cell metabolism: differential effects of the PPARß/δ agonist GW0742 and VEGF-A.

Peroxisome proliferator activated receptor ß/δ (PPARß/δ) has pro-angiogenic functions, but whether PPARß/δ modulates endothelial cell metabolism to support the dynamic phenotype remains to be established. This study characterised the metabolic response of HUVEC to the PPARß/δ agonist, GW0742, and compared these effects with those induced by VEGF-A. In HUVEC monolayers, flux analysis revealed that VEGF-A promoted glycolysis at the expense of fatty acid oxidation (FAO), whereas GW0742 reduced both glycolysis and FAO. Only VEGF-A stimulated HUVEC migration and proliferation whereas both GW0742 and VEGF-A promoted tubulogenesis. Studies using inhibitors of PPARß/δ or sirtuin-1 showed that the tubulogenic effect of GW0742, but not VEGF-A, was PPARß/δ- and sirtuin-1-dependent. HUVEC were reliant on glycolysis and FAO, and inhibition of either pathway disrupted cell growth and proliferation. VEGF-A was a potent inducer of glycolysis in tubulogenic HUVEC, while FAO was maintained. In contrast, GW0742-induced tubulogenesis was associated with enhanced FAO and a modest increase in glycolysis. These novel data reveal a context-dependent regulation of endothelial metabolism by GW0742, where metabolic activity is reduced in monolayers but enhanced during tubulogenesis. These findings expand our understanding of PPARß/δ in the endothelium and support the targeting of PPARß/δ in regulating EC behaviour and boosting tissue maintenance and repair.

Next-generation sequencing of the intrahepatic antibody repertoire delineates a unique B-cell response in HBV-associated acute liver failure.

Hepatitis B virus (HBV) is a major cause of acute liver failure (ALF) worldwide. While liver damage in classic acute hepatitis B is believed to be T-cell mediated, the pathogenesis of HBV-associated ALF remains largely unknown. Access to liver specimens from well-characterized patients with HBV-associated ALF provided us with the opportunity to perform next-generation sequencing (NGS) of the entire VH repertoires of IgM and IgG from the livers of four ALF patients, a control liver donor and a patient with chronic HBV infection. We found that ALF is not associated with expansion of specific B-cell lineages. However, NGS showed that the intrahepatic VH repertoires from ALF patients were characterized by the abundant presence of antibodies in germline configuration in contrast to their marginal prevalence in controls. Moreover, NGS identified a large number of VH genes in germline configuration with identical VDJ sequences in the IgM and IgG repertoires in all four ALF patients, indicating that isotype switch from IgM to IgG had occurred without somatic hypermutation. The results of this study indicate that the presence of intrahepatic antibodies in unmutated germline configuration is a broad phenomenon in the global antibody repertoire generated from total RNA derived from whole-liver tissue that is strongly associated with ALF, suggesting a major role of T cell-independent humoral immunity in the pathogenesis of ALF.

Role of humoral immunity against hepatitis B virus core antigen in the pathogenesis of acute liver failure.

Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a dramatic clinical syndrome leading to death or liver transplantation in 80% of cases. Due to the extremely rapid clinical course, the difficulties in obtaining liver specimens, and the lack of an animal model, the pathogenesis of ALF remains largely unknown. Here, we performed a comprehensive genetic and functional characterization of the virus and the host in liver tissue from HBV-associated ALF and compared the results with those of classic acute hepatitis B in chimpanzees. In contrast with acute hepatitis B, HBV strains detected in ALF livers displayed highly mutated HBV core antigen (HBcAg), associated with increased HBcAg expression ex vivo, which was independent of viral replication levels. Combined gene and miRNA expression profiling revealed a dominant B cell disease signature, with extensive intrahepatic production of IgM and IgG in germline configuration exclusively targeting HBcAg with subnanomolar affinities, and complement deposition. Thus, HBV ALF appears to be an anomalous T cell-independent, HBV core-driven B cell disease, which results from the rare and unfortunate encounter between a host with an unusual B cell response and an infecting virus with a highly mutated core antigen.

The cat as a naturally occurring model of renal interstitial fibrosis: Characterisation of primary feline proximal tubular epithelial cells and comparative pro-fibrotic effects of TGF-ß1.

Chronic kidney disease (CKD) is common in both geriatric cats and aging humans, and is pathologically characterised by chronic tubulointerstitial inflammation and fibrosis in both species. Cats with CKD may represent a spontaneously occurring, non-rodent animal model of human disease, however little is known of feline renal cell biology. In other species, TGF-ß1 signalling in the proximal tubular epithelium is thought to play a key role in the initiation and progression of renal fibrosis. In this study, we first aimed to isolate and characterise feline proximal tubular epithelial cells (FPTEC), comparing them to human primary renal epithelial cells (HREC) and the human proximal tubular cell line HK-2. Secondly, we aimed to examine and compare the effect of human recombinant TGF-ß1 on cell proliferation, pro-apoptotic signalling and genes associated with epithelial-to-mesenchymal transition (EMT) in feline and human renal epithelial cells. FPTEC were successfully isolated from cadaverous feline renal tissue, and demonstrated a marker protein expression profile identical to that of HREC and HK-2. Exposure to TGF-ß1 (0-10 ng/ml) induced a concentration-dependent loss of epithelial morphology and alterations in gene expression consistent with the occurrence of partial EMT in all cell types. This was associated with transcription of downstream pro-fibrotic mediators, growth arrest in FPTEC and HREC (but not HK-2), and increased apoptotic signalling at high concentrations of TGF- ß1. These effects were inhibited by the ALK5 (TGF-ß1RI) antagonist SB431542 (5 µM), suggesting they are mediated via the ALK5/TGF-ß1RII receptor complex. Taken together, these results suggest that TGF-ß1 may be involved in epithelial cell dedifferentiation, growth arrest and apoptosis in feline CKD as in human disease, and that cats may be a useful, naturally occurring model of human CKD.

Hepatitis E Virus Seroprevalence and Correlates of Anti-HEV IgG Antibodies in the Rakai District, Uganda.

A cross-sectional study was conducted of 500 human immunodeficiency virus (HIV)-infected adults frequency matched on age, sex, and community to 500 HIV-uninfected individuals in the Rakai District, Uganda to evaluate seroprevalence of anti-hepatitis E virus (HEV) IgG antibodies. HEV seroprevalence was 47%, and 1 HIV-infected individual was actively infected with a genotype 3 virus. Using modified Poisson regression, male sex (prevalence ratios [PR] = 1.247; 95% confidence interval [CI], 1.071-1.450) and chronic hepatitis B virus infection (PR = 1.377; 95% CI, 1.090-1.738) were associated with HEV seroprevalence. HIV infection status (PR = 0.973; 95% CI, 0.852-1.111) was not associated with HEV seroprevalence. These data suggest there is a large burden of prior exposure to HEV in rural Uganda.

Phenotypic heterogeneity of peripheral monocytes in healthy dogs.

Monocytes are key cells of the innate immune system. Their phenotypic and functional roles have been investigated in humans, mice and other animals, such as the rat, pig and cow. To date, detailed phenotypic analysis of monocytes has not been undertaken in dogs. Two important surface markers in human monocytes are CD14 and MHC class II (MHC II). By flow cytometry, we demonstrated that canine monocytes can be subdivided into three separate populations: CD14posMHC IIneg, CD14posMHC IIpos and CD14negMHC IIpos. Both light and transmission electron microscopy confirmed the monocytic identity of all three populations. The CD14posMHC IIneg population could be distinguished on an ultrastructural level by their smaller size, the presence of more numerous, larger granules, and more pseudopodia than both of the other populations.

Effector CD8+ T cell-derived interleukin-10 enhances acute liver immunopathology.

BACKGROUND & AIMS: Besides secreting pro-inflammatory cytokines, chemokines and effector molecules, effector CD8+ T cells that arise upon acute infection with certain viruses have been shown to produce the regulatory cytokine interleukin (IL)-10 and, therefore, contain immunopathology. Whether the same occurs during acute hepatitis B virus (HBV) infection and role that IL-10 might play in liver disease is currently unknown. METHODS: Mouse models of acute HBV pathogenesis, as well as chimpanzees and patients acutely infected with HBV, were used to analyse the role of CD8+ T cell-derived IL-10 in liver immunopathology. RESULTS: Mouse HBV-specific effector CD8+ T cells produce significant amounts of IL-10 upon in vivo antigen encounter. This is corroborated by longitudinal data in a chimpanzee acutely infected with HBV, where serum IL-10 was readily detectable and correlated with intrahepatic CD8+ T cell infiltration and liver disease severity. Unexpectedly, mouse and human CD8+ T cell-derived IL-10 was found to act in an autocrine/paracrine fashion to enhance IL-2 responsiveness, thus preventing antigen-induced HBV-specific effector CD8+ T cell apoptosis. Accordingly, the use of mouse models of HBV pathogenesis revealed that the IL-10 produced by effector CD8+ T cells promoted their own intrahepatic survival and, thus supported, rather than suppressed liver immunopathology. CONCLUSION: Effector CD8+ T cell-derived IL-10 enhances acute liver immunopathology. Altogether, these results extend our understanding of the cell- and tissue-specific role that IL-10 exerts in immune regulation. Lay summary: Interleukin-10 is mostly regarded as an immunosuppressive cytokine. We show here that HBV-specific CD8+ T cells produce IL-10 upon antigen recognition and that this cytokine enhances CD8+ T cell survival. As such, IL-10 paradoxically promotes rather than suppresses liver disease.

Endothelial HO-1 induction by model TG-rich lipoproteins is regulated through a NOX4-Nrf2 pathway.

Circulating levels of chylomicron remnants (CMRs) increase postprandially and their composition directly reflects dietary lipid intake. These TG-rich lipoproteins likely contribute to the development of endothelial dysfunction, albeit via unknown mechanisms. Here, we investigated how the FA composition of CMRs influences their actions on human aortic endothelial cells (HAECs) by comparing the effects of model CMRs-artificial TG-rich CMR-like particles (A-CRLPs)-containing TGs extracted from fish, DHA-rich algal, corn, or palm oils. HAECs responded with distinct transcriptional programs according to A-CRLP TG content and oxidation status, with genes involved in antioxidant defense and cytoprotection most prominently affected by n-3 PUFA-containing A-CRLPs. These particles were significantly more efficacious inducers of heme oxygenase-1 (HO-1) than n-6 PUFA corn or saturated FA-rich palm CRLPs. Mechanistically, HO-1 induction by all CRLPs requires NADPH oxidase 4, with PUFA-containing particles additionally dependent upon mitochondrial reactive oxygen species. Activation of both p38 MAPK and PPARß/δ culminates in increased nuclear factor erythroid 2-related factor 2 (Nrf2) expression/nuclear translocation and HO-1 induction. These studies define new molecular pathways coupling endothelial cell activation by model CMRs with adaptive regulation of Nrf2-dependent HO-1 expression and may represent key mechanisms through which dietary FAs differentially impact progression of endothelial dysfunction.

The role of hepatitis E virus infection in adult Americans with acute liver failure.

Acute hepatitis E virus (HEV) infection is a leading cause of acute liver failure (ALF) in many developing countries, yet rarely identified in Western countries. Given that antibody testing for HEV infection is not routinely obtained, we hypothesized that HEV-related ALF might be present and unrecognized in North American ALF patients. Serum samples of 681 adults enrolled in the U.S. Acute Liver Failure Study Group were tested for anti-HEV immunoglobulin (Ig) M and anti-HEV IgG levels. Subjects with a detectable anti-HEV IgM also underwent testing for HEV RNA. Mean patient age was 41.8 years, 32.9% were male, and ALF etiologies included acetaminophen (APAP) hepatotoxicity (29%), indeterminate ALF (23%), idiosyncratic drug-induced liver injury DILI (22%), acute hepatitis B virus infection (12%), autoimmune hepatitis (12%), and pregnancy-related ALF (2%). Three men ages 36, 39, and 70 demonstrated repeatedly detectable anti-HEV IgM, but all were HEV-RNA negative and had other putative diagnoses. The latter 2 subjects died within 3 and 11 days of enrollment whereas the 36-year-old underwent emergency liver transplantation on study day 2. At admission, 294 (43.4%) of the ALF patients were anti-HEV IgG positive with the seroprevalence being highest in those from the Midwest (50%) and lowest in those from the Southeast (28%). Anti-HEV IgG+ subjects were significantly older, less likely to have APAP overdose, and had a lower overall 3-week survival compared to anti-HEV IgG- subjects (63% vs. 70%; P = 0.018). CONCLUSION: Acute HEV infection is very rare in adult Americans with ALF (i.e., 0.4%) and could not be implicated in any indeterminate, autoimmune, or pregnancy-related ALF cases. Past exposure to HEV with detectable anti-HEV IgG was significantly more common in the ALF patients compared to the general U.S. POPULATION: (Hepatology 2016;64:1870-1880).

The Association of Cytokines and Micronutrients with Hepatitis E Virus Infection During Pregnancy and the Postpartum Period in Rural Bangladesh.

Hepatitis E virus (HEV) infection is severe during pregnancy, with a pregnant case fatality rate around 30%. In Bangladesh, plasma samples from 1,100 women during the first trimester (TM) and third TM of pregnancy and 3 months postpartum (PP) were tested for anti-HEV IgG. During this time, 40 women developed antibody responses to HEV. These seroconverters are classified as the cases (incidence = 46 infections per 1,000 person-years). All except one seroconversion occurred between the third TM and 3 months PP. The cases and 40 matched non-seroconverters (controls) underwent analysis of a panel of 10 cytokines, 12 vitamins and minerals, and two markers of inflammation. Throughout pregnancy, seroconverting cases displayed higher concentrations of both pro- and anti-inflammatory cytokines compared with the non-seroconverting controls, even prior to infection. In the first TM, seroconverters had lower circulating zinc concentrations (P = 0.03), an increased prevalence of vitamin D deficiency (25-hydroxy vitamin D [25(OH)2D] < 50 nmol/L, P = 0.08), and anemia (hemoglobin < 110 g/L, P = 0.05) compared with controls. There were no differences in C-reactive protein or α-1-acid glycoprotein. Antecedent micronutrient deficiencies may lead to dysregulated cytokine expression and immunologic compromise, increasing the risk of HEV infection, especially during pregnancy. This exploratory analysis reveals potential novel associations that deserve further study.

An Epidemiologic Investigation of a Case of Acute Hepatitis E.

Hepatitis E virus (HEV) is considered a zoonotic infection in developed nations. A case of acute hepatitis E in a researcher following a scalpel injury while working on a pig prompted a seroepidemiologic study to identify potential modes of transmission and determine the seroprevalence of HEV among animal handlers at the institute. Sera from personnel (n = 64) in two animal facilities and age/sex-matched blood donors (n = 63) as controls were tested for IgG anti-HEV and, if positive, for IgM anti-HEV and HEV RNA. Sera and stool from pigs aged 6 to 12 weeks from the breeding farm and older pigs from animal facilities were tested similarly. The median age of personnel was 36 years, 74% were white, 56% were male, and 74% had direct exposure to pigs. The prevalence of anti-HEV was 3.1% among personnel compared to 3.2% among blood donors; none were positive for IgM anti-HEV or HEV RNA. IgG anti-HEV was detected in sera from 10% of pigs aged 6 to 8 weeks, 80% aged 10 weeks, 100% aged 12 weeks, and 76% aged >12 weeks. HEV RNA was detected in stool but not sera from three 12-week-old pigs. Sequencing revealed HEV genotype 3 with ∼10% difference between the patient and pig sequences. Parenteral transmission is a potential mode of acute HEV infection. The low and similar seroprevalence of anti-HEV between the at-risk group and age-matched blood donors suggests low transmission risk with universal precautions among animal handlers.

Bacillus anthracis Capsular Conjugates Elicit Chimpanzee Polyclonal Antibodies That Protect Mice from Pulmonary Anthrax.

The immunogenicity of Bacillus anthracis capsule (poly-γ-D-glutamic acid [PGA]) conjugated to recombinant B. anthracis protective antigen (rPA) or to tetanus toxoid (TT) was evaluated in two anthrax-naive juvenile chimpanzees. In a previous study of these conjugates, highly protective monoclonal antibodies (MAbs) against PGA were generated. This study examines the polyclonal antibody response of the same animals. Preimmune antibodies to PGA with titers of >10(3) were detected in the chimpanzees. The maximal titer of anti-PGA was induced within 1 to 2 weeks following the 1st immunization, with no booster effects following the 2nd and 3rd immunizations. Thus, the anti-PGA response in the chimpanzees resembled a secondary immune response. Screening of sera from nine unimmunized chimpanzees and six humans revealed antibodies to PGA in all samples, with an average titer of 10(3). An anti-PA response was also observed following immunization with PGA-rPA conjugate, similar to that seen following immunization with rPA alone. However, in contrast to anti-PGA, preimmune anti-PA antibody titers and those following the 1st immunization were ≤300, with the antibodies peaking above 10(4) following the 2nd immunization. The polyclonal anti-PGA shared the MAb 11D epitope and, similar to the MAbs, exerted opsonophagocytic killing of B. anthracis. Most important, the PGA-TT-induced antibodies protected mice from a lethal challenge with virulent B. anthracis spores. Our data support the use of PGA conjugates, especially PGA-rPA targeting both toxin and capsule, as expanded-spectrum anthrax vaccines.

Immunoglobulin with High-Titer In Vitro Cross-Neutralizing Hepatitis C Virus Antibodies Passively Protects Chimpanzees from Homologous, but Not Heterologous, Challenge.

The importance of neutralizing antibodies (NAbs) in protection against hepatitis C virus (HCV) remains controversial. We infused a chimpanzee with H06 immunoglobulin from a genotype 1a HCV-infected patient and challenged with genotype strains efficiently neutralized by H06 in vitro. Genotype 1a NAbs afforded no protection against genotype 4a or 5a. Protection against homologous 1a lasted 18 weeks, but infection emerged when NAb titers waned. However, 6a infection was prevented. The differential in vivo neutralization patterns have implications for HCV vaccine development.

Declining prevalence of hepatitis E antibodies among Danish blood donors.

BACKGROUND: The increasing incidence of reported hepatitis E cases in Europe has focused attention on hepatitis E virus (HEV) and the risk of transfusion-transmitted hepatitis E. The aim of this study was to investigate the prevalence of antibodies to HEV (anti-HEV) among Danish blood donors in 2013 and to compare it to previous studies in Denmark. In addition we wanted to compare the relative reactivity of two different assays. STUDY DESIGN AND METHODS: Samples from 504 blood donors were collected and analyzed for anti-HEV with an in-house assay developed at the National Institutes of Health (NIH). In addition the samples were analyzed with the Wantai anti-HEV assay. Demographic information and possible HEV exposure was collected by self-administered questionnaire. RESULTS: Using the NIH assay the prevalence of anti-HEV among Danish blood donors was 10.7% and with the Wantai assay the prevalence of anti-HEV was 19.8% (p < 0.001). In both cases the presence of anti-HEV was significantly correlated with increasing age. In addition, anti-HEV as measured by the Wantai test was significantly associated with contact with children (p = 0.01), but in multivariate analysis only age was associated with anti-HEV in both assays. By the NIH assay, the prevalence had declined from 20.6% in 2003 to 10.7% in 2013. CONCLUSIONS: Anti-HEV prevalence had decreased by half among Danish blood donors over 10 years, but was still highly prevalent. The difference in reactivity of the two assays demonstrates the importance of using the same assay when comparing the anti-HEV prevalence in populations over time.