Influenza vaccine studies

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Influenza vaccine
FLUBLOK® FDA Package Insert
Clinical Pharmacology
Indications and Usage
Warnings and Precautions
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Clinical Studies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

Clinical Studies

Efficacy Against Culture-Confirmed Influenza

The efficacy of Flublok was evaluated in a randomized, observer-blind, placebo-controlled multicenter trial conducted in the U.S. during the 2007-2008 influenza season (Study 1). The study enrolled and vaccinated 4648 healthy adults (mean age 32.5 years) randomized in a 1:1 ratio to receive a single dose of Flublok (n=2344) or saline placebo (n=2304). Among enrolled subjects, 59% were female, 67% were white, 19% African-American, 11% Latino/Hispanic, 2% Asian and < 1% other. The two groups were similar in demographics. Culture-confirmed influenza was assessed by active and passive surveillance for influenza-like illness (ILI) beginning 2 weeks post-vaccination until the end of the influenza season, approximately 7 months post- vaccination. ILI was defined as having at least 2 of 3 symptoms (no specified duration) in the following categories: 1) fever ≥ 100ºF; 2) respiratory symptoms (cough, sore throat, runny nose/stuffy nose); or 3) systemic symptoms (myalgias, arthralgias, headache, chills/sweats, tiredness/malaise). For subjects with an episode of ILI, nasal and throat swab samples were collected for viral culture.

The primary efficacy endpoint was Centers for Disease Control-defined influenza-like illness (CDC-ILI) with a positive culture for an influenza virus strain antigenically resembling a strain represented in Flublok. CDC-ILI is defined as fever of ≥100°F oral accompanied by cough, sore throat, or both on the same day or on consecutive days (1). Attack rates and vaccine efficacy (VE), defined as the relative reduction in the influenza rate for Flublok relative to placebo, were calculated for the total vaccinated cohort (n=4,648). The pre-defined success criterion for the primary efficacy analysis was that the lower bound of the 95% confidence interval (CI) of VE should be at least 40%. Vaccine efficacy against antigenically matched culture-confirmed CDC-ILI could not be determined reliably because 96% of the influenza isolates obtained from subjects in Study 1 were not antigenically matched to the strains represented in the vaccine. An exploratory analysis of VE of Flublok against all strains regardless of antigenic match isolated from any subject with an ILI, not necessarily CDC-defined ILI, demonstrated an efficacy estimate of 44.8% (95% CI 24.4, 60.0). See Table 2 for a presentation of VE by case definition and antigenic similarity.[1]

Influenza clinical study.jpg

=Clinical trials of vaccines

A vaccine is assessed in terms of the reduction of the risk of disease produced by vaccination, its efficacy. In contrast, in the field, the effectiveness of a vaccine is the practical reduction in risk for an individual when they are vaccinated under real-world conditions.[2] Measuring efficacy of Influenza vaccines is relatively simple, as the immune response produced by the vaccine can be assessed in animal models, or the amount of antibody produced in vaccinated people can be measured,[3] or most rigorously, by immunising adult volunteers and then challenging with virulent influenza virus.[4] In studies such as these, Influenza vaccines showed high efficacy and produced a protective immune response. For ethical reasons, such challenge studies cannot be performed in the population most at risk from influenza - the elderly and young children. However, studies on the effectiveness of flu vaccines in the real world are uniquely difficult. The vaccine may not be matched to the virus in circulation; virus prevalence varies widely between years, and influenza is often confused with other flu-like illnesses.[5]

Nevertheless, multiple clinical trials of both live and inactivated Influenza vaccines have been performed and their results pooled and analyzed in several recent meta-analyses. Studies on live vaccines have very limited data, but these preparations may be more effective than inactivated vaccines.[4] The meta-analyses examined the efficacy and effectiveness of inactivated vaccines in adults,[6] children,[7] and the elderly.[8][9] In adults, vaccines show high efficacy against the targeted strains, but low effectiveness overall, so the benefits of vaccination are small, with a one-quarter reduction in risk of contracting influenza but no effect on the rate of hospitalization.[6] In children, vaccines again showed high efficacy, but low effectiveness in preventing "flu-like illness", in children under two the data are extremely limited, but vaccination appeared to confer no measurable benefit.[7] In the elderly, vaccination does not reduce the frequency of influenza, but may reduce pneumonia, hospital admission and deaths from influenza or pneumonia.[8][9] The measured effectiveness of the vaccine in the elderly varies depending on whether the population studied is in residential care homes, or in the community, with the vaccine appearing more effective in an institutional environment. This apparent effect may be due to selection bias or differences in diagnosis and surveillance.

Overall, the benefit of influenza vaccination is clearest in the elderly, with vaccination in children of questionable benefit. Vaccination of adults is not predicted to produce significant improvements in public health. The apparent contradiction between vaccines with high efficacy, but low effectiveness, may reflect the difficulty in diagnosing influenza under clinical conditions and the large number of strains circulating in the population.[5]


  2. Fedson D. "Measuring protection: efficacy versus effectiveness". Dev Biol Stand. 95: 195–201. PMID 9855432.
  3. Stephenson I, Zambon M, Rudin A, Colegate A, Podda A, Bugarini R, Del Giudice G, Minutello A, Bonnington S, Holmgren J, Mills K, Nicholson K (2006). "Phase I evaluation of intranasal trivalent inactivated Influenza vaccine with nontoxigenic Escherichia coli enterotoxin and novel biovector as mucosal adjuvants, using adult volunteers". J Virol. 80 (10): 4962–70. PMID 16641287.
  4. 4.0 4.1 Treanor J, Kotloff K, Betts R, Belshe R, Newman F, Iacuzio D, Wittes J, Bryant M (1999). "Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) Influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses". Vaccine. 18 (9–10): 899–906. PMID 10580204.
  5. 5.0 5.1 Jefferson T (2006). "Influenza vaccination: policy versus evidence". BMJ. 333 (7574): 912–5. PMID 17068038.
  6. 6.0 6.1 Demicheli V, Rivetti D, Deeks J, Jefferson T. "Vaccines for preventing influenza in healthy adults". Cochrane Database Syst Rev: CD001269. PMID 15266445.
  7. 7.0 7.1 Smith S, Demicheli V, Di Pietrantonj C, Harnden A, Jefferson T, Matheson N, Rivetti A. "Vaccines for preventing influenza in healthy children". Cochrane Database Syst Rev: CD004879. PMID 16437500.
  8. 8.0 8.1 Rivetti D, Jefferson T, Thomas R, Rudin M, Rivetti A, Di Pietrantonj C, Demicheli V. "Vaccines for preventing influenza in the elderly". Cochrane Database Syst Rev. 3: CD004876. PMID 16856068.
  9. 9.0 9.1 Jefferson T, Rivetti D, Rivetti A, Rudin M, Di Pietrantonj C, Demicheli V (2005). "Efficacy and effectiveness of Influenza vaccines in elderly people: a systematic review". Lancet. 366 (9492): 1165–74. PMID 16198765.

Adapted from the FDA Package Insert.