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 effi cacy of live aerosol vaccines on preventing influenza A or B infections (confirmed by lab test), and its eff ectiveness 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 eff ectUnit of analysis issues

RISK OF BIAS ASSESSMENT

Study Methods Participants

Intervention

Outcomes

Notes

Vaccines efficacy or effectiveness (8 studies/12 data set)Edwards 1994a

Double-blind RCT[G]

1311 age 1-65

Aerosol administered influenza A vaccine

ILI, influenza; throat culture

High risk: incomplete outcome data

Edwards 1994b

Double-blind RCT[G]

1561Age 1-65

Aerosol administered influenza A vaccine

ILI, influenza; considered retrospectively reported ILI

High risk: incomplete outcome data[unclear risk]

Edwards 1994c

Double-blindRCT[G]

1676 age 1-65

Aerosol administered influenza A vaccine

ILI, influenza; considered retrospectively reported ILI

High risk: incomplete outcome data[unclear risk]

Edwards 1994d

Double-blind RCT[G]

1507Age 1-65

Aerosol administered influenza A vaccine

ILI, influenza; considered retrospectively reported ILI

High risk: incomplete outcome data[unclear risk]

Monto 1982 Randomised single-blind study[G]

306 students Intranasal influenza B vaccine

Clinical and laboratory confirmed cases

[low risk]

INCLUDED STUDY CHARACTERISTICS

Study Methods Participants

Intervention

Outcomes

Notes

Vaccines efficacy or effectiveness (8 studies/12 data set)Monto 2009 3rd season of

Ohmit 06[M]

1952 Age 18-49

FluMist Same as Ohmit ‘06 ‘08

[unclear risk]

Nichol 1999a RCT[G+I]

4561Age 18-64

Live attenuated influenza A and B vaccine

Clinical cases; working days lost and adverse effects

[low risk]

Ohmit 2006 Multicenter, randomized, placebo-controlled trial[G]

1247Age 18-46

FluMist, MedImmune

Local and systemic reactions within 7 daysLab tested influenza

Unclear risk: allocation concealment

Rytel 1977 Singe-blindRCT[G]

143 female student nurse18-35

Intranasal influenza A

ILI and adverse effects

Overall [unclear risk]

Zhilova 1986a

Semi-randomized double-blind placebo-controlled [G]

3961 students18-23

Intranasal live “mono” vaccine

ILI Overall [unclear risk]

Zhilova 1986b

Semi-randomized double-blind placebo-controlled [G]

3944 students18-23

Intranasal live “mono” vaccine

ILI Overall [unclear risk]

Study Methods Participants

Intervention

Outcomes

Notes

Vaccines safety (13 studies/14 data sets)Atmar 1990 Double-blind

Placebo-controlledRandomized [G]

74Age 18-40

intranasal Pulmonary function tests

Overall [unclear risk]

Betts 1977a RCT [G] 47 studentsAge ?

Live attenuated A

Physician observation

Overall [unclear risk]

Evans 1976 RCT [M] 162Age 18-61

Bivalent live attenuated

Reactions to immunization

Overall [unclear risk]

Hrabar 1977 double-blindRCT [G]

167 studentsYugoslavia

Cold-adapted recombinant vaccine

Medically examined next 5 days

Overall [unclear risk]

Keitel 1993a 2 RCT [G] ?Age 18-40

Cold-adapted recombinant vaccine

Mild upper respiratory symptoms

Overall [unclear risk]

Keitel 1993b 2 RCT [G] ?Age 18-40

H1N1 CR 125 Mild upper respiratory symptoms

Overall [unclear risk]

Lauteria 1974

Controlled trial [G+I]

37Age 18-24

Live attenuated A

4 days individual observation

Overall [unclear risk]

Rytel 1977 Singe-blindRCT[G]

143 female student nurse18-35

Intranasal influenza A

ILI and adverse effects

Overall [unclear risk]

INCLUDED STUDY CHARACTERISTICS

Study Methods Participants

Intervention

Outcomes

Notes

Vaccines safety (13 studies/14 data sets)Miller 1977 RCT [G] 43

Age 22-50Live attenuated B

5 days interview local and systemic reaction

Overall [unclear risk]

Monto 1982 Randomised single-blind study[G]

306 students Intranasal influenza B vaccine

Clinical and laboratory confirmed cases

[low risk]

Nichol 1999a RCT[G+I]

4561Age 18-64

Live attenuated influenza A and B vaccine

Clinical cases; working days lost and adverse effects

[low risk]

Ohmit 2006 Multicenter, randomized, placebo-controlled trial[G]

1247Age 18-46

FluMist, MedImmune

Local and systemic reactions within 7 daysLab tested influenza

Unclear risk: allocation concealment

Ohmit 2008 Multicenter, randomized, placebo-controlled trial[G]

2058 total972 from ‘06Age 18-46

FluMist, MedImmune

Local and systemic reactions within 7 daysLab tested influenza

Overall [unclear risk]

Rocchi 1979b Cluster RCT 496 military Age 18-20

Live attenuated influenza A

15 days symptoms

Overall [unclear risk]

Overall Quality of Evidence

Impact of the intervention

Comments

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-like illness

Aa Edwards cAa edwards dAa edwards aAa edwards bNichol 99aMonto 1982

Fair

Unclear risk + low risk

Low to Moderate

Live aerosol vaccines overall effectiveness of preventing ILI: NNV 46 (95% CI 29 to 115).

Influenza

Ohmit 2008Monto 2009Edwards c aEdwards d bRytel 1977Monto 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 Evidence

Impact of the intervention

Comments

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 bsumarokow

Poor

Low risk

Low to Moderate

Live aerosol vaccines overall efficacy: NNV 39 (95% CI 32 to 54).

GRADE PROFILE

Overall Quality of Evidence

Impact of the intervention

Comments

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 1977Evans1976Betts 77aAtmar 90Keitel 93bKeitel 93a

Poor

Unclear risk

Moderate High

RR 1.66 95% CI 1.22 to 2.27

Local Harm: cough

Ohmit 06 08Lauteria 74Rytel 77Rocchi 79bMonto 82

Poor

Unclear risk

Moderate High

RR 1.51 95% CI 1.08 to 2.10

Overall Quality of Evidence

Impact of the intervention

Comments

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 82Nichol 99a

FairLow risk

Moderate High

RR 1.5695% CI 1.26 to 1.94

Local Harm: sore throat

Ohmit 06 08Hrabar 77Monto 82Rocchi 79bAtmar 90Nichol 99a

Poor

Unclear risk

Moderate High

RR 1.6695% CI 1.49 to 1.86

Local Harm: combined endpoint

Rytel 77Monto 82Nichol 99a

Fair

Low risk

Moderate High

RR 1.5695% CI 1.31 to 1.87

Overall Quality of Evidence

Impact of the intervention

Comments

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 06Lauteria 74Rocchi 79bMonto 82

Poor

Unclear risk

High

RR 2.4795% CI 1.26 to 4.85

Systemic Harm: headache

Ohmit 06Rocchi 79b

Poor

Unclear risk

Moderate

RR 1.5495% CI 1.09 to 2.18

Systemic Harm: combined endpoint

Rytel 77Evans 76Miller 77Rocchi 79bMonto 82

Poor

Unclear risk

Moderate

RR 1.40 95% CI 0.82 to 2.38

Live aerosol vaccines have an overall eff ectiveness of 10% (95%CI 4% to 16%) and a NNV of 46 (95% CI 29 to 115).

The overall effi cacy 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