aa Langley 2011.
| Methods | Randomised, placebo‐controlled trial assessing the protective efficacy of a nasally administered meningococcal outer membrane protein adjuvanted trivalent influenza vaccine (OMP‐TIV) against laboratory‐confirmed influenza infection during the 2003 to 2004 influenza season in Canada in healthy adults. | |
| Participants | Healthy adults aged 18 to 64 years who gave informed consent were eligible to participate (1349 were enrolled at 28 sites in Canada). Exclusion criteria: belonging to a group for which annual influenza vaccination is recommended; presence of significant acute or chronic, uncontrolled medical or psychiatric illness; pregnancy; infection with HIV, hepatitis B, or hepatitis C virus; chronic use of any medication or product for symptoms of rhinitis or nasal congestion or any chronic nasopharyngeal complaint or use of such product within 7 days prior to immunisation; asthma; symptoms or diagnosis suggesting gag reflex impairment or predisposition to aspiration; use of systemic glucocorticosteroids or immunosuppressive medications; receipt of investigational drugs in the prior month; presence of febrile or upper respiratory tract illness on the day of immunisation; and known hypersensitivity to mercurials or chicken eggs. | |
| Interventions | The vaccine contains equal parts of 3 monovalent egg‐grown, formalin‐inactivated influenza antigens formulated with OMPs of Neisseria meningitidis serogroup B strain 8047. The vaccine tested in this study contained HA from each:
Vaccine was tested in 2 formulations: 1 containing 75 ± 15 μg/mL of HA from each of the 3 influenza strains and 1 with 150 ± 30 μg HA/mL. Both formulations are sterile, colourless to yellowish opalescent, and preserved with 0.01% thimerosal. The placebo control was sterile phosphate‐buffered isotonic saline with 0.01% thimerosal and was colourless. Participants (n = 1348) were randomised to 1 of the following 3 regimens:
Vaccine and placebo were administered by means of a VP3/100 nasal spray pump (Valois of America, Greenwich, CT, USA) with the participant in a sitting position, administering 0.10 mL of preparation in each nostril (0.20 mL in all). |
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| Outcomes |
Safety Participants were monitored for 30 minutes after the immunisation on days 0 and 14 for any immediate adverse events and then completed a questionnaire that graded selected complaints as 0 (none), grade 1 (mild), grade 2 (moderate), or grade 3 (severe). From days 0 to 7, participants self monitored evening oral temperature and completed a written memory aid of reactogenicity. On days 3, 7, 17, and 21 participants reported the maximum oral temperature and severity score in the previous days via an interactive voice response system. A clinic visit for participant assessment was initiated if symptom complaints exceeded grade 2. Prior to the day 14 dose participants were questioned about interim adverse events, and a physical exam was performed. Coding for adverse events was according to Medical Dictionary for Regulatory Activities (MeDRA, Chantilly, VA) version 6.1. The following outcomes were reported:
Immunogenicity Blood and nasal mucus samples were collected on days 0 and 28 for haemagglutinin inhibition reciprocal titres and salivary secretory IgA (sIgA) measurement, respectively. Effectiveness Telephone contacts with participants were made every 2 weeks to solicit adverse events and identify ILI. Spontaneous illness reports were received via toll‐free telephone call centre and reported to investigators. If the participant illness included at least 2 of the illness criteria and was severe enough to impede normal daily activities, then a nurse visit was initiated. The nurse verified symptoms, collected nose and throat swabs, and recorded the participant’s temperature. Samples were cultured on MDCK cells, and a multiplex RT‐PCR test was used to detect influenza A and B viruses (viruses A were subsequently subtyped by another RT‐PCR assay). The primary outcome measure for efficacy was CCI defined as fever (oral temperature > 37.8 °C) and cough and at least 1 of the following: sore throat, runny nose or nasal congestion, muscle or joint ache, headache, fatigue or chills (with symptoms sufficient to impede normal daily activities), and a positive nose and throat swab culture for influenza A or B virus. A co‐primary endpoint measure was a positive culture, defined as positive nose and throat swab culture for influenza A or B virus and at least 2 of the following 8 symptoms: fever, cough, sore throat, runny nose or nasal congestion, muscle or joint ache, headache, fatigue, or chills. The secondary outcome measure, ILI with evidence of influenza infection, required laboratory confirmation of influenza by either a positive culture for influenza A or B virus, or positive RT‐PCR for influenza A or B virus, or a 4‐fold rise in reciprocal titre for a circulating influenza strain between days 28 and 180 and fever and cough and at least 1 of sore throat, runny nose or nasal congestion, muscle or joint ache, headache, fatigue, or chills. |
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| Notes | Safety and primary endpoint estimates (CCI) were calculated on the ITI population, which included any participant who received at least 1 dose of test article (n = 1348, 455 in arm 1, 450 in arm 2, 443 in control arm).
For effectiveness estimates of culture positive and ILI, evaluable participants were used, i.e. those who had a complete regimen (i.e. 1 dose of placebo in the placebo group, at least 1 dose of 30 µg, 2 doses of 15µg, n = 1347).
A total of 1326 participants completed the study (452 in arm 1, 442 in arm 2, 432 in control arm). Industry funded |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | “The study was double‐blind, randomised and placebo controlled.” |
| Allocation concealment (selection bias) | Low risk | “Subjects were assigned centrally within blocks and stratified within each site by age ≤49 and >49 years, and history of prior influenza immunization within 2 years.” |
| Blinding (performance bias and detection bias) All outcomes | Low risk | “Neither the subject nor the site study team (staff performing clinical safety or efficacy evaluations and investigators) were aware of patient assignment. One research nurse at each site was responsible for randomization, maintenance of the treatment log, test article preparation and administration.” “This staff member did not perform any safety or efficacy observations and could not reveal treatment assignment to participants or other study staff.” “Both lots are sterile, colorless to yellowish opalescent and preserved with 0.01% thimerosal. The placebo control was sterile phosphate‐buffered isotonic saline with 0.01% thimerosal, and was colorless.” |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | About 98% of the initially enrolled participants completed the study. |
| Summary assessment | Low risk | Low risk of bias |