Immunogenicity, Safety, and Efficacy of a Standalone Universal Influenza Vaccine, FLU-v, in Healthy Adults: A Randomized Clinical Trial.

Background: FLU-v is a broad-spectrum influenza vaccine that induces antibodies and cell-mediated immunity. Objective: To compare the safety, immunogenicity, and exploratory efficacy of different formulations and dosing regimens of FLU-v versus placebo. Design: Randomized, double-blind, placebo-controlled, single-center phase 2b clinical trial. (ClinicalTrials.gov: NCT02962908; EudraCT: 2015-001932-38). Setting: The Netherlands. Participants: 175 healthy adults aged 18 to 60 years. Intervention: 0.5-mL subcutaneous injection of 500 µg of adjuvanted (1 dose) or nonadjuvanted (2 doses) FLU-v (A-FLU-v or NA-FLU-v) or adjuvanted or nonadjuvanted placebo (A-placebo or NA-placebo) (2:2:1:1 ratio). Measurements: Vaccine-specific cellular responses at days 0, 42, and 180 were assessed via flow cytometry and enzyme-linked immunosorbent assay. Solicited information on adverse events (AEs) was collected for 21 days after vaccination. Unsolicited information on AEs was collected throughout the study. Results: The AEs with the highest incidence were mild to moderate injection site reactions. The difference between A-FLU-v and A-placebo in the median fold increase in secreted interferon-γ (IFN-γ) was 38.2-fold (95% CI, 4.7- to 69.7-fold; P = 0.001) at day 42 and 25.0-fold (CI, 5.7- to 50.9-fold; P < 0.001) at day 180. The differences between A-FLU-v and A-placebo in median fold increase at day 42 were 4.5-fold (CI, 2.3- to 9.8-fold; P < 0.001) for IFN-γ-producing CD4+ T cells, 4.9-fold (CI, 1.3- to 40.0-fold; P < 0.001) for tumor necrosis factor-α (TNF-α), 7.0-fold (CI, 3.5- to 18.0-fold; P < 0.001) for interleukin-2 (IL-2), and 1.7-fold (CI, 0.1- to 4.0-fold; P = 0.004) for CD107a. At day 180, differences were 2.1-fold (CI, 0.0- to 6.0-fold; P = 0.030) for IFN-γ and 5.7-fold (CI, 2.0- to 15.0-fold; P < 0.001) for IL-2, with no difference for TNF-α or CD107a. No differences were seen between NA-FLU-v and NA-placebo. Limitation: The study was not powered to evaluate vaccine efficacy against influenza infection. Conclusion: Adjuvanted FLU-v is immunogenic and merits phase 3 development to explore efficacy. Primary Funding Source: SEEK and the European Commission Directorate-General for Research and Innovation, European Member States within the UNISEC (Universal Influenza Vaccines Secured) project.

Folate therapy and in-stent restenosis after coronary stenting.

BACKGROUND: Vitamin therapy to lower homocysteine levels has recently been recommended for the prevention of restenosis after coronary angioplasty. We tested the effect of a combination of folic acid, vitamin B6, and vitamin B12 (referred to as folate therapy) on the risk of angiographic restenosis after coronary-stent placement in a double-blind, multicenter trial. METHODS: A total of 636 patients who had undergone successful coronary stenting were randomly assigned to receive 1 mg of folic acid, 5 mg of vitamin B6, and 1 mg of vitamin B12 intravenously, followed by daily oral doses of 1.2 mg of folic acid, 48 mg of vitamin B6, and 60 microg of vitamin B12 for six months, or to receive placebo. The angiographic end points (minimal luminal diameter, late loss, and restenosis rate) were assessed at six months by means of quantitative coronary angiography. RESULTS: At follow-up, the mean (+/-SD) minimal luminal diameter was significantly smaller in the folate group than in the placebo group (1.59+/-0.62 mm vs. 1.74+/-0.64 mm, P=0.008), and the extent of late luminal loss was greater (0.90+/-0.55 mm vs. 0.76+/-0.58 mm, P=0.004). The restenosis rate was higher in the folate group than in the placebo group (34.5 percent vs. 26.5 percent, P=0.05), and a higher percentage of patients in the folate group required repeated target-vessel revascularization (15.8 percent vs. 10.6 percent, P=0.05). Folate therapy had adverse effects on the risk of restenosis in all subgroups except for women, patients with diabetes, and patients with markedly elevated homocysteine levels (15 micromol per liter or more) at baseline. CONCLUSIONS: Contrary to previous findings, the administration of folate, vitamin B6, and vitamin B12 after coronary stenting may increase the risk of in-stent restenosis and the need for target-vessel revascularization.