In healthy adults Naisi Zhao LIVE AEROSOL VACCINES

 Live aerosol vaccines  Nasal spray  2~49 years of age  CDC recommends it for healthy children 2~8 years old  For healthy adults, is exposure to live aerosol vaccine associated with serious or severe harms?  Evaluate the efficacy of live aerosol vaccines on preventing influenza A or B infections (confirmed by lab test), and its effectiveness to prevent influenza-like illness (ILI) and its consequences? BACKGROUND

 Searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2), MEDLINE (January 1966 to May 2013) and EMBASE (1990 to May 2013).  2 independent reviewers  Inclusion criteria  RCT or quasi-RCT  Healthy adults (aged 16 to 65 years)  Live aerosol vaccine compared with placebo or no intervention  Comparative studies to assess serious and rare harms. METHODOLOGY

 Experimental studies  Random sequence generation: selection bias  Allocation concealment: selection bias  Blinding: performance bias and detection bias  Incomplete outcome data: attrition bias  Non-experimental studies  Measures of treatment effect  Unit of analysis issues RISK OF BIAS ASSESSMENT

StudyMethodsParticipantsInterventionOutcomesNotes Vaccines efficacy or effectiveness (8 studies/12 data set) Edwards 1994aDouble-blind RCT [G] 1311 age 1-65 Aerosol administered influenza A vaccine ILI, influenza; throat culture High risk: incomplete outcome data Edwards 1994bDouble-blind RCT [G] 1561 Age 1-65 Aerosol administered influenza A vaccine ILI, influenza; considered retrospectively reported ILI High risk: incomplete outcome data [unclear risk] Edwards 1994cDouble-blind RCT [G] 1676 age 1-65 Aerosol administered influenza A vaccine ILI, influenza; considered retrospectively reported ILI High risk: incomplete outcome data [unclear risk] Edwards 1994dDouble-blind RCT [G] 1507 Age 1-65 Aerosol administered influenza A vaccine ILI, influenza; considered retrospectively reported ILI High risk: incomplete outcome data [unclear risk] Monto 1982Randomised single-blind study [G] 306 studentsIntranasal influenza B vaccine Clinical and laboratory confirmed cases [low risk] INCLUDED STUDY CHARACTERISTICS

StudyMethodsParticipantsInterventionOutcomesNotes Vaccines efficacy or effectiveness (8 studies/12 data set) Monto rd season of Ohmit 06 [M] 1952 Age FluMistSame as Ohmit ‘06 ‘08 [unclear risk] Nichol 1999aRCT [G+I] 4561 Age Live attenuated influenza A and B vaccine Clinical cases; working days lost and adverse effects [low risk] Ohmit 2006Multicenter, randomized, placebo- controlled trial [G] 1247 Age FluMist, MedImmune Local and systemic reactions within 7 days Lab tested influenza Unclear risk: allocation concealment Rytel 1977Singe-blind RCT [G] 143 female student nurse Intranasal influenza A ILI and adverse effects Overall [unclear risk] Zhilova 1986aSemi- randomized double-blind placebo- controlled [G] 3961 students Intranasal live “mono” vaccine ILIOverall [unclear risk] Zhilova 1986bSemi- randomized double-blind placebo- controlled [G] 3944 students Intranasal live “mono” vaccine ILIOverall [unclear risk]

StudyMethodsParticipantsInterventionOutcomesNotes Vaccines safety (13 studies/14 data sets) Atmar 1990Double-blind Placebo- controlled Randomized [G] 74 Age intranasalPulmonary function tests Overall [unclear risk] Betts 1977aRCT [G]47 students Age ? Live attenuated A Physician observation Overall [unclear risk] Evans 1976RCT [M]162 Age Bivalent live attenuated Reactions to immunization Overall [unclear risk] Hrabar 1977double-blind RCT [G] 167 students Yugoslavia Cold-adapted recombinant vaccine Medically examined next 5 days Overall [unclear risk] Keitel 1993a2 RCT [G]? Age Cold-adapted recombinant vaccine Mild upper respiratory symptoms Overall [unclear risk] Keitel 1993b2 RCT [G]? Age H1N1 CR 125Mild upper respiratory symptoms Overall [unclear risk] Lauteria 1974Controlled trial [G+I] 37 Age Live attenuated A 4 days individual observation Overall [unclear risk] Rytel 1977Singe-blind RCT [G] 143 female student nurse Intranasal influenza A ILI and adverse effects Overall [unclear risk] INCLUDED STUDY CHARACTERISTICS

StudyMethodsParticipantsInterventionOutcomesNotes Vaccines safety (13 studies/14 data sets) Miller 1977RCT [G]43 Age Live attenuated B 5 days interview local and systemic reaction Overall [unclear risk] Monto 1982Randomised single-blind study [G] 306 studentsIntranasal influenza B vaccine Clinical and laboratory confirmed cases [low risk] Nichol 1999aRCT [G+I] 4561 Age Live attenuated influenza A and B vaccine Clinical cases; working days lost and adverse effects [low risk] Ohmit 2006Multicenter, randomized, placebo- controlled trial [G] 1247 Age FluMist, MedImmune Local and systemic reactions within 7 days Lab tested influenza Unclear risk: allocation concealment Ohmit 2008Multicenter, randomized, placebo- controlled trial [G] 2058 total 972 from ‘06 Age FluMist, MedImmune Local and systemic reactions within 7 days Lab tested influenza Overall [unclear risk] Rocchi 1979bCluster RCT496 military Age Live attenuated influenza A 15 days symptoms Overall [unclear risk]

Overall Quality of EvidenceImpact of the interventionComments Studies (# Studies addressing each outcome and references) Overall Quality of the Body of Evidence (for all studies addressing each outcome) Expected Impact of the intervention* (Based on the main findings from good quality studies addressing the intervention) Influenz a-like illness Aa Edwards c Aa edwards d Aa edwards a Aa edwards b Nichol 99a Monto 1982 Fair Unclear risk + low risk Low to Moderate Live aerosol vaccines overall effectiveness of preventing ILI: NNV 46 (95% CI 29 to 115). Influenz a Ohmit 2008 Monto 2009 Edwards c a Edwards d b Rytel 1977 Monto 1982 Poor Unclear risk Low to Moderate Live aerosol vaccines overall effectiveness of preventing ILI: NNV 46 (95% CI 29 to 115). GRADE PROFILE

Overall Quality of EvidenceImpact of the interventionComments Studies (# Studies addressing each outcome and references) Overall Quality of the Body of Evidence (for all studies addressing each outcome) Expected Impact of the intervention* (Based on the main findings from good quality studies addressing the intervention) Influenza cases (clinically defined without clear definition) Zhilova a b sumaroko w Poor Low risk Low to Moderate Live aerosol vaccines overall efficacy: NNV 39 (95% CI 32 to 54). GRADE PROFILE

Overall Quality of EvidenceImpact of the interventionComments Studies (# Studies addressing each outcome and references) Overall Quality of the Body of Evidence (for all studies addressing each outcome) Expected Impact of the intervention* (Based on the main findings from good quality studies addressing the intervention) Local Harm: upper respiratory infection symptoms Rytel 1977 Evans1976 Betts 77a Atmar 90 Keitel 93b Keitel 93a Poor Unclear risk Moderate High RR % CI 1.22 to 2.27 Local Harm: cough Ohmit Lauteria 74 Rytel 77 Rocchi 79b Monto 82 Poor Unclear risk Moderate High RR % CI 1.08 to 2.10

Overall Quality of EvidenceImpact of the interventionComment s Studies (# Studies addressing each outcome and references) Overall Quality of the Body of Evidence (for all studies addressing each outcome) Expected Impact of the intervention* (Based on the main findings from good quality studies addressing the intervention) Local Harm: coryza Monto 82 Nichol 99a Fair Low risk Moderate High RR % CI 1.26 to 1.94 Local Harm: sore throat Ohmit Hrabar 77 Monto 82 Rocchi 79b Atmar 90 Nichol 99a Poor Unclear risk Moderate High RR % CI 1.49 to 1.86 Local Harm: combined endpoint Rytel 77 Monto 82 Nichol 99a Fair Low risk Moderate High RR % CI 1.31 to 1.87

Overall Quality of EvidenceImpact of the interventionComments Studies (# Studies addressing each outcome and references) Overall Quality of the Body of Evidence (for all studies addressing each outcome) Expected Impact of the intervention* (Based on the main findings from good quality studies addressing the intervention) Systemic Harm: myalgia Ohmit 06 Lauteria 74 Rocchi 79b Monto 82 Poor Unclear risk High RR % CI 1.26 to 4.85 Systemic Harm: headache Ohmit 06 Rocchi 79b Poor Unclear risk Moderate RR % CI 1.09 to 2.18 Systemic Harm: combined endpoint Rytel 77 Evans 76 Miller 77 Rocchi 79b Monto 82 Poor Unclear risk Moderate RR % CI 0.82 to 2.38

 Live aerosol vaccines have an overall effectiveness of 10% (95%CI 4% to 16%) and a NNV of 46 (95% CI 29 to 115).  The overall efficacy is 53% (95% CI 38% to 65%) and the NNV is 39 (95% CI 32 to 54).  Many more recipients experienced local symptoms after vaccine administration than placebo administration. CONCLUSIONS