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Influenza A virus is a major causative agent of respiratory diseases in humans. It causes significant morbidity, mortality and economic losses each year worldwide with about 3-5 million clinical infections per annum. Its ability to mutate rapidly leads to seasonal epidemics and with its high frequency of genetic reassortment it causes pandemics. Conventional methods of studying viral pathogenesis do not allow for monitoring viral spread in real time during an infection. Whole body bioluminescent imaging of infected animals will overcome many of the problems associated with the current methods. In this work the wild type Influenza A/WSN/33 was engineered to carry a luciferase reporter gene in segment 1, based on a well established reverse genetics system for Influenza A viruses. The novel reporter WSN virus will enable less expensive, non-invasive in vivo imaging of viral replication and better evaluation of novel therapeutics.

BACKGROUND: Triplex vaccine was developed to enhance CMV specific T-cells and prevent CMV reactivation, early after hematopoietic stem cell transplantation (HCT). OBJECTIVE: To determine safety and efficacy of Triplex. DESIGN: First-in-patient phase 2 trial (ClinicalTrials.gov: NCT02506933). SETTINGS: Three U.S. HCT centers. PARTICIPANTS: 102 CMV-seropositive HCT recipients, at high-risk for CMV reactivation. INTERVENTION: Intramuscular injections on days 28 and 56 post-HCT of Triplex or placebo. Triplex is a recombinant attenuated poxvirus, modified vaccinia Ankara, expressing immunodominant CMV antigens. MEASUREMENTS: The primary outcomes were: CMV events (≥1250 IU/mL; CMV viremia requiring antivirals; or end-organ disease); non-relapse mortality; severe (grade 3, 4) GVHD, all evaluated through 100 days post-HCT, and grade 3-4 adverse events (AEs, probably or definitely attributable to injection) within 2 weeks post-vaccination. RESULTS: 102 patients received the first vaccination (51/group), 91 (89.2%) received both vaccinations (46 Triplex, 45 placebo). CMV reactivation occurred in 5 Triplex (9.8%), compared to 10 placebo (19.6%) recipients (hazard ratio, 0.46; 95% CI, 0.16 to 1.4; P=0.075). No Triplex recipient experienced non-relapse mortality during the first 100 days or serious AEs, no grade 3-4 AEs related to vaccination within 2 weeks post-vaccination was observed. Incidence of severe acute GVHD was similar between groups, post-injection (hazard ratio, 1.1; 95% CI, 0.53 to 2.4; P=0.23). Significantly higher levels of long lasting pp65-specific T-cells with effector memory phenotype were measured in Triplex compared to placebo recipients. LIMITATIONS: The lower-than-expected CMV event incidence in the placebo group reduced the power of the trial. CONCLUSIONS: No vaccine associated safety concerns were identified. Triplex elicited and amplified CMV-specific immune responses, and fewer Triplex vaccinated patients experienced CMV viremia. PRIMARY FUNDING SOURCE: National Cancer Institute and Helocyte Inc.