H epatitis C virus (HCV) has emerged as the major etiological agent of liver disease. Approximately 170 million individuals are infected worldwide, and the majority are at risk for developing serious progressive liver disease, with HCV being the leading indication for liver transplantation. The HCV single-stranded RNA genome encodes a single polyprotein, which is cleaved by viral and cellular proteases to produce the structural proteins; core E1 and E2 and nonstructural proteins; p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B. The only approved treatment for HCV infection is interferon-␣ in combination with ribavirin, which is toxic and only effective in 50% of individuals with genotype I infections. Clearly, there is a need for more effective therapies and for the development of prophylactic and/or therapeutic vaccines.Cellular and humoral responses are generated during acute infection, but they are insufficient to achieve viral clearance in the majority of individuals, with approximately 60%-80% of new infections becoming persistent. 1,2 Neutralizing antibody (nAb) responses often provide the first-line adaptive defense against infection by limiting virus spread. However, little is known about the impact of the humoral immune response on HCV pathobiology. Serum antibodies (Abs) from chronically HCVinfected individuals demonstrate broadly reactive neutralizing properties in vitro and yet fail to control viral infection in vivo. [3][4][5] The reasons for their lack of effect are poorly understood. HCV may escape neutralization by

The viral life cycle of the hepatitis C virus (HCV) has been studied mainly using different in vitro cell culture models. Studies using pseudoviral particles (HCVpp) and more recently cell culture-derived virus (HCVcc) suggest that at least three host cell molecules are important for HCV entry in vitro: the tetraspanin CD81, the scavenger receptor class B member I, and the tight junction protein Claudin-1. Whether these receptors are equally important for an in vivo infection remains to be demonstrated. We show that CD81 is indispensable for an authentic in vivo HCV infection. Prophylactic treatment with anti-CD81 antibodies completely protected human liver-uPA-SCID mice from a subsequent challenge with HCV consensus strains of different genotypes. Administration of anti-CD81 antibodies after viral challenge had no effect. M ore than 170 million people worldwide are infected with the hepatitis C virus (HCV). The lack of an effective HCV vaccine and the high cost and considerable side effects of the current standard therapies have a major impact on global public health. HCV is now a leading cause of liver cirrhosis, hepatocellular carcinoma, and liver transplantation. 1 The precise mechanism by which HCV attaches to and enters host cells remains unclear. Pileri et al. 2 identified the tetraspanin CD81 (TAPA-1) as a putative receptor for HCV. This 21-kDa surface molecule, composed of four transmembrane and two extracellular domains, efficiently bound recombinantly produced E2, one of the two viral envelope proteins. Experiments using pseudoviral particles (HCVpp) containing the HCV envelope proteins [3][4][5][6] or the recently developed infectious HCV cell culture system 7-11 have shown that CD81 expression on the target cell is essential for HCV infection of transformed hepatocytes in vitro.Despite the evidence provided by numerous in vitro experiments, definitive proof of the role of CD81 in HCV infection in vivo is missing. It is well known that cell lines are not necessarily representative for the tissue or organ of origin. Moreover, other molecules, such as scavenger receptor class B member I, 12,13 C-type lectins L-SIGN and DC-SIGN, 14-17 low-density lipoprotein receptor, 18,19 glycosaminoglycans, 20,21 and more recently, Claudin-1 22 and lipoprotein lipase, 23 have been identified as putative HCV receptors or coreceptors. In addition, all these experiments have been performed using HCVpp or cellculture-derived virus (HCVcc), which have different characteristics compared with natural HCV particles. 24 More recently, Molina et al. 25 reported that infection of primary hepatocyte cultures with serum-derived HCV could be inhibited by using anti-CD81 antibodies or via transduction of small interfering RNA that inhibited CD81 membrane expression.We therefore investigated whether HCV infection could be prevented in vivo by administering anti-CD81 mAbs to human liver-uPA-SCID mice. uPA-SCID mice are immunodeficient mice that suffer from a severe, transgene-induced liver disease. 26 These animals can be successful...

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Background Cancer patients are at higher risk of developing severe COVID-19. However, safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment is unclear. Patients and Methods In this interventional prospective multi-cohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted- or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until three months post-booster) were assessed. Anti-SARS-CoV-2 receptor binding domain (RBD) antibody levels were followed over time (until 28 days post-booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) towards the wild-type Wuhan strain were analyzed 28 days post-booster. Results Local and systemic adverse events (AEs) were mostly mild to moderate (only 1-3% of patients experiencing severe AEs). Local, but not systemic, AEs occurred more frequently after booster dose. 28 days post-booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group (234.05IU/mL [95%CI 122.10-448.66] and NT50 of 24.54 [95% CI 14.50-41.52]) compared to healthy individuals (1844.93IU/mL [95% CI 1383.57-2460.14] and NT50 of 122.63 [95% CI 76.85-195.67]), irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab, only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (<200IU/mL) and only one had NT50 above the limit of detection. During the study period, five cancer patients tested positive for SARS-CoV-2 infection, including a case of severe COVID-19 in a patient receiving rituximab, resulting in a 2-week hospital admission. conclusion The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections.

Control of hepatitis C virus (HCV) infection remains a huge challenge of global medical importance. Using a variety of in vitro approaches, neutralizing antibodies (nAbs) have been identified in patients with acute and chronic hepatitis C. The exact role these nAbs play in the resolution of acute HCV infection still remains elusive. We have previously shown that purified polyclonal antibodies isolated from plasma obtained in 2003 from a chronic HCV patient (Patient H) can protect human liver chimeric mice from a subsequent challenge with the autologous HCV strain isolated from Patient H in 1977 (H77). In this study we investigated whether polyclonal antibodies isolated from Patient H in 2006 (H06), which display high cross-genotype neutralizing activity in both the HCV pseudoparticle (HCVpp) and HCV cell culture (HCVcc) systems, were also able to prevent HCV infection of different genotypes (gt) in vivo. Following passive immunization with H06-antibodies, chimeric mice were challenged with the consensus strains H77C (gt1a), ED43 (gt4a), or HK6a (gt6a). In accordance with previous results, H06-antibodies prevented infection of chimeric mice with the autologous virus. However, the outcome of a homologous challenge is highly influenced by the amount of challenge virus injected. Depending on the viral genotype used, H06-antibodies were able to protect up to 50% of chimeric mice from a heterologous challenge. Animals in which the antibody pretreatment failed displayed a clear delay in the kinetics of viral infection. Sequence analysis of the recovered viruses did not suggest antibody-induced viral escape. Conclusion: Polyclonal anti-HCV antibodies isolated from a chronic HCV patient can protect against an in vivo challenge with different HCV genotypes. However, the in vivo protective efficacy of cross-genotype neutralizing antibodies was less than predicted by cell culture experiments. (HEPATOLOGY 2011;53:755-762)

End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation in the Western world. However, immediate re-infection of the grafted donor liver by circulating virus is inevitable and progresses much faster than the original disease. Standard antiviral therapy is not well tolerated and usually ineffective in liver transplant patients while anti-HCV immunotherapy is hampered by the extreme genetic diversity of the virus and its ability to spread via cell-cell contacts. We have generated a human monoclonal antibody against SR-BI, mAb16-71, that can efficiently prevent infection of Huh-7.5 hepatoma cells and primary hepatocytes by cell-culture-derived HCV (HCVcc). Using an Huh7.5 co-culture system we demonstrated that mAb16-71 interferes with direct cell-to-cell transmission of HCV. Finally we evaluated the in vivo efficacy of mAb16-71 in ‘human liver uPA-SCID mice’ (chimeric mice). A two-week anti-SR-BI therapy that was initiated one day before viral inoculation completely protected all chimeric mice from infection with serum-derived HCV of different genotypes. Moreover, a 9-day post-exposure therapy that was initiated 3 days after viral inoculation (when viremia was already observed in the animals) suppressed the rapid viral spread observed in untreated control animals. After cessation of anti-SR-BI-specific antibody therapy, a rise of the viral load was observed. Conclusion Using in vitro cell culture and human liver-chimeric mouse models, we show that a human monoclonal antibody targeting the HCV co-receptor SR-BI completely prevents infection and intrahepatic spread of multiple HCV genotypes. This strategy may be an efficacious way to prevent infection of allografts following liver transplantation in chronic HCV patients, and may even hold promise for the prevention of virus rebound during or following anti-viral therapy.

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