A cell culture-derived influenza vaccine provides consistent protection against infection and reduces the duration and severity of disease in infected individuals.

BACKGROUND: Current knowledge of the consistency of protection induced by seasonal influenza vaccines over the duration of a full influenza season is limited, and little is known about the clinical course of disease in individuals who become infected despite vaccination. METHODS: Data from a randomized double-blind placebo-controlled clinical trial undertaken in healthy young adults in the 2008-2009 influenza season were used to investigate the weekly cumulative efficacy of a Vero cell culture-derived influenza vaccine. In addition, the duration and severity of disease in vaccine and placebo recipients with cell culture-confirmed influenza infection were compared. RESULTS: Vaccine efficacy against matching strains was consistently high (73%-82%) throughout the study, including the entire period of the influenza season during which influenza activity was above the epidemic threshold. Vaccine efficacy was also consistent (68%-83%) when calculated for all strains, irrespective of antigenic match. Vaccination also ameliorated disease symptoms when infection was not prevented. Bivariate analysis of duration and severity showed a significant amelioration of myalgia (P = .003), headache (P = .025), and fatigue (P = .013) in infected vaccinated subjects compared with placebo. Cough (P = .143) and oropharyngeal pain (P = .083) were also reduced in infected vaccinated subjects. CONCLUSIONS: A Vero cell culture-derived influenza vaccine provides consistently high levels of protection against cell culture-confirmed infection by seasonal influenza virus and significantly reduces the duration and severity of disease in those individuals in which infection is not prevented. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT00566345.

Clinical development of a Vero cell culture-derived seasonal influenza vaccine.

BACKGROUND: Cell culture technologies have the potential to improve the robustness and flexibility of influenza vaccine supply and to substantially shorten manufacturing timelines. We investigated the safety, immunogenicity and efficacy of a Vero cell culture-derived seasonal influenza vaccine and utilized these studies to establish a serological correlate of vaccine protection. METHODS: Two multicenter, randomized, double-blind phase III trials were undertaken in the US during the 2008-2009 Northern hemisphere influenza season, in young (18-49 years) and older (50-64 years and ≥ 65 years) adult subjects. 7250 young adults were randomized 1:1 to receive either Vero-derived vaccine or placebo. 3210 older adult subjects were randomized 8:1 to receive either Vero-derived vaccine or a licensed egg-derived vaccine. Serum hemagglutination inhibition antibody titers were assessed 21 days post-vaccination. Vaccine efficacy in preventing cell culture-confirmed influenza infection was determined for the young adult population. Local and systemic adverse events were recorded in both studies. RESULTS: The Vero-derived vaccine was safe and well tolerated in both young and older adults. All US and European immunological licensing thresholds were comfortably met in both populations. Vaccine efficacy in young adults was 79% against A/H1N1 viruses antigenically matching the corresponding vaccine strain and 78.5% for all antigenically matched influenza viruses. A hemagglutination inhibition antibody titer of ≥ 1:15 provided a reliable correlate of protection for the Vero-derived influenza vaccine, with no additional benefit at titers >1:30. Bridging of the correlate of protection established in the young adult population to the older adult immunogenicity data demonstrated the likely effectiveness of the Vero-derived vaccine in the older adult population. CONCLUSIONS: A Vero cell culture-derived seasonal influenza vaccine is safe, immunogenic and protects against infection with influenza virus. The novel vaccine technology has the potential to make a substantial contribution to improving influenza vaccine supply. CLINICAL TRIAL REGISTRATION: The studies are registered with ClinicalTrials.gov, numbers NCT00566345 and NCT00782431.

Efficacy, safety, and immunogenicity of a Vero-cell-culture-derived trivalent influenza vaccine: a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: The use of cell-culture technologies for the manufacture of influenza vaccines might contribute to improved strain selection and robust vaccine supplies. We investigated the safety, immunogenicity, and protective efficacy of a Vero-cell-culture-derived influenza vaccine, and assessed the correlation between vaccine efficacy and haemagglutination inhibition antibody titre. METHODS: In a double-blind, placebo-controlled, phase 3 trial undertaken in 36 centres in the USA, healthy adults (aged 18-49 years) were randomly assigned in a 1:1 ratio to one injection of either placebo or Vero-cell-culture-derived influenza vaccine during the 2008-09 season. Randomisation was done in blocks by use of the random number generator algorithm, and participants were allocated by use of a centralised telephone system. The primary objective was the efficacy of the vaccine in preventing cell-culture-confirmed influenza infection with viruses that were antigenically matched to one of the vaccine strains. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00566345. FINDINGS: 7250 participants were randomly assigned to vaccine (n=3626) and placebo (n=3624). 7236 were analysed for the primary outcome (n=3619 and n=3617, respectively). Overall protective efficacy for antigenically matched influenza infection was 78·5% (95% CI 60·8-88·2). The vaccine was well tolerated with no treatment-related serious adverse events. Adverse events were mainly mild and transient. An HI titre of at least 1:15 provided a reliable correlate of cell-culture-derived influenza vaccine-induced protection; no additional benefit was noted with titres greater than 1:30. INTERPRETATION: The data indicate that existing correlates of protection afforded with egg-derived seasonal influenza vaccines also apply to this vaccine. FUNDING: Federal (US Government) funds from the Office for Preparedness and Response, Biomedical Advanced Research and Development Authority, under contract to DynPort Vaccine Company.

Safety and pharmacokinetic evaluation of intravenous vaccinia immune globulin in healthy volunteers.

BACKGROUND: Vaccinia immune globulin (VIG) administered via the intramuscular route has historically been used for the treatment of complications of smallpox vaccination. Intravenous formulations of VIG are required to improve tolerability and pharmacokinetic profile. METHODS: We conducted 2 separate studies to evaluate the feasibility of administration of an intravenous formulation of antivaccinia immune globulin (VIGIV). The first study assessed the pharmacokinetics and safety of a newly manufactured lyophilized VIG product for intravenous administration (VIGIV-lyo). Seventy-eight healthy volunteers received an intravenous infusion of VIGIV-lyo at doses of 100 mg/kg, 200 mg/kg, or 500 mg/kg. In the second study, we evaluated the safety of a liquid product of VIGIV (VIGIV-liq) in 33 healthy volunteers receiving an intravenous infusion of 100 mg/kg VIGIV-liq. RESULTS: The geometric mean titer of VIG at the target dose (100 mg/kg) after intravenous administration is 2.5 times higher than the predicted geometric mean titer after intramuscular injection (P<.001). The pharmacokinetics of VIGIV-lyo are linear for doses from 100 mg/kg through 500 mg/kg. Administration of the 200-mg/kg and 500-mg/kg doses of VIGIV-lyo does not result in markedly higher adverse event rates. The adverse event rates observed with the liquid product are comparable to those seen with the lyophilized product. CONCLUSIONS: These 2 studies suggest that intravenous administration of VIG is well tolerated and results in a more favorable pharmacokinetic profile than does VIG administered intramuscularly.