The 50% human infectious dose measured is higher than previous estimates and similar to that of other RNA viruses. Clinical Trials Registration NCT00138476.

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.

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...

ClincalTrials.gov identifier: http://www.clinicaltrials.gov/ct2/show/NCT00280033?term= NCT00280033&rank=1 NCT00280033 .

for the DMID 13-0032 H7N9 Vaccine Study Group IMPORTANCE Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China.OBJECTIVE To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014.INTERVENTIONS The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 μg of hemagglutinin (actual doses approximately 50% higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700). MAIN OUTCOMES AND MEASURESProportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer Ն40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7.RESULTS Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 μg plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59%; 95% CI, 48%-68%). The peak seroconversion occurred at day 29 in 62 participants (62%; 95% CI, 52%-72%). The day 42 geometric mean titer was 33.0 (95% CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 μg of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82%; 95% CI, 73%-89%). The day 42 geometric mean titer was 81.4 (95% CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 μg doses (n = 34 [35%; 95% CI, 25%-45%] vs n = 47 [47%; 95% CI, 37%-58%], respectively; P = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant.CONCLUSIONS AND RELEVANCE Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59% of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes.