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Background Hepatitis C virus (HCV) causes chronic liver disease that often leads to cirrhosis and hepatocellular carcinoma. In animal studies, chimpanzees were protected against chronic infection following experimental challenge with either homologous or heterologous HCV genotype 1a strains which predominates in the USA and Canada. We describe a first in humans clinical trial of this prophylactic HCV vaccine. Methods HCV E1E2 adjuvanted with MF59C.1 (an oil-in-water emulsion) was given at 3 different dosages on day 0 and weeks 4, 24 and 48 in a phase 1, placebo-controlled, dose escalation trial to healthy HCV-negative adults. Results There was no significant difference in the proportion of subjects reporting adverse events across the groups. Following vaccination subjects developed antibodies detectable by ELISA, CD81 neutralization and VSV/HCV pseudotype neutralization. There was no significant difference between vaccine groups in the number of responders and geometric mean titers for each of the three assays. All subjects developed lymphocyte proliferation responses to E1E2 and an inverse response to increasing amounts of antigen was noted. Conclusions The vaccine was safe and generally well tolerated at each of the 3 dosage levels and induced anti-body and lymphoproliferative responses. A larger study to further evaluate safety and immunogenicity is warranted.

The intranasal monovalent adjuvanted Norwalk VLP vaccine was well tolerated and highly immunogenic and is a candidate for additional study.

MVA62 was well tolerated and elicited different patterns of T cell and Ab responses when administered alone or in combination with the JS7 DNA vaccine.

When given by a bifurcated needle, vaccinia virus vaccine can be diluted to a titer as low as 10(7.0) pfu per milliliter (approximately 10,000 pfu per dose) and induce local viral replication and vesicle formation in more than 97 percent of persons.

Although a cure for HCV is on the near horizon, emerging drug cocktails will be expensive, associated with side-effects and resistance making a global vaccine an urgent priority given the estimated high incidence of infection around the world. Due to the highly heterogeneous nature of HCV, an effective HCV vaccine which could elicit broadly cross-neutralizing antibodies has represented a major challenge. In this study, we tested for the presence of cross-neutralizing antibodies in human volunteers who were immunized with recombinant glycoproteins gpE1/gpE2 derived from a single HCV strain (HCV1 of genotype 1a). Cross neutralization was tested in Huh-7.5 human hepatoma cell cultures using infectious recombinant HCV (HCVcc) expressing structural proteins of heterologous HCV strains from all known major genotypes, 1–7. Vaccination induced significant neutralizing antibodies against heterologous HCV genotype 1a virus which represents the most common genotype in North America. Of the 16 vaccinees tested, 3 were selected on the basis of strong 1a virus neutralization for testing of broad cross-neutralizing responses. At least 1 vaccinee was shown to elicit broad cross-neutralization against all HCV genotypes. Although observed in only a minority of vaccinees, our results prove the key concept that a vaccine derived from a single strain of HCV can elicit broad cross-neutralizing antibodies against all known major genotypes of HCV and provide considerable encouragement for the further development of a human vaccine against this common, global pathogen.

Modified vaccinia virus Ankara (MVA) is a highly attenuated vaccinia virus that is under consideration as an alternative to the conventional smallpox vaccine Dryvax. MVA was attenuated by extensive passage of vaccinia virus Ankara in chicken embryo fibroblasts. Several immunomodulatory genes and genes that influence host range are deleted or mutated, and replication is aborted in the late stage of infection in most nonavian cells. The effect of these mutations on immunogenicity is not well understood. Since the structural genes appear to be intact in MVA, it is hypothesized that critical targets for antibody neutralization have been retained. To test this, we probed microarrays of the Western Reserve (WR) proteome with sera from humans and macaques after MVA and Dryvax vaccination. As most protein sequences of MVA are 97 to 99% identical to those of other vaccinia virus strains, extensive binding cross-reactivity is expected, except for those deleted or truncated. Despite different hosts and immunization regimens, the MVA and Dryvax antibody profiles were broadly similar, with antibodies against membrane and core proteins being the best conserved. The responses to nonstructural proteins were less well conserved, although these are not expected to influence virus neutralization. The broadest antibody response was obtained for hyperimmune rabbits with WR, which is pathogenic in rabbits. These data indicate that, despite the mutations and deletions in MVA, its overall immunogenicity is broadly comparable to that of Dryvax, particularly at the level of antibodies to membrane proteins. The work supports other information suggesting that MVA may be a useful alternative to Dryvax.

Smallpox vaccination with replication deficient vaccinia strains such as Modified Vaccinia-Ankara (MVA) may induce protective immunity with improved safety and tolerability profiles compared with currently available smallpox vaccines. Ninety subjects were randomized equally to 6 groups in a partially blinded, randomized control clinical trial. IMVAMUNE ® (MVA-BN ® , Bavarian Nordic A/S, Kvistgård, Denmark) vaccine or placebo was administered at Study Day 0 and 28 by subcutaneous or intramuscular injection and five groups were challenged with Dryvax ® at study Day 112. Vaccination with two doses of IMVAMUNE ® was safe and well-tolerated compared to Dryvax ® . IMVAMUNE ® produced comparable cellular and humoral immune responses to one dose of Dryvax ® and the immunity induced appears robust 90 days post vaccination by evidence of attenuated primary cutaneous reaction responses following Dryvax ® . IMVAMUNE ® vaccination prior to Dryvax ® reduced virus replication at the Dryvax ® site, decreased the size of the primary cutaneous lesion, and decreased the time to healing but did not completely ameliorate the immune response. MO 63110,, E-mail address: E-mail: freyse@slu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In a recent study, IMVAMUNE ® , a highly attenuated vaccinia strain derived from MVA-572 (obtained from Dr. Anton Mahr), does not replicate in human cells and was safe and immunogenic in humans [9]. The present study sought to evaluate the safety and immunogenicity of a range of doses and routes of administration of IMVAMUNE ® . Potential surrogate efficacy of MVA-induced immune responses was evaluated by the ability of two doses of IMVAMUNE ® to reduce the clinical effects of a Dryvax ® challenge. Keywords NIH Public Access Author Manuscript Methods Vaccines and DiluentsIMVAMUNE ® (Bavarian Nordic A/S, Kvistgård, Denmark), a modified vaccinia Ankara vaccine (lot no. 130303), is a non-replicating virus in human cells used as the MVA smallpox vaccine in this study. Lyophilized vaccine was reconstituted with sterile water for injection (WFI) (Impfstoffwerk Dessau-Thornau GmbH, Germany). The reconstituted vaccine contains approximately 2 × 10 8 TCID 50 per ml. The placebo was sterile saline for injection (American Regent Laboratories, Inc, Shirley, NY). Licensed smallpox vaccine (Dryvax ® , Wyeth Laboratories, Marietta, PA) (lot no. 4008284), a replicating vaccinia virus provided by the Centers for Disease Control and Prevention in Atlanta, GA, was used as both the comparator vaccine and the virus in the challenge portion of this study.Reconstituted IM...