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Intervention Review

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Vaccines for preventing influenza in healthy adults

  1. Tom Jefferson1,*,
  2. Carlo Di Pietrantonj2,
  3. Alessandro Rivetti2,
  4. Ghada A Bawazeer3,
  5. Lubna A Al-Ansary4,
  6. Eliana Ferroni5

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 7 JUL 2010

Assessed as up-to-date: 3 JUN 2010

DOI: 10.1002/14651858.CD001269.pub4


How to Cite

Jefferson T, Di Pietrantonj C, Rivetti A, Bawazeer GA, Al-Ansary LA, Ferroni E. Vaccines for preventing influenza in healthy adults. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD001269. DOI: 10.1002/14651858.CD001269.pub4.

Author Information

  1. 1

    The Cochrane Collaboration, Roma, Italy

  2. 2

    Azienda Sanitaria Locale ASL AL, Servizio Regionale di Riferimento per l'Epidemiologia, SSEpi-SeREMI - Cochrane Vaccines Field, Alessandria, Piemonte, Italy

  3. 3

    King Saud University, Department of Clinical Pharmacy & KKUH, Riyadh, Saudi Arabia

  4. 4

    College of Medicine, King Saud University, Department of Family & Community Medicine, Holder of "Shaikh Abdullah S. Bahamdan" Research Chair for Evidence-Based Health Care and Knowledge Translation, Riyadh, Saudi Arabia

  5. 5

    Public Health Agency of Lazio Region, Infectious Diseases Unit, Rome, Italy

*Tom Jefferson, The Cochrane Collaboration, Via Puglie 23, Roma, 00187, Italy. jefferson.tom@gmail.com. jefferson@assr.it.

Publication History

  1. Publication Status: Edited (no change to conclusions), comment added to review
  2. Published Online: 7 JUL 2010

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This is not the most recent version of the article. View current version (13 MAR 2014)

 
Characteristics of included studies [ordered by study ID]
Atmar 1990

MethodsDouble-blind placebo-controlled randomised trial


Participants74 healthy volunteers aged 18 to 40 years (data on 17 asthmatics were not extracted)


InterventionsCold - recombinant vacc. A (H1N1); n = 16
versus
Cold - recombinant vacc. A (H3N2); n = 13
versus
Cold - recombinant vacc. B; n = 17
versus
Placebo; n = 26
Intranasal


OutcomesPulmonary function tests (performed on day 0, 3 to 4, 7 after vaccination):
- Forced respiratory volume in 1 second (FEV1)
- Forced expiratory vital capacity (FVC)
- FEV1/FVC
- Forced expiratory flow rate 25 to 75% (FEF 25 to 75)


NotesThe authors report several non-significant drops in FEV and FVC up to 7 days post inoculation and a higher incidence of ILI (17/46 versus 4/26) in the vaccinated arms. Safety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Beran 2009a

MethodsRandomised double blind, placebo controlled study conducted in Czech Republic during the 2005 to 2006 influenza season. This was defined retrospectively as starting the first week with two culture-confirmed cases in the study area and ending the last week with one culture-confirmed case in the study area. Randomisation was generated by GSK (sponsor) using SAS program, in 2:1 blocking scheme using a minimisation procedure (no explanation of why to use such method or ratio). Allocation concealment method was not explicitly mentioned. However, authors mentioned that placebo and vaccine treatments were indistinguishable in appearance and that blinding to treatment assignment was maintained until study analysis


ParticipantsSelf-referred healthy adults (n = 6203), predominately Caucasian (99.8%), aged between 18 and 64 years (mean 35 + 13 years) of both genders (TIV group: F 55.3%, placebo group: F 54.2%) and with no history of influenza vaccination within the last 3 influenza seasons. A subset of participants who were randomly selected for vaccine safety and reactogenicity were given a calibrated thermometer and a diary card to record symptoms. The method of selection of this subset was not explained. Use of antimicrobial/influenza antiviral therapy seem to be allowed but was not quantified


InterventionsTIV vaccine: 0.5 ml single dose by IM injection or placebo (normal saline) administered intramuscularly. Use of more than one lot was not reported.

TIV contain hemagglutinin antigens of

  • A/New Caledonia/20/99 (H1N1) IVR-116 virus as an A/New Caledonia/20/99-like strain
  • A/New York/55/2004 (H3N2) X-157 virus as an A/California/7/2004-like strain
  • B/Jiangsu/10/2003 virus as a B/Shanghai/361/2002-like strain.


Two modes of surveillance were used.
Passive: started on the day of vaccination, participants self report through a toll free number of ILI symptoms
Active: started 2 weeks after vaccination day: a biweekly telephone contact of the subjects by someone (not clear who) for ILI symptoms

It is not clear if the surveillance included the entire cohort or just a subset, or why the authors did carry out harms surveillance using the 2 surveillance methods already in-place


OutcomesSerological

Blood samples were collected for the specified subset and were tested/analyzed at GSK Biologicals SSW Dresden, Germany

Blood sample obtained prior to vaccination and at 21 days following vaccination. Serum samples were stored at -20°C until blinded analyses were conducted

Hemagglutination-inhibition test was done using chicken red blood cells with the three virus strains present in the TIV used as antigens. The serum titre was expressed as the reciprocal of the highest dilution that showed complete inhibition of hemagglutination

Serology was not a primary outcome in this study

Effectiveness

Incidence of culture-confirmed ILI (primary outcome, reported as the attack rate in the efficacy cohort)

Nasal and throat swab collected by a nurse on the same day

swab samples were stored at 28°C and transferred within 5 days of the onset of ILI symptoms

Sample sent to the National Reference Laboratory for Influenza (NRL, Prague, Czech Republic) for conventional influenza virus culture using Madin Darby Canine Kidney (MDCK) cells

Confirmation of influenza A or B was determined using the following:

  • hemagglutination assay with turkey and guinea pig erythrocytes
  • hemagglutination inhibition was used to identify virus type, subtype and drift variant
  • direct immunoperoxidase assay using anti-influenza A and anti-influenza B nucleoprotein antibodies


There were 814 reported ILI episodes, only 46 gave positive culture 

Clinical

Incidence of ILI symptoms (secondary outcome, reported as attack rate in the ATP cohort)

IL was defined as fever (oral temperature greater or equal to 37.8°C) plus cough and/or sore throat. An ILI episode was defined as the period from the first day of ILI symptoms until the last day of ILI symptoms. A new episode was taken into account only after the complete resolution of the previous one. To count as a separate episode at least 7 days free of any symptoms should pass

Number of events was 370 reported events (254 in TIV and 120 in placebo)

Number of subjects reporting at least one event (240 in TIV and 113 in placebo) was used to calculate the attack rate

Reasons to exclude from the ATP cohort include:

  • protocol violation (inclusion/exclusion criteria): seems that the selected subset have certain criteria but not mentioned by the authors
  • underlying medical condition: not specified what? Or why not excluded from the efficacy cohort as well since participants are reported to be healthy
  • forbidden by the protocol: protocol not clear
  • subjects not exposed during the influenza season: not understood what it meant (did the patient travel after getting the study treatment?)


Immunogenicity: blood sample obtained prior to vaccination and at 21 days following vaccination. Performed only for a subset of patient not all efficacy cohort

Safety

Data on serious adverse events (SAEs) began at the receipt of vaccine/placebo and continued until the end of the study.  However safety was solicited from a subset of subjects (no mention of method used to randomly select them, no justification for not collecting SAEs from all participants, especially with the presence of two surveillance methods)

Reactogenicity:  defined as the presence and intensity of the following symptoms within 4 days of vaccination: pain, redness and swelling (found to occur more in the TIV group) other general symptoms of fatigue, fever, headache, muscle aches, shivering and joint pain (found to occur more in the TIV group)

The intensities of adverse events were recorded according to a standard 0 to 3 grade scale: "absent", "easily tolerated", "interferes with normal activity" and "prevents normal activity"


NotesThe authors report that due to the atypical nature of the influenza season during this study we were unable to assess TIV efficacy


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskGeneration of allocation schedule

b) computer random-number generator                     

Concealment of treatment allocation

No explicit description of the method of concealment, authors only mentioned that treatments were numbered and that they were indistinguishable in appearance)

Exclusion of allocated participants from the analysis of the trial

a) Did the report mention explicitly the exclusion of allocated

participants from the analysis of trial results? Yes

b) If so did the report mention the reason(s) for exclusion?

yes, details were reported in the study flow chart. Of the 6213 enrolees, 10 were excluded because the identification number assigned to the same 4 subjects who were

Measures to implement double blinding 

a) Did the report mention explicitly measures to implement and protect double blinding? No, authors reported that the blinding assignment was maintained until study analysis 

b) Did the author(s) report on the physical aspect of compound administration - (i.e. appearances, colour, route administration). Authors mentioned the treatments were indistinguishable in appearance 

Medium risk of bias. Basis for selection of follow up and allocation concealment not described

Beran 2009b

MethodsA randomised, double-blind, placebo-controlled study conducted during the 2006 to 2007 influenza season at 15 centres located in the Czech Republic and Finland. The protocols and study documents were approved by the ethics committee of each country. Participants were randomised to receive 1 dose of TIV (lot 1 or lot 2 of Fluarix) or placebo (normal saline solution) at the first study visit (day 0) by intramuscular injection. Each 0.5 mL dose of TIV contained 15 mg of each of the hemagglutinin antigens of strains A/New Caledonia/20/99(H1N1) IVR-116, A/Wisconsin/67/2005(H3N2), and B/Malaysia/2506/2004 (from the Victoria lineage). 

From the day of vaccination, passive and active surveillance (biweekly contact) to detect ILI cases. For each case of suspected ILI, a nasal and throat swab specimen (composed of a swab of both nasal sinuses and a second swab of the throat) was collected for culture (as much as possible on the same day as the ILI report and, at the latest, 5 days after the ILI onset). Each subject was provided with a calibrated thermometer to measure temperature and a diary card to record temperatures and symptoms during the ILI episode. Blinded analysis was carried out at GSK biologicals in Dresden, Germany.

Blood samples for the evaluation of influenza vaccine immunogenicity were obtained from  the randomly selected, planned subset of ?500 participants just prior to vaccination and 21-28 days later. Frozen aliquots of culture supernatants from positive viral cultures were sent to J. Treanor’s laboratory  University of Rochester Vaccine Evaluation Unit Influenza Serology Laboratory, Rochester, New York) for identification of virus-matching isolates by  conventional hemagglutination-inhibition testing (using H1 and H3 antisera from the CDC and B/Malaysia antiserum from the WHO)


ParticipantsEligible participants were:

  • self-referred women or men who were
  • between 18 and 64 years of age
  • who had no significant clinical disease at the time of vaccination


Who provided written informed consent


InterventionsIntervention 1 dose of TIV (lot 1 or lot 2 of Fluarix), IM injection, at the first day of the study (Day 0).
Each 0.5 mL dose of TIV contained 15 mg of each of the hemagglutinin antigens of strains A/New/Caledonia/20/99(H1N1) IVR-116, A/Wisconsin/67/2005(H3N2), and B/Malaysia/2506/2004 (from the Victoria lineage).

Comparator placebo (normal saline solution), IM injection, at the first day of the study (Day 0)


OutcomesSerological  (only carried out for the TIV group)

Effectiveness 

Evaluate efficacy of TIV versus placebo in the prevention of culture-confirmed influenza A and/or B due to strains antigenically matched to the vaccine (their primary objective).

Secondary objectives

  • Evaluation of TIV in the prevention of culture-confirmed influenza due to strains antigenically matched to the vaccine for  each of the 2 vaccine lots
  • Evaluation of TIV in the prevention of culture-confirmed Influenza A and/or B attributable to any influenza A or B strain
  • Evaluation of TIV in the prevention of ILI which was less-stringently- defined as at least 1 systemic symptom (fever and/or myalgia) and 1 respiratory symptom (cough and/or sore throat).


Safety vaccine reactogenicity and immunogenicity in a random subset of subjects by obtaining blood samples prior to vaccination and 21-28 days later. However, no harms data are reported


NotesThe authors conclude that TIV is efficacious against culture-confirmed influenza in healthy adults


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNo details provided of either randomisation or allocation concealment. There is no mention of appearance of the injection content.

Attrition reasons for the whole cohort are as follows

  • Administration of vaccines forbidden in the protocol
  • Administration of medication forbidden in the protocol
  • Underlying medical condition forbidden by the protocol
  • Subjects not exposed during the influenza season
  • Randomisation code broken at the investigation site
  • Protocol violation (inclusion/exclusion criteria)


The additional stated reasons for the 'Safety' subset study:

  • Non compliance with blood sampling


Essential serological data missing

Betts 1977a

MethodsRandomised controlled trial carried out from April 1976 at Rochester University. Vaccine and placebo were randomly administered in double blind manner, thus any description of allocation procedure is given. Thirty-six days after immunisation all subjects were challenged with wild type virus (A/Victoria/3/75, H3N2) and antibody response determined in serum and nasal secretions (before vaccination, 36 later and 21 days after challenge, not for analysis).


Participants47 healthy male and female university students with absent or low HAI titre (i.e. little or no immunity) to both A/Scotland/74 and A/Victoria/3/75


InterventionsLive attenuated A/Scotland/74 (H3N2) versus placebo, one 0.5 ml-dose intranasal. On day 37 after immunisation subjects were challenged with A/Victoria/3/75


OutcomesA physician examined the subjects 1 day and 4 days after the received vaccine or placebo. Temperature was observed only one day after. Observed symptoms were: Mild sore throat and rhinorrhea : Vacc 4/23 ; placebo 3 /24 ; Fever (Temp > 37.50 °C); none had it


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Boyce 2000

MethodsOpen label/single blind randomised controlled trial to assess safety and immunogenicity of adjuvanted and unadjuvanted subunit influenza vaccine, prepared with the strains recommended for and isolated in the 1997 to 1998 season


Participants74 healthy adults aged between 10 and 40 years, who did not receive influenza immunisation during the 6 months preceding the trial


Interventions1) M-59 adjuvanted subunit trivalent flu vaccine (prepared with A/Bayern/795 H1N1, A/Wuhan/359/95 H3N2, B/Beijing/184/93 -like strains, each 15 mcg/ 0.5 ml-dose)
2) Unadjuvated vaccine (prepared with the same strains at the same concentrations as the adjuvanted preparation)
3) Placebo (consisting of 0.5 ml sterile saline)
All preparation were intranasal administered in two doses 28 days apart. 24 individuals received their first dose of adjuvanted (n = 12) or unadjuvanted (n = 12) subunit vaccine in open label manner. After it was stated that they tolerated the first dose, the randomised phase of the trial (n = 50) was begun. In this phase 18 subjects received two doses of unadjuvanted vaccine, 19 adjuvanted and 13 placebo


OutcomesAfter each immunisation, subjects were observed for 30 minutes, were examined after 2 days and then completed a diary card reporting symptoms occurred within 7 days after. Local reactions: nasal symptoms, unpleasant taste, bloody nasal discharge, sneezing. Systemic reactions: chills, pulmonary, nausea, malaise, myalgia or arthralgia, urticarial rash, headache, Oral temperature >= 38°C, stay at home, due to use of analgesic or antipyretic. Data were not given separately for randomised and open-label phase of the study


NotesIt is not possible to consider separately safety data for the two study phases. Safety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Bridges 2000a

MethodsRandomised controlled trial, double blind conducted in USA during the 1997 to 1998 influenza season. Follow up lasted from November to March. Influenza period was defined as the period during which clinical specimens collected from ill subjects yielded influenza viruses: Dec 8 1997 through Mar 2, 1998 and lasted 12 weeks. Volunteers were randomly allocated to receive vaccine or placebo using a table of random number. Pharyngeal swab and paired sera were collected from ill people


Participants1184 healthy factory employees: 595 treated and 589 placebo. Age of participants was 18 to 64


InterventionsCommercial trivalent, inactivated, intramuscular vaccine. Schedule and dose were not indicated. Vaccine composition was: A/Johannesburg/82/96, A/Nanchang/933/95 and B/Harbin/7/94. Placebo was sterile saline for injection. Vaccine was recommended but did not match circulating strain


OutcomesInfluenza-like illness, influenza, days ill, physician visits, times any drug was prescribed, times antibiotic was prescribed, working days lost, admissions, adverse effects. They were defined as follow: Influenza-like illness: fever = 37.7 °C with cough or sore throat); upper respiratory illness: cough with sore throat or fever = 37.7 °C. Local adverse effects were arm soreness and redness. Systemic adverse effect were: fever, sore throat, coryza, myalgia, headache and fatigue, but authors reported no data. Surveillance was passive


NotesFor analysis we chose the Influenza-like illness definition. ITT was performed. Systemic adverse effects were not reported. Circulating strain was A/Sidney/5/97-like


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Bridges 2000b

MethodsRandomised controlled trial, double blind conducted in USA during 1998 to 1999 influenza season. Follow up lasted from November to March. The influenza period was defined as the period during which clinical specimens collected from ill subjects yielded influenza viruses: Jan 4, 1998 through Mar 14, 1999 and lasted 10 weeks. Volunteers were randomly allocated to receive vaccine or placebo using a table of random number. Pharyngeal swab and paired sera were collected from ill people


Participants1191 healthy factory employees: 587 treated and 604 placebo. Age of participants was 19 to 64


InterventionsCommercial trivalent, inactivated, intramuscular vaccine. Schedule and dose were not indicated. Vaccine composition was: A/Beijing/262/95, A/Sydney/5/97 and B/Harbin/7/94. Placebo was sterile saline for injection. Vaccine was recommended and matched circulating strain


OutcomesInfluenza-like illness, influenza, days ill, physician visits, times any drug was prescribed, times antibiotic was prescribed, working days lost, admissions, adverse effects. They were defined as follow: Influenza-like illness: fever = 37.7 °C with cough or sore throat); upper respiratory illness: cough with sore throat or fever = 37.7 °C. Local adverse effects were arm soreness and redness. Systemic adverse effect were: fever, sore throat, coryza, myalgia, headache and fatigue, but authors reported no data. Surveillance was passive


NotesFor analysis we chose the influenza-like illness definition. ITT was performed. Systemic adverse effects were not reported. Circulating strain was A/Sidney/5/97-like and B/Beijing/184/93-like


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Caplan 1977

MethodsRandomised controlled trial to assess reactogenicity and safety of monovalent whole virus- and split virus vaccines prepared with strain A/Victoria/3/75 from different U.S. manufacturer


Participants208 healthy adult volunteers aged between 18 and 64 years, recruited from the University of Maryland, USA


InterventionsMonovalent whole-virus vaccine (Merck Sharp & Dohme, Merrell-National Laboratories) or monovalent split virus vaccine (Parke, Davis and Company ; Wyeth Laboratories) administered in different antigen concentrations (200, 400 or 800 CCA) versus placebo. All from A/Victoria75. One dose intramuscular


OutcomesTemperature >= 100°F (37.8°C) ; feverishness; pain or burning; tenderness; malaise or myalgia; nausea or vomiting; headache; other. 21-day follow up. Safety outcomes are also given in cumulative % for each category : Local, systemic, bothersome; febrile; or scores for systemic reactions


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

DeStefano 2003

MethodsCase control study


ParticipantsData from Vaccine Safety Datalink (large database of cases of disease following vaccination) in the USA


InterventionsImmunisation with influenza and other vaccines assessed by means of medical records


OutcomesCases: Physician diagnosis of multiple sclerosis or optic neuritis in medical record
Controls: Up to 3 controls per case were selected from automated HMO member files, at least 1 year of HMO enrolment, matched on age (within 1 year) and gender


NotesRare events (safety)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Eddy 1970

MethodsControlled clinical trial, single blind conducted in South Africa during the 1969 influenza season. Follow up lasted from May to July. The first clinical case of influenza appeared on May 21 1969, and the last 6 weeks later. The epidemic period lasted 6 weeks. The control subjects were selected by drawing a 1-in-4 systematic sample from a ranked list of the personnel numbers


Participants1758 healthy male black African employees: 1254 treated and 413 placebo. Age of participants was 18 to 65


InterventionsMonovalent inactivated parenteral vaccine. Schedule and dose were single injection, 1 ml. Vaccine composition was: A2/Aichi/2/68 (Hong Kong variant). Placebo was sterile water. Vaccine was recommended and matched circulating strain


OutcomesInfluenza-like illness, working days lost, days ill. Influenza-like illness was not defined; case features were generically described in results section. All ill persons were admitted to hospital until recovery. Surveillance was passive


NotesThe word "double blinding" was not used, but the control group received an injection of "dummy vaccine". Poor reporting, poor quality study. Circulating strain was A2/Hong Kong/68 virus
Efficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)High riskC - Inadequate

Edwards 1994a

MethodsRandomised controlled trial, double blind conducted in USA during 1986 to 1987 influenza season. Follow up lasted the whole epidemic period. The epidemic period in any study year started on the day that the first influenza A virus isolate was obtained in Nashville and ended on the day that the last isolate was obtained and lasted 8 weeks. Subjects were recruited from seven organisations and assigned to one of the study groups using a permuted block randomisation scheme that was stratified by treatment center and age group. Sealed randomisation envelopes contained vaccine codes. Pharyngeal swab and paired sera were collected from ill people


Participants1311 healthy children and adults of metropolitan Nashville. 85% of people were older than 16: 872 treated and 439 placebo. Age of participants was 1 to 65


InterventionsBivalent, live cold adapted, aerosol administered influenza A vaccine and the commercial inactivated intramuscularly administered influenza vaccine. Schedule and dose were: single dose; cold adapted 107-107,6 pfu/ml; inactivated 15 micrograms each strain. Vaccine composition was: cold adapted: Texas/1/85 H1N1 and Bethesda/1/85 H3N2; inactivated: Chile/1/83 H1N1 and Mississippi/1/85 H3N2 . Placebo was allantoic fluid. Vaccine was recommended but did not match circulating strain


OutcomesInfluenza-like illness, influenza. They were defined as follows: fever of abrupt onset with at least one of the following: chills, headache, malaise, myalgia, cough, pharyngitis or other respiratory complaints (only patients who presented for culture were considered); throat culture. Surveillance was passive


NotesInfluenza B strain contained in the commercial and monovalent vaccines was not described. Strains used yearly to develop cold adapted and inactivated vaccines were antigenically comparable. Since cold adapted influenza B vaccines were not sufficiently characterised to include in the study, authors used monovalent inactivated influenza B vaccine in all subjects in cold adapted arm and as placebo in the control group of inactivated arm. Only cold adapted comparison was included in analysis. Circulating strain was Taiwan/1/86. Effectiveness data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Edwards 1994b

MethodsRandomised controlled trial, double blind conducted in USA during 1987 to 1988 influenza season. Follow up lasted the whole epidemic period. The epidemic period in any study year started on the day that the first influenza A virus isolate was obtained in Nashville and ended on the day that the last isolate was obtained and lasted 14 weeks. Subjects were recruited from seven organisations and assigned to one of the study groups using a permuted block randomisation scheme that was stratified by treatment center and age group. Sealed randomisation envelopes contained vaccine codes. Pharyngeal swab and paired sera were collected from ill people


Participants1561 healthy children and adults of metropolitan Nashville. 85% of people were older than 16: 1029 treated and 532 placebo. Age of participants was 1 to 65


InterventionsBivalent, live cold adapted, aerosol administered influenza A vaccine and the commercial inactivated intramuscularly administered influenza vaccine. Schedule and dose were: single dose; cold adapted 107-107.6 pfu/ml; inactivated 15 micrograms each strain. Vaccine composition was: cold adapted: Kawasaki/9/86 H1N1 and Bethesda/1/85 H3N2; inactivated: Taiwan/1/86 H1N1 and Leningrad/360/86 H3N2. Placebo was allantoic fluid. Vaccine was recommended but did not match circulating strain


OutcomesInfluenza-like illness, influenza. They were defined as follows: fever of abrupt onset with at least one of the following: chills, headache, malaise, myalgia, cough, pharyngitis or other respiratory complaints (ILI retrospectively reported were considered); fourfold antibody rise between post-vaccination and spring sera. Surveillance was passive


NotesInfluenza B strain contained in the commercial and monovalent vaccines was not described. Strains used yearly to develop cold adapted and inactivated vaccines were antigenically comparable. Since cold adapted influenza B vaccines were not sufficiently characterised to include in the study, authors used monovalent inactivated influenza B vaccine in all subjects in cold adapted arm and as placebo in the control group of inactivated arm. Only cold adapted comparison was included in analysis. Circulating strain was Sichuan/2/87 (H3N2) (antigen drift from vaccine strain) and B/Victoria/2/87
Effectiveness data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Edwards 1994c

MethodsRandomised controlled trial, double blind conducted in USA during 1988 to 1989 influenza season. Follow up lasted the whole epidemic period. The epidemic period in any study year started on the day that the first influenza A virus isolate was obtained in Nashville and ended on the day that the last isolate was obtained and lasted 11 weeks. Subjects were recruited from seven organisations and assigned to one of the study groups using a permuted block randomisation scheme that was stratified by treatment center and age group. Sealed randomisation envelopes contained vaccine codes. Pharyngeal swab and paired sera were collected from ill people


Participants1676 healthy children and adults of metropolitan Nashville. 85% of people were older than 16: 1114 treated and 562 placebo. Age of participants was 1 to 65


InterventionsBivalent, live cold adapted, aerosol administered influenza A vaccine and the commercial inactivated intramuscularly administered influenza vaccine. Schedule and dose were: single dose; cold adapted 107-107,6 pfu/ml; inactivated 15 micrograms each strain. Vaccine composition was: cold adapted: Kawasaki/9/86 H1N1 and Los Angeles/2/87 H3N2; inactivated: Taiwan/1/86 H1N1 and Sichuan/2/87 H3N2. Placebo was allantoic fluid. Vaccine was recommended and matched circulating strain


OutcomesInfluenza-like illness, influenza. They were defined as follows: fever of abrupt onset with at least one of the following: chills, headache, malaise, myalgia, cough, pharyngitis or other respiratory complaints (ILI retrospectively reported were considered); fourfold antibody rise between postvaccination and spring sera. Surveillance was passive


NotesInfluenza B strain contained in the commercial and monovalent vaccines was not described. Strains used yearly to develop cold adapted and inactivated vaccines were antigenically comparable. Since cold adapted influenza B vaccines were not sufficiently characterised to include in the study, authors used monovalent inactivated influenza B vaccine in all subjects in cold adapted arm and as placebo in the control group of inactivated arm. Only cold adapted comparison was included in analysis. Circulating strain was Taiwan/1/86 (H1N1) and B/Yamata/16/88. Effectiveness data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Edwards 1994d

MethodsRandomised controlled trial, double blind conducted in USA during 1989 to 1990 influenza season. Follow up lasted the whole epidemic period. The epidemic period in any study year started on the day that the first influenza A virus isolate was obtained in Nashville and ended on the day that the last isolate was obtained and lasted 11 weeks. Subjects were recruited from seven organisations and assigned to one of the study groups using a permuted block randomisation scheme that was stratified by treatment center and age group. Sealed randomisation envelopes contained vaccine codes. Pharyngeal swab and paired sera were collected from ill people


Participants1507 healthy children and adults of metropolitan Nashville. 85% of people were older than 16: 999 treated and 508 placebo. Age of participants was 1 to 65


InterventionsBivalent, live cold adapted, aerosol administered influenza A vaccine and the commercial inactivated intramuscularly administered influenza vaccine. Schedule and dose were: single dose; cold adapted 107-107,6 pfu/ml; inactivated 15 micrograms each strain. Vaccine composition was: Kawasaki/9/86 H1N1 and Los Angeles/2/87 H3N2; inactivated: Taiwan/1/86 H1N1 and Shanghai/11/87 H3N2 . Placebo was allantoic fluid. Vaccine was recommended and matched circulating strain


OutcomesInfluenza-like illness, influenza. They were defined as follows: fever of abrupt onset with at least one of the following: chills, headache, malaise, myalgia, cough, pharyngitis or other respiratory complaints (ILI retrospectively reported were considered); fourfold antibody rise between postvaccination and spring sera. Surveillance was passive


NotesInfluenza B strain contained in the commercial and monovalent vaccines was not described. Strains used yearly to develop cold adapted and inactivated vaccines were antigenically comparable. Since cold adapted influenza B vaccines were not sufficiently characterised to include in the study, authors used monovalent inactivated influenza B vaccine in all subjects in cold adapted arm and as placebo in the control group of inactivated arm. Only cold adapted comparison was included in analysis. Circulating strain was Shanghai/11/87 (H3N2). Effectiveness data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

El'shina 1996

MethodsRandomised controlled trial


Participants432 healthy subjects aged between 18 and 22 years who did not receive any influenza immunisation during the previous 2 to 3 years


InterventionsPolymer-subunit influenza vaccine "Grippol" prepared with the strains A/Victoria/36/88, Wib - 26 , B/Panama 45/90. Two types containing 5 or 2.5 mcg hemagglutinin of each strain respectively were compared with whole-virion inactivated trivalent vaccine (reference preparation, containing 35 mcg of hemagglutinin) and placebo (consisting of sterile physiological solution). One 0.5-ml dose subcutaneously administered


OutcomesAfter immunisation subjects were placed under medical observation. Fever (48 hours follow up) : weak (37.1 to 37.5°C) , moderate (37.6 to 38.5 °C) , severe (? 38.6 °C).Systemic reactions (3 to 4 days follow up): feeling unwell, sore throat, hyperaemia of nasopharynx, head cold, cough, headache, blocked nose, dizziness, shivering, drowsiness, nausea, hoarseness. Local reaction : All (moderate weak); pain at site of injection


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Evans 1976

MethodsRandomised controlled trial


Participants162 healthy subjects aged 18 to 61 years


InterventionsBivalent live attenuated vaccine WRL 105 (recombinant of A/Okuda/57 and A/Finland/4/74) containing 107.0 EID50 virus/ 0.5 ml dose vs. placebo. Both preparations were administered intranasally 3 to 4 weeks apart


OutcomesReactions to immunisation were observed for 7 days after each dose. Local symptoms (referable to the upper respiratory tract, mainly nasal obstruction, nasal discharge or sore throat) reported as mild moderate or severe. General symptoms (mainly headache fever or myalgia).These two are further reported in different intensity class (mild, moderate, severe, lasting for at least 4 days) reported as mild moderate or severe. Use of analgesics


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Forsyth 1967

MethodsFrom this report, only the first phase of the first trial is of interest for the purposes of this review, in which administration of whole virus, oil adjuvanted influenza vaccine Invirin (GSK) or placebo in semi-randomised allocation. The trial was performed in November to December 1962


ParticipantsMedical students (n = 380) at the Queen's University of Belfast, UK


InterventionsTrivalent aqueous vaccine (Invirin, Glaxo) one 0.25 ml dose I.M. containing strains A/Singapore/1/57, A/England/1/61, B/England/939/59. Placebo (phosphate-buffered saline) was administered as control. Subjects born on odd days were given placebo (n = 186), those born on even days received vaccine (n = 194)


OutcomesLocal reactions: pain, erythema, tenderness, bruises. Stratified by means of scores ranging from 0 to 3 depending on their severity. Systemic reactions: coryza, migraine, paroxysmal tachycardia. All assessed at day 0, 1, 3, 7, 21 after inoculation. Data are referred to a 3-day follow up


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Goodeve 1983

MethodsRandomised controlled trial, double blind


Participants119 healthy young adults from the Medical and Science Faculties of Sheffield University, UK, aged 18 to 19 years without egg allergy


InterventionsPurified subunit monovalent B/Hong Kong/73 flu vaccine prepared in 4 antigen concentration 40, 20, 10, 5 mcg of HA per each 0.5 ml dose VS saline placebo (0.5 ml dose) subcutaneously administered. Participants were divided in 5 groups of equal dimensions (no further description), each group received one of the tested coded preparations. Artificial challenge one month later with live attenuated RB77 virus


OutcomesLocal and systemic reactions were assessed by means of questionnaires completed by participants 24 hours after immunisation. Local reactions (including redness, swelling, itching), local pain (including pain on pressure, pain on contact, continuous pain)


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Hammond 1978

MethodsControlled clinical trial, double blinded conducted in Australia during 1976 influenza season. Follow up lasted the whole epidemic period. Epidemic influenza was defined by virus isolation and serology tests and lasted from middle April to middle August 1976 (17 weeks). Coded identical-looking vials were sequentially administered to enrolled participants. Throat swab was collected from ill people. Serological confirmation was performed on all subjects


Participants225 medical students or staff members: 116 treated and 109 placebo. Age of participants was not indicated


InterventionsTrivalent parenteral subunit vaccine. Schedule and dose were: single dose. Vaccine composition was: 250 IU of A/Victoria/3/75, 250 IU of A/Scotland/840/74 and 300 IU of B/Hong Kong/8/73. Placebo was diphtheria and tetanus toxoids. Vaccine was recommended and matched circulating strain


OutcomesInfluenza-like illness, influenza. Clinical illnesses were not defined. Influenza was defined as respiratory illness which was associated with the isolation of influenza virus, a four-fold or greater rise in antibody titre occurring between post-vaccination and post-epidemic sera, or both. Surveillance was active


NotesClinical illness was not defined and data were included in analysis as "clinical cases without clear definition". Circulating strain was A/Vic/3/75-like. Efficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Hrabar 1977

MethodsRandomised controlled trial, double blind, carried out during the season 1976 to 1977


Participants167 students at the technical school in Zagreb, former Republic of Yugoslavia, without sensitivity to egg proteins, pregnancy, acute or chronic diseases


InterventionsCold-adapted recombinant A/Victoria/3/75 vaccine administered in 3 different antigen concentration (107.5, 106.5, 105.5 EID50 /0.5 ml) versus placebo. One 0.5 ml dose intranasal


OutcomesSubjects were medically examined on each of the successive 5 days after immunisation (lasting for at least 1 day). Throat infection, granular palate, oedematous uvula, fever (no cases) as cases and subject-days. For the following outcomes, authors give the total number of observed cases, without indication of the corresponding arm: malaise, swollen tonsils, fever (1), rhinorrhea (1), conjunctivitis (7), laryngitis or hoarseness (3), cough (1), swollen tonsils (1), malaise (1). Surveillance was active


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Kaplan 1982

MethodsSurveillance population-based study conducted in USA, during the 1979 to 1980 and 1980 to 1981 influenza season. The study tested the association between influenza vaccination and Guillan-Barrè Syndrome. Reports form for each case was obtained from neurologists. All case reports were included. Follow up period was 01/09/79 to 31/03/80 and 01/09/80 to 31/03/81


ParticipantsUSA (minus Maryland) adult population, 18 years or older


InterventionsSeasonal parenteral vaccine


OutcomesCases of Guillain-Barré syndrome. Vaccine associated cases were defined as those with onset within the eight-week period after influenza vaccination


NotesVaccination rates in population were obtained from national immunisation survey
Rare events (safety)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Keitel 1988a

MethodsRandomised controlled trial, double-blind conducted in USA during 1983 to 1984 influenza season. Follow up lasted the whole epidemic period. Influenza period was defined as the interval during which community surveillance recovered influenza viruses from 10% or more of persons with febrile respiratory illness per calendar week (from January 8 to March 17, 1984) and lasted 9 weeks. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers according to prior vaccination experience. Specimens for culture and acute-convalescent blood specimens were obtained from ill people. At spring time volunteers were asked to record any illness occurred during epidemic period and blood specimens were collected


Participants598 healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies: 300 treated and 298 placebo. Age of participants was 30 to 60


InterventionsTrivalent, killed whole, intramuscularly administered vaccine. Schedule and dose were: single dose; 15 micrograms of hemagglutinin of each influenza strains. Vaccine composition was: A/Philippines/2/82 (H3N2), A/Brazil/11/78 (H1N1) and B/Singapore/222/79. Placebo was sterile saline for injection. Vaccine was recommended but did not match circulating strain


OutcomesOutcomes were: ILI, influenza. Illnesses were classified in "any", "flu-like" (lower respiratory and/or systemic illness) and "febrile" (oral temperature of 37.8 or higher). Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between post-vaccination (pre-epidemic), acute, convalescent and/or spring (post-epidemic) sera


NotesInfluenza-like illness and influenza were detected in three groups: first vaccinated, multi vaccinated and placebo. Febrile illnesses were included in analysis; first two groups cases were added up. Circulating strain was A/Victoria/7/83 (H1N1) and B/USSR/100/83. Efficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1988b

MethodsRandomised controlled trial, double-blind conducted in USA during 1984 to 1985 influenza season. Follow up lasted the whole epidemic period. Influenza period was defined as the interval during which community surveillance recovered influenza viruses from 10% or more of persons with febrile respiratory illness per calendar week (from January 6 to March 9, 1985) and lasted 9 weeks. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers according to prior vaccination experience. Specimens for culture and acute-convalescent blood specimens were obtained from ill people. At spring time volunteers were asked to record any illness occurred during epidemic period and blood specimens were collected


Participants697 healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies: 456 treated and 241 placebo. Age of participants was 30 to 60


Interventions456 trivalent, killed whole, intramuscularly administered vaccine: 241 treated and 30 - 60 placebo. Age of participants was: healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies


OutcomesOutcomes were: ILI, influenza. Illnesses were classified in "any", "flu-like" (lower respiratory and/or systemic illness) and "febrile" (oral temperature of 37.8 or higher). Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between postvaccination (pre-epidemic), acute, convalescent and/or spring (post-epidemic) sera. Surveillance was passive


NotesEfficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1993a

MethodsThis paper reports results of two randomised controlled trials carried out in the USA


ParticipantsHealthy volunteers recruited at Texas A&M University and Texas Medical Center, aged between 18 and 40 years


InterventionsTwo 0.5 ml doses of cold adapted recombinant influenza vaccines, 1 month apart , containing 107.1 TCID50 of each strain/dose. Two studies were carried out in which four groups were formed: 1) placebo 1st and 2nd dose. 2) 1st : A/Kawasaki/9/86 (H1N1, CR 125) + A/Bethesda/1/85 (H3N2, CR90) + B/Ann Arbor/1/86 (B, CRB117)


OutcomesMild upper respiratory symptoms. Fever >= 37.8°C within one week after each inoculation


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1993b

MethodsThis paper reports about results of two randomised controlled trials carried out in the USA


ParticipantsHealthy volunteers recruited at Texas A&M University and Texas Medical Center , aged between 18 and 40 years


InterventionsA/Kawasaki/9/86 (H1N1, CR 125, but different lot from 1st) + A/Los Angeles/2/87 (H3N2, CR149) + B/Ann Arbor/1/86 (B, CRB117 but different lot from 1st)3) 1st : A/Kawasaki/9/86 (H1N1, CR125) + A/Bethesda/1/85 (H3N2, CR90)2nd : B/Ann Arbor/1/86 (B, CRB117)4) 1st : B/Ann Arbor/1/86 (B, CRB1172nd : A/Kawasaki/9/86 (H1N1, CR125) + A/Los Angeles/2/87 (H3N2, CR149)


OutcomesMild upper respiratory symptoms. Fever >= 37.8°C Within one week after each inoculation


NotesSee Keitel 1993 a. Safety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1997a

MethodsRandomised controlled trial, double-blind conducted in USA during 1985 to 1986 influenza season. Follow up lasted the whole epidemic period. Influenza period was defined by viral surveillance. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers according to prior vaccination experience. Specimens for culture and acute-convalescent blood specimens were obtained from ill people. At spring time volunteers were asked to record any illness occurred during epidemic period and blood specimens were collected


Participants830 healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies: 577 treated and 253 placebo. Age of participants was 30 to 60


InterventionsTrivalent, killed whole, intramuscularly administered vaccine. Schedule and dose were: single dose; 15 micrograms of hemagglutinin of each influenza strains. Vaccine composition was: A/Philippines/2/82 (H3N2), A/Chile/1/83 (H1N1) and B/USSR/100/83. Placebo was sterile saline for injection. Vaccine was recommended but did not match circulating strain


OutcomesInfluenza-like illness, influenza. Illnesses were classified in "any", "flu-like" (lower respiratory and/or systemic illness) and "febrile" (oral temperature of 37.8 or higher). Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between post-vaccination (pre-epidemic), acute, convalescent and/or spring (post-epidemic) sera. Surveillance was active


NotesInfluenza-like illness and influenza cases were detected in three groups: first vaccinated, multi vaccinated and placebo. Febrile illnesses were included in analysis; first two groups cases were added up. Circulating strains were B/Ann Arbor/1/86, A/Mississippi/1/85
Efficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1997b

MethodsRandomised controlled trial, double-blind conducted in USA during 1986 to 1987 influenza season. Follow up lasted the whole epidemic period. Influenza period was defined by viral surveillance. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers according to prior vaccination experience. Specimens for culture and acute-convalescent blood specimens were obtained from ill people. At spring time volunteers were asked to record any illness occurred during epidemic period and blood specimens were collected


Participants940 healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies: 723 treated and 217 placebo. Age of participants was 30 to 60


InterventionsTrivalent, killed whole, intramuscularly administered vaccine. Schedule and dose were: two doses; 15 micrograms of hemagglutinin of each influenza strains. Vaccine composition was: A/Mississippi/1/85/H3N2), A/Chile/1/83 (H1N1) and B/Ann Arbor/1/86 plus A/Taiwan/1/86 (H1N1). Placebo was sterile saline for injection. Vaccine was recommended but did not match circulating strain


OutcomesInfluenza-like illness, influenza. Illnesses were classified in "any", "flu-like" (lower respiratory and/or systemic illness) and "febrile" (oral temperature of 37.8 or higher). Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between postvaccination (pre-epidemic), acute, convalescent and/or spring (post-epidemic) sera. Surveillance was passive


NotesInfluenza-like illness and influenza cases were detected in three groups: first vaccinated, multi vaccinated and placebo. Febrile illnesses were included in analysis; first two groups cases were added up. Circulating strain was A/Taiwan/1/86. Effectiveness data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1997c

MethodsRandomised controlled trial, double-blind conducted in USA during 1987 to 1988 influenza season. Follow up lasted the whole epidemic period. Influenza period was defined by viral surveillance. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers according to prior vaccination experience. Specimens for culture and acute-convalescent blood specimens were obtained from ill people. At spring time volunteers were asked to record any illness occurred during epidemic period and blood specimens were collected


Participants934 healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies: 789 treated and 145 placebo. Age of participants was 30 to 60


InterventionsTrivalent, killed whole, intramuscularly administered vaccine. Schedule and dose were: single dose; 15 micrograms of hemagglutinin of each influenza strains. Vaccine composition was: A/Leningrad/360/86 (H3N2), A/Taiwan/1/86 (H1N1), B/Ann Arbor/1/86. Placebo was sterile saline for injection. Vaccine was recommended but did not match circulating strain


OutcomesInfluenza-like illness, influenza. Illnesses were classified in "any", "flu-like" (lower respiratory and/or systemic illness) and "febrile" (oral temperature of 37.8 or higher). Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between postvaccination (pre-epidemic), acute, convalescent and/or spring (post-epidemic) sera. Surveillance was passive


NotesInfluenza-like illness and influenza cases were detected in three groups: first vaccinated, multi vaccinated and placebo. Febrile illnesses were included in analysis; first two groups cases were added up. Circulating strains were A/Sichuan/1/87, B/Victoria/2/87. Effectiveness data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Langley 2005

MethodsRandomised controlled trial


ParticipantsHealthy adults aged 18 to 50 years


InterventionsInactivated A/New Caledonia/20/99 (H1N1) + A/Panama/2007/99 (H3N2) + B/Guangdong/120/2000 non covalent associated with outer membrane protein of N. meningitidis. Single nasal dose containing 15, 30, 45 mcg versus placebo (phosphate buffered saline) intranasal administered


OutcomesLocal : Within 7 days, graphic - rhinorrhea, congestion, itch/burn, nosebleed, red/puffy eyes, sneezing, sore throat. Systemic : within 7 days - cough, shortness of breath, headache, muscle/joint aches, poor appetite, fatigue within 48 hours, nasal mucosa inflammation, nasal discharge, pharyngeal inflammation, sinusitis, enlarged cervical/post-auricular nodes


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)High riskC - Inadequate

Lasky 1998

MethodsSurveillance population-based study conducted in USA (four states: Illinois, Maryland, North Carolina, Washington), during the 1992 to 1993 and 1993 to 1994 influenza season. Discharge diagnoses database were used to identify cases. Hospital charts were reviewed to confirm diagnosis. Follow up period was 01/09/92 to 28/02/93 and 01/09/93 to 28/02/94


ParticipantsApproximately 21 million people, 18 years or older


InterventionsSeasonal parenteral vaccine


OutcomesCases of Guillain-Barré syndrome. Vaccine associated cases were defined a priori as those with onset within the six-week period after influenza vaccination


NotesResults were stratified by age and adjusted by season and sex. Vaccination rates in population were estimated from a random-digit dialling telephone survey. Rare events (safety)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Lauteria 1974

MethodsControlled trial. Randomisation procedure was neither described nor mentioned. Subjects were paired according to age and sex , in each pair one individual received vaccine, the other placebo. Double blind


Participants37 volunteers aged 18 to 24 years, with titre of serum neutralising antibodies to A/Hong Kong/8/68 ? 1:16


InterventionsLive attenuated A/England/ 8/68 grown in presence of heated equine serum. Two 0.5 ml doses containing 104 TCID50 of this strain or placebo (0.85% NaCl) were administered intranasally 2 to 3 weeks apart


OutcomesIndividual observed for 4 days, beginning 24 hours after immunisation. Fever, myalgia, rhinitis, cough, pharyngitis


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Leibovitz 1971

MethodsControlled clinical trial conducted in USA during 1969 to 1970 influenza season. The study period was January 30 to May 18. Follow up lasted first seven weeks of training . Influenza was detected from February 11 to May 13 and lasted weeks. Subjects were allocated to vaccine or control group according to the last non-zero digit of the social security number. Blinding was not mentioned. Specimens for culture and acute-convalescent blood specimens were obtained from people hospitalised with acute respiratory disease


Participants9616 military trainees: 1682 treated and 7934 placebo. Age of participants was 18 to 20


InterventionsMonovalent inactivated, experimental, intramuscularly administered vaccine. Schedule and dose were: single dose, 556 CCA. Recombinant virus derived from HK/Aichi/68 and A0/PR8/34 was compared against no vaccination. Vaccine was not recommended but matched circulating strain


OutcomesOutcomes were: hospitalization for upper respiratory infection (without definition), hospitalization for influenza. Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between acute and convalescent sera. Surveillance was passive


NotesRecruitment and immunisation period overlapped outbreak period. Most of the illness were due to adenovirus. Illness during the first one or two weeks after vaccination were not excluded, but authors stated that this fact did not affect the results. Efficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)High riskC - Inadequate

Mastrangelo 2000

MethodsCase-control study assessing the association between influenza vaccines and cutaneous melanoma


Participants99 cases and 104 controls


InterventionsInfluenza vaccine exposure is not described


Outcomes


NotesThe authors report a protective effect of repeated influenza vaccination on the risk cutaneous melanoma (OR 0.43, 95% CI 0.19 to 1.00). The study is at high risk of bias because of the selective nature of cases (all patients in the authors' hospital), attrition bias (4 cases and 4 controls eliminated because of "failure to collaborate", recall bias (up to 5 years exposure data were based on patients' recollection) and ascertainment bias (non-blinded exposure survey)
Rare events (safety)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Mesa Duque 2001

MethodsRandomised controlled trial, double-blind conducted in Columbia during 1997 influenza season. Follow up lasted from March, 15 to August, 31. Influenza period was not defined. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers. Double-blind was ensured by pre-labelled, coded identical looking vials. Virologic surveillance was not performed


Participants493 bank employees: 247 treated and 246 placebo. Age of participants was 18 to 60


InterventionsSub-unit inactivated, intramuscularly administered vaccine. Schedule and dose were: single dose. Vaccine composition was: A/Wahan/359/95, A/Texas/36/91 and B/Beijing/184/93. Placebo was vitamin C. Vaccine was recommended and matched circulating strain


OutcomesEpisodes of clinical illness, working days lost (wdl), and adverse effects. Clinical disease was defined as upper respiratory illness (fever, sore throat and cough lasting more than 24 hours) according to ICD IX codes 381, 382, 460, 466, 480 and from 487 to 490. Local adverse effects were oedema, erythema, pain, swelling. Systemic adverse effects were fever, headache and indisposition within 5 days by vaccination. Surveillance was passive


NotesCirculating strains were not isolated from local cases but by WHO and Columbia surveillance system, and matched vaccine components. Wdl were detected all the year round, so they were not included in analysis. Efficacy and safety data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Miller 1977

MethodsRandomised controlled trial


Participants43 seronegative healthy adults aged between 22 and 50 years


InterventionsLive attenuated serum inhibitor resistant flu B vaccine R75 (a recombinant of B/Hong Kong/5/72 with B/Russia/69) containing 107.2 EID50 of R75 / 0.5 ml dose versus placebo (sucrose 5%). Intranasal, 2 doses, 2 weeks apart


OutcomesParticipants were interviewed during the 5 days following each immunisation. Local reaction (defined as immediate complains and comprising bad taste or burning, lasting for few moments). Systemic reaction (consisting essentially in headache and rhinorrhea)


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Mixéu 2002

MethodsRandomised controlled trial, double-blind conducted in Brazil during 1997 influenza season. Follow up lasted 6 to 7 months. Influenza period was not defined. Authors did not describe the methods used to ensure randomisation and blinding. Virologic surveillance was not performed


Participants813 flight crews of an airline company: 405 vaccinated and 408 given placebo. Age of participants was 18 to 64


InterventionsSplit trivalent, intramuscularly administered vaccine. Schedule and dose were: single dose. Vaccine composition was: A/Nanchang/933/95, A/Texas/36/91 and B/Harbin/7/94. Placebo was vaccine diluent . Vaccine was recommended and matched circulating strain


OutcomesInfluenza-like illness, working days lost. Clinical illness was defined as follow: fever > 37.6°C and cough, headache, myalgia, rhinorrhea, sore throat lasting at least 24 hours. Surveillance was passive


NotesLocal and systemic effects were reported together and therefore not included in the review. Only 294 treated subjects and 299 controls completed follow up. Efficacy data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Mogabgab 1970a

MethodsRandomised study conducted in USA during 1968 to 1969 influenza season. Influenza outbreak lasted 9 weeks, from December 9 to February 3. Randomisation methods were not described. Laboratory confirmation was obtained (by culture or 4-fold antibody titre increase in acute convalescent sera) on 20 men randomly selected each week among the ill


Participants1402 airmen previously unvaccinated: 881 vaccinated and 521 given placebo. Age of participants was 18 to 21


InterventionsMonovalent inactivated parenteral influenza A vaccine. Schedule and dose were: single dose. Vaccine composition was: A2/Aichi 2/68 300 CCA. Placebo was saline for injection. Vaccine was recommended and matched circulating strain


OutcomesInfluenza-like illness and influenza, complications and admissions. All respiratory illnesses were classified as febrile (38.3°C or greater), afebrile, pharyngitis, bronchitis or pneumonia (complications). Surveillance was passive


NotesCases occurring during the first 15 days after vaccination were not included in analysis. Circulating strain was A2/Hong Kong. Efficacy data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Mogabgab 1970b

MethodsRandomised study conducted in USA during 1968 to 1969 influenza season. Influenza outbreak lasted 9 weeks, from December 9 to February 3 and lasted. Randomisation methods were not described. Laboratory confirmation was obtained (by culture or 4-fold antibody titre increase in acute convalescent sera) on 20 men randomly selected each week among the ill


Participants1551 airmen previously unvaccinated: 1030 vaccinated and 521 given placebo. Age of participants was 18 to 21


InterventionsPolyvalent inactivated influenza A and B vaccine (the 1967 military formula). Schedule and dose were: single dose. Vaccine composition was: A/Swine/33 100 CCA, A/PR8/34 100 CCA, A1/AA/1/57 100 CCA, A2/Taiwan 1/64 400 CCA, B/Lee/40 100 CCA, B/Mass 3/66 200 CCA . Placebo was saline for injection. Vaccine was recommended but did not match circulating strain


OutcomesInfluenza-like illness and influenza cases, complications and admissions. All respiratory illnesses were classified as febrile (38.3°C or greater), afebrile, pharyngitis, bronchitis or pneumonia (complications). Surveillance was passive


NotesCases occurring during the first 15 days after vaccination were not included in analysis. Circulating strain was A2/Hong Kong. Efficacy data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Monto 1982

MethodsRandomised, single blind study conducted in USA during the 1979 to 1980 influenza season. Follow up lasted the whole epidemic period. The epidemic period was defined by first and last isolation (February 11 to march 18) and lasted 5 weeks. Each subject was given a serial number that had previously been assigned randomly by a code to either the vaccine or the placebo group. Specimens for culture were obtained from ill people. At spring time blood specimens were collected


Participants306 students: 154 vaccinated and 152 given placebo. Age of participants was not reported


InterventionsMonovalent, live attenuated, intranasal influenza B . Schedule and dose were: single dose. Vaccine composition was: the vaccine virus, cold recombinant, was produced by recombining the attenuated B/Ann Arbor/1/66 with a wild strain B/Hong Kong/8/73. Placebo was vaccine diluent. Vaccine was not recommended and did not match circulating strain


OutcomesClinical and laboratory confirmed cases and adverse effects. Patients suffered a respiratory illness if they had at least 2 respiratory symptoms. Cases were laboratory confirmed if they had an increase in antibody titre against 3 influenza B virus antigens, i.e. if there was a four-fold increase from an initial sample. Side effects were sore throat, coryza, hoarseness, cough, muscle aches, temperature >100 F occurring during the first three days after vaccination. Surveillance was active


NotesVaccine content was not recommended nor matching. Circulating strain was B/Singapore/79-like and B/Buenos Aires/79-like
Efficacy and safety data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Mutsch 2004

MethodsOne case-control study and case-series based in the German-speaking regions of Switzerland which assessed the association between an intranasal inactivated virosomal influenza vaccine and Bell's palsy


Participants250 cases that could be evaluated (from an original 773 cases identified) were matched to 722 controls for age, date of clinic visit. All were aged around 50


InterventionsImmunisation with influenza vaccine took place within 91 days before disease onset


Outcomes


NotesThe study reports a massive increase in risk (adjusted OR 84, 95% CI 20.1 to 351.9) within 1 to 91 days since vaccination. Despite its many limitations (case attrition - 187 cases could not be identified - and ascertainment bias - physicians picked controls for their own cases - confounding by indication - different vaccine exposure rate between controls and the reference population) it is unlikely that such a large OR could have been affected significantly by systematic error. The authors called for larger pre-licence safety trials, given the rarity of Bell's palsy. On the basis of this study the vaccine was withdrawn from commerce
Rare events (safety)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Nichol 1995

MethodsRandomised controlled trial conducted in the USA during 1994 to 1995 influenza season. Follow up lasted from December 1, 1994 through to March 31, 1995. Influenza period was not defined. Randomisation was performed according to a computer-generated randomisation schedule. Double blinding was ensured by preloaded, coded identical looking syringes. Virologic surveillance was not performed


Participants841 full-time employed: 419 treated and 422 placebo. Age of participants was 18 to 64


InterventionsSubvirion, trivalent, parenteral influenza A and B vaccine. Schedule and dose were: single dose; 15 micrograms each strain. Vaccine composition was: A/Texas/36/91, A/Shangdong/9/93, B/Panama/45/90. Placebo was vaccine diluent. Vaccine was recommended and matched circulating strain


OutcomesCases (symptom-defined), working days lost because of respiratory illness, side effects. Patients were defined as cases if they had at least one upper respiratory illness (a sore throat associated with either fever or cough that lasted at least 24 hours). Local adverse effects were defined as arm soreness. Systemic adverse effects were defined as fever, tiredness, "feeling under the weather", muscle ache, headache (within a week after vaccination). Surveillance was active


NotesCirculating strain was not indicated. Efficacy and safety data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Nichol 1999a

MethodsRandomised controlled trial conducted in USA during 1997 to 1998 influenza season. Follow up lasted from November to March. Site specific peak outbreak period was defined as weeks including 80% of the isolates of a specific area. Total outbreak period lasted from December 14, 1997 through to March 21, 1998. Total outbreak period was included in analysis and lasted 14 weeks. Subjects were recruited from seven organisations and assigned to one of the study groups using a permuted block randomisation scheme that was stratified by treatment center and age group. Sealed randomisation envelopes contained vaccine codes. Influenza virus surveillance was carried out in the area


Participants4561 healthy working adults: 3041 treated and 1520 placebo. Age of participants was 18 to 64


InterventionsTrivalent, live attenuated influenza A and B vaccine in a single dose. Vaccine composition was: A/Shenzhen/227/95, A/Wuhan/395/95, B/Harbin/7/94-like. Placebo was egg allantoic fluid. Vaccine was recommended but did not match circulating strain


OutcomesClinical cases (symptom-defined), working days lost and adverse effects. Case definition had three specifications: febrile illness (fever for at least 1 day and two or more symptoms for at least 2 days: fever, chills, headache, cough, runny nose, sore throat, muscle aches, tiredness); severe febrile illness (3 days of symptoms and 1 day of fever); febrile upper respiratory tract illness (3 days of upper respiratory tract symptoms and 1 day of fever). We chose the febrile illness outcome for analysis. Systemic adverse effects were defined as headache, muscle aches, chills, tiredness and fever. Surveillance was passive


NotesComplete follow up data were obtained for 2874 subjects in the treatment arm and for 1433 subject in the placebo arm. The outcome working days lost is presented as rate ratio, even if data are presented in a way that allows to compute difference in mean days lost but not to compute the standard error. Circulating strain was A/Sidney/5/97-like. Efficacy and safety data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Payne 2006

MethodsCase control study assessing the association between influenza and other vaccines (data not extracted for this review) and optic neuritis


ParticipantsUS military personnel aged at least 18 years


InterventionsCases (n = 1131) were subjects with a diagnosis of optic neuritis between 1.1.1998 and 31.12.2003. The following ICD-9 codes were considered : 377.30-32, 377.39.
Controls (n = 4524): subjects were matched to the cases on the basis of sex, deployment during the 18 weeks before diagnosis, military component. The study was carried out by using data from the Defense Medical Surveillance System, a longitudinal surveillance database


OutcomesDate of case diagnosis was ascertained and immunisation status (Anthrax, smallpox, Hepatitis b, influenza) verified by means of electronic record in respect of three time intervals: 6, 12, 18 weeks before onset. For controls vaccination status was determined for the three interval before index date. Results were focused on the 18-week time interval


NotesRare events (safety)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Phyroenen 1981

MethodsRandomised controlled trial carried out in the 1976 to 1977 season in Finland


Participants307 healthy adults


InterventionsOne of the following 4 preparations were administered to one of the 4 groups of participants: Live attenuated A/Victoria/3/75 ; two 2 ml doses (2 104.5 Bivalent subunit vaccine containing 1200 IU of A/Victoria/3/75 (H3N2) and 800 IU of B/Hong Kong/8/73 per dose (0.5 ml) B versus placebo (phosphate buffered saline). Participant received one dose subcutaneously administered. Vaccination were performed between Dec 15-23, 1976, epidemics occurred Feb to Jun 1977


OutcomesHarms assessed by questionnaires filled out by each subject within 3 days after immunisation. Fever: vacc 11/151; Pl 9/154 - muscle ache; vacc 26/ 151; Pl 12/154 - redness: vacc 53/151; Pl 3/154 - tenderness at vaccination site: vacc 89/151; Pl 12/154 - tenderness of axillary glands: vacc 6/151 ; Pl 2/154


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Powers 1995a

MethodsRandomised controlled trial conducted in USA during 1993 to 1994 influenza season. Follow up was not indicated. Influenza period was not defined. Subjects were randomly assigned to receive one of the following five vaccine preparations in a double-blinded manner: 15 mg of rHA0, 15 mg of rHA0 plus alum, 90 mg of rHA0, licensed and placebo. Spring sera were collected


Participants34 healthy university students: 26 treated and 8 placebo. Age of participants was: 18 to 45


InterventionsSubvirion licensed trivalent parenteral AB vaccine. Schedule and dose were: single dose; 15 micrograms each strain. Vaccine composition was: A/Texas/36/91 (H1N1), A/Beijing/32/92 (H3N2) and B/Panama/45/90. Placebo was saline for injection. Vaccine was recommended and matched circulating strain


OutcomesClinical and laboratory confirmed cases and adverse effects. An "influenza-like illness" was defined as the presence of any respiratory symptom(s) for >= 2 days, accompanied by fever or systemic symptoms of myalgias or chills. Laboratory evidence of influenza A (H3N2) virus infection was defined as either or both of the isolation of virus from nasopharyngeal secretion and a >= four-fold increase in serum HAI antibody titre between the 3-week post-vaccination (preseason) specimen and the corresponding post-season specimen collected in the following spring. Local adverse effects were erythema, pain, tenderness, induration, arm stiffness; systemic adverse effects: were headache, generalized myalgia, diarrhea, nausea, feverishness, temperature > 37.8°C


NotesEfficacy and safety data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Powers 1995b

MethodsSingle blind randomised controlled trial conducted in USA during 1974 to 1975 influenza season. Follow up lasted from winter to spring. A "two month" epidemic period was described by the authors with no reference to a definition and lasted 6 weeks. Study subjects were randomly assigned into three subgroups to receive either two doses of the vaccine (n = 47), one dose of vaccine and one dose of placebo (n = 48) or two doses of placebo (n = 48) at 14 days apart. Six months sera were collected on all study subjects


Participants34 healthy university students: 26 treated and 8 placebo. Age of participants was 18 to 45


InterventionsSubvirion monovalent parenteral vaccine. Schedule and dose were: single dose; 90 micrograms rHAO. Vaccine composition was: The recombinant HA vaccine contained full-length uncleaved haemagglutinin (HA0) glycoprotein from the influenza A/Beijing/32/92 (H3N2) virus. Placebo was saline for injection. Vaccine was not recommended but matched circulating strain


OutcomesClinical and laboratory confirmed cases. An "influenza-like illness" was defined as the presence of any respiratory symptom(s) for >= 2 days, accompanied by fever or systemic symptoms of myalgias or chills. Laboratory evidence of influenza A (H3N2) virus infection was defined as either or both of the isolation of virus from nasopharyngeal secretion and a >= four-fold increase in serum HAI antibody titre between the 3-week post-vaccination (preseason) specimen and the corresponding post-season specimen collected in the following spring


NotesSafety data were not included; effectiveness data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Powers 1995c

MethodsRandomised controlled trial conducted in USA during 1993 to 1994 influenza season. Follow up was not indicated. Influenza period was not defined. Subjects were randomly assigned to receive one of the following five vaccine preparations in a double-blinded manner: 15 mg of rHA0, 15 mg of rHA0 plus alum, 90 mg of rHA0, licensed and placebo. Spring sera were collected


Participants59 healthy university students: 51 treated and 8 placebo. Age of participants was 18 to 45


InterventionsSubvirion monovalent parenteral vaccine. Schedule and dose were: single dose; 15 micrograms rHAO. Vaccine composition was: The recombinant HA vaccine contained full-length uncleaved haemagglutinin (HA0) glycoprotein from the influenza A/Beijing/32/92 (H3N2) virus. Placebo was saline for injection. Vaccine was not recommended but matched circulating strain


OutcomesClinical and laboratory confirmed cases. An "influenza-like illness" was defined as the presence of any respiratory symptom(s) for >= 2 days, accompanied by fever or systemic symptoms of myalgias or chills. Laboratory evidence of influenza A (H3N2) virus infection was defined as either or both of the isolation of virus from nasopharyngeal secretion and a >= four-fold increase in serum HAI antibody titre between the 3-week post-vaccination (preseason) specimen and the corresponding post-season specimen collected in the following spring


NotesEfficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Reeve 1982

MethodsRandomised controlled trial carried out in Wien


Participants20 University students aged 20 to 24 years


InterventionsFirst phase: Cold-recombinant, live flu vaccine II RB-77 (B/Ann Arbor/1/66 and B/Tecumse/10/77) containing 107.2 EID50 per 0.5 ml dose versus placebo. One dose intranasal. During this phase, subjects live under sequestered condition and close contact between vaccine and placebo recipients was possible. 2nd phase: Three weeks after the 1st dose all subjects were immunised with one dose of the same vaccine


OutcomesDuring the 5 days following immunisation, subjects were medically observed and temperature recorded morning and evening. Occurring symptoms were attributed scores (0 to 3) depending on their severity (no, light, moderate, severe). Fever (oral temp > 38°C): 0 / 10 ; 0 / 10 sneezing: 1 / 10 ; 0 / 10 stuffy nose: 7 / 10 ; 1 / 10 running nose: 3 / 10 ; 0 / 10 afebrile subjective symptoms: 8 / 10 ; 2 / 10


NotesSafety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Rocchi 1979a

MethodsCluster-randomised controlled trial carried out during the 1976 to 1977 season


Participants496 healthy military recruits (aged 18 to 20 years) belonging to 4 different companies from "Scuola Allievi Sottoufficiali" in Viterbo, Italy


InterventionsOne of the following 4 preparations were administered to one of the 4 groups of participants: Live attenuated A/Victoria/3/75 ; two 2 ml doses (2 104.5 EID50/dose) oral. Live attenuated recombinant A/Puerto Rico/8/34 , A/Victoria/3/75 ; two 0.5 ml doses intranasal (107 EID50 /dose) Inactivated A/Victoria/3/75 (600 i.u.), B/Hong Kong/5/72 (300 i.u.) and AlPO4, intramuscular placebo (vaccine diluent) administered intranasally. The 2 doses were administered 2 to 3 weeks apart


OutcomesWithin 15 days after administration of the 1st dose. Malaise, myalgia, headache, sore throat, cough, fever equal to or more than 38.5 °C, fever equal to or more than 37.5 °C, three or more symptoms, any symptoms. Surveillance was passive


NotesUnits of randomisation appear to be companies. No description of allocation manner is mentioned. Blind (only for the cases of intranasal a administration). Influenza outbreak occurred when the immunisation began (intraepidermic study). Safety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Rocchi 1979b

MethodsAs above


Participants


Interventions


Outcomes


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Rytel 1977

MethodsSingle blind randomised controlled trial conducted in the USA during 1974 to 1975 influenza season. Follow up lasted from winter to spring. A "two month" epidemic period was described by the authors with no reference to a definition and lasted 6 weeks. Study subjects were randomly assigned into three subgroups to receive either two doses of the vaccine (n = 47), one dose of vaccine and one dose of placebo (n = 48) or two doses of placebo (n = 48) at 14 days apart. Six months sera were collected on all study subjects


Participants143 young adult female student nurse volunteers: 95 treated and 48 placebo. Age of participants was 18 to 35


InterventionsLive attenuated, bivalent, intranasal influenza A (containing 107,2 EID50) and B (containing 107,8 EID50 ) vaccines. Schedule and dose were single or double doses. Vaccine composition was: A/England/42/72 (H3N2) and B/Hong Kong/5/72. Placebo was 5% sucrose. Vaccine was not recommended and did not match circulating strain


OutcomesInfluenza and adverse effects. An influenza case was defined as the presence of an influenza-like illness (three or more symptoms of acute respiratory disease and temperature greater then 37.2) and virus isolation and/or four fold rise in antibody titre in sera obtained ad 30 days and 6 months following immunisation. Local adverse effects were upper respiratory symptoms and cough. These were subdivided into moderate and severe. A definition of general adverse effects (again distinguished among moderate and severe) was not given


NotesOne dose and two doses were analyzed together. Circulating strain was A/PortChalmers/1/73 (H3N2). Efficacy and safety data extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Saxen 1999

MethodsRandomised controlled trial, double blind conducted in Finland during 1996 to 1997 influenza season. Randomisation methods were not described


Participants216 health care workers: 211 treated and 427 placebo


InterventionsTrivalent inactivated intramuscular vaccine. Schedule and dose were: single dose; 15 micrograms each strain. Vaccine composition was: A/Wahan/359/95, A/Singapore/6/86 and B/Beijing/184/93. Placebo was saline for injection. Vaccine was recommended


OutcomesWorking days lost because of respiratory infections, episodes of respiratory infections, days ill and antimicrobial prescriptions. Respiratory infection was a common cold; febrile influenza-like illnesses were not detected. Local adverse effects were defined as local pain. Systemic adverse effects were defined as fever and fatigue


NotesEfficacy data were not extracted because episodes of respiratory infections were unclearly defined. Safety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Scheifele 2003

MethodsRandomised double-blind placebo controlled cross over trial assessing the association between exposure to the vaccine and onset of oculo-respiratory syndrome (ORS) in healthy adults with no previous history of ORS. The trial took place in five centres in Canada in September 2001 and was one of the conditions of registration of the vaccine, given the high incidence of ORS in the previous season. Centralised randomisation and allocation of centrally prepared coded opaque syringes took place. Cross over to either vaccine or placebo took place 5 to 7 days after the initial injection


ParticipantsSix hundred and fifty one adults with a mean age of 45 took part. Seventeen participants are unaccounted for


InterventionsFluviral (Shire) split trivalent containing A/New Caledonia/20/99 (H1N1); A/Panama/2007/99 (H3N2) ; B/Victoria/504/2000 with additional splitting with Triton X-100 splitting agent or saline placebo 0.5 mls. Additional splitting was necessary to test the hypothesis that large clumps of virions were responsible for the ORS seen the previous season


OutcomesORS (bilateral conjunctivitis, facial swelling - lip, lid or mouth, difficulty in breathing and chest discomfort, including cough, wheeze, dysphagia or sore throat). Local signs/symptoms (redness, swelling, pain). Follow up was by phone interview at 24 hours and 6 days after vaccination


NotesThe authors conclude that (mild) ORS is significantly associated with split TIV immunisation (attributable risk 2.9%, 0.6 to 5.2). Other adverse effects associated with TIV are hoarseness (1.3%, 0.3 to 1.3) and coughing 1.2%, 0.2 to 1.6). The study is good quality and the authors conclusions are robust. It is extraordinary that no one has looked for these symptoms before but it may be that the relatively young age of participants and the hypothesis contributed to this. Safety-only study


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Shoenberger 1979

MethodsSurveillance population-based study conducted in USA, during the 1976 to 1977 influenza season. The study tested the association between influenza vaccination and Guillan-Barrè Syndrome. Neurologists were directly contacted; physician and hospital records were reviewed . Suspected cases reported to CDC directly by patients or medical personnel were included only if accepted by a state health department. Follow up period was 01/10/76-31/01/77


ParticipantsUSA population


InterventionsMonovalent A/New Jersey/76 or bivalent A/New Jersey/76 and A/Victoria/75 parenteral vaccine


OutcomesCases of Guillain-Barré syndrome


NotesResults were stratified by age group and vaccine type. Vaccination rates in population were obtained from national immunisation survey
Rare events (safety)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Siscovick 2000

MethodsStudy assessing the association between influenza vaccination the previous year and the risk of primary (i.e. occurring in people with no previous history of cardiac disease) cardiac arrest. Case-control study on 360 cases and 418 controls


ParticipantsCases: subjects who experienced primary cardiac arrest, aged between 25 to 74 years
Controls: healthy subjects selected randomly from the community, who were matched to the cases for age and sex


InterventionsImmunisation with influenza vaccine, assessed by means of questionnaires


OutcomesCardiac arrest


NotesThe authors concluded that vaccination is protective against primary cardiac arrest (OR 0.51, 95% CI 0.33 to 0.79). The difficulty of case ascertainment (77% of potential cases had no ME report and/or autopsy), recall bias (spouses provided exposure data for 304 cases, while 56 survivor cases provided data jointly with their spouses) make the conclusions of this study unreliable. It is impossible to judge the reliability of this study because of a lack of details on the circulation of influenza in the study areas in the 12 months preceding cardiac arrest (the causal hypothesis is based on the effects of influenza infection on the oxygen supply to the myocardium through lung infection and inflammation). Rare events (safety)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Spencer 1977

MethodsControlled trial, single blind


Participants21 pairs of students and employers at the University of California, aged between 24 and 50 years who lived together or worked in close proximity


InterventionsRecombinant, live attenuated R 75 vaccine (B/Hong Kong/5/72 and B/Russia/69) containing 107.5 EID / dose versus placebo (allantoic fluid). Lyophilized vaccine was supplied by Smith, Kline and French Laboratories and diluted with 2.5 ml of a 5% sucrose solution just before administration. Both preparations were administered intranasally (5 drops/nostril). In each pair one individual received vaccine and the other one placebo. A second dose was administered 14 days apart


OutcomesAny clinical symptoms within 7 days after each immunisation (rhinitis, cough, pharyngitis, headache, malaise and myalgia were the prominent observed symptoms, but given as aggregates)


NotesReported safety data don't allow quantitative analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Sumarokow 1971

MethodsField trial conducted in Russia during the 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. The epidemic period was defined as the period of highest influenza morbidity and lasted 11 weeks, from the last ten days of January to the first ten days of April. Vaccinations were carried out using coded preparation. Sampling virological and serological survey of ill people was performed


Participants19,887 population: 9945 treated and 9942 placebo. Age of participants was 13 to 25


InterventionsLive allantoic intranasal vaccine. Schedule and dose were: 3 doses. Vaccine composition was not indicated. Placebo was not described. Vaccine was not recommended and did not match circulating strain


OutcomesClinical cases, deaths, severity of illness. Clinical outcomes were all the acute respiratory infections. Laboratory confirmation was obtained on a sample of ill participants by virus isolation or demonstration of seroconversion. Bronchitis, otitis and pneumonia were considered as complications. Passive surveillance was carried out


NotesA first study group with children 3 to 12 years old was excluded. A second study group with subjects aged 13 to 25 was included in analysis. The trial compared two live vaccines (allantoic intranasal vaccine and tissue vaccine for oral administration) against placebo. Only intranasal vaccine was included in analysis. Deaths from flu were not recorded. Circulating strain was A2/Hong Kong/68
Effectiveness data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Tannock 1984

MethodsControlled clinical trial, double blind, conducted in Australia during the 1981 influenza season. Follow up lasted from winter to spring. Influenza period was not defined. Voluntary were alternatively allocated to groups in a double blind manner. Six months sera were collected


Participants88 volunteer staff from Newcastle Hospital and the Commonwealth Steel Corporation: 56 treated and 32 placebo. Age of participants was 16 to 64


InterventionsTrivalent subunit parenteral vaccine. Schedule and dose were: 7 micrograms each, one or two doses. Vaccine composition was: A/Brazil/11/78, A/Bangkok/1/79, B/Singapore/222/79. Placebo was saline for injection. Vaccine was recommended and matched circulating strain


OutcomesInfluenza and adverse effects. A case of influenza was defined as a respiratory illness, retrospectively reported, associated with a 4-fold antibody titre increase between post-vaccination and post-epidemic sera. Local side effects were redness, swelling, warmth or irritation, pain on contact, pain with pressure, continuous pain, or restriction of arm movement; systemic reactions were fever, chills, sweating, drowsiness or insomnia


NotesOne dose and two doses were analyzed together; very high drop out . Circulating strain was A/Bangkok/1/79. Safety data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)High riskC - Inadequate

Waldman 1969a

MethodsRandomised controlled trial, double blind conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Randomisation methods were not described. One half of the volunteers gave serial blood and nasal wash samples


Participants524 school teachers: 465 treated and 118 placebo. Age of participants was not indicated


InterventionsMonovalent inactivated intramuscular vaccine. Schedule and dose were: 1 or 2 doses. Vaccine composition was: A/Hong Kong/68. Placebo was saline for injection. Vaccine was recommended and matched circulating strain


OutcomesClinical cases and side effects. Clinical case definition was based on the presence of a temperature > 100°F or a feverish feeling plus any 2 of the following symptoms: sore throat, muscle or joint pain, cough, stuffy or runny nose. Passive surveillance was carried out


NotesData concerning adverse effects were only partially reported by graph. Circulating strain was A2/Hong Kong/68. Effectiveness data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Waldman 1969b

MethodsRandomised controlled trial, double blind conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Randomisation methods were not described. One half of the volunteers gave serial blood and nasal wash samples


Participants590 school teachers: 471 treated and 119 placebo. Age of participants was not indicated


InterventionsPolyvalent inactivated intramuscular vaccine. Schedule and dose were: 1 or 2 doses. Vaccine composition was: A2/Japan/170/62 150 CCA, A2/Taiwan/1/64 150 CCA, B/Massachusetts/3/66 300 CCA. Placebo was saline for injection. Vaccine was recommended but did not match circulating strain


OutcomesClinical cases and side effects. Clinical case definition was based on the presence of a "temperature > 100°F or a feverish feeling plus any 2 of the following symptoms: sore throat, muscle or joint pain, cough, stuffy or runny nose. Passive surveillance was carried out.


NotesData concerning adverse effects were only partially reported by graph. Circulating strain was A2/Hong Kong/68. Efficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Waldman 1969c

MethodsRandomised controlled trial, double blind conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Randomisation methods were not described. One half of the volunteers gave serial blood and nasal wash samples


Participants597 school teachers: 479 treated and 118 placebo. Age of participants was not indicated


InterventionsMonovalent inactivated aerosol vaccine. Schedule and dose were: 1 or 2 doses. Vaccine composition was: A/Hong Kong/68. Placebo was saline for injection. Vaccine was recommended and matched circulating strain


OutcomesClinical cases and side effects. Clinical case definition was based on the presence of a "temperature > 100°F or a feverish feeling plus any 2 of the following symptoms: sore throat, muscle or joint pain, cough, stuffy or runny nose. Passive surveillance was carried out


NotesData concerning adverse effects were only partially reported by graph. Circulating strain was A2/Hong Kong/68. Efficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Waldman 1969d

MethodsRandomised controlled trial, double blind, conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Randomisation methods were not described. One half of the volunteers gave serial blood and nasal wash samples


Participants590 school teachers: 471 treated and 119 placebo. Age of participants was not indicated


InterventionsPolyvalent inactivated aerosol vaccine. Schedule and dose were: 1 or 2 doses. Vaccine composition was: A2/Japan/170/62 150 CCA, A2/Taiwan/1/64 150 CCA, B/Massachusetts/3/66 300 CCA. Placebo was saline for injection. Vaccine was recommended but did not match circulating strain


OutcomesClinical cases and side effects. Clinical case definition was based on the presence of a "temperature > 100°F or a feverish feeling plus any 2 of the following symptoms: sore throat, muscle or joint pain, cough, stuffy or runny nose". Passive surveillance was carried out.


NotesData concerning adverse effects were only partially reported by graph. Circulating strain was A2/Hong Kong/68. Efficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Waldman 1972a

MethodsRandomised controlled trial, double blind conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Identical looking coded vials were used to dispense material. Sampling virological and serological survey of ill people was performed. Two doses were administered but as outbreak occurred mostly between them only effectiveness of the first dose was assessed


Participants244 volunteer students and staff members: 195 treated and 49 placebo. Age of participants was not indicated


InterventionsMonovalent A aerosol vaccine. Schedule and dose were: 200 CCA . Vaccine composition was: A2/Aichi/1/68. Placebo was saline for injection. Vaccine was recommended and matched circulating strain


OutcomesClinical cases and adverse effects. Clinical cases were defined as febrile respiratory illness with oral temperature higher then 99.5 F. Local adverse effects were defined as pain and/or tenderness and redness and/or swelling. Systemic adverse effects were defined as general (fever, muscle pain, nausea or vomiting, diarrhea and malaise) or respiratory (runny and/or stuffy nose, sore throat, cough, shortness of breath). Passive surveillance was carried out


NotesIllness during the first one or two weeks after vaccination was not excluded, but authors stated that this fact did not affect the results. Circulating strain was A2/Aichi/2/68. Efficacy and safety data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Waldman 1972b

MethodsRandomised controlled trial, double blind conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Identical looking coded vials were used to dispense material. Sampling virological and serological survey of ill people was performed. Two doses were administered but as outbreak occurred mostly between them only effectiveness of the first dose was assessed


Participants239 volunteer students and staff members: 190 treated and 49 placebo. Age of participants was not indicated


InterventionsMonovalent A subcutaneous vaccine. Schedule and dose were: 200 CCA. Vaccine composition was: A2/Aichi/1/69. Placebo was saline for injection. Vaccine was recommended and matched circulating strain


OutcomesClinical cases and adverse effects. Clinical cases were defined as febrile respiratory illness with oral temperature higher then 99.5 F. Local adverse effects were defined as pain and/or tenderness and redness and/or swelling. Systemic adverse effects were defined as general (fever, muscle pain, nausea or vomiting, diarrhea and malaise) or respiratory (runny and/or stuffy nose, sore throat, cough, shortness of breath). Passive surveillance was carried out


NotesIllness during the first one or two weeks after vaccination was not excluded, but authors stated that this fact did not affect the results. Circulating strain was A2/Aichi/2/68. Efficacy and safety data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Waldman 1972c

MethodsRandomised controlled trial, double blind, conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Identical looking coded vials were used to dispense material. Sampling virological and serological survey of ill people was performed. Two doses were administered but as outbreak occurred mostly between them only effectiveness of the first dose was assessed


Participants243 volunteer students and staff members: 194 treated and 49 placebo. Age of participants was not indicated


InterventionsBivalent AB aerosol vaccine. Vaccine composition was: A2/Japan/170/62 150 CCA, A2/Taiwan/1/64 150 CCA and B/Massachusset/3/66 200 CCA. Placebo was saline for injection. Vaccine was recommended but did not match circulating strain


OutcomesClinical cases and adverse effects. Clinical cases were defined as febrile respiratory illness with oral temperature higher then 99.5 F. Local adverse effects were defined as pain and/or tenderness and redness and/or swelling. Systemic adverse effects were defined as general (fever, muscle pain, nausea or vomiting, diarrhea and malaise) or respiratory (runny and/or stuffy nose, sore throat, cough, shortness of breath). Passive surveillance was carried out


NotesIllness during the first one or two weeks after vaccination were not excluded, but authors stated that this fact did not affect the results. Circulating strain was A2/Aichi/2/68. Efficacy and safety data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Waldman 1972d

MethodsRandomised controlled trial, double blind, conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Identical looking coded vials were used to dispense material. Sampling virological and serological survey of ill people was performed. Two doses were administered but as outbreak occurred mostly between them only effectiveness of the first dose was assessed


Participants236 volunteer students and staff members: 187 treated and 49 placebo. Age of participants was not indicated


InterventionsBivalent AB subcutaneous vaccine. Vaccine composition was: A2/Japan/170/62 150 CCA, A2/Taiwan/1/64 150 CCA and B/Massachusset/3/66 200 CCA. Placebo was saline for injection. Vaccine was recommended but did not match circulating strain


OutcomesClinical cases and adverse effects. Clinical cases were defined as febrile respiratory illness with oral temperature higher then 99.5 F. Local adverse effects were defined as pain and/or tenderness and redness and/or swelling. Systemic adverse effects were defined as general (fever, muscle pain, nausea or vomiting, diarrhea and malaise) or respiratory (runny and/or stuffy nose, sore throat, cough, shortness of breath). Passive surveillance was carried out


NotesIllness during the first one or two weeks after vaccination was not excluded, but authors stated that this fact did not affect the results. Circulating strain was A2/Aichi/2/68. Efficacy and safety data were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Weingarten 1988

MethodsRandomised controlled trial, double blind conducted in USA during 1985 to 1986 influenza season. Follow up was not indicated. Epidemic influenza was defined according to population surveillance data (without better explanation), begun in December 1985 and concluded in February 1986. Participants were assigned using a random-number generator to receive either the influenza vaccine or placebo. Virologic surveillance was not performed


Participants179 healthy volunteer hospital employees: 91 treated and 88 placebo. Age of participants was 21 to 65


InterventionsSplit trivalent intramuscular vaccine. Schedule and dose were: single dose; 15 micrograms each strain. Vaccine composition was: A/Chile/1/83 (H1N1), A/Philippines/2/82 (H3N2), and B/USSR/100/83 . Placebo was saline for injection. Vaccine was recommended but did not match circulating strain


OutcomesClinical cases symptoms defined, wdl regardless of causes, and adverse effects. Influenza illness was defined by the CDC case definition: a documented temperature greater than 100 °F and at least the symptoms of cough or sore throat


NotesData regarding wdl and adverse effects were not complete and they were not considered. Most of the influenza infections were caused by type B.
Efficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Zhilova 1986a

MethodsSemi-randomised double blind placebo controlled clinical trial that took place in Leningrad, USSR during 1981 to 1982 influenza season. The study tested the reactogenicity, safety and effectiveness of an inactivated and a live attenuated vaccines, both administered singly or in combination. Allocation was made on the basis of school classes and it is unclear whether this is a cluster randomised, or clinical controlled trial. We have opted for the latter as the text mentions random selection to maintain "equivalence". "Double blind" is mentioned in the text. In January to May 1982 there was a rise in the level of ILI due to influenza and other agents


Participants3961 participants were enrolled. Participants were healthy "students" aged 18 to 23. Numbers in each of the four arms are uneven throughout the trial but no reason is given for this


InterventionsInactivated vaccine trivalent (Ministry of Health USSR) by subcutaneous injection 0.2 mls once (arm 1), or intranasal live "recombinant" "mono"vaccine 0.5 mls spray 2 to 3 times (Ministry of Health USSR) (arm 2), or combined (arm 3) or subcutaneous and intranasal spray NaCl saline placebo (arm 4). The strains contained were H1N1, H3N2 and B. Vaccine matching was not good


OutcomesSerological
Antibody titres - sub study on 1221 participants
Effectiveness
Influenza-like illness (not defined and from the text it is impossible to understand how many Influenza-like illness cases were matched to positive laboratory findings)
Safety data are not reported in sufficient detail to allow extraction


NotesThe authors conclude that simultaneous inoculation of the vaccines appeared to produce better humoral antibody responses, especially in the last season. However, the correlation between clinical protection and antibody rises is reported as dubious. The authors make the reasonable point that perhaps live attenuated vaccines work better because they stimulate production of secretory antibodies. This is a poorly reported study. No mention is made of how placebo could have been correctly used in the schedule (i.e. they should have had six arms instead of four with subcutaneous placebo, spray placebo separately as well combined - maybe this is a problem of translation). Efficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Zhilova 1986b

MethodsSemi-randomised double blind placebo controlled clinical trial that took place in Leningrad, USSR during 1982 to 1983 influenza season. The study tested the reactogenicity, safety and effectiveness of an inactivated and a live attenuated vaccines, both administered singly or in combination. Allocation was made on the basis of school classes and it is unclear whether this is a cluster randomised, or clinical controlled trial. We have opted for the latter as the text mentions random selection to maintain "equivalence". "Double blind" is mentioned in the text. In the season there was an outbreak of A (H3N2) lasting 4 to 5 weeks. However, influenza accounted for only up to 30% of isolates from ill people


Participants3944 participants were enrolled. Participants were healthy "students" aged 18 to 23. Numbers in each of the four arms are uneven throughout the trial but no reason is given for this


InterventionsInactivated vaccine trivalent (Ministry of Health USSR) by subcutaneous injection 0.2 mls once (arm 1), or intranasal live "recombinant" "mono" vaccine 0.5 mls spray 2 to 3 times (Ministry of Health USSR) (arm 2), or combined (arm 3) or subcutaneous and intranasal spray NaCl saline placebo (arm 4). The strains contained were H1N1, H3N2 and B
Vaccine matching was good


OutcomesSerological
Antibody titres - sub study on 1221 participants
Effectiveness
Influenza-like illness (not defined and from the text it is impossible to understand how many Influenza-like illness cases were matched to positive laboratory findings)
Safety data are not reported in sufficient detail to allow extraction
Passive surveillance was carried out


NotesThe authors conclude that simultaneous inoculation of the vaccines appeared to produce better humoral antibody responses, especially in the last season. However, the correlation between clinical protection and antibody rises is reported as dubious. The authors make the reasonable point that perhaps live attenuated vaccines work better because they stimulate production of secretory antibodies. This is a poorly reported study. No mention is made of how placebo could have been correctly used in the schedule (i.e. they should have had six arms instead of four with subcutaneous placebo, spray placebo separately as well combined - maybe this is a problem of translation). Efficacy data only were extracted


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Ambrosch 1976Data tables and figure missing

Aoki 1986Randomised controlled trial, single blind. Outcomes were clinical cases and adverse effects. Follow up data were not reported by arms

Atmar 1995No outcomes of interest

Ausseil 1999No design (average days of sick leave in vaccinated and not vaccinated subjects during 1996 and 1997 in staff personal of an international banking institution)

Banzhoff 2001No design (cohort), no safety outcomes

Belongia 2009Case control study, no harm assessment

Belshe 2001No original data

Benke 2004Questionnaire survey; non comparative analysis

Betts 1977bTrial with swine vaccine (Hsw1N1, A/New Jersey/76)

Beyer 1996Review

Carlson 1979No adequate control, no outcome of interest

Cate 1977Trial with swine vaccine (Hsw1N1, A/New Jersey/76)

Chlibek 2002The study is not a randomised controlled trial

Chou 2007Case report

Clover 1991Randomised controlled trial. More than 75% of the study population is out of the range of age stated in the protocol

Confavreux 2001Participants are MS cases

Das Gupta 2002The study does not contain effectiveness data

Davies 1972Cohort with efficacy outcomes. Experimental and control group were separately selected

Davies 1973The study was not randomised. Subjects volunteered for immunisation and comparison was made with a randomly selected non immunised control group

De Serres 2003aNo comparison, absence of adequate control group

De Serres 2003bNo control

De Serres 2004Population at risk of further Oculo-respiratory syndrome episodes

Dolin 1977Trial with swine vaccine (Hsw1N1, A/New Jersey/76)

Edmonson 1970Influenza B vaccine was used as control

El'shina 1998Major inconsistencies in the study text

Finklea 1969Randomised controlled trial, double blind. Two bivalent inactivated influenza vaccines, with the same viral composition, differing in purification procedures, were compared.
Outcomes were clinical cases and adverse effects.
Raw data about clinical cases were not reported by arm.
Circulating virus showed significant antigenic differences from the A2 vaccine strain

Foy 1981Absence of adequate control

Frank 1981No usable safety data (scores)

Freestone 1976Conference proceedings

Gerstoft 2001The study is not a randomised controlled trial

Greenbaum 2002No outcome of interest

Gross 1999Outcome measures outside inclusion criteria

Grotto 1998The study is not a randomised controlled trial

Gruber 1994Randomised controlled trial conducted in USA on 41 cystic fibrosis (CF) patients and 89 family members, recruited through a clinic. Subjects were randomly assigned in a double-blinded fashion by family to receive either intranasal live cold-adapted influenza A vaccine or the recommended intramuscular trivalent inactivated influenza vaccine.
The study lasted 3 years (from 1989 to 1991). Subjects were immunised each fall staying in the same assigned vaccine group. The live vaccine arm counted 20 CF and 33 family members; the trivalent vaccine arm 21 and 56 respectively.
69 of them (17 CF patients and 52 family members) dropped out. The reasons were stated in the article.
The live vaccine was the same all over the period: A/Kawasaki/9/86 (H1N1) 107,3 pfu, A/Los Angeles/2/87 107,3 pfu.
The viral strains used in the inactivated vaccines were:
- 1989-1990: A/Taiwan/1/86 (H1N1), A/Shaghai/11/87 (H3N2), B/Yagamata/16/88,15 mg/dose of each
- 1990-1991: A/Taiwan/1/86 (H1N1), A/Shaghai/16/89 (H3N2), B/Yagamata/16/88,15 mg/dose of each
- 1991-1992: A/Taiwan/1/86 (H1N1), A/Beijing/353/89 (H3N2), B/Panama/45/90, 15 mg/dose of each
Live vaccine recipient also received monovalent inactivated influenza B vaccine (identical to that contained in the trivalent vaccine) as intramuscular placebo. Allantoic fluid was the placebo for aerosol administration.
Data were extracted and loaded for family members only.
Outcomes were clinical and laboratory confirmed cases, working days lost (WDL), admissions, deaths and adverse effects.
Clinical cases were classified as "respiratory illness" or "febrile respiratory illness". Laboratory-confirmed cases were defined by an influenza virus isolation from a throat swab.
Adverse effects were defined as temperature > 38°C, rhinorrhea, sore throat, cough, increasing sputum, redness, swelling, chills. Results are expressed as % of subject-days with symptoms.
Subjects were followed throughout the period. Owing to the drop outs, vaccinated were counted as subject-years: 54 in the live vaccine arm; 56 in the trivalent vaccine arm.
The influenza illness surveillance period for study subjects was defined as the interval from the date of the first influenza isolate from population under routine surveillance to 2 weeks after the last isolate for each year.
Viral strains circulating during the outbreaks were:
- 1989-1990: A/Shaghai/11/87 (H3N2)
- 1990-1991: A/Beijing/353/89 (H3N2), B/Panama/45/90-like
- 1991-1992: A/Beijing/353/89 (H3N2).
This trial was excluded since it was not placebo controlled and authors didn't specify if the strains used to develop cold adapted and inactivated vaccines were antigenically comparable or not

Haber 2004Analysis of temporal trends of Guillan Barrè Syndrome (GBS) 1990-2003, comparison with temporal trends of non-GBS Adverse Event reports from the Vaccine Adverse Event Reporting System (VAERS)

Haigh 1973The study is not randomised: all the volunteers were immunised on a single day and the intention to allocate patients randomly was not strictly adhered to

Halperin 2002Outcome measures outside inclusion criteria

Hobson 1970Polivalent influenza vaccine was used as control

Hobson 1973Randomised controlled trial. Clinical outcomes were side effects only

Hoskins 1973Influenza B vaccine was used as control

Hoskins 1976aThe trial was excluded since it was not placebo/do-nothing controlled

Hoskins 1976bThe trial was excluded since it was not placebo/do-nothing controlled

Hoskins 1979No control group

Howell 1967The study is not prospective. It appears as an historical cohort

Hurwitz 1983Report of GBS surveillance 1978-79, non-comparative study

Jianping 1999The study is not a randomised controlled trial

Keitel 2001Efficacy outcome measures outside inclusion criteria. The safety data are presented in a non-analysable way

Khazeni 2009the study is review and a cost effectiveness analysis

Kiderman 2001Tables and text show inconsistencies that do not allow data extraction

Kunz 1977No adequate control

Langley 2004Review

Liem 1973Liem reported the results of 9 placebo controlled clinical trials and two field studies, involving a total of about 10000 subjects, carried out in several countries to assess the efficacy of killed influenza spray vaccines. Studies were conducted during the years 1969-71.
Allocation of the subjects to the arms of the trials was done according to a pre-determined randomisation scheme. 8 of them were double-blind. The field studies were not randomised. The attack rate for influenza among the population study was very low, and in two of the trials vaccination procedure started too late, when the outbreak was ongoing. The attack rates, exclusively based on the serologically confirmed cases, are only reported by a graph and it is impossible to derive the crude data

Mackenzie 1975No design (allocation is arbitrary and groups with different characteristics were formed)

Mair 1974Influenza B vaccine was used as control

Maynard 1968Influenza B vaccine was used as control

McCarthy 2004Review

Mendelman 2001The study does not repot original results

Merelli 2000Review

Meyers 2003aReview

Meyers 2003bReview

Monto 2000The study is not a randomised controlled trial

Morris 1975Design is unclear (no standard random allocation. Only 25 out of 30 seem to have been immunized, but in the method description 30 were considered for exposure to natural influenza A/Scotland/840/74. One of these was prior excluded because had tonsillitis

Mostow 1977Outcomes were safety only. Absence of adequate control

Muennig 2001The study is not a randomised controlled trial

Nichol 1996Same data as Nichol 1995

Nichol 1999bThe study is a review

Nichol 2001The study is not a randomised controlled trial

Nichol 2003The study contain data from previous studies

Nichol 2004Re-analysis of Nichol 1999 (already included)

Pyhala 2001The study is not a randomised controlled trial

Rimmelzwaan 2000Outcome measures outside inclusion criteria

Rocchi 1979cVery poor reporting, unclear definition, no description of methods

Ruben 1972Absence of adequate control

Ruben 1973The study was excluded since both arms contained the same vaccine strains

Safranek 1991Re-assessment of Schoenberger 1979

Sarateanu 1980Absence of adequate control

Schonberger 1981Review of the evidence of the aetiology of GBS, no original data presented

Schwartz 1996Report about Nichol 1995

Skowronski 2002Non-comparative (survey)

Skowronski 2003Population at risk of further ORS episodes

Smith 1977aThe article reports a little part of the Hoskins trial. It compared illness occurring among a group of vaccinated boys against non vaccinated controls that had no part in the trial

Smith 1977bTrial with swine vaccine (Hsw1N1, A/New Jersey/76)

Spencer 1975Authors didn't report crude data on the clinical outcomes

Spencer 1979Reporting doesn't allow one to understand the methods used to allocate subjects and to conceal allocation. Clinical outcome data are not reported

Taylor 1969No outcomes of interest, rhinovirus vaccine as control

Treanor 2001Outcome measures outside inclusion criteria

Treanor 2002Outcome measures outside inclusion criteria

Tyrrell 1970None of the 3 studies reported in this paper are includible for the following reasons
1. No design, no comparison, no outcomes
2. Probable controlled clinical trial, but subjects age probably out of range (schools)
3. No design, even if an unvaccinated control group for school 3 and ICI is present

Warshauer 1976The study was not randomised. Data reporting was not complete

Wilde 1999Pneumococcal vaccine was used as control

Williams 1973No placebo/do-nothing control

Wood 1999The study is not a randomised controlled trial

Wood 2000The study is not a randomised controlled trial

 
Comparison 1. Inactivated parenteral vaccine versus placebo or do-nothing

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Influenza-like illness2119139Risk Ratio (M-H, Random, 95% CI)0.80 [0.71, 0.89]

    1.1 WHO recommended - matching vaccine
106984Risk Ratio (M-H, Random, 95% CI)0.70 [0.59, 0.83]

    1.2 WHO recommended - vaccine matching absent or unknown
912062Risk Ratio (M-H, Random, 95% CI)0.93 [0.79, 1.09]

    1.3 Monovalent not WHO recommended - vaccine matching
159Risk Ratio (M-H, Random, 95% CI)1.02 [0.28, 3.70]

    1.4 Monovalent not WHO recommended - vaccine matching - high dose
134Risk Ratio (M-H, Random, 95% CI)0.46 [0.09, 2.30]

 2 Influenza1731325Risk Ratio (M-H, Random, 95% CI)0.39 [0.30, 0.52]

    2.1 WHO recommended - matching vaccine
811285Risk Ratio (M-H, Random, 95% CI)0.27 [0.16, 0.46]

    2.2 WHO recommended - vaccine matching absent or unknown
610331Risk Ratio (M-H, Random, 95% CI)0.56 [0.41, 0.77]

    2.3 Monovalent not WHO recommended - vaccine matching
29675Risk Ratio (M-H, Random, 95% CI)0.22 [0.10, 0.52]

    2.4 Monovalent not WHO recommended - vaccine matching - high dose
134Risk Ratio (M-H, Random, 95% CI)0.11 [0.00, 2.49]

 3 Physician visits22308Risk Ratio (M-H, Random, 95% CI)0.87 [0.40, 1.89]

    3.1 WHO recommended - matching vaccine
11178Risk Ratio (M-H, Random, 95% CI)0.58 [0.37, 0.91]

    3.2 WHO recommended - vaccine matching absent or unknown
11130Risk Ratio (M-H, Random, 95% CI)1.28 [0.90, 1.83]

 4 Days ill44800Mean Difference (IV, Random, 95% CI)-0.29 [-0.72, 0.15]

    4.1 WHO recommended - matching vaccine
33670Mean Difference (IV, Random, 95% CI)-0.48 [-0.62, -0.34]

    4.2 WHO recommended - matching absent or unknown
11130Mean Difference (IV, Random, 95% CI)0.66 [0.16, 1.16]

 5 Times any drugs were prescribed22308Mean Difference (IV, Random, 95% CI)-0.01 [-0.03, 0.01]

    5.1 WHO recommended - matching vaccine
11178Mean Difference (IV, Random, 95% CI)-0.02 [-0.04, -0.00]

    5.2 WHO recommended - matching absent or unknown
11130Mean Difference (IV, Random, 95% CI)0.0 [-0.00, 0.00]

 6 Times antibiotic was prescribed22308Mean Difference (IV, Random, 95% CI)-0.02 [-0.03, -0.01]

    6.1 WHO recommended - matching vaccine
11178Mean Difference (IV, Random, 95% CI)-0.02 [-0.03, -0.01]

    6.2 WHO recommended - matching absent or unknown
11130Mean Difference (IV, Random, 95% CI)-0.01 [-0.03, 0.01]

 7 Working days lost55393Mean Difference (IV, Random, 95% CI)-0.13 [-0.25, -0.00]

    7.1 WHO recommended - matching vaccine
44263Mean Difference (IV, Random, 95% CI)-0.21 [-0.36, -0.05]

    7.2 WHO recommended - matching absent or unknown
11130Mean Difference (IV, Random, 95% CI)0.09 [0.00, 0.18]

 8 Hospitalisations514877Risk Ratio (M-H, Random, 95% CI)0.89 [0.65, 1.20]

    8.1 WHO recommended - matching vaccine
22580Risk Ratio (M-H, Random, 95% CI)0.37 [0.12, 1.12]

    8.2 WHO recommended - vaccine matching absent or unknown
22681Risk Ratio (M-H, Random, 95% CI)0.85 [0.38, 1.91]

    8.3 Monovalent not WHO recommended - vaccine matching
19616Risk Ratio (M-H, Random, 95% CI)0.96 [0.85, 1.08]

 9 Pneumonia22953Risk Ratio (M-H, Random, 95% CI)0.80 [0.13, 4.93]

    9.1 WHO recommended - matching vaccine
11402Risk Ratio (M-H, Random, 95% CI)0.59 [0.04, 9.43]

    9.2 WHO recommended - vaccine matching absent or unknown
11551Risk Ratio (M-H, Random, 95% CI)1.01 [0.09, 11.13]

 10 Clinical cases (clinically defined without clear definition)45926Risk Ratio (M-H, Random, 95% CI)0.63 [0.41, 0.99]

    10.1 WHO recommended - matching vaccine
33723Risk Ratio (M-H, Random, 95% CI)0.56 [0.27, 1.16]

    10.2 WHO recommended - vaccine matching absent or unknown
12203Risk Ratio (M-H, Random, 95% CI)0.83 [0.69, 0.99]

 11 Local harms16Risk Ratio (M-H, Random, 95% CI)Subtotals only

    11.1 Local - tenderness/soreness
146833Risk Ratio (M-H, Random, 95% CI)3.11 [2.08, 4.66]

    11.2 Local - erythema
63388Risk Ratio (M-H, Random, 95% CI)4.01 [1.91, 8.41]

    11.3 Local - induration
2543Risk Ratio (M-H, Random, 95% CI)2.24 [0.48, 10.59]

    11.4 Local - arm stiffness
150Risk Ratio (M-H, Random, 95% CI)1.62 [0.54, 4.83]

    11.5 Local - combined endpoint (any or highest symptom)
125171Risk Ratio (M-H, Random, 95% CI)2.87 [2.02, 4.06]

 12 Systemic harms13Risk Ratio (M-H, Random, 95% CI)Subtotals only

    12.1 Systemic - myalgia
52676Risk Ratio (M-H, Random, 95% CI)1.54 [1.12, 2.11]

    12.2 Systemic - fever
82775Risk Ratio (M-H, Random, 95% CI)1.17 [0.80, 1.72]

    12.3 Systemic - headache
83667Risk Ratio (M-H, Random, 95% CI)1.30 [0.84, 2.03]

    12.4 Systemic - fatigue or indisposition
63456Risk Ratio (M-H, Random, 95% CI)1.37 [0.94, 2.02]

    12.5 Systemic - nausea/vomiting
31667Risk Ratio (M-H, Random, 95% CI)2.68 [0.55, 13.08]

    12.6 Systemic - combined endpoint (any or highest symptom)
82603Risk Ratio (M-H, Random, 95% CI)1.29 [1.01, 1.64]

 
Comparison 2. Live aerosol vaccine versus placebo or do-nothing

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Influenza-like illness612688Risk Ratio (M-H, Random, 95% CI)0.90 [0.84, 0.96]

    1.1 WHO recommended - matching vaccine
24254Risk Ratio (M-H, Random, 95% CI)0.92 [0.76, 1.12]

    1.2 WHO recommended - vaccine matching absent or unknown
38150Risk Ratio (M-H, Random, 95% CI)0.89 [0.82, 0.97]

    1.3 Non WHO recommended - vaccine matching absent or unknown
1284Risk Ratio (M-H, Random, 95% CI)0.92 [0.73, 1.16]

 2 Influenza68524Risk Ratio (M-H, Random, 95% CI)0.38 [0.27, 0.55]

    2.1 WHO recommended - matching vaccine
24254Risk Ratio (M-H, Random, 95% CI)0.44 [0.24, 0.81]

    2.2 WHO recommended - vaccine matching absent or unknown
23843Risk Ratio (M-H, Random, 95% CI)0.36 [0.16, 0.82]

    2.3 Non WHO recommended - vaccine matching absent or unknown
2427Risk Ratio (M-H, Random, 95% CI)0.21 [0.08, 0.56]

 3 Complications (bronchitis, otitis, pneumonia)119887Risk Ratio (M-H, Random, 95% CI)0.25 [0.03, 2.24]

    3.1 Non WHO recommended - vaccine matching absent or unknown
119887Risk Ratio (M-H, Random, 95% CI)0.25 [0.03, 2.24]

 4 Influenza cases (clinically defined without clear definition)323900Risk Ratio (M-H, Random, 95% CI)0.89 [0.71, 1.11]

    4.1 WHO recommended - matching vaccine
11931Risk Ratio (M-H, Random, 95% CI)0.63 [0.49, 0.80]

    4.2 WHO recommended - vaccine matching absent or unknown
12082Risk Ratio (M-H, Random, 95% CI)1.05 [0.88, 1.25]

    4.3 Non WHO recommended - vaccine matching absent or unknown
119887Risk Ratio (M-H, Random, 95% CI)0.98 [0.92, 1.05]

 5 Local harms11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Local - upper respiratory infection symptoms
6496Risk Ratio (M-H, Random, 95% CI)1.66 [1.22, 2.27]

    5.2 Local - cough
4852Risk Ratio (M-H, Random, 95% CI)1.24 [0.69, 2.22]

    5.3 Local - coryza
24782Risk Ratio (M-H, Random, 95% CI)1.56 [1.26, 1.94]

    5.4 Local - sore throat
55391Risk Ratio (M-H, Random, 95% CI)1.73 [1.44, 2.08]

    5.5 Local - hoarseness
1306Risk Ratio (M-H, Random, 95% CI)1.21 [0.51, 2.83]

    5.6 Local - combined endpoint (any or highest symptom)
34921Risk Ratio (M-H, Random, 95% CI)1.56 [1.31, 1.87]

 6 Systemic harms6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 Systemic - myalgia
3713Risk Ratio (M-H, Random, 95% CI)2.28 [0.81, 6.45]

    6.2 Systemic - fever
3713Risk Ratio (M-H, Random, 95% CI)1.28 [0.43, 3.79]

    6.3 Systemic - fatigue or indisposition
2413Risk Ratio (M-H, Random, 95% CI)1.52 [0.66, 3.49]

    6.4 Systemic - headache
1370Risk Ratio (M-H, Random, 95% CI)2.33 [0.52, 10.33]

    6.5 Systemic - combined endpoint (any or highest symptom)
51018Risk Ratio (M-H, Random, 95% CI)1.40 [0.82, 2.38]

 
Comparison 3. Inactivated aerosol vaccine versus placebo or do-nothing

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Influenza-like illness41674Risk Ratio (M-H, Random, 95% CI)0.58 [0.40, 0.83]

    1.1 WHO recommended - matching vaccine
2841Risk Ratio (M-H, Random, 95% CI)0.47 [0.19, 1.13]

    1.2 WHO recommended - vaccine matching absent or unknown
2833Risk Ratio (M-H, Random, 95% CI)0.63 [0.37, 1.07]

 2 Local harms4716Risk Ratio (M-H, Random, 95% CI)1.09 [0.85, 1.40]

    2.1 Local - sore throat
2151Risk Ratio (M-H, Random, 95% CI)0.82 [0.43, 1.56]

    2.2 Local - combined endpoint (any or highest symptom)
3565Risk Ratio (M-H, Random, 95% CI)1.15 [0.88, 1.50]

 3 Systemic harms41018Risk Ratio (M-H, Random, 95% CI)1.00 [0.77, 1.31]

    3.1 Systemic - myalgia
2151Risk Ratio (M-H, Random, 95% CI)0.90 [0.36, 2.25]

    3.2 Systemic - fatigue or indisposition
2151Risk Ratio (M-H, Random, 95% CI)1.40 [0.52, 3.75]

    3.3 Systemic - headache
2151Risk Ratio (M-H, Random, 95% CI)1.52 [0.85, 2.72]

    3.4 Systemic - combined endpoint (any or highest symptom)
3565Risk Ratio (M-H, Random, 95% CI)0.83 [0.54, 1.27]

 
Comparison 4. 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Influenza-like illness33065Risk Ratio (M-H, Random, 95% CI)0.71 [0.57, 0.88]

    1.1 Standard recommended parenteral - non matching - 1 dose
32715Risk Ratio (M-H, Random, 95% CI)0.74 [0.57, 0.95]

    1.2 Standard recommended parenteral - non matching - 2 doses
1350Risk Ratio (M-H, Random, 95% CI)0.66 [0.44, 0.98]

 2 Influenza12072Risk Ratio (M-H, Random, 95% CI)0.47 [0.26, 0.87]

    2.1 Standard recommended parenteral - non matching
12072Risk Ratio (M-H, Random, 95% CI)0.47 [0.26, 0.87]

 3 Hospitalisations12072Risk Ratio (M-H, Random, 95% CI)0.83 [0.41, 1.68]

    3.1 Standard recommended parenteral - non matching
12072Risk Ratio (M-H, Random, 95% CI)0.83 [0.41, 1.68]

 4 Pneumonia12072Risk Ratio (M-H, Random, 95% CI)1.01 [0.14, 7.17]

    4.1 Standard recommended parenteral - non matching
12072Risk Ratio (M-H, Random, 95% CI)1.01 [0.14, 7.17]

 
Comparison 5. 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Influenza-like illness44580Risk Ratio (M-H, Random, 95% CI)0.35 [0.25, 0.48]

    1.1 WHO recommended parenteral - matching vaccine - 1 dose
44226Risk Ratio (M-H, Random, 95% CI)0.35 [0.23, 0.53]

    1.2 WHO recommended parenteral - matching vaccine - 2 doses
1354Risk Ratio (M-H, Random, 95% CI)0.35 [0.22, 0.57]

 2 Influenza11923Risk Ratio (M-H, Random, 95% CI)0.07 [0.02, 0.31]

    2.1 WHO recommended parenteral - matching vaccine
11923Risk Ratio (M-H, Random, 95% CI)0.07 [0.02, 0.31]

 3 Hospitalisations11923Risk Ratio (M-H, Random, 95% CI)0.35 [0.13, 0.94]

    3.1 WHO recommended parenteral - matching vaccine
11923Risk Ratio (M-H, Random, 95% CI)0.35 [0.13, 0.94]

 4 Pneumonia11923Risk Ratio (M-H, Random, 95% CI)0.59 [0.05, 6.51]

    4.1 WHO recommended parenteral - matching vaccine
11923Risk Ratio (M-H, Random, 95% CI)0.59 [0.05, 6.51]

 5 Working days lost11667Mean Difference (IV, Random, 95% CI)-0.45 [-0.60, -0.30]

    5.1 WHO recommended parenteral - matching vaccine
11667Mean Difference (IV, Random, 95% CI)-0.45 [-0.60, -0.30]

 6 Days ill11667Mean Difference (IV, Random, 95% CI)-0.45 [-0.60, -0.30]

    6.1 WHO recommended - matching vaccine
11667Mean Difference (IV, Random, 95% CI)-0.45 [-0.60, -0.30]

 
Comparison 6. 1968 to 1969 pandemic: inactivated polyvalent aerosol vaccine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Influenza-like illness21000Risk Ratio (M-H, Random, 95% CI)0.66 [0.46, 0.95]

    1.1 Inactivated polyvalent aerosol vaccine versus placebo - non matching - 1 dose
2644Risk Ratio (M-H, Random, 95% CI)0.64 [0.32, 1.27]

    1.2 Inactivated polyvalent aerosol vaccine versus placebo - non matching - 2 doses
1356Risk Ratio (M-H, Random, 95% CI)0.65 [0.44, 0.97]

 
Comparison 7. 1968 to 1969 pandemic: inactivated monovalent aerosol vaccine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Influenza-like illness21009Risk Ratio (M-H, Random, 95% CI)0.54 [0.32, 0.91]

    1.1 Inactivated monovalent aerosol vaccine versus placebo - matching - 1 dose
2650Risk Ratio (M-H, Random, 95% CI)0.49 [0.17, 1.41]

    1.2 Inactivated monovalent aerosol vaccine versus placebo - matching - 2 doses
1359Risk Ratio (M-H, Random, 95% CI)0.57 [0.38, 0.86]

 
Comparison 8. 1968 to 1969 pandemic: live aerosol vaccine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Influenza cases (clinically defined without clear definition)119887Risk Ratio (M-H, Random, 95% CI)0.98 [0.92, 1.05]

    1.1 Non-matching
119887Risk Ratio (M-H, Random, 95% CI)0.98 [0.92, 1.05]

 2 Complications (bronchitis, otitis, pneumonia)119887Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.03, 2.24]

    2.1 Non-matching
119887Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.03, 2.24]

 
Table 1. Study datasets by type of vaccine and outcomes

Vaccine typeEfficacy onlyEfficacy and safetySafety onlyTotal

Inactivated parenteral167932

Live aerosol73919

Inactivated aerosol2226

Total25122057