Expert Review of Vaccines

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierv20

Safety of live attenuated influenza vaccine (LAIV)

in children and adults with asthma: a systematic
literature review and narrative synthesis

Allyn Bandell, Christopher S. Ambrose, Jon Maniaci & Henry Wojtczak

To cite this article: Allyn Bandell, Christopher S. Ambrose, Jon Maniaci & Henry Wojtczak
(2021): Safety of live attenuated influenza vaccine (LAIV) in children and adults with asthma:
a systematic literature review and narrative synthesis, Expert Review of Vaccines, DOI:
10.1080/14760584.2021.1925113

To link to this article: https://doi.org/10.1080/14760584.2021.1925113

© 2021 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis
Group.

Published online: 24 Jun 2021.

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EXPERT REVIEW OF VACCINES
https://doi.org/10.1080/14760584.2021.1925113

SYSTEMATIC REVIEW

Safety of live attenuated influenza vaccine (LAIV) in children and adults with
asthma: a systematic literature review and narrative synthesis
Allyn Bandella, Christopher S. Ambrosea, Jon Maniacib and Henry Wojtczakc
a
Medical Affairs, AstraZeneca, Gaithersburg, MD, USA; bDivision of Pulmonary and Sleep Medicine, Children’s Hospital of Philadelphia, PA, USA;
c
Pediatric Specialty Clinic, University of New Mexico Children’s Hospital, NM, USA

ABSTRACT ARTICLE HISTORY

Introduction: Asthma is one of the most common chronic respiratory conditions worldwide and can be Received 26 January 2021
exacerbated by influenza. Findings from early trials demonstrated a higher risk of medically significant Accepted 29 April 2021
wheezing in otherwise healthy young children (aged 6 − 23 months) following administration of the
KEYWORDS
Ann Arbor-backbone live attenuated influenza vaccine (LAIV-AA). In more recent years, several addi­
Adults; asthma; children; live
tional studies have investigated the safety of LAIV-AA in older children (2 − 17 years of age) and adults attenuated influenza
with asthma or prior wheezing, but these findings have not yet been systematically evaluated. vaccine; safety; wheeze
Areas covered: We conducted a systematic literature review to assess and synthesize the evidence
from all available studies on the safety of LAIV-AA in people aged 2 − 49 years with a diagnosis of
asthma or recurrent wheezing.
Expert opinion: Fourteen studies over 20 years, involving a total of 1.2 million participants, provided
evidence that LAIV-AA was well tolerated with no safety concerns in individuals aged 2 − 49 years with
a diagnosis of asthma or recurrent wheezing. These data can help inform guidelines for use of LAIV-AA
in children and adults with a history of asthma or recurrent wheezing.

1. Introduction B (A/AA and B/AA), is approved for use in those aged 2–

49 years of age in the US and multiple additional countries
Asthma is one of the most prevalent chronic respiratory con­
[13], and those aged 2–17 years of age in Europe [14]. An early
ditions worldwide, affecting an estimated 339 million people
pragmatic, randomized, placebo-controlled safety study of
globally [1]. Among children, asthma is the most common
children aged 1–17 years found a significant increase in ill­
chronic disease, with an estimated 14% of all children globally
nesses coded as reactive airway disease in children aged 18–
having been diagnosed with asthma at some point in their
35 months (risk ratio 4.06; 90% confidence interval: 1.29 to
lives [2,3]. Influenza can be associated with asthma complica­
17.86) [15]. Subsequently, in a randomized study of children
tions as it can cause further inflammation of the airways and
aged 6–59 months without a recent episode of wheezing or
lungs, worsening asthma symptoms, and triggering acute
severe asthma, prospectively defined medically significant
asthma exacerbations [4]. Children with asthma have higher
wheezing was increased in children aged 6–23 months who
rates of influenza associated hospitalization compared with
received LAIV-AA compared with those who received inacti­
healthy children/children without asthma [5,6].
vated influenza vaccine (IIV) [13,16]. This study also demon­
Vaccination remains the most effective method of prevent­
strated a higher risk of hospitalization in children aged 6–
ing influenza [7,8], with public health and medical experts,
11 months following administration of LAIV-AA [13].
along with stakeholder groups such as the United States (US)
As a result, clinical guidance via prescribing information
Advisory Committee on Immunization Practices (ACIP) and
and vaccination policy guidelines recommended against the
Canada’s National Advisory Committee on Immunization
use of LAIV-AA in children younger than 2 years of age, as well
recommending that children and adults with asthma receive
as individuals 2 years and older with a history of asthma or
an annual influenza vaccine [4,9,10]. In the United Kingdom
wheezing. Current US Food and Drug Administration (FDA)
(UK), influenza vaccination is offered to everyone 6 months
label warnings for use of LAIV-AA in the US note that children
and older with severe asthma [11]. Influenza vaccination is
younger than 5 years of age with recurrent wheezing and
effective in reducing the number and severity of respiratory
persons of any age with asthma may be at increased risk of
infections and can prevent asthma exacerbations. Importantly,
wheezing following the administration of LAIV-AA [13,17]. In
influenza vaccination demonstrated vaccine effectiveness of
the US ACIP recommendations, LAIV-AA is listed as
59–78% for the prevention of asthma attacks leading to emer­
a contraindication in children aged 2 − 4 years who have
gency visits and/or hospitalizations [12].
received an asthma diagnosis, or who have had a wheezing
Live attenuated influenza vaccine (Ann Arbor-backbone;
episode diagnosed by a healthcare provider in the preceding
LAIV-AA), developed using master donor viruses type A and

CONTACT Allyn Bandell Allyn.Bandell@AstraZeneca.com 1 MedImmune Way, Gaithersburg, Maryland 20878, USA
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
2 A. BANDELL ET AL.
Article highlights
● Influenza has been associated with asthma complications and exacer­
bations; vaccinating against influenza is effective in reducing the
number and severity of respiratory infections and can prevent asthma
exacerbation.
● Findings from early randomized controlled trials suggested a higher
risk of wheezing in children aged 6–23 months following administra­
tion of LAIV. At that time, limited data were available in older
children and adults with a history of asthma or recurrent wheezing.
As a result, initial clinical guidance warned against the use of LAIV-AA
in individuals with a history of asthma or recurrent wheezing.
● Since initial approval, multiple studies have been conducted evaluat­
ing the safety of LAIV-AA in individuals aged 2–49 years with
a diagnosis of asthma or recurrent wheezing. This systematic litera­
ture review assessed and synthesized the available evidence regard­
ing the safety of LAIV-AA in this population.
● No studies found an increased risk of significant asthma-related
clinical outcomes measured post-vaccination with LAIV; including
no significant differences in the risk of asthma exacerbations, wheez­
ing, or hospitalizations in LAIV-AA recipients with a history of mild to
moderate asthma or recurrent wheezing compared with controls. The
only event increased after LAIV-AA was runny nose/nasal congestion.
● Gaps in the literature include a lack of data in individuals with active
wheezing or diagnosed with severe asthma.
12 months. Much like the FDA, the ACIP list asthma in persons
aged 5 years or over as a precaution for the use of LAIV-AA [9].
Over the 8 years since the US approval, the safety and
efficacy of LAIV-AA in children with a history of asthma or
recurrent respiratory infections had been demonstrated
[18,19]. As a result, children aged 2 − 17 years with a history
of mild to moderate asthma or recurrent wheeze are within
the EU indication. Use of LAIV-AA in children and adolescents
with severe asthma or active wheezing are listed as a special
Figure 1. Full methodology of the systematic literature review, including the search, screening, data extraction, and narrative synthesis processes. LAIV,
live attenuated influenza vaccine.
precaution and warning because these individuals have not
been adequately studied in clinical trials. Similar to the US, the
EMA recommends that LAIV-AA should not be used in infants
and toddlers below 24 months of age because of safety con­
cerns regarding increased rates of hospitalization and wheez­
ing in this population [14].
Following the significant use of LAIV-AA in children in
recent years, a number of studies have investigated the safety
of LAIV-AA in individuals with asthma or prior wheezing.
Findings from these studies have not yet been reviewed as
a whole. The aim of this systematic literature review was to
assess the available evidence regarding the safety of LAIV-AA
in individuals aged 2–49 years with a diagnosis of asthma (any
severity) or recurrent wheezing.
2. Methods
This systematic literature review evaluated studies relating to
the safety of LAIV-AA in children and adults aged 2–49 years.
The systematic review has been registered with PROSPERO
(https://www.crd.york.ac.uk/prospero/), ID CRD42020171839.
Figure 1 shows the full methodology, including the search,
screening, data collection, and narrative synthesis processes.
2.1. Search strategy and eligibility criteria
The systematic literature search was conducted using the
electronic databases PubMed and The Cochrane Database of
Systematic Reviews. The following search terms were used:
(‘Live attenuated influenza vaccine’ OR LAIV) AND ‘safety’

AND ‘asthma’ OR (‘respiratory sounds’ OR ‘respiratory’ AND
‘sounds’ OR ‘respiratory sounds’ OR ‘wheezing’ OR ‘respira­
tory’). There were no time restrictions applied to the search
criteria.
Table 1 provides an overview of the eligibility criteria for
this systematic literature review. Studies were excluded if they
did not contain data on Ann Arbor LAIV.
2.2. Study selection
Initially, study titles and abstracts were screened for eligibility
and were excluded if they clearly did not meet the inclusion
criteria. Thereafter, full texts of potentially relevant studies
were obtained and reviewed independently by two reviewers
to determine eligibility for inclusion. Studies containing dupli­
cate information or not meeting the inclusion criteria upon
further review were excluded. Ambiguous decisions were
resolved after discussion with the authors.
2.3. Data extraction
Data were extracted into an Excel document to collate and
summarize the study design and results. Data extracted
included study design, setting, time period, participants, LAIV-
AA formulation, comparator, outcome, events in the vacci­
nated and comparator groups, types of event measured, and
key results. Any studies that did not contain data meeting the
inclusion criteria during data extraction were subsequently
excluded. Meta-analysis was not considered appropriate for
this collection of studies due to the variability in outcomes
measured, which included hazard ratios, relative risk, odds
Table 1. Eligibility criteria for studies to be included in the systematic literature
review.
Criteria
Population/ ● Children or adults (any sex), aged 2–49 years,
participants/ with a diagnosis of asthma (any severity) or
conditions recurrent wheezing
Interventions or ● Vaccination with A/Ann Arbor- and/or B/AA-
exposures backbone LAIV-AA administered intranasally
● Any formulation (monovalent, bivalent, trivalent,
or quadrivalent)
Comparisons or ● Placebo, trivalent or quadrivalent IIV,
control groups unvaccinated or intra-patient comparison
Outcomes of interest ● Primary outcome measures:Incidence rates of
clinical events in risk window
● Risk measures expressed as relative risk, odds
ratio, incidence rate ratio, hazard ratio, relative
incidence, or other appropriate measure
● Hospitalization rate in risk window
● Any relevant reactogenic respiratory outcome
relating to vaccine safety (e.g. asthma exacerba­
tion or wheezing within 180 days)
Setting ● Primary care, inpatient, emergency, or
outpatient visits in any country
Study design ● Randomized controlled trials, observational
studies, retrospective and prospective outcome
studies
Language ● English
Country ● Any
IIV, inactivated influenza vaccine; LAIV, live attenuated influenza vaccine.
EXPERT REVIEW OF VACCINES 3
ratios, spirometry values, change in asthma control test scores,
incidence of asthma exacerbation, and rates of adverse events.
Hence, a narrative synthesis was performed.
2.4. Synthesis
A narrative synthesis was undertaken to synthesize the find­
ings of the included studies. First, the results of each study
were assessed systematically, highlighting the important char­
acteristics (outcomes, age groups investigated, comparators
etc.) and key results (safety and reactogenicity data). The
studies were then grouped by key outcomes and findings in
relation to age group and presented in tabular form. This
allowed for comparison of studies with similar outcomes mea­
sured and to help identify any patterns. Studies with out­
comes not repeated or measured in other studies could not
be grouped and were assessed separately. The key implica­
tions of the studies were then summarized descriptively fol­
lowing the comparison of the study outcomes.
3. Results
The initial literature search identified 84 records, and from these,
28 full-text articles were assessed for eligibility (Figure 2).
Fourteen articles were then excluded as they did not meet the
eligibility criteria for the following reasons: no measures of
asthma or wheezing (one article), did not report incidence
rate/risk measure (four articles), insufficient data regarding
safety of LAIV-AA with asthma (one article), duplicate data
from other studies (four articles), participants not being within
the age range (one article), no comparison for healthy controls
(one article), LAIV-AA was not assessed (one article), and no
results available as the article was a protocol (one article).
A total of 14 studies were retained for the narrative synth­
esis of the systematic literature review. Detailed characteristics
of the studies included in the review are presented in Table 2.
Study design was diverse and included: randomized, non-
randomized, retrospective, prospective, observational, and
non-interventional analysis. The number of subjects with
asthma or recurrent wheezing in the studies ranged substan­
tially, from 48 [20] to 166,174 [21]. The included studies were
conducted from 1997–1998 [20] to 2016–2017 [22], over 20
influenza seasons.
The method of comparison also varied within the studies;
nine studies used IIV as a control [18,21,23–29], two used
unvaccinated controls [28,29], three used a reference time
period self-control (a specific time frame pre-vaccination or
post-vaccination) [23,30,31], one used placebo [20], One used
a cohort without asthma [32], and one used baseline asthma
symptoms as the control [22]. The majority of studies (12; 86%)
evaluated the safety of LAIV-AA in children and adolescents
(aged 2–18 years), whereas only two were performed in adults
aged 18–49 years [28,31].
The key results from the studies in terms of outcomes
measured are presented in Table 2 with the study details.
Notably, no studies found an increased risk of significant
clinical outcomes measured post-vaccination with LAIV-AA in
children and adolescents with a history of wheeze or asthma.
Specifically, no significant differences in the risk of asthma
4 A. BANDELL ET AL.
Figure 2. PRISMA flow diagram of systematic literature review search strategy and screening process. LAIV, live attenuated influenza vaccine; PRISMA,
Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
exacerbations, wheezing, or healthcare utilization were identi­
fied in LAIV-AA recipients compared with the controls. In two
studies, there was a higher incidence of a runny or stuffy nose
in children following LAIV-AA [18,24]. LAIV-AA was associated
with lower odds of inpatient or emergency department visits
for asthma exacerbation compared with IIV [26] in one study,
and in another, significantly higher incidences of wheezing
were noted in those receiving inactivated trivalent influenza
vaccine compared with trivalent LAIV-AA [18].
To aid further comparison, study findings are presented by
risk ratio in Figure 3, and by type of outcome measured and
age group in Table 3. Approximately 79% of studies evaluated
medically attended acute/lower respiratory illness, hospitaliza­
tions, emergency department visits, and healthcare utilization,
which were investigated across a wide range of age groups,
from infants to adults. LAIV-AA was not associated with an
increased risk for any of the measured outcomes in any age
group investigated (Table 3). Figure 3 demonstrates the range
of findings with no outcomes being statistically increased in
LAIV-AA recipients versus controls.
There was no difference seen in the risk of an asthma
associated event when comparing the outcomes measured
in children and adults. In the two studies performed in adults
aged 18 − 49 years, the outcomes investigated included
medically attended lower respiratory events, hospitalizations
[28,31], vaccine safety signals, and wheezing [28]. All other
outcomes were only assessed in children aged 2–18 years.
4. Discussion
The results of this systematic literature review demonstrated
that LAIV-AA was well tolerated in adults (18–49 years of age)
and children (2–17 years of age) with a diagnosis of asthma or
a history of recurrent wheezing. No safety concerns were
associated with LAIV-AA in children and adolescents with
asthma across a wide range of asthma-related outcomes
investigated by the studies included in this review. Only
runny nose/nasal congestion was associated with LAIV,
which is a minor and well-known reactogenicity event asso­
ciated with the intranasal replication of LAIV-AA [33].A
 EXPERT REVIEW OF VACCINES 5

Figure 3. Key findings grouped by study. Studies not reporting outcomes by ratio are not presented here. CI; confidence interval; IIV, inactivated influenza
vaccine; ED, emergency department; LAIV, live attenuated influenza vaccine; LRE, lower respiratory events; LRTI, lower respiratory tract infection; MAARI, medically
attended acute respiratory illness; SCRI, self-controlled risk interval. *During days 0–14 post-LAIV3. †During days 0–14 in children aged 5–9 years; reference period is
before day 0 and after 14 or 42 days post-LAIV. ‡During the 1–42-day risk interval post-vaccination. §Any hospitalization during the 42-day risk interval post-vaccination.
‖
Risk ratio/relative risk. ¶Ratio of odds ratios. #Incidence rate ratio. **Adjusted hazard ratio. ††Adjusted ratio of rate ratios. ‡‡Ratio covers different types of statistical
analysis. The x-axis scale uses a log10 scale.

Table 2. Baseline characteristics and key results for included studies in the systematic literature review.
Study design, Type and
Influenza including vaccine Number of subjects (with asthma/ definition of Primary safety
Reference season used vs control recurrent wheeze) and age group asthma/wheezing outcome Key results
Redding 1997 Randomized 48 Stable diagnosed Spirometry values ● No significant changes in
et al. double blind, 9–17 years moderate to (FEV1) FEV1 or asthma symptoms
[20] placebo- severe asthma within each group post-
controlled defined as FEV1 vaccination and between
study. Intranasal < 80% predicted LAIV3 and placebo groups
LAIV3 vs after ● No SAEs in either treatment
intranasal withholding group
placebo albuterol for
8 hours
(Continued )
6 A. BANDELL ET AL.

Table 2. (Continued).
Study design, Type and
Influenza including vaccine Number of subjects (with asthma/ definition of Primary safety
Reference season used vs control recurrent wheeze) and age group asthma/wheezing outcome Key results
Piedra 1998–2002 Non-randomized, 11,096 History of Risk ratio of SAEs ● No significant increases in
et al. community- 2–18 years* wheezing or and MAARI risk of healthcare
[30] based open- mild, utilization attributed to
label trial. LAIV3 intermittent MAARI and asthma rates
vs pre- asthma compared with pre-
vaccination Mild, vaccination periods
period intermittent ● No SAEs attributed to LAIV3
asthma defined
as those not
using steroids,
or
bronchodilator
therapy daily or
every other day
Gaglani 1998–1999 and Retrospective 2196 Mild-intermittent Risk ratio of MAARI ● No increased risk for
et al. 2001 − 2002 analysis of an 2–18 years* asthma or during 0–14 and MAARI or asthma
[23] open-label field reactive airways 0–42 days post- exacerbation post-
trial. LAIV3 (for disease or LAIV3 were vaccination in LAIV3
those without intermittent compared with recipients with
asthma), TIV (for wheezing respective intermittent wheezing
those with Children with reference
asthma) vs intermittent periods
reference wheezing were (before day 0
period† defined as those and after 14 or
with a history of 42 days)
asthma or
reactive airways
disease or
wheezing who
did not use
steroids (oral or
inhaled)
Fleming 2002–2003 Phase III 2229 Clinical diagnosis Incidence of ● No significant differences
et al. randomized, 6–17 years of asthma asthma in incidence of asthma
[18] open-label defined as an exacerbation exacerbation post-
study. Intranasal ICD9 diagnosis (acute wheezing vaccination between
LAIV3 vs TIV code of 493 plus illness groups
1 or more associated with ● Percentage of subjects with
prescriptions for hospitalization, reactogenicity events was
asthma unscheduled similar between groups,
medication clinic visit, or except for runny nose/nasal
within the new congestion, which was sig­
previous prescription) nificantly higher with LAIV3,
12 months and wheeze, which was
significantly higher with TIV
Ambrose 2002–2003 and Retrospective 1940 Mild or moderate Rates and rate ● No significant differences
et al. 2004–2005 evaluation of 2 2–5 years asthma or difference of in rates of wheezing,
[24] randomized, a history of wheezing lower respiratory illness,
multinational wheezing endpoints and hospitalizations post-
trials. LAIV3 vs Diagnosis based LAIV3 vs TIV
TIV on investigator ● The incidence of reacto­
judgment genicity events was similar
among LAIV3 and TIV
● In both studies, the inci­
dence of runny/stuffy nose
was generally higher post-
LAIV, and the differences
were significant after dose
2 in study 1 and dose 1 in
study 2

(Continued )
 EXPERT REVIEW OF VACCINES 7

Table 2. (Continued).
Study design, Type and
Influenza including vaccine Number of subjects (with asthma/ definition of Primary safety
Reference season used vs control recurrent wheeze) and age group asthma/wheezing outcome Key results
Tennis 2007–2009 Retrospective 42,424‡ Asthma was Type and number ● Among children with
et al. evaluation of 4 24–59 months identified based of asthma, there was a trend
[25] cohorts of on claims hospitalizations toward fewer LAIV LAIV3
children. LAIV3 diagnosis; for or ED visits recipients having inhaled
(formulation those with within 42 days corticosteroid dispensed in
based on years a single post-vaccination the past 12 months
studied) vs TIV outpatient compared with TIV
diagnosis, recipients
a claim for ● Among children with
inhaled SABA wheezing, the frequency of
was required. SABA and inhaled corticos­
Recurrent teroid use were generally
wheezing was similar in both LAIV3 and
identified based TIV recipients
on a claim for ● No evidence of increased
inhaled SABA in rates of ED visits or hospi­
the prior talizations 42 days post-
12 months with vaccination with LAIV3
no asthma compared with TIV
diagnosis
Ray et al. 2007–2014 Retrospective case- 154,994 History of asthma Odds ratio of acute ● LAIV-AA was associated
[26] centered 2–17 years was defined as asthma with significantly lower
analysis. those who exacerbations odds of inpatient/ED visits
Monovalent received at least 1–14 days (risk), for asthma exacerbation
LAIV-AA, LAIV3 1 ICD9 diagnosis and 29–42 days during the risk interval
and LAIV4 code for asthma (comparison), compared with IIV for all
(formulation (493.xx) any after subgroups except those
based on years time prior to IIV/ immunization with a remote history of
studied) vs IIV LAIV-AA asthma only
immunization. ● LAIV-AA was associated
Asthma severity with significantly lower
was categorized odds (P = 0.04) of asthma
into [1] current exacerbation compared
or recent, with IIV among children
persistent with all asthma types and
asthma; [2] among those with current
current or or recent, not persistent
recent, not asthma
persistent
asthma; or [3]
remote history
of asthma
Diagnosis based
on investigator
judgment
Nordin 2007–2016 Retrospective 4771 Asthma defined as Adjusted ratio of ● No increase in lower
et al. observational 2–17 years at least two rate ratios of respiratory events,
[27] cohort study asthma acute, medically primarily asthma
using a pre-post diagnoses (ICD9 attended lower exacerbations or
-guideline- diagnosis codes respiratory wheezing, or
controlled 493.xx) on events hospitalization risk in the
design. different days at LAIV-AA guideline group
Guideline outpatient, ED, vs the IIV group (increase
recommended or inpatient of LAIV-AA use from 23%
Monovalent visits in the to 68% in children with
LAIV-AA, LAIV3 12 months prior asthma in the guideline
and LAIV4 to vaccination group compared with an
(formulation increase of LAIV-AA use of
based on years only 7% to 11% in the IIV
studied) cohort control group)
vs guideline IIV
cohort
(Continued )
8 A. BANDELL ET AL.

Table 2. (Continued).
Study design, Type and
Influenza including vaccine Number of subjects (with asthma/ definition of Primary safety
Reference season used vs control recurrent wheeze) and age group asthma/wheezing outcome Key results
Duffy 2008–2011 Retrospective 11,761 For all cohorts, Incidence rate ratio ● No significant differences
et al. observational 2–49 years asthma was of lower in risk of having
[31] cohort study. defined as any respiratory tract a healthcare visit for any
LAIV3 and of the following events, reason post-vaccination
monovalent in the previous including days 1 to 14 compared
LAIV-AA vs self- 12 months: [1] asthma with days 29 to 42
controlled risk a diagnosis of exacerbation ● No significantly increased
interval method asthma (ICD-9 and wheezing risk of lower/upper respira­
code 493.xx) for tory AEs or healthcare visits
at least 2 clinic post-vaccination days 1 to
visits, or at least 14 compared with days 29
1 ED visit, or at to 42 in children 2–4 years
least 1 with recurrent wheezing
hospitalization; ● No increased risk of medi­
[2] for those cally attended lower
over 5 years of respiratory tract AEs
age, definition (including asthma exacer­
also included at bation or wheezing) in the
least 2 SABA 14 days post-vaccination
medications
dispensed; [3] at
least 1 SABA
and 1 other
asthma
medication
dispensed.
Recurrent
wheezing was
defined as
a child younger
than 5 years of
age who had at
least one of the
following in the
prior 12 months:
[1] at least 2
visits for acute
bronchiolitis,
bronchitis not
specified as
acute or chronic,
chronic
bronchitis, other
disease of the
trachea or
bronchi,
wheezing, or
other respiratory
distress or
insufficiency; [2]
at least 2 SABA
medications
dispensed; [3] at
least 1 SABA
and at least 1
other asthma
medication
dispensed
Tennis 2009–2010 Retrospective 166,174 Asthma diagnosis Frequency and ● Among children with
et al. evaluation of 4 24–59 months* and treatment type of ED visits asthma or recurrent
[21] cohorts of within the or wheezing, hospitalizations
children. LAIV3 previous hospitalizations and ED visits for lower
(formulation 12 months, or within 42 days respiratory conditions
based on years recurrent post-vaccination were not more frequent
studied) vs TIV wheezing (with post-LAIV3 compared with
a treatment post-TIV
occurring ≥1
time in the
previous
12 months but
no asthma
diagnosis)
(Continued )
 EXPERT REVIEW OF VACCINES 9

Table 2. (Continued).

Study design, Type and

Influenza including vaccine Number of subjects (with asthma/ definition of Primary safety
Reference season used vs control recurrent wheeze) and age group asthma/wheezing outcome Key results
Baxter 2013–2014 Prospective, non- 62,040§ History of Hazard ratios of ● Risk of any medically
et al. randomized, 2–49 years wheezing or medically attended event not
[28] observational asthma attended events significantly increased
cohort study. (complementary and with the LAIV4 group vs
LAIV4 vs IIV and analysis) hospitalizations both the IIV and
unvaccinated during periods unvaccinated groups
individuals at risk ● Among children with
immediately a history of asthma or
after LAIV4 wheezing, risk of wheezing
vaccination vs post-vaccination was not
incidence rates higher with the LAIV4
during reference group vs both the IIV and
periods later in unvaccinated groups
the follow-up
period and vs
rates in IIV and
unvaccinated
controls
Turner 2013–2014 Prospective, 188 Physicians Primary outcome ● No risk factors were
et al. multicenter, 2–17 years* diagnosis of related to identified for occurrence
[32] open-label, asthma/ asthma: of an acute AE when
phase IV recurrent Incidence of assessed for the presence
intervention wheeze. Those delayed of physician-diagnosed
study. Cohort with a history of symptoms up to asthma/recurrent wheeze
with egg allergy severe but 72 hours post- or allergic rhinitis
and asthma/ stable asthma vaccination, ● Children with recurrent
recurrent were not incidence of wheeze or asthma were not
wheeze vs excluded adverse events more likely to experience
cohort with egg of non-allergic AEs or wheeze/cough com­
allergy without cause post- pared with those without
asthma. Both vaccination, asthma/wheezing within
vaccinated with change in nasal 72 hours post-LAIV3
LAIV3 airway patency ● Wheeze/cough was not
(formulation more common in children
based on years receiving regular inhaled
studied) corticosteroids
● No SAEs were attributable
to LAIV3

Caspard 2013–2015 Prospective, non- 11,463 Diagnosis of Any hospitalization ● Up to 6 months,

et al. interventional 2–17 years asthma (LAIV3/4 documented in hospitalization incidences
[29] cohort study. and IIV the linked were lower after LAIV-AA
LAIV3/4 vs IIV recipients with Hospital than after IIV, no
and asthma Episodes significant differences
unvaccinated matched by use Statistics between hospitalizations
individuals of oral steroid database within post-LAIV3/4 compared
prescription 42 days and up with unvaccinated
and/or hospital to 6 months individuals
admission in post-vaccination ● No medically attended
past 12 months) event of interest occurred
at an increased rate post-
LAIV3/4 vs IIV and unvacci­
nated controls

(Continued )
10 A. BANDELL ET AL.

Table 2. (Continued).

Study design, Type and

Influenza including vaccine Number of subjects (with asthma/ definition of Primary safety
Reference season used vs control recurrent wheeze) and age group asthma/wheezing outcome Key results
Turner 2016–2017 Prospective, 478 Current physician- Change in asthma ● No significant change in
et al. multicenter, 2–18 years diagnosed control before asthma control by child
[22] open-label, moderate to and in the age or asthma severity, as
phase IV severe asthma 4 weeks after assessed by age-
intervention and prescribed LAIV4 as appropriate
study. LAIV4 vs regular inhaled assessed by (c) questionnaires
baseline asthma corticosteroids; ACT score or ● No associations between
control/ children 2– TRACK score, baseline asthma control
symptoms 5 years were and by severity and odds of asthma
also eligible if classification exacerbations
they had 2 or ● The rate of acute AEs after
more immunization was in line
exacerbations of with the reported rate of
wheezing in the AEs described in the litera­
previous year ture for the normal popu­
requiring oral lation
steroids or
hospitalization
*Age group is for asthma and wheezing cohorts included in the review only, †Before day 0, after days 14 and 42, ‡N is for seasons 1 and 2 for both LAIV-AA and TIV
recipients in the asthma/recurrent wheezing cohort. §N is for total number in study; N for complementary analysis in those with a history of wheezing or asthma
not stated.
(c)ACT, (Children’s) Asthma Control Test; AE, adverse event; ED, emergency department; FEV1, forced expiratory volume; ICD, International Classification of Diseases;
IIV, inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; LAIV3, trivalent live attenuated influenza vaccine; LAIV4, quadrivalent live attenuated
influenza vaccine; MAARI, medically attended acute respiratory illness; SABA, short-acting beta-agonist; SAEs, serious adverse events; SCRI, self-controlled risk
interval; TIV, trivalent influenza vaccine; TRACK, Test for Respiratory and Asthma Control for Kids.

Table 3. Key study findings by outcome measured and age group.

Outcomes investigated Findings Age groups

Medically attended lower ● No increased risk with LAIV-AA compared with IIV [27],*[28], unvaccinated ● 2–17 years [27]
respiratory events controls [28], or the self-controlled risk interval [31] ● 2–49 years [28,31]

Hospitalizations/emergency
department visits/healthcare
utilization
● No increased risk with LAIV-AA compared with IIV/TIV [18,21,24–29], ● 2–17 years [26,27,29]
a reference period [28], unvaccinated individuals [28,29], pre-vaccination ● 2–49 years [28,31]
[30] or the self-controlled risk interval [31] ● 24–59 months [21,25]
● Hospitalization incidence lower after LAIV-AA than IIV [29] ● 2–5 years [24]
● 6–17 years [18]
● 2–18 years [30]

Vaccine safety signals ● No clinically meaningful safety signals associated with LAIV-AA [28] ● 2–49 years [28]

Wheezing ● No increased risk with LAIV-AA compared with IIV [27,28], TIV [24], or ● 2–17 years [27]
unvaccinated controls [28] ● 2–49 years [28]
● 2–5 years [24]

Acute asthma exacerbations
● LAIV-AA was associated with lower odds of inpatient/emergency ● 2–17 years [26] (This is for all age groups in
department visits for asthma exacerbation compared with IIV for all the analysis except for those with remote
subgroups except those with a remote history of asthma only [26] asthma)
● No increased risk with LAIV-AA compared with TIV [18] or reference periods ● 6–17 years [18]
[23] ● 2–18 years [23]

Serious adverse events ● No serious adverse events attributable to LAIV-AA [20,30,32] ● 2–17 years [32]
● 2–18 years [30]
● 9–17 years [20]

Reactogenicity events ● Incidence among LAIV-AA and TIV similar (apart from incidence of runny ● 2–5 years [24]
nose/nasal congestion, which was significantly higher with LAIV3 [18,24], ● 6–17 years [18]
and wheeze, which was significantly higher with TIV [18]

Medically attended acute ● No increased risk with LAIV-AA compared with reference [23] and pre- ● 2–18 years [23,30]
respiratory illness vaccination periods [30]

Change in FEV1 ● No significant changes within group after vaccination with LAIV-AA or ● 9–17 years [20]
between LAIV-AA and placebo groups [20]

Change in asthma control ● No significant changes after LAIV-AA compared with pre-vaccination [22] ● 2–18 years [22]

*Study was looking at LAIV-AA guidelines, the population was not all vaccinated with LAIV.
FEV1, forced expiratory volume; IIV, inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; TIV, trivalent influenza vaccine.
 EXPERT REVIEW OF VACCINES 11

strength of this review was the comprehensive approach, 5. Conclusions

which allowed for a detailed assessment of all studies avail­
The evidence from this systematic literature review demonstrated
able to date despite methodological differences. A total of
that LAIV-AA was well tolerated in children and adults aged
471,802 participants with asthma or recurrent wheezing from
2 − 49 years with mild to moderate asthma or recurrent wheeze,
the included studies were evaluated as part of this systematic
with no safety concerns or increased risk identified for any of the
review (in studies where N is specified for each treatment
respiratory outcomes measured when comparing LAIV-AA with
group; LAIV-AA participants N = 55,849, controls
injectable influenza vaccines or non-vaccine controls.
N = 356,753), which adds to the robustness of the findings.
There was a wide range in the number of participants across
the studies. The largest of which was from a US vertically
integrated healthcare system which included 166,174 partici­ 6. Expert opinion
pants with asthma or recurrent wheezing, of whom 9,278 (6%)
Although randomized controlled trials have demonstrated a higher
received LAIV-AA [21].
risk of reactive airway disease and wheezing events in children
The 14 studies evaluated support the safety of LAIV-AA in
6 − 23 months following administration of LAIV-AA [13,15,16],
individuals 2–49 years of age with asthma across a range of out­
multiple studies in individuals 2 − 49 years of age with asthma or
comes, and when compared with placebo, trivalent or quadrivalent
a history of recurrent wheezing have shown no increased risk of
IIV, reference periods, or unvaccinated or intra-patient controls,
significant adverse events following LAIV-AA. Fourteen studies that
across 20 influenza seasons. Although two large studies investi­
included a total of 471,802 participants with asthma or recurrent
gated the safety of LAIV-AA in adults (total of 73,801 participants)
wheezing found no significant safety concerns or increased risk for
[28,31], no data are available for adults older than 49 years of age.
any asthma-related outcomes measured. The evidence presented
As studies were primarily undertaken in persons with mild to
in the studies in this review may help inform clinical guidelines for
moderate asthma or a history of recurrent wheezing (Table 2), this
the use of LAIV-AA in children and adults with mild to moderate
analysis provides reassurance of the safety of LAIV-AA in this popu­
asthma or recurrent wheeze [30,31]. Due to limited data, the safety
lation. However, given the limited data on the safety of LAIV-AA in
of LAIV-AA in individuals with severe asthma or active wheezing
children and adults with severe asthma, conclusions on the safety
has not been established.
of LAIV-AA in this population will require further investigation
When licensed and recommended vaccines already exist,
before informed guidance for this population can be developed.
newer vaccines, particularly those with a novel mechanism of
A limitation of this systematic review is the different methodol­
action, face a high hurdle to demonstrate safety in specific
ogies and different outcomes used in the studies included. As
subpopulations. It is not always possible to conduct the neces­
a result, a formal meta-analysis could not be conducted.
sary studies prior to approval and thus data obtained post-
Treatment administration (LAIV, IIV, or no vaccine) was not con­
licensure becomes particularly important. While prospective,
trolled in the non-randomized studies, so observed differences
double-blind, randomized studies remain the gold standard
between treatment groups may be confounded by differences
for evidence, high-quality, non-randomized studies can greatly
between the groups at baseline. The included articles studied
contribute to our understanding of vaccine safety and effec­
a range of different LAIV-AA formulations including monovalent,
tiveness in the real world. When possible, such studies should
trivalent and quadrivalent. The solicited sides effects of these for­
be conducted in a consistent manner to enable pooling of
mulations have a high degree of homogeneity suggesting similar
data across studies; such harmonization would rely on explicit
safety profiles regardless of valency. Despite these limitations, the
guidance from vaccine experts and policymakers regarding
overall results were consistent across studies in this review, provid­
best practices.
ing confidence in the findings.
Several of the included studies recommended that the guide­
lines (specific to the US) for use of LAIV-AA in children with asthma
or wheezing should be reconsidered in the light of the evidence Acknowledgment(s)
demonstrating no additional risk compared with study controls. India Wright, MSc and Talya Underwood MPhil (Cantab) performed the
Duffy et al [31] stated that the precaution in the US guidance systematic literature review and provided medical writing support, and
regarding increased risk of wheezing after LAIV-AA in those with editorial support was provided by Rachael Cazaly, BSc, all of Core Medica,
intermittent or mild persistent asthma or children 2–4 years old London, UK, supported by AstraZeneca according to Good Publication
Practice guidelines (Link). The Sponsor was involved in the study design,
with recurrent wheezing might not be warranted. Similarly, Piedra
collection, analysis, and interpretation of data, as well as data checking of
et al [30] suggested that expanding the current recommendations information provided in the manuscript. However, ultimate responsibility
to include children with mild intermittent asthma should be con­ for opinions, conclusions, and data interpretation lies with the authors.
sidered. The UK has retained a recommendation against use of
LAIV-AA in those with an acute asthma exacerbation in the pre­
vious 72 hours, as there are no available data on the safety of LAIV-
AA vaccination in this setting (and such children should be offered
Declaration of interest
IIV [34]). However, the study by Turner et al [22] provided evidence A Bandell and CS Ambrose are employees of and shareholders in
for the revised UK guidance for the 2019/20 influenza season that AstraZeneca. The authors have no other relevant affiliations or financial
involvement with any organization or entity with a financial interest in or
‘children with asthma on inhaled corticosteroids may safely be
financial conflict with the subject matter or materials discussed in the
given LAIV, irrespective of the dose prescribed.’ manuscript apart from those disclosed.
12 A. BANDELL ET AL.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
Funding
This paper received writing support, funded by AstraZeneca.
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