Broadly Neutralizing Immune Responses against Hepatitis C Virus Induced by Vectored Measles Viruses and a Recombinant Envelope Protein Booster

Abstract

Hepatitis C virus (HCV) is the prototype member of the Hepacivirus genus within the family Flaviviridae. The virus is transmitted almost exclusively by the parenteral route, and acute infections, which are frequently subclinical, progress to chronicity in about 70% of cases. Persistent HCV carriers may develop liver cirrhosis, hepatocellular carcinoma, and end-stage liver disease. Despite an efficient preventive campaign based on the identification of HCV-infected blood donors, the prevalence of the virus among American young adults has not declined (35). Recent advances have improved treatment options for infections with certain viral genotypes, although limitations in efficacy remain and a preventive vaccine is not available.HCV is an enveloped virus, with a positive-sense, singlestranded RNA genome. The genome is translated into a polyprotein which is proteolytically processed into 10 individual proteins (reviewed in reference 64). The structural proteins, core protein (C) and two envelope glycoproteins (E1 and E2), form the physical viral particle; C functions to encapsidate the RNA genome, while E1 and E2 mediate virus attachment and entry into host cells. E1 and E2 are highly glycosylated type I transmembrane proteins with an N-terminal ectodomain. Residues within the transmembrane domains are important for heterodimerization and dimer retention in the endoplasmic reticulum (ER) (22,46). Replacement of the E1 or E2 transmembrane domains can direct transport of the corresponding chimeric proteins to the plasma membrane (1, 10). E2 also encompasses well-conserved antibody neutralization determinants, which are located near the binding sites for viral entry factors CD81 and scavenger receptor B1 (20,29). There is also some evidence for the existence of neutralizing determinants in E1 (45). Patient neutralizing antibodies have been identified that target virus interactions with its coreceptors and block glycoprotein-mediated membrane fusion (31).A major hurdle in the development of an effective HCV vaccine is the lack of an immunization strategy to elicit broadly protective antibodies and sustained cell-mediated immunity (32, 66). Studies with chimpanzees have shown the importance of total anti-E1/E2 antibody titers in conferring protection (15). Moreover, neutralizing immunity and functional CD4 ϩ and CD8 ϩ Tcell responses induced early in HCV infection correlate with clearance or viral control in patients (7,37,51).In contrast, the measles virus (MV) vaccine has an outstanding record of efficacy and safety. The MV Moraten vaccine strain is credited with the temporary elimination of indigenous measles transmission on the American continent (14), and the World Health Organization is implementing a global measles eradication program (72,73). After completion of the two-dose vaccination schedule, nearly 100% of recipients develop lasting neutralizing immunity that may be lifelong (2). In addition, the availability of established production methods makes MV an appealing platform for delivering foreign antigens (r...

Engineering a Therapeutic Lectin by Uncoupling Mitogenicity from Antiviral Activity

“…An intergenotypic HCVcc reporter virus, i.e. BiGluc-Con1/Jc1, was tested in Huh-7.5 cells (Figure S2) (Reyes-del Valle et al, 2012). The addition of H84T to the inoculum decreased HCV in a dose-dependent manner and to levels comparable to inhibition by CD81 antibody, a positive control that blocks the cellular receptor for HCV (Figure S2A and data not shown).…”

The core domain of hepatitis C virus glycoprotein E2 generates potent cross‐neutralizing antibodies in guinea pigs

“…In addition, cocktails of broadly neutralizing monoclonal antibodies (NMAbs) can prevent and clear established HCV infection in small animal models of HCV . However, previous vaccination studies conducted in animals using full‐length or truncated forms of E2, and a phase I clinical trial of a recombinant HCV glycoprotein vaccine elicited limited cross‐genotype neutralization . Like the glycoproteins of other viruses that have evolved advanced immune evasion mechanisms, such as human immunodeficiency virus 1 and influenza virus, HCV E2 is also highly glycosylated and undergoes rapid sequence change in multiple variable regions .…”

A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based on a Recombinant Measles Virus Vaccine Platform

“…Hence, genes expressing foreign antigens up to 6 kb can be cloned into the MV backbone (36) and elicit coexpression of MV proteins and inserted genes. Besides marker genes (37) or immune modulators (38), expression of antigens from foreign pathogens like hepatitis B or C virus (39,40), HIV (41), West Nile virus (WNV) (42,43), dengue virus (44), Chikungunya virus (CHIKV) (45), or SARS-CoV (19) by recombinant MVs has already been demonstrated. Thereby, robust immune responses against vector and foreign antigens are induced after vaccination of transgenic, MV-susceptible type I interferon receptor-deficient (IFNAR Ϫ/Ϫ )-CD46Ge mice (46) or nonhuman primates with recombinant MVs, in general.…”