The safety and efficacy of live attenuated influenza vaccine in young children with asthma or prior wheezing

Article (PDF Available)inEuropean Journal of Clinical Microbiology 31(10):2549-57 · March 2012with15 Reads
DOI: 10.1007/s10096-012-1595-9 · Source: PubMed
Abstract
In the European Union and Canada, an Ann Arbor strain live attenuated influenza vaccine (LAIV) is approved for use in children aged 2-17 years, including those with mild to moderate asthma or prior wheezing. The safety and efficacy of LAIV versus trivalent inactivated influenza vaccine (TIV) in children with asthma aged 6-17 years have been demonstrated. However, few data are available for children younger than 6 years of age with asthma or prior wheezing. Safety and efficacy data were collected for children aged 2-5 years with asthma or prior wheezing from two randomized, multinational trials of LAIV and TIV (N = 1,940). Wheezing, lower respiratory illness, and hospitalization were not significantly increased among children receiving LAIV compared with TIV. Increased upper respiratory symptoms and irritability were observed among LAIV recipients (p < 0.05). Relative efficacies were consistent with the results observed in the overall study populations, which demonstrated fewer cases of culture-confirmed influenza illness in LAIV compared with TIV recipients. Study results support the safety and efficacy of LAIV among children aged 2-17 years with mild to moderate asthma or a history of wheezing. Data regarding LAIV use are limited among individuals with severe asthma or active wheezing within the 7 days before vaccination.
ARTICLE
The safety and efficacy of live attenuated influenza vaccine
in young children with asthma or prior wheezing
C. S. Ambrose & F. Dubovsky & T. Yi & R. B. Belshe &
S. Ashkenazi
Received: 6 January 2012 / Accepted: 16 February 2012 / Published online: 14 March 2012
#
The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract In the European Union and Canada, an Ann Arbor
strain live attenuated influenza vaccine (LAIV) is approved
for use in children aged 217 years, including those with mild
to moderate asthma or prior wheezing. The safety and efficacy
of LAIV versus trivalent inactivated influenza vaccine (TIV)
in children with asthma aged 617 years have been demon-
strated. However, few data are available for children younger
than 6 years of age with asthma or prior wheezing. Safety and
efficacy data were collected for children aged 25 years with
asthma or prior wheezing from two randomized, multinational
trials of LAIV and TIV (N0 1,940). Wheezing, lower respira-
tory illness, and hospitalization were not significantly in-
creased among children receiving LAIV compared with TIV.
Increased upper respiratory symptoms and irritability were
observed among LAIV recipients (p<0.05). Relative effica-
cies were consistent with the results observed in the overall
study populations, which demonstrated fewer cases of culture-
confirmed influenza illness in LAIV compared with TIV
recipients. Study results support the safety and efficacy of
LAIVamong children aged 217 years with mild to moderate
asthma or a history of wheezing. Data regarding LAIV use are
limited among in dividuals with severe asthma or active
wheezing within the 7 days before vaccination.
Introduction
Worldwide, the reported prevalence of wheezing illness
among children ranges from 7 to 23%; estimates are lower
in countries in Asia and Northern/East ern Europe and higher
in North America and Oceania [1]. Because children with a
history of wheezing or asthma have a higher risk of com-
plications related to influenza infections [2], the vaccination
of children with asthma against seasonal influenza is rec-
ommended by the World Health Organization (WHO) and
many national health authorities.
In many countries, an Ann Arbor strain live attenu-
ated influenza vaccine (LAIV) is approved for eligible
children 2 years of age, while some trivalent inactivated
influenza vaccines (TIV) are approved for use in eligible
children 6 months of age. LAIV is not approved for use in
children <24 months old because an increase in postvaccina-
tion medically attended wheezing was observed between days
7 and 28 after the first vaccination in children aged 6
23 months [3, 4]; this increase was observed among children
aged 623 months with and without a history of wheezing. In
the European Union and Canada, LAIV is approved for use in
children 2yearsofagewithmildtomoderateasthmaora
history of wheezing, with a warning/precaution against use in
individuals with severe asthma or active wheezing [5, 6].
The safety and efficacy of LAIV compared with TIV was
evaluated in 2,229 children aged 617 years with a clin ical
diagnosis of a sthma [7]. In this study, LAIV recipients
C. S. Ambrose (*)
:
F. Dubovsky
:
T. Yi
Medical and Scientific Affairs, MedImmune, LLC,
One MedImmune Way,
Gaithersburg, MD 20878, USA
e-mail: ambrosec@medimmune.com
R. B. Belshe
St. Louis University School of Medicine,
1100 S. Grand Blvd., DRC-8th Floor,
St. Louis, MO 63104, USA
S. Ashkenazi
Schneider Childrens Medical Center,
14 Kaplan St.,
Petach Tikva 49202, Israel
S. Ashkenazi
Sackler Faculty of Medicine, Tel Aviv University,
Ramat Aviv 69978, Israel
Eur J Clin Microbiol Infect Dis (2012) 31:25492557
DOI 10.1007/s10096-012-1595-9
experienced 35% fewer cases of culture-confirmed influen-
za illness, with no change in asthma symptomatology com-
pared with children who received TIV. Data regarding the
safety and efficacy of LAIV among children aged 6 months
to 5 years with asthma or a history of wheezing were
collected in the studies by Belshe et al. and Ashkenazi et
al., which enrolled healthy children and those with asthma
or a history of wheezing [4, 8]. The objective of the current
analysis is to present the safety and efficacy data from these
two studies for the subgroups of children 24 months of age
with asthma or a history of wheezing.
Materials and methods
Data collection
Safety and efficacy data were collected from two random-
ized, multination al trials of LAIV and TIV in children aged
671 months [4, 8]. In the study by Belshe et al. (study 1),
children aged 659 months (N0 8,475) were randomized 1:1
to receive LAIV or TIV during the 20042005 influenza
season [4]. Children with mild or moderate asthma or a
history of wheezing were included in the study; those with
severe asthma or with an episode of wheezing within 42 days
before study initiation were excluded. Subjects previously
unvaccinated against influenza received two doses of vac-
cine 2842 days apart; previously vaccinated subjects re-
ceived one dose on day 0 (n/N0 1,899/8,475). Twenty-one
percent of subjects (n/N0 1,793/8,475) reported a history of
any wheezin g at e nrolment; 4% of subjects ( n/N 0 3 38/
8,475) reported a diagnosis of asthma. Predefined reactoge-
nicity events (REs) wer e analyzed for 11 days postvaccina-
tion. Adverse events ( AEs), including wheezing, were
analyzed for 42 days postvaccination. Medically significant
wheezing (MSW) was prospectively defined as the presence
of wheezing during a physical examination conducted by a
healthcare provider with a prescription for a daily broncho-
dilator, respiratory distress, or hypoxemia; however, other
medically attended wheezing episodes were also recorded.
Serious AEs (SAEs), including h ospitalizations, were ana-
lyzed for 180 days after the final dose.
In the study by Ashkenazi et al. (study 2), children aged
671 months (N0 2,187) were randomized 1:1 to receive
two dose s of LAIV or TIV 35±7 da ys apart during the
20022003 influenza s eason [8]. Children enrolled were
required to have a history of recurrent respiratory tract
infections (RTIs), defined as 2 medically attended episodes
of common colds, acute otitis media, bronchitis, pneumonia,
bronchiolitis, or other RTIs in the previous 12 months; sub-
jects with an episode of a respiratory illness with wheezing
within 7 days before study initiation were excluded. Forty-
six percent of subjects (n/N0 1,007/2,187) reported a history
of wheezing at enrolment; 23% of subjects (n/N0 502/2,187)
reported a diagno sis of asthma. Predefined REs were
recorded for 11 da ys postvacc ination. The i ncidence of
medically documented wheezing was analyzed for 42 days
postvaccination; this could not be classified as medically
attended wheezin g because the protocol mandated office
visits for any observed wheezing events. Other AEs were
recorded for 28 days postvaccination. SAEs, including hos-
pitalizations, were recorded for the duration of the study,
which was approximately 180 days.
Data analysis
The population for the current analysis was s ubjects in
studies 1 or 2 who wer e 24 months of age with a diagnosis
of asthma or a history of wheezing at enrolment. Bas ed on
the differences between the studies in data collection, inclu-
sion/exclusion criteria, geography, and influenza season, the
two study populations were analyzed separately. In both
studies, investigators reported at enrolment whether a child
had a prior diagnosis of asthma or had a medical history of
wheeze; for those subjects with a reported history of
wheeze, investigators stated whether the child had wheezed
in the 12 months before enrolment. Additi onal information
was collected regarding past medication use for wheeze or
asthma and whether wheeze was documented by a healthcare
provider.
The primary endpoints of interest wer e those related to
wheezing events; these endpoints were constructed in order
to be consistent with the primary analyses of the original
studies while enabling comparison between studies. In both
studies, wheezing endpoints were analy zed for 42 d ays
postvaccination in LAIV versus TIV recipients. In study 1,
the available wheezing endpoints were any wheezing, med-
ically attended wheezing, and medically significant wheez-
ing; in study 2, the wheezing endpoi nts available were any
wheezing and m edically documented wheezing. For the
primary endpoints of interest, the analysis population was
further stratified into three groups according to medical
history at enrolment: (1) children with a history of wheez-
ing/asthma with a wheezing episode within 12 months be-
fore study initiation, (2) children with a history of wheezing/
asthma but without a wheezing episode in the 12 months
before study initiation, and (3) children with a diagnosis of
asthma regardless of the timing of their most recent wheezing
episode.
Secondary outcomes, which were evaluated in all sub-
jects with a history of wheeze or asthma, included rates of
REs for 10 days postvaccination, AEs for 28 days postvac-
cination, all-cause hospitalization for 180 days, and the
relative efficacy of LAIV compared with TIV against
culture-confirmed influenza illness during the influenza sur-
veillance periods. AEs were summarized by system organ
2550 Eur J Clin Microbiol Infect Dis (2012) 31:25492557
class and preferred term using Medical Dictionary for Reg-
ulatory Activi ties (MedDRA) version 8.0. Additionally, AEs
due to lower respiratory tract illness (LRI) and wheezing
were summarized. All reported AEs considered to be related
to wheezing, asthma, b ron chial ob stru ction, or b ron cho-
spasm (including bronchiolitis) were grouped into wheezing
events of sp ecial interest for analysis. Lower respiratory
AEs included all wheezing events plus any term that referred
to disease of the lower respiratory system or to respiratory
difficulty.
The safety population, defined as subjects who received 1
dose and were followed for safety, was used in analyzing the
safety endpoints (wheezing endpoints, REs, AEs, all-cause
hospitalizations). Rate differences were calculated as LAIV
incidence minus TIV incidence. Two-sided 95% asymptotic
confidence intervals (CIs) were computed based on inverting
two one-sided tests and the score test statistic. To be consistent
with the original studies, relative efficacy calculations used the
per-protocol population, generally defined as subjects who did
not experience a major protocol violation during the study.
The relative efficacy of LAIV compared with TIVand its 95%
CI were computed based on the methods used in the original
studies.
Results
Subject demographics
The analysis population included 1,940 children aged 24
71 months with asthma or a history of wheeze, of whom
1,145 were enrolled in study 1 and 795 were enrolled in
study 2. Within each study, the LAIV and TIV treatment
groups were well matched for age, gender, race, and wheez-
ing/asthma history (Table 1). Consistent with the study
inclusion criteria and site locations, subjects in study 2 were
older, more likely to be white, to have wheezed in the last
12 months, and to have been diagnosed with asthma com-
pared with subjects in study 1. For children with a history of
wheezing, investigators reported that wheezing had been
documented by a healthcare professional in 95% and 98%
of patients in studies 1 and 2, respectively. In study 1, LAIV
recipients reported less prior inhaled corticosteroid use
(Table 2); in study 2, LAIVrecipients reported less prior use of
systemic corticosteroids. Otherwise, prior medication use was
similar between LAIV and TIV recipients in both studies.
Rates of wheezing
In both treatment groups and in both studies, the rates of
wheezing were higher in children with a diagnosis of asthma
or wheezing in the last 12 months versus those without
wheezing in the last 12 months. Additionally, a higher
percentage of subjects in study 2 experienced a wheezing
episode after vaccination compared with study 1. In both
studies, there were no significant differences in the rates of
any wheezing, or medically significant, medically attended,
or medically documented wheezing among children receiv-
ing LAIV versus TIV overall or when stratified according to
medical history (Fig. 1)
Reactogenicity events
The incidence of REs was similar among LAIV and TIV
recipients in each study and tended to be less frequent after a
second vaccination. The most common REs reported in both
studies were runny or stuffy nose and cough (Fig. 2). In both
studies, the incidence of runny or stuffy nose was generally
higher among LAIV recipients tha n TIV recipients. The
differences were significant after dose 2 in study 1 and after
dose 1 in study 2. For other REs, there were no significant
differences between LAIV and TIV recipients.
Adverse events
For both studies, the proportions of subjects reporting 1
AE were similar among LAIV and TIV recipients. Similarly,
in both studies, there were no differences in the rates of LRI
or wheezing for LAIV versus TIV recipients after either
dose (Table 3). In study 1, there were no signifi cant differ-
ences between LAIV and TIV recipients when events were
categorized by organ class or individual terms. In study 2,
the rate of events categorized as infections was higher
among LAIV recipients after dose 1 (LAIV, 35.2%; TIV,
27.8%; p<0.03). The biggest driver of this difference at the
individual term level and the only term with a rate difference
1.0% was upper respiratory tract infection (LAIV, 16.5%;
TIV, 13.9%; p0 0.32). Additionally, in study 2 after dose 1,
rhinorrhea (LAIV, 8.1%; TIV, 3.1%; p0 0.002) and irritability
(LAIV, 2.0%; TIV, 0.3%; p0 0.04) were more common among
LAIV recipients; presurgical antibiotic prophylaxis was more
common among TIV recipients after dose 2 (LAIV, 0%; TIV,
1.6%; p0 0.01).
Hospitalizations
There were few hospitalizations in the populations studied.
In study 1, there were 25 hospitalizations in 25 subjects for
180 days after vaccination; in study 2, there were 36 hospi-
talizatio ns in 32 subjects. In both studies, there were no
significant differences in the incidence of hospitalization
among children who received LAIV and TIV. In study 1,
hospitalization rates were 2.4% among LAIV recipients and
1.9% among TIV recipients, for a rate difference of 0.5%
(95% CI
1.2 to 2.4). In study 2, hospitalization rates were
4.7% among LAIV recipients and 3.3% among TIV
Eur J Clin Microbiol Infect Dis (2012) 31:25492557 2551
recipients, for a rate difference of 1.3% (95% CI 1.5 to
4.2). Hospitalization rates within 90 days after vaccination
were also similar for each treatment group in each study
(study 1: LAIV, 1.2%; TIV, 1.4%; study 2: LAIV, 3.4%;
TIV, 3.3%). A review of all hospitalization diagnoses dem-
onstrated that, in study 1, there were ten hospitalizations due
to LRI (e.g., pneumonia, croup, wheezing, bronchospasm;
LAIV, n0 6; TIV, n 0 4), five of which occurred within
90 days after vaccination (LAIV, n 0 2; TIV, n0 3). In study
2, there were 18 hospitalizations due to LRI (LAIV, n0 11;
TIV, n0 7), 15 of which occurred within 90 days after
vaccination (LAIV, n0 8; TIV, n0 7).
Relative efficacy
In studies 1 and 2, the relative efficacy of LAIV versus TIV
among children with a history of wheezing or asthma was
consistent with that observed in the overall study cohorts. In
Table 1 Demographics of children with asthma or a history of wheezing
Study 1 (Belshe et al. [4]) Study 2 (Ashkenazi et al. [8])
LAIV (N0 572) TIV (N0 573) LAIV(N0 406) TIV (N0 389)
Age, months, mean (SD) 37 (10) 37 (10) 45 (14) 46 (14)
Gender, n (%)
Male 329 (58) 334 (58) 228 (56) 232 (60)
Female 243 (42) 239 (42) 178 (44) 157 (40)
Race
a
, n (%)
Asian 17 (3) 21 (4) 3 (1) 4 (1)
Black 16 (3) 16 (3) 4 (1) 2 (1)
White 528 (92) 521 (91) 397 (98) 378 (97)
Other 11 (2) 15 (3) 2 (1) 5 (1)
With history of wheeze in last 12 months, n (%) 259 (45) 275 (48) 287 (71) 279 (72)
Without history of wheeze in last 12 months, n (%) 313 (55) 298 (52) 119 (29) 110 (28)
Diagnosis of asthma, n (%) 124 (22) 131 (23) 209 (51) 215 (55)
LAIV: Ann Arbor strain live attenuated influenza vaccine, TIV: trivalent inactivated influenza vaccine
a
Race was determined by parent/guardian report
Table 2 Reported prior medication use for wheeze or asthma by history of wheeze or asthma
Any history of wheeze/asthma Diagnosed with asthma
Study 1 (Belshe et al. [4]) Study 2
(Ashkenazi et al. [8])
Study 1 (Belshe et al. [4]) Study 2
(Ashkenazi et al. [8])
LAIV
(N0 572)
TIV
(N0 573)
LAIV
(N0 406)
TIV
(N0 389)
LAIV
(N0 124)
TIV
(N0 131)
LAIV
(N0 209)
TIV
(N0 215)
Medication ever taken for
wheeze or asthma, n (%)
503 (88) 498 (87) 386 (95) 369 (95) 120 (97) 129 (98) 209 (100) 213 (99)
Short-acting beta-agonist
(inhaled or oral), n (%)
462 (81) 463 (81) 349 (86) 331 (85) 115 (93) 120 (92) 200 (96) 198 (92)
Long-acting beta-agonist
(inhaled or oral), n (%)
17 (3) 21 (4) 45 (11) 46 (12) 5 (4) 8 (6) 30 (14) 37 (17)
Cromoglycate and related
products, n (%)
1 (<1) 10 (2)* 26 (6) 19 (5) 0 (0) 3 (2) 12 (6) 10 (5)
Leukotriene receptor
antagonist, n (%)
42 (7) 44 (8) 25 (6) 27 (7) 29 (23) 31 (24) 18 (9) 22 (10)
Theophylline, n (%) 5 (1) 2 (<1) 12 (3) 10 (3) 2 (2) 1 (1) 8 (4) 6 (3)
Inhaled corticosteroids, n (%) 167 (29) 199 (35)** 236 (58) 216 (56) 61 (49) 79 (60) 160 (77) 154 (72)
Systemic corticosteroids, n (%) 130 (23) 116 (20) 84 (21) 117 (30)* 39 (32) 42 (32) 51 (24) 80 (37)*
Other asthma medication, n (%) 39 (7) 33 (6) 60 (15) 63 (16) 11 (9) 12 (9) 22 (11) 29 (14)
LAIV: Ann Arbor strain live attenuated influenza vaccine, TIV: trivalent inactivated influenza vaccine
*p0.01 for LAIV vs. TIV; **p0 0.05 for LAIV vs. TIV
2552 Eur J Clin Microbiol Infect Dis (2012) 31:25492557
all instances, children receiving LAIV had fewer cases of
culture-confirmed influenza illness than TIV recipients
(Fig. 3). In study 1, for all community-acquired strains, the
relative efficacy of LAIV versus TIV reached statistical
significance (relative efficacy, 46.6%; 95% CI 18.6 to
65.4), despite the small number of subjects in the analysis
population. In study 2, the difference was not statistically
significant.
Discussion
The Ann Arbor strain LAIV has been evaluated in multiple
randomized controlled studies in children with a medical
history of wheezing and asthma. The first study evaluated
the effect on pulmonary function, as measured by spirome-
try, in children aged 9 years and older with moderate to
severe asthma. In this small study (N0 48), no changes in
pulmonary function were detected after vaccination with
LAIV versus placebo [9].
Subsequently, t hree large, randomized, TIV-controlled
studies were conducted in children with a history of asthma
or wheezing to further characterize the clinical outcomes
after receipt of LAIV. Collectively, these studies included
4,169 children aged 217 years who were diagno sed with
asthma or had a medically confirmed history of wheezing.
All of the studies were prospectively designed to evaluate
the effect of LAIV on asthma exacerbations and/or wheez-
ing. The first study by Fleming et al. compared LAIV and
TIV in 2,229 children aged 617 years with a clinical
0
5
10
15
20
25
30
Wheeze Medically Attended Wheeze
Any History of Wheeze/Asthma History of Wheeze/Asthma
With No Wheeze in Last 12 mo
History of Wheeze/Asthma
With Wheeze in Last 12 mo
Diagnosed With Asthma
Medically Significant Wheeze
LAIV TIV LAIV TIV LAIV TIV LAIV TIV
(N=572) (N=573) (N=259) (N=275)(N=313) (N=298) (N=124) (N=131)
9.3
7.2
4.2
10.3
8.6
6.1 6.1
3.8
1.9
5.0
4.4
2.3
13.1
11.2
6.9
16.0
13.1
10.2
15.3
12.1
5.6
14.5
9.9
7.6
Incidence rate, %
0
5
10
15
20
25
30
Wheeze Medically Documented Wheeze
Any History of Wheeze/Asthma History of Wheeze/Asthma
With Wheeze in Last 12 mo
History of Wheeze/Asthma
With No Wheeze in Last 12 mo
Diagnosed With Asthma
LAIV TIV LAIV TIV LAIV TIV LAIV TIV
(N=406) (N=389) (N=287) (N=279)(N=119) (N=110) (N=209) (N=215)
18.5
13.5
19.8
14.4
7.6
4.2
5.5
4.5
23.0
17.4
25.4
18.3
23.9
18.2
27.9
22.3
Incidence rate, %
Study 1
Study 2
Fig. 1 Rates of wheezing for 42 days following vaccination by history
of wheeze or asthma. LAIV: live attenuated influenza vaccine, TIV:
trivalent inactivated influenza vaccine. There were no statistically
significant differences between the incidence of wheezing in LAIV
versus TIV recipients
Eur J Clin Microbiol Infect Dis (2012) 31:25492557 2553
diagnosis of asthma [7]. The study demonstrated that chil-
dren who received LAIV experienced 35% fewer cases of
culture-confirmed influenza illness, with asthma exacerbation
rates, mean peak expiratory flow rate findings, asthma symp-
tom scores, or nighttime awakening scores that were similar to
TIV recipients.
a
b
Runny/stuffy nose
Cough
Decreased appetite
Irritability
Abdominal pain
Decreased activity/tiredness
Headache
Vomiting
Sore throat
Muscle ache
Chills
38.0° C
39.0° C
40.0° C
0
10
20
30
40
50
60
70
Fever
*
LAIV dose 1
TIV dose 1
LAIV dose 2
TIV dose 2
Incidence, %
Runny/stuffy nose
Cough
Decreased apetite
Irritability
Abdominal pain
Decreased activity/tiredness
Headache
Vomiting
Sore throat
Muscle ache
Chills
C
°
38.0
C
°
39.0
C
°
40.0
0
10
20
30
40
50
60
70
Fever
**
LAIV dose 1
TIV dose 1
LAIV dose 2
TIV dose 2
Incidence, %
Fig. 2 Reactogenicity of LAIV
and TIV for 10 days following
vaccination by dose. a
Percentage of subjects
experiencing each event in
study 1. b Percentage of
subjects experiencing each
event in study 2. LAIV: live
attenuated influenza vaccine,
TIV: trivalent inactivated
influenza vaccine. *p<0.05,
**p<0.01
2554 Eur J Clin Microbiol Infect Dis (2012) 31:25492557
The current analysis provides the data from two studies
regarding the safety and efficacy of LAIV in children aged
25 years with a history of asthma or wheezing. Similar to
the results observed by Fleming et al., there were no statis-
tically significant increases in wheezing, LRI, or hospitali-
zation among children receiving LAIV versus TIV. The type
and incidence of REs and AEs observed in this study were
consistent with those observed after vaccination with LAIV
and TIV in other studies of young children. As expected, a
higher rate of runny nose/nasal congestion was observed
among LAIV recipients; this difference also likely explains
the few unsolicited AEs that were increased among LAIV
recipients (rhinorrhea and upper respiratory tract infection).
These findings are supported by the results of a large, non-
randomized study of LAIV c onducted over 4 years that
included 2,196 healthy children aged 18 months to 18 years
with a history of intermittent wheezing or asthma and found
no increased risk for medically attended acute respiratory
illness or asthma after vaccination with LAIV [10].
In the original analysis of Belshe et al.s study [4], a post
hoc trend toward an increased rate of all-cause hospitaliza-
tion was observed among children aged 647 months, but
not among those aged 4859 months with a history of any
prior wheezing. Follow ing additional review of the data,
Table 3 Rates of adverse events (any, wheezing illness, and lower respiratory illness) for 28 days following vaccination
Following dose 1 Following dose 2
LAIV, n (%) TIV, n (%) Rate difference,
%
a
(95% CI)
LAIV, n (%) TIV, n (%) Rate difference,
%
a
(95% CI)
Study 1
Subjects, N 572 573 335 338
Total number of events, n 294 304 122 145
Subjects reporting 1 events 197 (34.4) 194 (33.9) 0.6 (4.9 to 6.1) 85 (25.4) 101 (29.9) 4.5 (11.3 to 2.3)
Lower respiratory illness 54 (9.4) 61 (10.6) 1.2 (4.7 to 2.3) 24 (7.2) 34 (10.1) 2.9 (7.3 to 1.4)
Wheezing illness 31 (5.4) 37 (6.5) 1.0 (3.9 to 1.7) 9 (2.7) 16 (4.7) 2.0 (5.2 to 0.9)
Study 2
Subjects, N 406 389 391 378
Total number of events, n 425 361 339 329
Subjects reporting 1 events 222 (54.7) 195 (50.1) 4.6 (2.4 to 11.5) 195 (49.9) 185 (48.9) 0.9 (6.1 to 8.0)
Lower respiratory illness 31 (7.6) 37 (9.5) 1.9 (5.9 to 2.0) 41 (10.5) 43 (11.4) 0.9 (5.4 to 3.6)
Wheezing illness 21 (5.2) 25 (6.4) 1.3 (4.7 to 2.0) 17 (4.3) 19 (5.0) 0.7 (3.8 to 2.4)
LAIV: Ann Arbor strain live attenuated influenza vaccine, TIV: trivalent inactivated influenza vaccine
a
Rate difference 0 LAIV rate TIV rate; none of the rate differences are statistically significant
0
5
10
15
20
TIV
LAIV
Any Strain
Matched Strains
Study 1 Study 2
Any StrainMatched Strains
RE = 46.6%
(95% CI: 18.6, 65.4)
RE = 20.1%
(95% CI: –71.3, 63.1)
RE = 39.9%
(95% CI: –25.9, 72.3)
RE = 46.0%
(95% CI: –23.3, 77.7)
6.5
2.4
3.4
2.6
13.0
3.1
5.6
4.8
Subjects With Influenza Illness, %
Fig. 3 Relative efficacy of
LAIV and TIV in children aged
25 years with a history of
wheeze or asthma. Any strain
refers to any community-
acquired strain. LAIV: live
attenuated influenza vaccine,
TIV: trivalent inactivated
influenza vaccine, RE: relative
efficacy, CI: confidence interval
Eur J Clin Microbiol Infect Dis (2012) 31:25492557 2555
officials at the U.S. Food and Drug Administration conclud-
ed that, for children 24 months of age who received LAIV,
there was little influence of history of wheezing on hospi-
talization and the rates of hospi talization were either similar
to or actually higher in the TIV arm and stated that the
relationship of history of wheezing to a potential risk of all-
cause hospit alization was likely a statistical blip [11].
Additionally, no such trend was observed in Ashkenazi et
al.s study [8]. The current analysis, which incorporates data
from two distinct studies, provides a more comprehensive
view of the safet y of LAIV in young children with asthma or
a history of wheezing.
Because LAIV vaccination entails nasopharyngeal repli-
cation of attenuated influenza viruses, some may raise con-
cern regardi ng the long-term effects on airway function.
However, it is rhinovirus-induced wheezing in the first 2
3 years of life, and not illness due to influenza, that has been
correlated with allergic sensitization and subsequent asthma
pathogenesis [12, 13]. Furthermore, a recent study demon-
strated that allergic sensitization to aeroallergens precedes
rhinovirus-induced wheezing, and viral wheeze did not lead
to subsequent allergic sensitization [14]. The current analy-
sis, the study by Fle ming et al., and multiple additional
studies conducted in young children without asthma dem-
onstrate that LAIV vaccination in children 2 years of age
and older is not associated with subsequent wheezing or
lower respiratory illness [ 7 , 15]. In fact, in children aged
617 years with asthma, there was an 18% reduction (p0 0.02)
in wheezing in the 15 days after vaccination in LAIV versus
TIV recipients [7].
It should be noted that the safety of Ann Arbor strain
LAIV has not been extensively studied among severe asth-
matics (e.g., individuals currently requiring therapy with
oral glucocorticosteroids or high-dose inhaled glucocorti-
costeroids) or individuals with recent active wheezing with-
in the 7 days before vaccination. Additionally, the high rates
of postvaccination wheezing in both treatment groups also
highlight the difficulty of using non-controlled, passively
collected surveillance data to evaluate vaccine safety in
children with asthma or a history of wheezing [16].
Both studies analyzed demonstrated fewer cases of
culture-confirmed influenza illness among LAIV versus
TIV recipients in the original overall study populations [4,
8]. The current analysis demonstrates consistent results
among the cohorts of children with a history of asthma/
wheezing, with one analysis reaching statistical significance
despite the small study population. These data support the
conclusion that Ann Arbor strain LAIV continues to provide
a high level of protection against influenza illness in young
children with asthma or a history of wheezing. The efficacy
of the vaccine in this subset of children is important because
annual vaccination against seasonal influenza is generally
recommended in this population.
Strengths of the current analysis include the randomization
of study subjects to LAIV versus TIV that provided two
treatment groups with similar baseline characteristics, the pro-
spective collection of history of asthma and wheezing at enrol-
ment, and the prospective definitions of the w heezing
endpoints. The analysis also benefits from the ability to analyze
children of similar age from two separate studies conducted in
different influenza seasons. The primary limitation of the cur-
rent analysis is the post hoc definition of the study cohorts, but
this was addressed in part by the analysis of the three subpo-
pulations that varied based on the severity and recency of
wheezing illness. Additionally, the identification of subjects
with a diagnosis of asthma or history of wheezing relied on
investigator judgment; there was no validation of investigator
assessments. However, the proportions of subjects with prior
receipt of inhaled and systemic corticosteroids help to validate
that the identified children had significant wheezing disease.
In conclusion, in the European Union and Canada, LAIV
is currently approved for use among children aged 2
17 years, including those with mild to moderate asthma or
a history of wheezing. The results of the current analysis and
previous studies suppo rt the saf ety an d efficacy of Ann
Arbor strain LAIV in these populations.
Acknowledgments This analysis was supported by MedImmune,
LLC. Editorial assistance was provided by Complete Healthcare Com-
munications , In c., Chadds Ford, PA, USA, and funded by MedI-
mmune. Drs. Ambrose, Dubovsky, and Yi are employees o f
MedImmune. Dr. Belshe has s erved on advisory b oards and as a
consultant for MedImmune. Drs. Belshe and Ashkenazi have received
research support and speaker compensation from MedImmune.
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution License which permits any use, distribution,
and reproduction in any medium, provided the original author(s) and
the source are credited.
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    • "LAIV is temperature sensitive, so it only replicates in the cooler upper respiratory tract (33°C), but cannot damage the warmer lower respiratory tract (37°C). Because of safety concerns, it is only recommended for healthy, non-pregnant individuals 2–49 years of age [10, 11]. In the 2014–2015 influenza season, the overall vaccine effectiveness was as low as 19% [12], due to antigenic drifts in circulating H3N2 viruses. "
    [Show abstract] [Hide abstract] ABSTRACT: Influenza A virus is a significant public health threat, but little is understood about the viral RNA structure and function. Current vaccines and therapeutic options to control influenza A virus infections are mostly protein-centric and of limited effectiveness. Here, we report using an ensemble defect approach to design mutations to misfold regions of conserved mRNA structures in influenza A virus segments 7 and 8. Influenza A mutant viruses inhibit pre-mRNA splicing and attenuate viral replication in cell culture, thus providing evidence for functions of the targeted regions. Targeting these influenza A viral RNA regions provides new possibilities for designing vaccines and therapeutics against this important human respiratory pathogen. The results also demonstrate that the ensemble defect approach is an efficient way to test for function of RNA sequences.
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    • "The vaccine provided no protection against hospitalization in children , especially those with asthma [24]. Although health authorities usually recommend influenza vaccination in asthmatic patients, vaccination coverages remain significantly lower than expected, especially in children [25]. "
    [Show abstract] [Hide abstract] ABSTRACT: Annual administration of the seasonal influenza vaccine, especially to persons known to be at elevated risk for developing serious complications, is the focus of current efforts to reduce the impact of influenza. The main factors influencing estimated inactivated influenza vaccine efficacy and effectiveness, the results obtained in different population groups, current vaccination strategies and the possible advantages of new vaccines are discussed. The available evidence suggests that influenza vaccines are less effective in the elderly than in young adults, but vaccination is encouraged by public health institutions due to higher mortality and complications. There is no consensus on universal vaccination of children yet economic studies suggest that yearly paediatric vaccination is cost saving. The benefits of herd immunity generated by paediatric vaccination require further study. Newer vaccines should be more and more-broadly protective, stable, easy to manufacture and administer and highly immunogenic across all population groups.
    Article · Jan 2016
    • "On the other hand, LAIV, which replicates slowly due to its temperature-sensitive (ts), cold-adapted (ca) and attenuated (att) phenotype, generates more robust humoral and cellular immunity (Maassab and Bryant, 1999). Due to safety concerns in the young and asthmatics, and limited efficacy in the elderly, LAIV is only recommended for immunocompetent , non-asthmatic patients between the ages of 2–49 (Ambrose et al., 2012; Belshe et al., 2008; Powers et al., 1991). One study has found that combining inactivated and LAIVs is well-tolerated and efficacious in elderly individuals (Tang, 2012; Treanor and Betts, 1998). "
    [Show abstract] [Hide abstract] ABSTRACT: The diverse host range, high transmissibility, and rapid evolution of influenza A viruses justify the importance of containing pathogenic viruses studied in the laboratory. Other than physically or mechanically changing influenza A virus containment procedures, modifying the virus to only replicate for a single round of infection similarly ensures safety and consequently decreases the level of biosafety containment required to study highly pathogenic members in the virus family. This biological containment is more ideal because it is less apt to computer, machine, or human error. With many necessary proteins that can be deleted, generation of single-cycle infectious influenza A viruses (sciIAV) can be achieved using a variety of approaches. Here, we review the recent burst in sciIAV generation and summarize the applications and findings on this important human pathogen using biocontained viral mimics. Copyright © 2015. Published by Elsevier B.V.
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