Drugs 2011; 71 (12): 1591-1622
0012-6667/11/0012-1591/$55.55/0

ADIS DRUG EVALUATIONª 2011 Adis Data Information BV. All rights reserved.

Live Attenuated Influenza Vaccine(FluMist; Fluenz)A Review of its Use in the Prevention of Seasonal Influenza
in Children and Adults
Natalie J. Carter and Monique P. CurranAdis, a Wolters Kluwer Business, Auckland, New Zealand
Various sections of the manuscript reviewed by:
S. Ashkenazi, Schneider Children’s Medical Center, Petah-Tikva, Israel; D.M. Fleming, Research andSurveillance Centre, The Royal College of General Practitioners, Birmingham, United Kingdom;
R. Samakoses, Infectious Disease Unit, Phramongkutklao Hospital, Bangkok, Thailand; T. Vesikari,
Department of Virology/Vaccine Research, University of Tampere Medical School, Tampere, Finland.
Data Selection
Sources: Medical literature (including published and unpublished data) on ‘intranasal live attenuated influenza vaccine’ was identified bysearching databases since 1996 (including MEDLINE, EMBASE and inhouse AdisBase), bibliographies from published literature, clinical
trial registries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information(including contributory unpublished data) was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘live attenuated intranasal vaccine’ or ‘intranasal live attenuatedinfluenza vaccine’ or (‘live’ and ‘attenuated’ and ‘intranasal’ and ‘vaccine’ and ‘cold-adapted’). Searches were last updated 16 August
2011.
Selection: Studies in children or adults who received intranasal live attenuated influenza vaccine. Inclusion of studies was based mainly on
the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred.
Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: intranasal live attenuated influenza vaccine, protective efficacy, reactogenicity, tolerability, immunogenicity.

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1592
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1593
2. Protective Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1595
2.1 In Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1595
2.1.1 Placebo-Controlled Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1595
2.1.2 Comparator Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1597
2.1.3 Pooled Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1599
2.1.4 Coadministration with Other Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1599
2.2 In Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1600
2.2.1 Placebo-Controlled Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1600
2.2.2 Placebo- and Active Comparator-Controlled Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1600
2.3 Indirect (Herd) Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1601
3. Reactogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1601
3.1 In Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1602
3.1.1 Placebo-Controlled Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1602
3.1.2 Active-Comparator Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1603
3.1.3 Asthma or Wheezing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1604

Carter & Curran

1592

3.2 In Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1604
3.2.1 Placebo-Controlled Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1604
3.2.2 Active-Comparator Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1605
4. Immunogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1605
4.1 Comparative Immunogenicity of Frozen and Refrigerator-Stable Intranasal
Live Attenuated Influenza Vaccine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1605
4.2 In Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1606
4.3 In Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1608
4.4 In Patients with HIV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1610
4.4.1 Children with HIV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1610
4.4.2 Adults with HIV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611
4.5 Studies on Viral Shedding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611
4.6 Transmission Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1612
4.7 Cell-Mediated Immunity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1612
4.8 Cross Immunogenicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1614
4.9 Coadministration with Other Vaccines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1614
5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1614
6. Place of Intranasal Live Attenuated Influenza Vaccine in the Prevention of Seasonal Influenza . . . 1615

Abstract

Live attenuated influenza vaccine (LAIV) is an intranasally administered trivalent, seasonal influenza vaccine that contains three live influenza viruses (twotype A [H1N1 and H3N2 subtypes] and one type B).
LAIV was effective in protecting against culture-confirmed influenza caused byantigenically matched and/or distinct viral strains in children aged £71 months
enrolled in three phase III trials. LAIV was superior to trivalent inactivatedinfluenza vaccine (TIV) in protecting against influenza caused by antigenicallymatching viral strains in a multinational phase III trial in children aged 6–59 months.
LAIV was also significantly more effective than TIV in decreasing the incidence of
culture-confirmed influenza illness in two open-label studies (in children withrecurrent respiratory tract illnesses aged 6–71 months and in children and adolescents with asthma aged 6–17 years).
LAIV did not differ significantly from placebo in preventing febrile illnesses inadults (primary endpoint) enrolled in a phase III trial. However, LAIV significantly reduced the incidence of febrile upper respiratory tract illnesses (URTI),
severe febrile illnesses, febrile URTI-related work absenteeism and healthcare
provider use. In another well designed trial in adults, LAIV significantly reduced
the incidence of symptomatic, laboratory-confirmed influenza compared withplacebo (but not intramuscular TIV).
LAIV was generally well tolerated in most age groups, with the majority ofadverse events being mild to moderate in severity, and runny nose/nasal congestion being the most common. In a large phase III trial, LAIV, compared with TIV,
was associated with an increased incidence of medically significant wheezing in vaccinenaive children aged <24 months and an increased incidence of hospitalization inchildren aged 6–11 months; LAIV is not approved for use in children <24 months.
LAIV was not always associated with high rates of seroconversion/
seroresponse, particularly in older children and adults, or in subjects with detectable levels of haemagglutination-inhibiting antibodies at baseline. However,
LAIV did elicit mucosal (nasal) IgA antibody responses and strong cell-mediatedimmunity responses. Only one confirmed case of LAIV virus transmission to aplacebo recipient (who did not become ill) occurred in a transmission study
conducted in young children. The immunogenic response to LAIV in young
healthy children was not affected by concomitant administration with othercommonly administered childhood vaccines.

ª 2011 Adis Data Information BV. All rights reserved.

Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

1593

In conclusion, intranasal LAIV seasonal influenza vaccine is effective and welltolerated in children, adolescents and adults. LAIV was more effective than TIV
in children, although this advantage was not seen in adults. In the US, LAIV isindicated for the active immunization of healthy subjects aged 2–49 years against
influenza disease caused by virus subtypes A and type B contained in the vaccine.

1. Introduction
Seasonal influenza epidemics cause serious
illness throughout the world each year.[1] In theUS, an estimated 25–50 million cases of influenza
occur annually and approximately 225 000 ofthese cases result in hospitalization.[1] Furthermore, during the last three decades, an estimated3349–48 614 influenza-related deaths occurredannually in the US.[1]Annual vaccination is the most effective strategy
for the prevention and control of influenza, and
the Advisory Committee on Immunization Practices (ACIP; a branch of the US Centers for Disease Control and Prevention [CDC]) recommends
that all individuals aged ‡6 months, who arewithout contraindications, should receive an annual influenza vaccine containing the influenza
viral strains that are considered to be the most
likely to circulate in the next influenza season.[2]Trivalent inactivated influenza vaccines (TIVs)
have been in use for many decades and may be as
much as 60–100% effective in preventing influenzarelated morbidity and mortality in healthy adolescents and adults.[3] However, TIVs are least
effective in young children and the elderly, two of
the populations who are most at risk of developing influenza-related complications (section 6).[4]A variety of other factors may limit the widespreaduse of TIVs, including their mode of delivery via
intramuscular injection, which is invasive andrequires administration by trained staff who must
adhere to blood and sharps precautions.[4] Other
limitations of TIVs include extended production
times (which has led to vaccine shortages in thepast) and decreased efficacy against influenza viralstrains that are antigenically distinct from thosecontained in the vaccine.[4]Many of the limitations of TIVs have potentiallybeen overcome with the more recently availableª 2011 Adis Data Information BV. All rights reserved.

live attenuated influenza vaccine (FluMist;
Fluenz) [LAIV].[4] LAIV uses novel technology
allowing administration of the vaccine via anoninvasive, intranasal route.[3] The vaccine istrivalent, containing three live, cold-adapted (ca),temperature-sensitive (ts), attenuated (att) influenza viruses: two type A strains (subtypes H1N1
and H3N2) and one type B strain (table I).[5,6]Each of the LAIV viruses is a 6 : 2 genetic reassortment virus generated through the processof reverse genetics technology and containing six
gene segments from master donor viruses (MDVs)
and two gene segments from a wild-type influenza virus that is predicted to be one of the main
circulating viruses in the upcoming influenza
season.[5,6] The gene segments from the MDVs
act as a genetic backbone and give the virus its ca,
ts and att phenotype, whereas the other two genesegments encode the haemagglutinin and neuraminidase glycoproteins of the wild-type virus,
which are responsible for eliciting a protective
immune response to influenza.[5,6]A trivalent formulated vaccine bulk is preparedby blending three different monovalent bulks ofeach of the three virus strains. Each monovalentbulk has been prepared from purified harvests
derived by the inoculation and growth of a mastervirus seed into embryonated, specific, pathogenfree eggs.[6]To induce immune responses, LAIV viruses
infect and replicate in mucosal cells of the nasopharynx;[2,6] thus, it is said that LAIV must ‘infectto protect’.[10] Of note, LAIV viruses are unable
to replicate in the lower respiratory tract andlungs because of the warmer temperature of thesetissues.[6] In addition, the LAIV viral proteins arepresented to the immune system in their native
form and, thus, the immune responses induced by
LAIV may be similar to those induced by natural
influenza infection.[6,11]
Drugs 2011; 71 (12)Carter & Curran

1594

Table I. Influenza viral strains contained in the live attenuated influenza vaccines administered in immunogenicity or clinical studies reviewed
in this article. Unless otherwise specified, influenza viral strains stated here were also those recommended by the WHO[7] for the season andhemisphere in which they were administered
Season

H1N1

H3N2

B

Northern Hemisphere1995/1996

A/Texas/36/91

A/Shangdong/9/93

B/Panama/45/90

1996/1997

A/Texas/36/91

A/Wuhan/359/95

B/Harbin/7/94

1997/1998

A/Shenzhen/227/95

A/Wuhan/359/95

B/Harbin/7/94

1998/1999

A/Beijing/262/95

A/Sydney/5/97

B/Harbin/7/94

1999/2000

A/Beijing/262/95

A/Sydney/5/97

B/Harbin/7/94 or B/Yamanashi/166/98

2000/2001

A/New Caledonia/20/99

A/Sydney/5/97a

B/Yamanashi/166/98

2001/2002

A/New Caledonia/20/99

A/Panama/2007/99

B/Victoria/504/2000b

2002/2003

A/New Caledonia/20/99

A/Panama/2007/99

B/Hong Kong/330/2001

2003/2004

A/New Caledonia/20/99

A/Panama/2007/99

B/Hong Kong/330/2001
B/Jilin/20/2003

2004/2005

A/New Caledonia/20/99

A/Wyoming/3/2003

2005/2006

A/New Caledonia/20/99c

A/California/7/2004c

2006/2007c

A/New Caledonia/20/99

B/Shanghai/361/2002c

A/Wisconsin/67/2005c

B/Malaysia/2506/2004c

2007/2008

A/Solomon Islands/3/2006

A/Wisconsin/67/2005

B/Malaysia/2506/2004

2008/2009

A/Brisbane/59/200c

A/Brisbane/10/2007c

B/Florida/4/2006c

2009/2010

A/Brisbane/59/200c

A/Brisbane/10/2007c

B/Brisbane/60/2008c

2010/2011

A/California/7/2009c

A/Perth/16/2009c

B/Brisbane/60/2008c

2011/2012cc

B/Brisbane/60/2008c

Southern Hemisphere
1999

A/California/7/2009

A/Perth/16/2009d

A/Beijing/262/95c

A/Sydney/5/97c

B/Beijing/184/93c

2000

A/New Caledonia/20/99

c

A/Moscow/10/99

2001

A/New Caledonia/20/99c

A/Moscow/10/99c

2002

A/New Caledonia/20/99

A/Panama/2007/99

B/Victoria/504/2000

2003

A/New Caledonia/20/99c

A/Moscow/10/99c

B/Hong Kong/330/2001c

2004

A/New Caledonia/20/99c

A/Fujian/411/2002c

2005

A/New Caledonia/20/99c

A/Wellington/1/2004

A/New Caledonia/20/99

c

c

2007

A/New Caledonia/20/99

c

2008

A/Solomon Islands/3/2006c

A/Brisbane/10/2007c

B/Florida/4/2006c

2009

A/Brisbane/59/2007c

A/Brisbane/10/2007c

B/Florida/4/2006c

2010

A/California/7/2009c

A/California/7/2009

c

2006

2011

c

A/California/7/2004

B/Beijing/184/93 or B/Shangdong/7/97c
B/Sichuan/379/99c

B/Hong Kong/330/2001cc

A/Wisconsin/67/2005

B/Shanghai/361/2002c
B/Malaysia/2506/2004cc

B/Malaysia/2506/2004c

A/Perth/16/2009c

B/Brisbane/60/2008c

A/Perth/16/2009c

B/Brisbane/60/2008caThis strain was used instead of the WHO recommended strain (A/Moscow/10/99) because of industry-wide technical problems.[8,9]bThis strain was replaced with B/Yamanashi/166/98 in one study because of manufacture delays.[8]cNo LAIV studies were conducted in this season and hemisphere. Therefore, strains given here are those recommended by the WHO for
inclusion in seasonal influenza vaccines for this season and hemisphere.[7]dNo LAIV studies were conducted in the Southern Hemisphere prior to 2001, and WHO recommended influenza viral strains pre-dating 1999
were not available.

LAIV is approved in various countries, including the US,[12] the EU[13] and Canada.[14] In
the US, LAIV is approved for use in subjects aged
2–49 years as an active immunization against influenza disease caused by the influenza virusª 2011 Adis Data Information BV. All rights reserved.

strains contained in the vaccine.[12] Initial approval of LAIV in the US was for the frozen
formulation of the vaccine.[15,16] However, someproviders had difficulties storing a frozen vaccine, and a new refrigerator-stable formulation
Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

was developed in an effort to ameliorate thisproblem.[15,16] The refrigerator-stable formulation was approved in the US in 2007, and has
been in use since the 2007/2008 influenza season
in the Northern Hemisphere.[15]This review focuses on the protective efficacy,
reactogenicity and immunogenicity of both thefrozen and refrigerator-stable formulations of LAIV
in children, adolescents and adults. The approvalof LAIV in the US is only for individuals aged
2–49 years;[12] although some of the studies uponwhich the US approval of this vaccine was based
included children younger, or adults older, than
the approved age range.
Unless otherwise stated, each dose of LAIV
administered in the studies discussed in this review
contained 106.5–7.5 fluorescent focus units (FFUs)
of live attenuated influenza virus reassortants ofeach of the three virus strains recommended forthe season and hemisphere in which it was administered (table I). The frozen formulation ofLAIV was administered at a dose of 0.5 mL, andthe refrigerator-stable formulation was administered at a dose of 0.2 mL.
2. Protective Efficacy
LAIV provides direct protective efficacy (seetable II for definitions) in children (section 2.1) andin healthy adults (section 2.2) and indirect (herd)
protective efficacy in a community (section 2.3).
2.1 In Children

Various placebo- and active-comparator trials
have investigated the efficacy of LAIV in children(see table III for study design details and the ageof the children).[8,9,17-22]
Most vaccine-naive children aged 2–8 years
received the recommended two doses of LAIV,
administered ‡1 month apart (section 5); one study
included an additional treatment arm in which
vaccine-naive children aged 6 to <36 months received only one dose of LAIV[18] (see table III for
further details).
In the majority of trials, children were included ifthey were in good health;[8,9,17-19,22] children witha history of mild or moderate asthma were inª 2011 Adis Data Information BV. All rights reserved.

1595

Table II. Definition of absolute and relative vaccine efficacy
Absolute efficacy

Relative efficacy

1 minus the relative risk ofdeveloping influenza (or theincidence of influenza) in theactive vaccine group vs theplacebo group · 100

1 minus the relative risk ofdeveloping influenza (or theincidence of influenza) in one
active vaccine group vs the otheractive vaccine group · 100

cluded in one trial[19] and another trial specified thatchildren attend daycare at least 12 hours/week.[9]Two trials were conducted in special patient populations: one in children with a history of recurrent
respiratory tract infections (RTIs)[20] and the otherin children with a clinical diagnosis of asthma.[21]In general, exclusion criteria were underlying
chronic illness,[8,9,17,18,20-22] known or suspected
immune system disorder[8,9,18-22] (or a household
member with immunosuppression[9,18,20]), immunosuppressive therapy[20,21] and/or treatment with immunoglobulins,[9,20] aspirin or aspirin-containing
products[9,19,20,22] or previous treatment with an
influenza vaccine (either LAIV, TIV or investigational vaccines).[9,18,20] Some studies specifically
excluded children with clinically diagnosed respiratory illness with wheezing within the previous
2[9] or 6[19] weeks.
Generally, in the placebo-controlled trials, theinfluenza strains circulating during an influenza
season were well matched with those contained in
the season’s LAIV.[8,9,17] However, two influenza
type B viruses antigenically distinct from that in
LAIV were in circulation in year 2 of two studies[8,9] and caused >77% of cases of influenza B
illness in that year in one of the studies.[8] An
antigenically distinct strain of H3N2 caused 66 of
71 cases of influenza in year 2 of another study.[17]2.1.1 Placebo-Controlled Studies

Culture-confirmed influenza caused by strains
antigenically matching those contained in thevaccine occurred in 2–3% of LAIV recipientsand 11–13% of placebo recipients in year 1, and
2–3% of LAIV recipients and 10–30% of placebo
recipients in year 2 (table IV).[8,9] Across allstudies, culture-confirmed influenza caused byany viral strain (including antigenically matchingor non-antigenically matching strains) occurredin 1–5% of LAIV recipients and 13–18% of placebo
Drugs 2011; 71 (12)Carter & Curran

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Table III. Design of key live attenuated influenza vaccine (LAIV) studies conducted in healthy children or in special populations of children
Study (location)

Subject age(season[s]; hemisphere)

Trial
designDosage regimen

Primary endpoint

Belshe et al.[17,23,24](US)

15–71 mo
(1996/1997, 1997/1998;
NH)r, db, mc

1 or 2 doses of IN F-LAIV or
PL (y1);a
1 dose of IN F-LAIV or PL (y2)bFirst episode of culture-confirmed
influenza illness in each year

Bracco Neto et al.[18](South Africa and SouthAmerica)

6 to <36 mo(2001 and 2002; SH)r, db, mc

2 doses of RS-LAIV, 1 dose of
RS-LAIV + PLS or 2 doses of PLEor PLS (y1);1 dose of RS-LAIV or PLS (y2)First episode of culture-confirmed
influenza illness caused by communityacquired influenza subtypes similar to
those contained in y1 vaccine

Tam et al.[8](Asia)

12 to <36 mo(2000/2001, 2001/
2002; NH)r, db, mc

2 doses of IN RS-LAIV or PL (y1)1 dose IN RS-LAIV or PL (y2)First episode of culture-confirmed
influenza illness caused by a subtype
antigenically similar to that in the vaccine
after receipt of the second dose of
vaccine (or PL) during y1

Vesikari et al.[9](Europe and the Middle
East)

6 to <36 mo(2000/2001, 2001/
2002; NH)r, db, mc

2 doses of IN RS-LAIV or PL (y1)1 dose IN RS-LAIV or PL (y2)Efficacy of a primary series of 2 doses of
LAIV vs PL against culture-confirmed
influenza caused by subtypes
antigenically similar to those containedin the vaccine in the first season

Ashkenazi et al.[20](Europe and Israel)c

6–71 mo(2002/2003; NH)r, ol, mc

2 doses of IN RS-LAIV or
IM TIVFirst episode in a study child of cultureconfirmed influenza illness caused by acommunity-acquired subtype
antigenically similar to those containedin the vaccine

Belshe et al.[19](US, Asia, Europe andthe Middle East)

6–59 mo(2004/2005; NH)r, db, mc

1 or 2 doses of IN RS-LAIV or
IM TIVd

Efficacy of LAIV vs TIV in preventing
culture-confirmed influenza-like illness(using CDC definition and modified forage) caused by a well matched influenza
strainFleming et al.[21](Europe and Israel)c

6–17 y(2002/2003; NH)r, ol, mc

1 dose of IN RS-LAIV or
IM TIV

Incidence of culture-confirmed influenza
illness caused by a community-acquired
subtype antigenically similar to thosecontained in the vaccine

11 to <24 mo(2002/2003; NH)r, db, mc

2 doses of IN RS-LAIV or IN PL+ 1 dose SC MMRFirst episode (occurring ‡15 d after last
vaccine dose) of culture-confirmed
influenza illness caused by a subtype
antigenically similar to those containedin the vaccine

Placebo-controlled studies

Active-comparator studies

Coadministration study
Lum et al.[22](Europe, Asia and
Mexico)a

The majority of study centres used a 2-dose vaccination regimen in y1.

b

Subjects received the same vaccine in y1 as y2[9,17,18] or were rerandomized in y2.[8]cIn special populations; in children with asthma[21] or recurrent respiratory tract infections.[20]dSubjects received 1 dose of vaccine if they had previously received an influenza vaccination and 2 doses if they had not.

CDC = Centers for Disease Control and Prevention; db = double-blind; F-LAIV = frozen LAIV; IM = intramuscular; IN = intranasal; mc =multicentre; MMR = measles, mumps and rubella vaccine; NH= northern hemisphere; ol = open-label; PL = placebo; PLE = excipient PL;
PLS = saline PL; r = randomized; RS-LAIV = refrigerator-stable LAIV; SC = subcutaneous; SH = southern hemisphere; TIV = trivalent
inactivated vaccine; yx = year x.

recipients in year 1, and 2–5% of LAIV recipients and 12–32% of placebo recipients in year 2(table IV).[8,9,17]ª 2011 Adis Data Information BV. All rights reserved.

LAIV was 73–84% more effective than placebo in year 1 (primary endpoint in one trial[9]) and
74–89% more effective in year 2 with regard to
Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

preventing culture-confirmed influenza caused byan influenza subtype antigenically similar to
those contained in the vaccine (see table IV for
the trials that assessed this endpoint and for 95%
CIs).[8,9,18] Furthermore, in all trials, LAIV was
70–93% more effective than placebo in year 1 and
47–87% more effective in year 2 in preventing
culture-confirmed influenza of any subtype (seetable IV for 95% CIs).[8,9,17,18]
When results of one study were stratified according to H3N2 influenza strain type, LAIV was
100% effective in protecting against H3N2 strains
contained in the vaccine, and 86% effective inprotecting against the antigenically distinct H3N2
strain that became the predominant cause of illness in the second study year.[17] In another study,
LAIV was 48% effective against all influenza
strains (predominantly influenza B viruses) thatwere determined to be antigenically distinct fromthose contained in the vaccine.[8]Although a single dose of LAIV was clinicallyeffective (56–58% vs placebo) in preventing cultureconfirmed influenza in the trial that compared theefficacy of one versus two doses of LAIV in vaccinenaive children, two doses of LAIV was shown tobe more effective than one dose (table IV), confirming the additive protection that the recommended two-dose regimen (section 5) provides tochildren.[18]2.1.2 Comparator Studies

LAIV was superior to TIV in protecting against
culture-confirmed influenza-like illness in children
and adolescents, according to data from a large,
phase III study in children aged 6–59 months[19]and from open-label studies in children with recurrent RTIs[20] or in children and adolescentswith asthma[21] (table IV).
Phase III Trial

Relative to TIV, LAIV reduced the attack
rate of culture-confirmed influenza-like illness
caused by well matched influenza strains by
44.5% (95% CI 22.4, 60.6) and the attack rate ofculture-confirmed influenza-like illness caused byany viral strain (either well matched or mismatched) by 54.9% (95% CI 45.4, 62.9) [see table IV
for actual attack rates].[19] The statistical superª 2011 Adis Data Information BV. All rights reserved.

1597

iority of LAIV over TIV for both of these endpoints was established when the lower boundof the 95% CI was greater than the prespecified
level of zero. When stratified according to patient age, LAIV continued to be superior to TIV
after one dose for preventing culture-confirmed
influenza-like illness caused by matching viralstrains in subjects aged 36–59 months (reduction
in attack rate 65.6%; 95% CI 36.3, 82.4), but notin those aged 6–23 months (29.1%; 95% CI -21.2,
59.1) or 24–35 months (32.6%; 95% CI -25.8,
64.5).[19]With respect to the reduction in attack rate,
LAIV was superior to TIV in the subgroups with
culture-confirmed influenza-like illness caused
by influenza A/H1N1 (3 cases; 89.2% reduction;p < 0.001) and influenza A/H3N2 (37 cases; 79.2%
reduction; p < 0.001), but there was no statisticallysignificant difference between the two vaccines inthose with culture-confirmed influenza-like illness
caused by influenza B (n = 115 cases; 16.1% reduction; p = 0.19).[19]An additional analysis of data from this trial
indicated that LAIV recipients with breakthroughinfluenza may have had less severe disease thanTIV recipients with breakthrough influenza.[25]For example, significantly fewer LAIV thanTIV recipients had febrile disease (78% vs 88%,
p = 0.001).
Special Patient Populations

Culture-confirmed influenza caused by antigenically matching strains occurred in 24 of 1050
LAIV recipients and 50 of 1035 TIV recipientswith recurrent RTIs,[20] and in 46 of 1109 LAIV
recipients and 70 of 1102 TIV recipients withasthma[21] (primary endpoint in both trials; seetable IV for corresponding attack rates). Thistranslated into a relative efficacy, that was significantly in favour of LAIV, of 52.7% (90% CI
27.2, 69.8; 95% CI 21.6, 72.2) in the recurrent RTI
study,[20] and 34.7% (90% CI 9.4, 53.2; 95% CI
3.9, 56.0) in the asthma study[21] (table IV).
In both studies, when primary endpoint results
were stratified according to influenza subtype, therelative vaccine efficacy remained significantly infavour of LAIV in participants with influenza A/
H1N1 (100.0%; 90% CI 55.2, 100.0[20] and 100.0%;
Drugs 2011; 71 (12)StudyVaccine[no. of doses]

No. of subjects

No. of influenza
cases

Attack rate (%)

Absolute vaccine efficacy (%) [95% CI]
LAIV vs PL

Relative vaccine efficacy (%) [95% CI]
LAIV vs TIV unless otherwise stateda/m viral strain[any viral strain]

a/m viral strain[any viral strain]

a/m viral strain

a/m viral strain

any viral strain

37.3 [9.5, 56.9]a36.0 [8.5, 55.6]a24.1 [-104.2, 75.7]b

0.5 [-57.7, 38.5]b52.7 [21.6, 72.2]

52.4 [24.6, 70.5]

44.5 [22.4, 60.6]d,f54.9 [45.4, 62.9]f

34.7 [3.9, 56.0]

31.9 [1.1, 53.5]

any viral strain

1598ª 2011 Adis Data Information BV. All rights reserved.

Table IV. Efficacy of intranasal live attenuated influenza vaccine (LAIV) in preventing influenza A or B in children enrolled in phase III studies (see table III for study design details andvaccine dosage regimens). Children were randomized to receive intranasal LAIV, intramuscular trivalent inactivated influenza vaccine (TIV) or placebo (PL).[8,9,17-22] Analyses wereconducted in the intent-to-treat[9,17] or per-protocol[8,18-22] population

Placebo-controlled studies
Belshe et al.[17,23,24]

Bracco Neto et al.[18]Tam et al.[8]c

Vesikari et al.[9]F-LAIVy1: 1070

[14d]

[1.3]

PL

y1: 532[94d][17.7]

93 [87, 96]

F-LAIVy2: 917

[15d]

[1.6]

PL

y2: 441[56d][12.7]

RS-LAIV [2]y1: 94473.5 [63.6, 81.0]

72.0 [61.9, 79.8]

RS-LAIV [1] + PL

y1: 935

57.7 [44.7, 67.9]

56.3 [43.1, 66.7]

RS-LAIV [2 (y1); 1 (y2)]y2: 33873.6 [33.3, 91.2]

46.6 [14.9, 67.2]

RS-LAIV [1 + PL (y1); 1(y2)]

y2: 684

65.2 [31.2, 82.8]

46.4 [21.1, 63.5]

RS-LAIVy1: 1653

56d [81]

3.4 [4.9]

72.9 [62.8, 80.5]

70.1 [60.9, 77.3]

PL

y1: 1111139d [182]12.5 [16.4]

RS-LAIVy2: 771

12 [33]

1.6 [4.3]

84.3 [70.1, 92.4]

64.2 [44.2, 77.3]

PLy2: 494

49 [59]9.9 [11.9]
83.5 [72.6, 90.6]d83.8 [74.2, 90.2]

89.0 [82.7, 93.3]

85.3 [78.3, 90.4]

RS-LAIVy1: 1059

19 [23]

1.8 [2.2]

PL

y1: 725

79 [97]

10.9 [13.4]

RS-LAIVy2: 658

22 [31]

3.3 [4.7]

PL

y2: 461

140 [148]

30.4 [32.1]

RS-LAIV1050

24d [29]

2.3 [2.8]

TIV

1035

50d [60]

4.8 [5.8]

RS-LAIV

3916

1.4 [3.9*]

TIV

3936

2.4 [8.6]

RS-LAIV1109

46d [50]

4.1 [4.5]

TIV

1102

70d [73]

6.4 [6.6]

LAIV + MMR765

9 [23]

1.2 [3.0]

PL + MMR

385

21 [32]

5.5 [8.3]

87 [78, 93]

Active-comparator studies
Ashkenazi et al.[20]eBelshe et al.[19]Fleming et al.[21]Coadministration study
Lum et al.[22]aRS-LAIV + RS-LAIV vs RS-LAIV + PL.

b

RS-LAIV + RS-LAIV/RS-LAIV vs RS-LAIV + PL/RS-LAIV.

78.4 [50.9, 91.3]

63.8 [36.2, 79.8]

dPrimary endpoint.

e

In special populations; in children with asthma[21] or recurrent respiratory tract infections.[20]fThe statistical superiority of LAIV over TIV was established when the lower bound of the 95% CI was greater than the prespecified level of zero.

a/m = antigenically matched; F-LAIV = frozen LAIV; MMR = measles, mumps and rubella vaccine; RS-LAIV = refrigerator-stable LAIV; yx = year x. * p < 0.001 vs TIV.

Carter & Curran

Drugs 2011; 71 (12)c Y2 results given here are for the subgroup of subjects who received RS-LAIV or PL in both y1 and y2 of the study.

Intranasal Live Attenuated Influenza Vaccine: A Review

90% CI 18.5, 100.0[21]) or B (68.0%; 90% CI 43.0,
82.9[20] and 36.3%; 90% CI 6.6, 56.8[21]) illness,but there was no significant between-group difference with influenza A/H3N2 illness.
Similar results were seen for culture-confirmed
influenza caused by any viral strain (either antigenically matching or mismatching) [table IV].[20,21]
A subgroup analysis of the study in children
with recurrent RTIs indicated that breakthroughdisease may be less severe in LAIV than in TIV
recipients.[26] A higher percentage of LAIV thanTIV recipients with breakthrough influenza had
afebrile disease (26% vs 5%, p = 0.005) and fewerdays of school or daycare (1.6 vs 3.1 days; p = 0.025)
were missed with LAIV versus TIV administration.[26] However, there was no between-groupdifference in these measures in the study in children and adolescents with asthma.[21]2.1.3 Pooled Analyses

LAIV demonstrated efficacy in children aged
‡2 years (i.e. in children within the LAIV approved
age range; n = 1048–4166), according to a subgroup
analysis[27] of data from three studies[8,17,19] (seesections 2.1.1 and 2.1.2). In seasons where influenza
was predominantly caused by influenza strains
matching those contained in the vaccines, the efficacy of LAIV compared with placebo was 69.2%(95% CI 52.7, 80.4) and 94.6% (95% CI 88.6, 97.5).
In a season where influenza was predominantly
caused by mismatched strains of influenza virus,
the absolute efficacy of LAIV compared withplacebo was 87% (95% CI 77.0, 92.6), and during
a late season epidemic, the absolute efficacy was
73.8% (95% CI 40.4, 89.4). Relative to TIV, influenza caused by matched or mismatched strains
of influenza occurred in 52.5% (95% CI 26.7,
68.7) and 54.4% (95% CI 41.8, 64.5) fewer LAIV
recipients.
An analysis[28] of data from the three activecomparator studies discussed in section 2.1.2[19-21]
suggested that the relative efficacy of LAIV
compared with TIV against antigenically similar
strains of influenza virus may increase over time.
Across the studies, the relative efficacy of LAIV
compared with TIV ranged from 25% to 60% at
0–4 months post-vaccination, and from 49% to
89% at >4–8 months post-vaccination. However,ª 2011 Adis Data Information BV. All rights reserved.

1599

the relative efficacy of LAIV compared with TIV
against mismatched strains remained unchanged
over time.
When data from four of the studies discussed
in sections 2.1.1[17] and 2.1.2[19-21] were stratified
according to patient age in a subgroup analysis,[29]the efficacy of LAIV against all influenza strains
compared with placebo or TIV did not appear
to be affected by age, as evidenced by relative or
absolute efficacies that were similar across age
groups within each study.
LAIV was associated with fewer influenzaassociated complications in children aged
6–83 months than placebo or TIV, according toan analysis[30] of pooled data from eight randomized, double-blind, placebo-controlled[8,9,17,18,22,31]
or active-comparator[19,20] trials. This was measured in terms of the incidence of influenzaassociated acute otitis media, which occurred innumerically fewer LAIV recipients than placebo(0.4% vs 2.9%) or TIV (0.6% vs 1.2%) recipients,
leading to an absolute and relative pooled LAIV
efficacy of 85% (95% CI 78.3, 89.8) and 54% (95%CI 27.0, 71.7), respectively.
2.1.4 Coadministration with Other Vaccine

The efficacy of LAIV in young children did
not appear to be affected by coadministration
with the measles, mumps and rubella (MMR)
vaccine, according to results of a noninferiority
trial (see table III for trial design details andvaccine dosage regimens).[22] For example, cultureconfirmed influenza caused by an influenza subtype
that was antigenically similar to those containedin LAIV occurred in 1.2% of LAIV plus MMR
recipients and 5.5% of placebo plus MMR recipients, and culture-confirmed influenza causedby any influenza subtype occurred in 3.0% of
LAIV plus MMR recipients and 8.3% of placebo
plus MMR recipients (see table IV for actual event
numbers). Therefore, LAIV plus MMR was 78%
more effective than placebo plus MMR in preventing culture-confirmed influenza caused by an
influenza subtype antigenically similar to thosecontained in the LAIV vaccine, and 64% more
effective in preventing culture-confirmed influenza caused by any influenza subtype (see table
IV for 95% CIs).
Drugs 2011; 71 (12)Carter & Curran

1600

Table V. Design of key live attenuated influenza vaccine (LAIV) efficacy studies conducted in healthy adults
Study

Subject age(season)Dosage regimen

Key inclusion criteria

Key exclusion criteria

Primary endpoint
A case of symptomatic illnessa
that was confirmed as influenza
A or B by isolation of the virus incell culture or with real-time
PCR assayMonto
18–49 yet al.[33] (2007/2008)

1 dose of IN RS-LAIV, In good health
IM TIV or
PL (either IN or IM)

Any medical condition forwhich routine vaccination
with TIV is recommended

Nichol18–64 yet al.[32] (1997/1998)

1 dose of IN F-LAIV or In good health;PL
worked outside of thehome for ‡30 h/wk;
had health insurance

Any medical condition for which The proportion of participantsroutine vaccination with TIV is reporting ‡1 febrile illnessb
recommended; previously
during peak outbreak periods
received TIV containing
influenza viral strains for the
1997/1998 influenza season;
working with high-risk people;
acute febrile or respiratory tract
illness in previous 72 haSymptomatic influenza was defined as illness characterized by ‡1 respiratory symptom (cough or congestion) and by ‡1 constitutional
symptom (fever, feverishness, chills or body aches).

b

A febrile illness was defined as one in which symptoms were present for ‡2 consecutive days, with fever on ‡1 day, and ‡2 of the following
symptoms on ‡1 day: fever, chills, headache, runny nose, sore throat, cough, muscle aches and/or tiredness/weakness.

F-LAIV = frozen LAIV; IM = intramuscular; IN = intranasal; PCR = polymerase chain reaction; PL = placebo; RS-LAIV = refrigerator-stable LAIV;
TIV = trivalent inactivated influenza vaccine.

2.2 In Adults

The protective efficacy of LAIV in healthy adults
has been investigated in two randomized, doubleblind, multicentre trials (one placebo-controlled[32]and one placebo- and active-comparator-controlled;[33] see table V for key study design details).
2.2.1 Placebo-Controlled Study

During the peak outbreak period (median duration of 7 weeks), febrile illnesses (primary endpoint; table V) occurred in a similar proportion ofLAIV as placebo recipients.[32] Overall, 373 of
2833 LAIV recipients and 207 of 1420 placebo
recipients reported one or more febrile illnesses
during the peak outbreak period (see table VI for
actual event numbers), and this difference was
not statistically significant.
However, LAIV was significantly more effective than placebo for other endpoints.[32] For example, compared with placebo, LAIV significantly
reduced the number of febrile illnesses meeting
criteria for febrile upper respiratory tract infections (URTIs) [24% reduction; 95% CI 12.7, 33.2;
p < 0.001] or for severe febrile illnesses (19% reduction; 95% CI 7.4, 28.8; p = 0.002) during thepeak outbreak period. According to the studyª 2011 Adis Data Information BV. All rights reserved.

investigators, these endpoints were expected to havea higher degree of specificity than the primary endpoint for true influenza illnesses (febrile URTIs) orfor more severe illnesses (severe febrile illnesses).[32]Furthermore, LAIV significantly (p < 0.001)
reduced the overall number of days of febrile illness (days per 1000 persons per 7-week outbreakperiod: 1188 vs 1541 days), antibacterial use (196vs 343 days) or over-the-counter medication use(577 vs 752 days) compared with placebo during
the peak outbreak period.[32] There was no significant difference between the LAIV and placebogroups with regard to the number of days missedfrom work because of a febrile illness (days per1000 persons per 7-week outbreak period: 173 vs
200 days) or the number of days with one or more
visits to a healthcare provider (44 vs 52 days). However, when this analysis was performed using only
those episodes of febrile illness that met the criteria for URTI, the between-group difference wassignificantly (p < 0.001 vs placebo) in favour of
LAIV for both comparisons.
2.2.2 Placebo- and Active Comparator-Controlled
Study

Symptomatic, laboratory-confirmed influenza
occurred in 6.9% of LAIV recipients, 3.4% of TIV
Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

recipients and 10.8% of placebo recipients in aplacebo- and active comparator-controlled trial(primary endpoint; see tables V and VI for actual
event numbers and endpoint definitions).[33] Relative to placebo, both vaccines significantly (positive value for lower limit of 95% CI) reduced theincidence of symptomatic, laboratory-confirmed
influenza in the trial, with the absolute vaccine
efficacy being 36% in the LAIV group and 68% in
the TIV group (table VI). However, in terms of
the relative vaccine efficacy, TIV was associatedwith a 50% greater reduction in the incidence ofthe primary endpoint than LAIV (table VI).
When stratified according to influenza type,
TIV was associated with a 60% greater reductionin the incidence of influenza A than LAIV (95%CI 33, 77).[33] Although preliminary evidence suggested that neither vaccine was more effective
than the other in preventing influenza B, too few
episodes of influenza B occurred during the study
to allow for an accurate analysis to be conducted.
2.3 Indirect (Herd) Immunity

1601

control group of unvaccinated elementary school
children from previous years (change from baseline of 0.61% vs 1.79%; p = 0.029; see table VIII
for further details). Moreover, there appeared to
be an indirect effect of immunizing elementary
school children on high school children; the risein high school absenteeism was 0.32% in the intervention group versus 1.80% in the control
group (p = 0.028) [table VIII].[34]In another study, significantly fewer episodesof fever or influenza-like illness were reported inchildren or adults during the peak influenza week
in households with children attending intervention schools than in those with children attending
comparison schools (table VIII).[36]Scott and White Health Plan members within
the intervention area were at a lower risk of
medically attended acute respiratory illnesses
than those in the comparison areas during theinfluenza epidemic and postepidemic periods in athird study (table VIII).[35]3. Reactogenicity

LAIV appeared to provide indirect (herd)
protection for the community, according to results of three large community-based studies[34-36](see table VII for study design details).
In a study in which 44% of children from elementary schools in Carroll County (2005/2006)
were vaccinated (see table VII), there was a reduction in the rise in absenteeism in elementary
school children during that year compared with a

LAIV was well tolerated in children and adolescents[8,18,19,23,24,37] and in healthy adults,[32,33]
according to data from individual randomized
clinical trials (see sections 2 and 4 for details ofstudy design and vaccine dosage), a large safety
analysis[38] and integrated multistudy analyses.[12,39]
Most adverse events were of mild to moderate
severity.

Table VI. Efficacy of live attenuated influenza vaccine (LAIV) [frozen formulation] in preventing influenza A or B in healthy adults. Results of
two double-blind, multicentre phase III[32] or IV[33] trials. Subjects were randomized to receive a single intranasal (IN) dose of LAIV or placebo(PL),[32] or a single dose of IN LAIV, intramuscular (IM) trivalent inactivated influenza vaccine (TIV) or IN or IM PL.[33] Unless otherwise
specified, analyses were conducted in the intent-to-treat population
Study

Vaccine(no. of subjects)

No. of subjects
with influenzaa

Attack ratea (%)

Vaccine efficacy (%) [95% CI]
Absolute (LAIV or TIV vs PL)

Relative (TIV vs LAIV)

Monto et al.[33]LAIV (814)

56b

6.9

36 [0, 59]

50 [20, 69]

TIV (813)

28b

3.4

68 [46, 81]

PL (325)

35b

10.8

LAIV (2833)

373

13.2b

PL (1420)

207

14.6b

Nichol et al.

[32]

a

No. (%) of subjects with culture-confirmed, symptomatic influenza during the 6-mo study period,[33] or the no. reporting ‡1 febrile illness
during the peak outbreak period (median duration of 7 wk).[32]bPrimary endpoint.

ª 2011 Adis Data Information BV. All rights reserved.

Drugs 2011; 71 (12)Carter & Curran

1602

Table VII. Design details of three open-label, community-based trials investigating the indirect (herd) immunity of live attenuated influenza
vaccine (LAIV) in the US
Study

Intervention group(no. of subjects)

Comparison group(no. of subjects)

Intervention received

Data source(s)Davis et al.[34]Healthy students attending aschool in Carroll County
during the 2005/2006
school year (28 674)

Healthy students attending apublic school between fall2001 and spring 2005 (Carroll
County; some elementary
schools were excluded) or2006 (Frederick County)[39 493]5319 of 12 090 (44%)
healthy elementaryschool students in Carroll
County received a single
dose of F-LAIV during the
2005/2006 school year

Local medical centres,
hospitals, school records
and government websites

Glezen et al.[35]

SWHP members in the
Temple-Belton area
(50 665)

SWHP members in the
Bryan-College Station andWaco areas (67 036)

5247 of 10 418
elementary-school
students (aged 4–11 y) in
the Temple-Belton area
received RS-LAIV during
the 2007/2008 influenza
seasonMedical records from
SWHP and the Scott andWhite Memorial Hospital

King et al.[36]Public elementary or parochialschools across four US
states; 11 of the 28
participating schools were
designated as intervention
schools (5840)

Public elementary or parochialschools across four US
states; 17 of the 28
participating schools were
designated as comparison
schools (9451)

Healthy children aged ‡5 ywithin the intervention
schools were offered
F-LAIV during the fallof 2004 (2004/2005
influenza season);children <9 y received 2
doses and older children
received 1 doseHouseholdquestionnaires, school
and medical records

F = frozen; RS = refrigerator-stable; SWHP = Scott and White Health Plan.

3.1 In Children and Adolescents
3.1.1 Placebo-Controlled Studies

Runny nose (or nasal congestion) was the mostcommon solicited reactogenicity event occurringin children and adolescents in individual placebocontrolled trials (see sections 2.1.1 and 4.2),[8,18,23,24]
and in analyses of pooled tolerability data in children
and/or adolescents aged 2–6 years (n = 876–1759)[12]or 2–17 years (n = 10 693)[39] who received LAIV.
The incidence of runny nose or nasal congestion and of other solicited reactogenicity eventsoccurring at an incidence of ‡1% in LAIV recipients aged ‡2 years and at a higher frequency
in LAIV than placebo recipients in the smaller
pooled analysis of data obtained from two placebocontrolled, paediatric efficacy studies[8,12,23,24] areshown in figure 1.
The incidence and nature of solicited reactogenicity adverse events was similar in a larger
pooled analysis of 14 placebo-controlled trials.[39]Runny nose/nasal congestion (rate difference
6.8%, p < 0.01), headache (rate difference 6.9%,ª 2011 Adis Data Information BV. All rights reserved.

p = 0.02) and tiredness/decreased activity (ratedifference 2.1%, p = 0.03) all occurred at a significantly higher rate in LAIV than placebo recipients after the first vaccine dose. All other solicitedreactogenicity events occurring after the first
vaccine dose had between-group rate differencesof <3%, and these differences were not statistically significant.
Solicited reactogenicity events occurring after
the second vaccine dose in year 1 or after revaccination in year 2 were generally similar in nature
to those occurring after the first vaccine dose inyear 1.[12,39] However, the incidence appeared tobe numerically lower after the second vaccine
dose in year 1, or after revaccination in year 2,
than after the first vaccine dose in year 1.[12,39] In
the larger pooled analysis, decreased appetite
was the only solicited adverse event to occur at asignificantly different rate in LAIV versus placebo recipients after the second vaccine dose inyear 1 (rate difference -2.9%, p = 0.04) and afterrevaccination in year 2 (rate difference 3.9%,
p = 0.03).[39]Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

Unsolicited adverse events generally occurred
at a similar incidence in LAIV and placebo recipients, with 29.7% of LAIV recipients and27.6% of placebo recipients reporting at least one
adverse event after the first vaccine dose, according to results of the larger pooled analysis.[39]General disorders occurred at a significantly
higher incidence in LAIV than placebo recipients
after the first vaccine dose (rate difference 2.2%,
p < 0.01), and this was mostly attributed to thesignificantly higher incidence of pyrexia occurringin the LAIV group (rate difference 2.1%, p < 0.01).
The incidence of unsolicited adverse events
generally occurred at a numerically lower incidence after the second vaccine dose in year 1, or
revaccination in year 2, than after the first vaccine dose in year 1. For example, in the larger
pooled analysis, the total number of adverse
events occurring after the first and second vaccine
doses in year 1, and after revaccination in year 2,
was 1380, 893 and 955, respectively (statisticalanalyses not performed).[39] Ear disorders (ratedifference 0.3%) and lower respiratory tract illnesses (rate difference 1.0%) both occurred insignificantly (p < 0.05) fewer LAIV than placebo
recipients after the second vaccine dose in year 1;
no significant differences between the two treatment groups were seen after revaccination in year 2.
Serious adverse events were uncommon in
LAIV recipients, with no significant differences
between LAIV and placebo recipients in the larger
pooled analysis.[39] The incidence of serious adverse events occurring up to 42 days after vacci-

1603

nation in year 1 or year 2 was 0.5% in LAIV recipients and 0.6% in placebo recipients.
3.1.2 Active-Comparator Studies

Reactogenicity events were common in recipients of LAIV (n = 4108; one dose) or TIV (n = 4118;
one dose), according to an analysis of pooled
tolerability data from six randomized, activecomparator studies in children or adolescents aged
2–17 years; individual trials not identified).[39]However, runny nose/nasal congestion occurredin significantly (p < 0.01) more LAIV than TIV
recipients after either the first or second vaccine
dose in year 1 (rate differences 11.8% and 4.1%),
but muscle aches were less frequent in LAIV thanTIV recipients after one dose (p = 0.04).
In the 10 days after vaccine administration,
more LAIV than TIV recipients reported morethan one unsolicited adverse event after the firstdose (21% vs 18%; p < 0.01); however, there wasno significant between-group difference after thesecond dose (16% vs 16%).[39] Significant rate differences (p < 0.05) in unsolicited adverse events inyear 1 were reported for infections and infestations(rate difference 1.5% after one dose), respiratory,
thoracic and mediastinal disorders (rate difference 1.5% after one dose; mainly attributable tonasal congestion and rhinorrhoea), nervous system disorders (0.6% after one dose; mainly attributable to headache) and surgical and medical
procedures (rate difference -0.4% after the seconddose). Serious adverse events were infrequent,

Table VIII. Indirect protective efficacy of intranasal live attenuated influenza vaccine. Results of open-label, community-based studies conducted in the US (see table VII for trial design details)
Study (season; hemisphere)

Primary (or key) endpoint

Davis et al.[34] (2005/2006; NH)

0.61*/0.61/0.32*;
Change from baseline in percentage ofabsenteeism during the peak influenza wk/total 0.05/-0.07/0.07
influenza outbreak period (%) [for elementary-/
middle-/high-school students]

Glezen et al.[35] (2007/2008; NH)

No. (rate per 1000 person/y) of MAARIs during 11 152 (18.3)/8090 (10.6)a 16 462 (20.5)/11 776 (11.7)
influenza epidemic/postepidemic period

King et al.[36] (2004/2005; NH)

No. (%) of episodes of fever or influenza-like1220 (40)**/979 (32)**
illness during peak influenza wk [children/adults]aPrimary (or key) endpoint resultintervention groupcomparison group
1.79/1.84/1.80;
2.31/2.56/2.32

2874 (52)/2429 (44)The risk ratio for MAARI rates in the intervention vs comparison groups was 0.90 (95% CI 0.88, 0.92) for the epidemic period and 0.91
(95% CI 0.88, 0.93) for the postepidemic period.

MAARI(s) = medically attended acute respiratory illness(es); NH = northern hemisphere; * p < 0.03, ** p < 0.001 vs comparison group.

ª 2011 Adis Data Information BV. All rights reserved.

Drugs 2011; 71 (12)Carter & Curran

1604

70

Subjects (%)

60

LAIV (n = 876–1759)
Placebo (n = 424–1034)

50
40
30
20
10
0
‡

R
un
ny

n
co ose
ng /n
es as
D
tio alec
Irer n
as rita
ed bilDec
ap ity
re
pe
as
tit
ed
e
ac
So tivit
y
re
th
ro
at
H
ea
da
ch
e
Fe
M
ve
us
r
cl
e
ac
he
s
C
hi
lls
Fe
ve
r

†

Fig. 1. Reactogenicity of live attenuated influenza vaccine (LAIV) in
healthy young children. Solicited reactogenicity events occurring in ‡1%of LAIV recipients and at a higher rate in LAIV than in placebo (PL)recipients in two randomized, double-blind, multicentre trials conductedin children aged 12–36 months[8] or 15–71 months.[24] Results are froman analysis of pooled data from the subgroup of children in these trials
who were within the approved age range for LAIV administration (i.e.
‡2 y) [available in the manufacturer’s US prescribing information[12]].
Subjects received 1 or 2 doses of LAIV or PL in year 1 of each study, anda further single dose in year 2. Results presented here are those obtained within the first 10 d after the first vaccine dose in year 1. - indicatesa fever of 100–101 F (37.8–38.3 C) obtained orally; ‡ indicates a feverof 101–102 F (38.3–38.9 C) obtained orally.

occurring in 0.75% of LAIV recipients and 1.01%
of TIV recipients.
Results of a post hoc analysis of a large(n = 7852) active-comparator trial in children
aged 6–59 months demonstrated that children
aged 6–11 months who received LAIV had a significantly higher rate of hospitalization (for any
cause) than those who received TIV (6.1% vs
2.6%; rate difference 3.5%; p = 0.002).[19] No significant between-group differences were demonstrated
in children aged 12–23 months or ‡24 months.
The majority of hospitalizations occurring during
this period were as a result of gastrointestinal or
respiratory tract infections, which generally occurred >6 weeks after vaccine administration.
3.1.3 Asthma or Wheezing

LAIV has been associated with an increased incidence of wheezing illness in young children.[12,19,38]
In a large (n = 9689) safety analysis, which enrolled healthy children aged 1–17 years, the risk of
medically attended asthma events occurring was
significantly higher in LAIV than placebo reª 2011 Adis Data Information BV. All rights reserved.

cipients aged 18–35 months (relative risk 4.06;
90% CI 1.29, 17.86).[38] On the basis of these results, an active-comparator trial was conducted
to further evaluate the safety (and efficacy) of
LAIV in children aged 6–59 months (see section
3.1.2 for further reactogenicity results).[19]Overall (vaccine-naive and vaccine-experienced
subjects in the 42-day period after one or two
doses), the incidence of medically significant
wheezing was not significantly different with LAIV
or TIV. However, in vaccine-naive children(n = 6472), more episodes of medically significant
wheezing occurred in the 42 days after vaccination with one dose of LAIV than TIV (adjusted
rate difference 0.77%; 95% CI 0.12, 1.46).[19]Further analysis revealed that the between-groupdifference in the incidence of medically significant wheezing in vaccine-naive subjects over the
42-day post-vaccination period after one dose wasprimarily seen in children aged <24 months (3.2%of LAIV recipients vs 2.0% of TIV recipients; adjusted rate difference 1.18; 95% CI 0.13, 2.29) and,
although not statistically significant, in those aged
<12 months (3.8% of LAIV recipients vs 2.1% of
TIV recipients; adjusted rate difference 1.6%;
95% CI -0.18, 3.53).[19] There was no significant
difference demonstrated in the incidence of medically significant wheezing between vaccine-naive
children aged ‡24 months who received LAIV andthose who received TIV.
On review of hospital records for children aged
<24 months who were hospitalized with medicallysignificant wheezing in the first 42 days after the
first dose of vaccine, there was no significant difference between LAIV and TIV recipients in theseverity of medically significant wheezing, or in
the duration of hospitalization, associated diagnoses or treatment received.[19] None of the episodes of medically significant wheezing occurringin this study required treatment in an intensive
care unit or with mechanical ventilation, and no
deaths occurred as a result of this adverse event.[19]3.2 In Adults
3.2.1 Placebo-Controlled Studies

Runny nose was the most commonly reported
solicited adverse event occurring in the total
Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

the vaccine in the serum of blood taken just before (pre-vaccination; day 0) and after (postvaccination; day 21–42, depending on the study)administration of the vaccine.[16,18,23,24,37,40-45] Insome studies, immunogenicity was also determinedby assessing the level of influenza-specific IgA antibodies to vaccine haemagglutinins in pre- (day 0)
and post-vaccination (days 1–28, depending on
study) nasal wash specimens using kinetic enzymelinked immunosorbent spot assay (ELISA).[37,46]
Key immunogenicity endpoints and terms areshown in table IX.
Immunogenicity criteria have not been established for seasonal LAIVs and those set for seasonal, inactivated influenza vaccines do not apply
to seasonal LAIVs.[47] Therefore, immunogenicity results in this section were unable to be reviewed in light of any pre-set criteria.
4.1 Comparative Immunogenicity of Frozen
and Refrigerator-Stable Intranasal Live
Attenuated Influenza Vaccine

Refrigerator-stable LAIV was as immunogenic
as frozen LAIV in healthy volunteers participating
70

LAIV
Placebo60

4. Immunogenicity
Immunogenicity was determined by assessing
the level of haemagglutination-inhibiting (HI)antibodies against all three haemagglutinin antigen components (i.e. H1N1, H3N2 and B) ofª 2011 Adis Data Information BV. All rights reserved.

Subjects (%)

40
30
20
10

n
nu
si
tis

tio

ng
co
N

as

al

us
M

es

C
hi

lls

gh
ou

he
s

cl

e

ac

C

t

kn

ro
a

ea
w

s/
es

dn
Ti
re

es
s

ch
e
So

re

th

da
ea

H

ny

no

se

0

un

No significant differences were reported in theincidence of adverse events between LAIV or TIV
and placebo in an active-comparator trial (n = 1952),
except runny nose/nasal congestion, which wasreported in significantly more LAIV than placebo recipients (52.3% vs 37.7%; p = 0.001), andarm soreness, which was reported in significantly
more TIV than placebo recipients (52.6% vs21.3%; p < 0.001).[33] Differences in the incidenceof adverse events between LAIV and TIV were
not reported.[33] None of the serious adverse
events were considered to be vaccine related.

50

R

3.2.2 Active-Comparator StudySi

population of LAIV recipients during the first
7 days after vaccine administration in a large(n = 4561) placebo-controlled trial in patients aged
18–64 years,[32] and in the subgroup of subjects inthis trial who were within the approved age range(i.e. 18–49 years) for LAIV administration (figure2).[12] Incidences of these and other solicited (orunsolicited) adverse events occurring in ‡1% of
LAIV recipients in the subgroup analysis and at ahigher rate than in placebo recipients are shownin figure 2.[32]In the total patient population of this trial (i.e.
not just in those in the approved age range), theincidences of runny nose (between-group difference 17.7%; 95% CI 14.7%, 20.7%) and sore throat(10.3%; 95% CI 7.7%, 12.9%) were significantly
higher in LAIV than in placebo recipients.[32] Thiswas confirmed when the upper limit of the 95%
confidence interval for the difference in incidence
rates between the LAIV and placebo groups exceeded the prespecified limit of 10%.[32] However,there was no between-group difference in the duration of the two adverse events, with both occurring
for a median duration of 2 days in both groups.[32]None of the serious adverse events or study
withdrawals was considered to be related to thestudy vaccine.[32]1605Fig. 2. Reactogenicity of live attenuated influenza vaccine (LAIV) in
healthy, working adult subjects. Solicited and unsolicited (nasal
congestion and sinusitis) adverse events occurring in ‡1% of LAIV
recipients and at a higher rate in LAIV than in placebo (PL) recipientsin a randomized, double-blind, multicentre trial (n = 4561).[32] Although the trial enrolled subjects aged 18–64 years, incidences given
here are for the group of adults who are within the approved age
range for LAIV administration (i.e. 18–49 years) [available in the
manufacturer’s US prescribing information[12]]; the number of subjects in this subgroup was not specified. All subjects received a single
intranasal dose of LAIV or PL, and filled out a reactogenicity symptom card for 7 days following vaccination.

Drugs 2011; 71 (12)Carter & Curran

1606

Table IX. Immunogenicity endpoints and terms
Term

Definition

Endpoints
GMT of HI
antibodies

Geometric mean titre (GMT) of
haemagglutination-inhibiting (HI) antibodies

GMT ratio

Between-group ratio of post-vaccination HI
antibody GMTs

Mucosal (nasal) IgA
response

See text (sections 4.2[46] and 4.3[37]) for
definition in each study

Seroconversion rate

The proportion of subjects with a ‡4-foldincrease from baseline in post-vaccination
serum HI antibody titre[8,16,18,44-46] or a rise inserum HI antibody titre from £1 : 4 at baseline
to 1 : 8 post-vaccination[46]Seroprotection rate

The proportion of subjects with a postvaccination HI titre of ‡1 : 40

Seroresponse rate

The proportion of subjects with a ‡4-foldincrease from baseline in post-vaccination
serum HI antibody titre

logical response to both vaccine formulations
than older children and adults (statistical analyses not performed).
In addition, subjects with strain-specific seronegativity at baseline appeared to have a numerically higher immunological response to either
vaccine formulation than those who did not.[16]In subjects aged 5–8 years, the seroconversion rate
was 4–32% in seropositive subjects and 39–100%
in seronegative subjects, and in subjects aged
9–49 years, the seroconversion rate was 1–4% inseropositive subjects and 12–55% in seronegative
subjects (values estimated from a graph; statisticalanalyses not performed). For both LAIV formulations, the highest seroconversion rates were seenfor HI antibodies to H3N2 virus in subjects who
were seronegative for these antibodies at baseline.

Other terms
Seronegative

A baseline serum HI antibody titre of£1 : 4[8,16,18,24,43-45]aSeropositive

A baseline[16,43,46] or post-vaccination[23,40]
serum HI antibody titre of >1 : 4[16,46] or‡1 : 8[23,40,43]

Serosusceptible

A baseline serum HI antibody titre of£1 : 8[16,37,41,43]aa

In general, the term ‘seronegative’ was used for young children(aged £8 y) and ‘serosusceptible’ was used for older children(aged ‡9 y) and adults, in whom previous natural exposure to thethree major human influenza subtypes was likely.

in a phase III equivalency trial (see table X fortrial design details and vaccine dosage regimens).[16] The immunogenicities of the two vaccine formulations were shown to be equivalent
with respect to the ratio of the adjusted postvaccination HI antibody geometric mean titres(GMTs) against each of the LAIV viral strains insubjects receiving refrigerator-stable LAIV compared with those receiving frozen LAIV (primary
endpoint) [see table XI for quantitative data andequivalency criteria].[16]The seroconversion or seroresponse rates foreach of the three vaccine viruses were similar inboth age groups after administration of both LAIV
formulations.[16] Seroconversion/seroresponse rates
were 11–62% in subjects aged 5–8 years and
10–15% in those aged 9–49 years (values estimatedfrom a graph), indicating that young children
may potentially have a more robust immunoª 2011 Adis Data Information BV. All rights reserved.

4.2 In Children

The immunogenicity of LAIV (refrigeratorstable[8,18] or frozen[23,24] formulation) in healthy
young children was investigated in three clinical
trials, each of 2 years in duration (see tables III
and X for study design details and vaccine dosage
regimens).[8,18,23,24]
In general, LAIV was associated with numerically or significantly higher seroconversion rates
than placebo for all three viral strains in all trials(US,[24] South American and South African,[18]and Asian[8]) and, where reported, in both study
years[8,18] (table XII). Where investigated, thesebetween-group differences occurred in both thetotal immunogenicity population and in the subgroups of patients who were seronegative to a
specific LAIV viral strain at baseline.[8,18] In general, serum HI antibodies to the H3N2 or B antigens in year 1 of the US study were observed
after one vaccine dose, whereas two vaccine doses
were required to induce serum HI antibodies tothe H1N1 antigen.[24] Of interest, in year 2 of the
Asian study, the subgroups of subjects who received LAIV in the second study year generally
had numerically higher rates of seroconversion
than those who received placebo in the second
study year, irrespective of serological status andwhether they had received LAIV or placebo inyear 1 of the study (table XII).[8]Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

1607

Table X. Key trial design details and vaccine regimens for the key trials reviewed in the immunogenicity section. The primary objective ofsome of the trials was to assess the protective efficacy of live attenuated influenza vaccine (LAIV);[8,18,23,24,37] hence, immunogenicity wasassessed in a subgroup of study participants in some of these trials[8,18,23,24]
DesignSubject age

Country (season[s];hemisphere)

Vaccine dosage regimenar, db, mc

5–49 yUS (2003/2004; NH)

If aged 5–8 y: 2 doses of RS-LAIV or F-LAIV, 46–60 d apart;if aged 9–49 y: 1 dose of RS-LAIV or F-LAIVr, db, tc

18–45 yUS (1995/1996; NH)

Vaccination: 1 dose of LAIV + IM PL, TIV + IN PL or IM PL + IN PL;
IN challenge (28 d after last vaccination): wild-type influenza
vaccine strain to which subject was serosusceptible at baseline

Belshe et al.[23,24]

r, db, mc

15–71 moUS (1996/1997,
1997/1998; NH)

y1: 1 or 2 doses of F-LAIV or PL, 60 – 14 d apart;y2: 1 dose of F-LAIV or PL

Bracco Neto
et al.[18]r, db, mc

6 to <36 moSouth Africa andSouth America(2001, 2002; SH)y1: 2 doses of RS-LAIV, 1 dose of RS-LAIV + PLS or 2 doses of
PLE or PLS;y2: 1 dose of RS-LAIV or PLS

Tam et al.[8]r, db, mc

12 to <36 mo

Asia (2000/2001,
2001/2002; NH)

y1: 2 doses of RS-LAIV or PL, ‡28 d apart; y2: 1 dose of RSLAIV or PLb

Trial
Comparative trial
Block et al.[16]AdultsTreanor et al.[37]ChildrenPatients with HIV infection
King et al.[41]r, db, tc

18–58 yUS (1997/1998; NH)

1 dose of F-LAIV or PL

Levin et al.[42]r, ac

5 to <18 yUS (2004/2005; NH)

1 dose of F-LAIV or TIV

Block et al.[43]nc, mc

5–49 yUS (2003/2004; NH)

1 dose of F-LAIV

Belshe et al.[48]challenge
after r, db
trial[24]

34–91 moUS (1997/1998; NH)

Vaccination: see regimen for Belshe et al.;[23,24]
IN challenge (6–8 mo after last vaccine dose): monovalent,cold-adapted, influenza A/H1N1 vaccine containing same
H1N1 viral strain as used in LAIV during y2 of previous trial[24]r, db

9–36 moFinland (1998/1999;NH)

1 dose of F-LAIV or PL

Viral shedding studies

Transmission study
Vesikari et al.[49]Coadministration studies
Nolan et al.[44]r, pb,c mc

12–15 moUS (May-Oct 2001
and 2002; NH) andAustralia (Nov
2000–May 2001, Nov
2001–May 2002; SH)

One of three regimens: (i) d0: LAIV + MRR + VAR, d42: LAIV,
d72: IN PL (LAIV + MMR + VAR arm); (ii) d0: LAIV, d42: LAIV,
d72: MMR + VAR (LAIV alone arm); or (iii) d0: MMR + VAR + IN
PL, d42 and d72: LAIV (MMR + VAR + IN PL arm)

Breiman et al.[45]r, pb,d mc

6–36 mo

Asia and SouthAmerica (2002; SH)

d0: LAIV + OPV, LAIV alone or OPV + IN PL; d28–42: LAIV
recipients received a second dose of LAIVa

Unless otherwise specified, all LAIV or PL vaccines were administered intranasally and, in the studies of 2-y duration, subjects received thesame vaccine in y2 as they did in y1. TIV was administered intramuscularly, MMR and VAR subcutaneously and OPV orally. TIV wasadministered at a dose of 0.5 mL in adults and children aged ‡36 mo at a dose of 0.25 mL in children aged 6–35 mo. Each dose of TIV
contained 15 mg of haemagglutinin from each of the three influenza virus strains recommended by the WHO for that season andhemisphere [i.e. the same strains used in the LAIV vaccine in each study].

b

Subjects were rerandomized to treatment in y2 of this study.

c

The study was db in terms of whether the child was receiving LAIV or IN PL in the LAIV + MMR + VAR and MMR + VAR + IN PL arms;
otherwise study vaccines were administered in an open-label manner, because no subcutaneous PL was used in the trial.

d

The study was db in terms of whether the child was receiving LAIV or IN PL in the LAIV + OPV or OPV + IN PL arms; otherwise study
vaccines were administered in an open-label manner, as no oral PL was used in the trial.

ac = active-comparator; db = double-blind; dx = day x; F = frozen; IM = intramuscular; IN = intranasal; mc = multicentre; MMR = measles,
mumps and rubella vaccine; nc = noncomparative; NH = northern hemisphere; OPV = oral poliovirus vaccine; pb = partially-blind; PL = placebo;
PLE = excipient PL; PLS = saline PL; r = randomized; RS = refrigerator-stable; SH = southern hemisphere; tc = two-centre; TIV = trivalent
inactivated influenza vaccine; VAR = varicella vaccine; yx = year x.

ª 2011 Adis Data Information BV. All rights reserved.

Drugs 2011; 71 (12)Carter & Curran

1608

Table XI. Immunogenicity of the refrigerator-stable (RS) and frozen (F) formulations of live attenuated influenza vaccine (LAIV). Geometricmean titre (GMT) ratios in healthy subjects who received RS-LAIV or F-LAIV in an equivalency trial (see table X for trial design details andvaccine dosage regimens).[16] Both vaccine formulations met the WHO recommendations for the preparation of the influenza vaccine for the
2003/2004 influenza season in the Northern Hemisphere (table I)
GMT ratio (95% CI)aAge group

No. of subjects

H1N1

H3N2

B

5–8 y

332

1.24 (1.02, 1.49)

1.02 (0.88, 1.19)

1.00 (0.81, 1.24)

9–49 y546

1.14 (0.94, 1.36)

1.12 (0.95, 1.32)

0.96 (0.83, 1.10)aRS-LAIV and F-LAIV were considered to have equivalent immunogenicity because the 95% CIs for all of these GMT ratios were withinprespecified limits (>0.5 but <2.0). GMTs were determined in serum samples collected 28–35 d after the last vaccine dose: GMTs were
adjusted for baseline serostatus.

Although year-2 seroconversion rates were not reported in the US study, significantly (p < 0.01) more
LAIV than placebo recipients were seropositive for
GMT antibody titres against H1N1 (82% vs 20% of
subjects), H3N2 (100% vs 65%) or B (100% vs 46%)
antigen, according to year-2 results.[23]In general, post-vaccination GMTs were numerically[18,24] or significantly (p-value not stated)[23] higher in LAIV recipients than in placebo
recipients, irrespective of baseline serostatus, inboth study years of the US[23,24] and South African/
South American studies.[18] In the South African/
South American study (year 1), GMTs of HI
antibodies to the three vaccine antigens were
21.7–73.1 in recipients of two LAIV doses, 11.5–
20.6 in recipients of one LAIV dose plus placebo
and 4.7–9.2 in the recipients of placebo, indicating that subjects who received two doses of LAIV
(i.e. the recommended dose [section 5]) may
potentially have a more robust immunological response than those who received only one dose (between-group statistical analyses not performed).[18]In the Asian study, the geometric mean foldrise (GMFR) in HI antibody GMTs showed significant (p < 0.05) increases from pre- to postvaccination in all LAIV recipients in year 1.[8]However, in year 2, GMFRs reflecting significantly(p < 0.05) higher HI antibody GMTs were seen
only in subjects who received LAIV in year 2 ofthe study, regardless of whether they had received
LAIV or placebo in year 1.
According to results of a 2-year extension (seetable XIII for trial design details and vaccine dosage regimens) of the US study, a response to LAIV
was maintained over 4 years.[40] Serum samples
taken post-vaccination in year 4 demonstratedª 2011 Adis Data Information BV. All rights reserved.

that at least 79% of LAIV recipients were seropositive for HI antibodies against H1N1, H3N2
or B viral strains in both groups (i.e. yearly andfirst-time) [table XIII]. However, post-vaccination
HI antibody GMTs to H3N2 and B antigen weresignificantly higher in the group of control children who had received LAIV vaccination for the
first time in year 4 of the study than in the groupof children who had received LAIV for 4 years
consecutively (table XIII).[40]In a subgroup analysis (n = 19) of the US trial,
a mucosal influenza-specific IgA response to
H1N1, H3N2 or B antigen was demonstrated in
62%, 69% and 85% of LAIV recipients, and 33%,
0% and 17% of placebo recipients.[46] The betweengroup differences in mucosal IgA response to
H3N2 and B were significantly (p = 0.01) in favourof LAIV. An influenza-specific mucosal IgA response was defined as a ‡4-fold rise in correctedvalues of the ratio of mean influenza-specific IgA :total secretory IgA, or as an influenza-specific IgAvalue of <5 milli optical density units (mOD)/min
pre-vaccination and ‡5 mOD/min post-vaccination.
Overall, subjects who were seropositive at baseline
were 4.5 times more likely to develop a mucosal
immune response than a seroresponse (p = 0.015),
indicating that mucosal immune response may be
the only indication of a vaccine take in seropositive children. No correlation between mucosal immune response and seroresponse wasshown in this study.
4.3 In Adults

The immunogenicity of trivalent LAIV in healthy
adults was investigated in a challenge study inDrugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

which the efficacy of LAIV (frozen formulation)
was compared with that of TIV (see table X for
study design details and vaccine dosage regimens).[37]No statistically significant differences were
demonstrated in the LAIV group versus theplacebo group with respect to GMTs of HI antibodies to vaccine viral strains or seroresponse
rates determined post-vaccination (table XIV).[37]However, post-vaccination GMTs and seroresponse rates to the viral strains were significantly
higher in the TIV group than in the placebogroup (p-values not stated; table XIV). The seroresponse to H1N1 and H3N2 observed in theplacebo group meant that interpretation of results was difficult, and it was thought the placebo
responses may have occurred because of the presence of asymptomatic intercurrent influenza
infection with an influenza A virus and/or variability in antibody assays.

1609

Although mucosal (nasal), strain-specific IgA
antibody responses (defined as a ‡2-fold increasein ELISA signal between pre- and post-vaccination
samples) to H1N1, H3N2 or B viruses appeared
to be more frequent in the LAIV-containing (14.3%,
32.1% and 17.9%) and TIV-containing (23.3%,
16.7% and 16.7%) groups than in the placebogroup (12.9%. 9.7% and 3.2%), these betweengroup differences were not significant.[37] The
nasal antibody responses seen in the placebogroup occurred mainly in those individuals who
also had serum antibody responses, further indicating that some participants may have had
asymptomatic exposure to circulating wild-typeviruses.
In the 92 of 103 randomized subjects who were
eligible for challenge, rates of seroresponse tochallenge with the wild-type H1N1, H3N2 or B viruses contained in the vaccines were not significantly

Table XII. Immunogenicity of live attenuated influenza vaccine (LAIV) [refrigerator-stable[8,18] or frozen[24] formulation] in healthy young
children in 2-y clinical studies (see tables III and X for study design details and vaccine dosage regimens).[8,18,24] The antigenic composition ofLAIV met the WHO recommendations for the preparation of the influenza vaccine for the 1996/1997 and 1997/1998 influenza seasons[24] orthe 2000/2001 and 2001/2002 influenza seasons[8] in the northern hemisphere, or for the 2001 and 2002 influenza seasons in the southernhemisphere[18] (table I)
Study (location)

Vaccine [y1/y2]

Seroconversion rates after 1 y (2 y) [% of subjects]a
all subjects
no.

Belshe et al.[23,24](US)seronegative subjects

H1N1

H3N2

B

LAIV
PL

Bracco Neto et al.[18](South Africa andSouth America)

Tam et al.[8](Asia)

a

no.

H1N1

H3N2

B

56–78

61

96

96

27–40

2

11

3

LAIV + LAIV

113

56

80***

69***

NS

74***

92***

89***

LAIV + PLS

112

26

56***

55***

NS

32***

60***

75***

PL + PL

109

4

9

11

NS

7

8

16

LAIV + LAIV/LAIV

133

(28)

(14*)

(10***)

NS(66***)(36***)(20***)LAIV + PLS/LAIV

265

(33)

(17***)

(8**)

NS

54***

(45***)(14***)PL + PL/PLS

126

(2)

(3)

(1)

NS

(2)

(5)

(1)

LAIV

111

60

61

57

61–82

85

95

74

PL

75

11

4

4

47–63

14

2

5

LAIV/LAIV

50

(28)

(32)

(26)

4–21

(82)

(75)

(52)
(41)

PL/LAIV

45

(20)

(38)

(31)

16–32

(32)

(75)

LAIV/PL

50

(4)

(0)

(2)

6–24

(9)

(0)

(4)

PL/PL

26

(4)

(12)

(12)

11–21

(7)

(18)

(10)

Where specified, post-vaccination serum samples were collected 4 wk[24] or 35 – 7 d[18] after the last vaccination in each year. In children
who received only one vaccine dose in y1, post-vaccination serum was collected on day 35–49 post-vaccination.

NS = not stated; PL = placebo; PLS = saline PL; yx = year x; * p = 0.003, ** p = 0.002, *** p £ 0.001 vs PL + PL (y1) or PL + PL/PL (y2).

ª 2011 Adis Data Information BV. All rights reserved.

Drugs 2011; 71 (12)Carter & Curran

1610

Table XIII. Immunogenicity of live attenuated influenza vaccine (LAIV) [frozen formulation] in healthy children aged 15–71 mo. Results of an
open-label extension[40] of a double-blind trial[23,24] (see table X for details of the design of the original study) in which subjects received a single
intranasal dose of LAIV each year for 2 y (yearly). As a control, a cohort of vaccine-naive children (aged 3–10 y) were randomized to receive twodoses of LAIV or placebo (PL) in the final study year (first time). The antigenic composition of LAIV met the WHO recommendations for the
preparation of the influenza vaccine for the 1998/1999 and 1999/2000 influenza seasons in the northern hemisphere (table I). Analyses wereconducted in subjects who had received at least one dose of LAIV in each of 4 study years (yearly) or in the final study year (first time)
Endpointa

Vaccine group

No. of children

Antigen
H3N2

B

First time

151–156

4.7/17.7

55.5/137.8*

12.3/34.9*

Yearly107–1097.8-/13.6

44.5/66.1

22.6-/27.4

Seropositive pre-/post-vaccination

First time

151–156

34.2/79.5

90.3/10074.8/99.3(% of subjects)

Yearly107–10960.6-/79.4

98.2-/100

100-/100

GMT pre-/post-vaccination

a

H1N1

Post-vaccination serum samples were collected »30 d (in the first-time vaccine group) or »4–6 wk (in the yearly vaccine group) after the last
vaccine dose.

GMT = geometric mean titre. * p < 0.05 vs yearly vaccine group for post-vaccination values; - p < 0.05 vs first time vaccine group for prevaccination values.

different in subjects who had received an LAIVcontaining regimen (20% [2 of 10 subjects], 22%[2 of 9] and 20% [2 of 10]) compared with those
who had received placebo (50% [5 of 12], 50%[4 of 8] and 36% [4 of 11]). None of the subjects
who received a TIV-containing regimen had aseroresponse to virus challenge, and the difference
between the TIV-containing and placebo groups inseroresponse rates to H1N1 or H3N2 challenge
was statistically significant (p < 0.05) and in favour of the placebo group.[37]4.4 In Patients with HIV Infection
4.4.1 Children with HIV Infection

In contrast to the low number of adults with
HIV infection who achieved a seroresponse to
intranasal LAIV (section 4.4.2), 32% and 22% ofpreviously vaccinated children (n = 243) with HIV
infection (plasma HIV RNA <60 000 copies/mL)
who received LAIV (frozen formulation) had aseroresponse to H1N1 antigen at 4 and 24 weeks
after vaccination (see table X for study design
details and vaccine dosage regimens).[42] This did
not differ significantly from the percentage of TIV
recipients showing a response at these same timepoints (33% and 16%). However, significantly(p < 0.05) fewer LAIV than TIV recipients achieved
a seroresponse to H3N2 antigen at 4 weeks (14%vs 44%), and to B antigen at 4 (11% vs 34%) or
24 (11% vs 22%) weeks; rate of seroresponse toª 2011 Adis Data Information BV. All rights reserved.

H3N2 at week 24 did not differ significantly between the two vaccines (29% vs 34%).
Post-vaccination HI antibody GMTs at 4
and 24 weeks were significantly (p < 0.05) lower
in LAIV than in TIV recipients for H3N2 andB antigens, and seroprotection rates at 4 and
24 weeks were significantly (p < 0.05) lower in
LAIV than in TIV recipients for the B antigen.[42]Of note, a significant (p < 0.05) between-groupdifference in favour of TIV was observed forthe percentage of patients with seroprotective
titres against the H3N2 and B antigens atbaseline.
GMTs of anti-influenza neutralizing antibodies against all viral vaccine strains increased
significantly (p £ 0.02) from baseline to 4 and
24 weeks after vaccination in both treatment groups;
however, GMTs were significantly (p £ 0.002)
higher in TIV than LAIV recipients at 4 weeks after
vaccination for all three vaccine viral strains.[50]Despite this, a similar proportion of children ineach treatment group achieved protective levels(i.e. ‡1 : 40) of anti-influenza neutralizing antibodies at both timepoints.
Neither LAIV nor TIV affected HIV replication,
as demonstrated by the absence of significant differences in mean (or median) plasma HIV RNA
levels between baseline and study follow-up. The
median percentage of CD4+ cells contained in the
total lymphocyte pool also remained stablethroughout the study period.[42]Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

4.4.2 Adults with HIV Infection

LAIV (frozen formulation) did not appear
to be immunogenic in terms of the number ofpatients achieving seroresponse (£8% of HIVand nonHIV-infected subjects) in adults with(n = 57) or without (n = 54) asympomatic or mildly
symptomatic HIV infection (plasma HIV RNA<10 000 copies/mL; CDC class A1-2; >200 CD4
cells/mm3) [see table X for study design details
and vaccine dosage regimens].[41] This possiblyreflected the low percentage of patients who were
serosusceptible to the H1N1 (4% of patients with
HIV infection and 11% of patients without HIV
infection), H3N2 (4% and 4%) or B (31% and11%) antigens at baseline.
Overall, administration of the vaccine to theseotherwise healthy adults was not associated withan increase in HIV replication in terms of plasma
HIV RNA levels or CD4 cell counts.[41] However, two LAIV recipients and one placebo recipient had a ‡10-fold rise in HIV RNA levels
from baseline to one of the post-vaccination
follow-ups; levels returned to baseline (or nearbaseline) by the next follow-up visit in both of theLAIV recipients, but not in the placebo recipient.
Of note, these episodes occurred in patients with
HIV infection who were (as opposed to those
who were not) receiving antiretroviral therapy
during the study.
4.5 Studies on Viral Shedding

Infectious vaccine viruses may be cultured
from nasal secretions after vaccination with
LAIV, and this is known as viral shedding.[12,43]

1611

Various studies have investigated LAIV virus
shedding in specific groups of subjects, includingchildren,[24,48,49] adults[51] and subjects with orwithout HIV infection.[41,42] Where reported, therate of viral shedding in these studies ranged from
1.8% (1 of 55 subjects) in HIV-infected adult subjects at the day 3–5 follow-up visit[41] to 80% (78of 98 subjects) in young children aged 9–36 months
at some stage over the 21-day follow-up period(see section 4.6 for further results of the latterstudy).[49]In a large phase IV study in healthy subjects(see table X for trial design details and vaccine
dosage regimens), viral shedding occurred in
99 of 343 subjects (28.9%) overall.[43] Peak titresof nasal LAIV virus occurred on days 2–3 postvaccination and coincided with peak shedding
frequency, which occurred on day 2. Levels of
shed virus decreased to undetectable levels afterday 10 in children aged 5–8 years and after day 6in those aged 9–17 or 18–49 years. Mean titres ofshed virus were <3 log10 TCID50/mL in all groups.
A/H1N1, A/H3N2 and B vaccine strains wereshed by 13%, 5% and 12% of participants in thistrial;[43] however, it should be noted that the B
vaccine virus was the predominant virus (72% ofsubjects vs 31% and 12% of subjects who shed
H1N1 or H3N2 viruses) to be shed in young children aged 9–36 months in another trial.[49] The
incidence of viral shedding was shown to be associated with a number of factors, including patientage and baseline serostatus.[43]Similar findings were seen in a challenge study,
in which H1N1 virus shedding was shown to be
associated with post-vaccination (but pre-challenge)

Table XIV. Immunogenicity of live attenuated influenza vaccine (LAIV) [frozen formulation] in healthy adults. Results of a challenge study(see table X for trial design details and vaccine dosage regimens) in which the antigenic composition of LAIV and trivalent inactivated influenza
vaccine (TIV) met the WHO recommendations for the preparation of the influenza vaccine for the 1995/1996 influenza season in the northernhemisphere (table I).[37] Analyses are for results determined post-vaccination but pre-challenge
Seroresponse ratesa [%] (no. of subjects)

VaccineNo. of adults

GMT pre-/post-vaccination
H1N1

H3N2

B

H1N1

H3N2

B

LAIV + IM PL

29–30

4.8/9.8

6.1/14.3

18.8/19.4

7 (23)

10 (33)1 (3)TIV + IN PL

33

4.9/199.0*

11.0/99.5*

17.4/133.5*

30 (91)*25 (76)*25 (76)*

IM PL + IN PL

32–33

5.8/11.8

9.3/11.9

15.3/15.3

5 (16)

2 (6)

0 (0)

a

Serum samples were collected 28 d post-vaccination.

GMT = geometric mean titre; IM = intramuscular; IN = intranasal; PL = placebo. * indicates a statistically significant difference vs IM PL + IN PL(p-value not available).

ª 2011 Adis Data Information BV. All rights reserved.

Drugs 2011; 71 (12)Carter & Curran

1612

serum HI antibody levels in young children(n = 222) [see table X for trial design details andvaccine dosage regimens].[48] Regardless of whether
subjects had received LAIV or placebo, children
who were seropositive for HI antibodies to H1N1
post-vaccination but pre-challenge appeared to
be protected from the H1N1 challenge virus,
as demonstrated by the low rate of H1N1 virus
shedding seen in seropositive LAIV or placebo
recipients (2% and 0% of subjects).[48] However,
the rate of H1N1 virus shedding was significantly
lower in LAIV than placebo recipients (9% vs37%; p = 0.001) who were seronegative for H1N1
antibodies pre-challenge, suggesting that H1N1
HI antibodies were not the only factors protecting against H1N1 virus challenge in LAIV
recipients.
Pre-challenge levels of IgA antibody to H1N1
in nasal wash specimens were also associated withprotection against H1N1 virus challenge with regard to viral shedding rates.[48] In children withnasal wash IgA antibody present pre-challenge,
1% of LAIV recipients and 13% of placebo recipients shed H1N1 challenge virus. In contrast,
in children without nasal wash IgA antibody present pre-challenge, H1N1 challenge virus was shedin 12% and 36% of LAIV or placebo recipients(p < 0.01 vs placebo).
4.6 Transmission Study

The rate and probability of LAIV virus transmission was assessed in healthy young children ina double-blind trial (see table X).[49] All children
were required to attend daycare for at least 3 days
per week for at least 4 hours per day and to be incontact with at least four other study participants, including at least one subject who received
LAIV.
Despite the high rate of viral shedding occurring in this study (section 4.5), the rate of viraltransmission was low.[49] There was one confirmed
episode of LAIV virus transmission (a type B
vaccine strain) to a placebo recipient during the
21-day follow-up period, and two other episodes
which were regarded as possible but unconfirmed
transmissions. Thus, the rate of transmission (calculated using the one confirmed case) was 1.01%ª 2011 Adis Data Information BV. All rights reserved.

in the all-available transmission population (n = 99)
and 1.75% in the all-evaluable population (n = 57).
Importantly, the one confirmed case of transmission did not lead to disease, and the clinicalsigns and symptoms occurring in this child weresimilar to those seen in other study children, regardless of whether they had received LAIV orplacebo.
According to results of a post hoc exploratory
analysis using the Reed-Frost model, and assuming a single confirmed transmission, the probability of LAIV virus transmission was calculated
to be 0.58%, 1.16%, 1.73%, 2.3% and 2.87% inplacebo recipients who were in regular contact
with one, two, three, four or five LAIV-vaccinatedchildren, respectively.[49]Of note, the phenotypic characteristics of theLAIV virus strains (i.e. cold adaptation andtemperature sensitivity) were preserved in all shedviruses, indicating the phenotypic stability of thevaccine.[49]4.7 Cell-Mediated Immunity

LAIV (refrigerator-stable formulation, where
specified[31]) increased cell-mediated immunity(CMI), according to data from several trials.[31,52,53]
For example, LAIV (refrigerator-stable formulation) at a recommended dose (i.e. 107.0 – 0.5
FFUs) elicited a CMI response in young children(n = 162) participating in an exploratory immunogenicity study in the northern hemisphere (seetable XV).[31] The median number of interferong-secreting peripheral blood mononuclear cells in
post-vaccination serum samples after in vitro stimulation with inactivated monovalent H1N1, H3N2
or B influenza virus antigens increased by up to
130-fold in all children and 213-fold in seronegative
children who received LAIV at a dosage of 107
FFUs of live attenuated influenza virus reassortants(table XV). In contrast, no response was seen insamples from subjects who received LAIV at alower-than-recommended dose (i.e. 105.0 – 0.5 FFUs)[section 5] or placebo, and the response to TIV wasminimal.
A large (n = 2172) field study conducted on thebasis of these results indicated that, unlike TIV,
which only elicited CMI responses in children
Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

1613

Table XV. Effect of live attenuated influenza vaccine (LAIV) [refrigerator-stable formulation] on cell-mediated immunity in an exploratory
immunogenicity trial. Children aged 6 to <36 months received a single dose of LAIV containing 107 fluorescent focus units (FFUs) or <105 FFUs
of live attenuated influenza virus reassortants, trivalent inactivated influenza vaccine (TIV) or placebo (PL).a The antigenic composition ofLAIV met the WHO recommendations for preparation of the influenza vaccine for the 2001/2002 influenza season in the northern hemisphere(table I)
Vaccine (no. of children)

Median number of IFNa-secreting PBMCs (SFC per 106)b
all subjects

seronegative subjects

H1N1

H3N2

B

N1N1

H3N2

B

LAIV 107 FFUs (3–5)

55

67

130

55

104

213

LAIV <105 FFUs (3–11)

1

1

1

1

1

1

TIV (3–9)

3

3

1

1

1

1

PL (2–9)

1

1

1

1

1

1

a

The median number of IFNg-secreting PBMCs in pre-vaccination serum samples after in vitro stimulation with inactivated monovalent
H1N1, H3N2 or B influenza virus antigens was 1 SFC per 106 PBMCs in all treatment groups for all antigens, regardless of baseline
serostatus.

b

Assessed using enzyme-linked immunosorbent spot assay in post-vaccination serum samples (day 13).

IFN = interferon; PBMCs = peripheral blood mononuclear cells; SFC = spot-forming cells.

with detectable levels of pre-existing antibody
against influenza virus, LAIV at the recommended dose elicited CMI responses in children withno detectable antibody at baseline and in whom
the risk of acquiring influenza infection is potentially the highest.[31] CMI played a significant
role in protection against community-acquired
influenza infection, with further analyses indicating that the majority of children with ‡100
spot-forming cells (SFCs)/106 peripheral bloodmononuclear cells (PBMCs) could be considered
seroprotected against influenza infection.
CMI response to LAIV (2004/2005 northernhemisphere) was also seen in another study, which
reported a significantly (p £ 0.0056) higher adjusted
geometric mean percentage (aGMP) of influenza A
virus-reactive interferon (IFN)g-secreting CD4+
T cells and CD8 T cells (determined in PBMC
cultures that had been stimulated with a live wildtype H3N2 influenza virus of the same strain asthat contained in the vaccines) at day 10 and 28
post-vaccination than at baseline in children aged
5–9 years but not in recipients aged 22–49 years.[52]Furthermore, the T-cell response elicited by LAIV
appeared to be higher in children than in adults,
as demonstrated by a significantly (p £ 0.0363)
higher fold change in the aGMP of influenza A
virus-reactive IFNg-secreting CD4+ T cells and
CD8 T cells in children than in adults at day 10
or 28.
ª 2011 Adis Data Information BV. All rights reserved.

In this same study, LAIV was associated witha greater CMI response than TIV in children,with the fold change in the aGMP of influenza A
virus-reactive IFNg-secreting CD4+ T cells and
CD8 T cells being significantly (p £ 0.0226) higher
in children receiving LAIV than in those receiving
TIV at day 10 and 28.[52] CMI response to LAIV
and TIV did not differ significantly in the adult
population.
Further analysis revealed that CMI response(defined as the fold change from baseline to day 10
in the aGMP of influenza A virus-reactive IFNgsecreting CD4 T cells, CD8 T cells, CD56brightnatural killer [NK] cells and CD56dim NK cells)
was significantly (p < 0.05) and inversely correlated with pre-vaccination GMPs of these cells
in adults, and that the correlation appeared to
be stronger in LAIV than TIV recipients.[52] Although inverse correlations with baseline GMPs
were also seen in children, not as many reachedsignificance compared with the comparisons inadults.[52]LAIV (2004/2005 northern hemisphere) was
also shown to induce effector B-cell responses
7–12 days post-vaccination in children aged
5–9 years and adults aged 21–48 years, and these
responses were similar in magnitude to those seen
with TIV.[53] However, in contrast to TIV, which
increased the percentage of circulating memory B
cells 1 month post-vaccination, LAIV did not.
Drugs 2011; 71 (12)Carter & Curran

1614

4.8 Cross Immunogenicity

The cross immunogenicity of LAIV has notbeen formally assessed. However, in one of the
key immunogenicity studies conducted in young
children discussed in section 4.2 (see tables X andXII for study design details and immunogenicity
results), LAIV (frozen formulation) elicited an
HI antibody response to the H3N2 viral strain
contained in the vaccine for the second study
season (1997/1998), as well as to the antigenicallydistinct H3N2 influenza strain, A/Sydney/5/97, that
became a major cause of influenza in 1997.[23]Cross-reactive antibodies to this variant strain
were seen in 98% of children receiving LAIV and
60% of those receiving placebo. In addition, GMTsof HI antibody to this variant strain were significantly (p < 0.01) higher in LAIV than placebo
recipients (68 vs 12).
4.9 Coadministration with Other Vaccines

The immune response against LAIV (frozen
formulation) in young, healthy children aged
12–15 months was equivalent to the response
against LAIV when coadministered with the MMR
and varicella vaccines in terms of seroconversion
rates and post-vaccination GMTs for HI antibodies (see tables X and XVI for study design
details, immunogenicity results and equivalencecriteria).[44] The immune response was also sim-

ilar in baseline seronegative patients against
MMR and varicella vaccines with, and without,concomitant LAIV administration.
In healthy children aged 6–36 months, the immunogenicity of LAIV (refrigerator-stable formulation) when coadministered with the oral
poliovirus vaccine (OPV) was noninferior to thatof LAIV alone (table XVII), and the immunogenicity of OPV when coadministered with LAIV
was noninferior to that of OPV plus intranasal
placebo (data not shown), supporting the combined use of the two vaccines (see tables X and XVII
for study design details and noninferiority criteria).[45] Of interest, seroconversion rates to the
H1N1 component of LAIV (p = 0.002 after one
dose of LAIV and p = 0.015 after two doses) and
GMTs for this component (p-values not available) were significantly higher in the group ofpatients receiving LAIV plus OPV than in thegroup receiving LAIV alone (table XVII).
5. Dosage and Administration
Each dose of LAIV has been formulated tocontain 106.5–7.5 FFUs of each of three live attenuated virus reassortants that the WHO expects tobe circulating in the community in the upcoming
winter.[12] The refrigerator-stable formulation ofLAIV is used in preference to the frozen formulation because of improved storage convenience.

Table XVI. Immunogenicity of intranasal live attenuated influenza vaccine (LAIV) [frozen formulation] when coadministered with subcutaneous measles, mumps and rubella vaccine (MMR) and subcutaneous varicella vaccine (VAR).[44] Although there were three treatment
arms in this study (see table X for study design details and vaccine dosage regimens), seroconversion rates and GMTs for influenza vaccine
strains are only available for two of the treatment arms. The antigenic composition of LAIV met the WHO recommendations for the preparationof the influenza vaccine for the 2000/2001 influenza season in the northern hemisphere (table I)

Seroconversion rate (% of pts)

Vaccine regimen

No. of children

H1N1

H3N2

B

LAIV + MMR + VAR

286–319

42.6

97.9

95.6

LAIV alone

299–328

43.7

98.3

92.1

-1.0 [-8.7, 6.7]

-0.4 [-3.0, 2.0]

3.6 [-0.2, 7.5]
20.5

BGD in seroconversion rates [95% CI]a
GMT post-vaccination

LAIV + MMR + VAR

334

5.7

102.9

LAIV alone

338–339

5.7

112.3

17.7

0.98 [0.85, 1.13]

0.92 [0.81, 1.04]

1.16 [1.03, 1.30]

GMT ratioa [95% CI]a

Influenza strain

The immunogenicity of LAIV administered alone or in conjunction with MMR + VAR was considered equivalent when the lower limit of the
95% CI for the difference in seroconversion rates for the LAIV + MMR + VAR group minus the LAIV alone group was more than -10% for all
vaccine influenza virus strains, and when the lower limit of the 95% CI for the ratio of HI antibody GMTs in the LAIV + MMR + VAR groupcompared with the LAIV alone group was more than 0.5 for all strains.

BGD = between-group difference; GMT = geometric mean titre.

ª 2011 Adis Data Information BV. All rights reserved.

Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

1615

Table XVII. Immunogenicity of intranasal live attenuated influenza vaccine (LAIV) [refrigerator-stable formulation], when coadministered withoral poliovirus vaccine (OPV) [see table X for study design details and vaccine dosage regimens].[45] The antigenic composition of LAIV met the
WHO recommendations for the preparation of the influenza vaccine for the 2002 influenza season in the southern hemisphere (see table I).
Because OPV was obtained from a variety of sources, according to regional preferences and vaccine availability, the antigenic composition of
OPV varied across study sites
Seroconversion ratea,b (% of children)

GMT pre-/post-vaccinationb

Vaccine regimen

No. of children

H1N1

H3N2

B

H1N1

H3N2

B

LAIV + OPV

707–713

58.2*

60.4

25.2

7.6/32.8

7.9/49.0

2.9/4.8

LAIV

724

51.7

58.7

22.9

6.1/20.6

7.3/40.7

2.9/4.7

OPV + PL713–722

2.2

4.1

3.5

6.9/6.9

7.8/8.3

2.9/3.0a

The immunogenicity of LAIV when coadministered with OPV was considered noninferior to that of LAIV alone because the lower limit of the
90% CI for the difference between the two treatment arms (LAIV + OPV minus LAIV) in seroconversion rates was greater than -10%
(quantitative data not available). Seroconversion rates were defined as the proportion of subjects with a ‡4-fold increase from pre- to postvaccination in HI antibody levels.

b

At day 35 – 7 after second LAIV dose.

GMT = geometric mean titre; PL = placebo; * p = 0.015 vs LAIV.

In the US, LAIV is indicated for active immunization in individuals aged 2–49 years for theprevention of disease caused by the influenza
virus subtypes A and B contained in the vaccine.[12] The recommended dosage of LAIV inchildren aged 2–8 years who have not previously
received influenza vaccination is two 0.2 mL dosesof the refrigerator-stable formulation administered intranasally at least 1 month apart. Only
one annual dose of LAIV is recommended inchildren aged 2–8 years who have previously received influenza vaccination, and in children,
adolescents or adults aged 9–49 years.
Concomitant use of LAIV with aspirin (oraspirin-containing drugs) is contraindicated inchildren and adolescents aged 2–17 years, becauseof the association between aspirin and Reye’s
syndrome (a serious, acute encephalopathy thatis associated with liver dysfunction[54]) in thesetting of febrile illnesses, such as wild-type influenza infection.[12] Administration of LAIV toindividuals with known systemic hypersensitivity
reactions to egg proteins (a vaccine component),
gentamicin, gelatin or arginine, or those whohave previously had a life-threatening reaction to
influenza vaccination, is also contraindicated.[12]LAIV should not be administered to children
aged <24 months or, in the US, to individuals withasthma or children aged <5 years with recurrent
wheezing, unless the benefits of treatment are shownto outweigh the risks (section 3).[12] Because of lackof reactogenicity data in individuals with severeª 2011 Adis Data Information BV. All rights reserved.

asthma or active wheezing, LAIV should not be
administered to individuals with these conditions.
Careful consideration of the benefits and risks
of LAIV treatment is also recommended in individuals who have previously developed GuillainBarré syndrome within 6 weeks of influenza vaccine
administration, immunocompromised patients andpatients with medical conditions that may predispose them to complications following wildtype influenza infection.[12]Only limited data are available regarding theuse of LAIV in pregnant women. Although animalstudies do not indicate direct or indirect harmful
effects during pregnancy, the use of the LAIV vaccine is not recommended in pregnant women.[12]Local prescribing information should be consulted for other specific details of indications,warnings, contraindications and precautions.
6. Place of Intranasal Live AttenuatedInfluenza Vaccine in the Prevention of
Seasonal Influenza
Vaccination remains the most effective meansof preventing seasonal influenza,[2,55,56] and the
CDC recommends routine, annual vaccination of
all individuals aged ‡6 months.[2] However, thefocus should still be on individuals who are athigher risk of influenza-related complications
than others, particularly in times when vaccine isin short supply. Individuals at higher risk thanothers include (but are not limited to) children
Drugs 2011; 71 (12)1616

aged 6 months to 4 years, adults aged ‡50 years,
those with chronic diseases or immunosuppression,
those living in chronic-care facilities, pregnant
women and anyone who is in regular contact withsuch individuals.[2]In 2009, the CDC recommendations for routine influenza vaccination were predominantly
for individuals who were at higher risk or incontact with individuals at higher risk of influenzarelated complications, although recommendations
were also extended to children aged 5–18 years
for the first time that year.[57] Therefore, the only
group of individuals for whom routine vaccination was not specifically recommended at thistime were healthy non-pregnant adults aged
19–49 years who had no known risk factors for
influenza-related complications or were not in
contact with any high-risk individuals.[57] However,it was noted that influenza-related complications
still occurred in the latter group of individuals,
and that perhaps a proportion of them might
actually have medical conditions or age-relatedrisks for which they were unaware that routine
influenza vaccination was recommended.[2] Furthermore, the possibility of continued circulationof 2009 pandemic influenza A/H1N1-like virusesin the upcoming influenza season(s) was particularly concerning with regard to this group because the incidence of influenza-related complications was much higher in these individuals during
the 2009 influenza pandemic than during normal
influenza seasons. For these reasons, the CDC
recommendations for routine influenza vaccination
were expanded to include healthy non-pregnant
adults aged 19–49 years who had no risk factors
for complications or were not in regular contact
with people who did.[2]The 2010/2011 season represents the first season that the expanded CDC recommendations
took effect. Overall, in the US, the seasonal influenza vaccination coverage was estimated to be
43%, according to interim data obtained from the
Behavioral Risk Factor Surveillance System andNational Immunization Survey.[58] In particular,
the vaccination coverage in children aged 6 months
to 17 years was estimated to be 49%, a moderateincrease (6.75%) on the previous season. The highest
overall estimated vaccination rates were in chilª 2011 Adis Data Information BV. All rights reserved.

Carter & Curran

dren aged 6 months to 4 years (61%) and in adults
aged ‡65 years (69%).[58] Of note, there was no
significant increase in the rate of vaccination for
adults aged 18–49 years for this season from theprevious 2009/2010 season (30.2% vs 30.3%).
Thus, even in the 2010/2011 influenza season,
influenza vaccination coverage rates remained below the 80% (in children aged 6 months to 17 years,
noninstitutionalized adults aged 18–64 years
and pregnant women) and 90% (in noninstitutionalized high-risk adults aged 18–64 years,
noninstitutionalized adults aged >65 years, institutionalized adults aged >18 years and health-care
workers) targets set out in the US-based Healthy
People 2020 national objectives.[59]Barriers to routine seasonal influenza vaccination are most likely similar to those that havebeen identified as barriers to pandemic influenza
vaccination.[60] These include the perception thatthe vaccine is not needed, because the risk of influenza infection or associated complications isperceived to be low, and concerns regarding adverse events and/or the effectiveness of the vaccine.[60] The same questions and concerns are sharedby the general public and healthcare workers
alike, and are related to a lack of knowledge regarding influenza illness.[60] In order to convince
the public that seasonal influenza vaccination isimportant, it is likely that they must first be convinced that influenza can be serious and thatvaccination is effective in preventing the illness.[60]One way in which rates of vaccination may be
increased is by educating healthcare workers andencouraging them to receive routine seasonal influenza vaccination themselves.[60] Not only would
this prevent transmission of influenza virus to patients and other colleagues but, at the recommendation of a trusted healthcare worker, the generalpublic is more likely to accept vaccination also.[60]A number of influenza vaccines are available
for the prevention of seasonal influenza, including LAIV and numerous TIVs. According to
the CDC recommendations, neither LAIV nor
TIV is recommended over the other for seasonal
influenza protection in healthy non-pregnant individuals aged 2–49 years.[2] However, because
LAIV is not approved for use in children <2 years(because of the increased risk of hospitalization
Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

or wheezing[12] [section 3]) or in adults aged
50–64 years (because vaccine efficacy was notdemonstrated in this population[12]) or ‡65 years(reason not stated), TIV vaccines are recommended for use in these individuals.[2] TIV vaccines arealso recommended in the US for use in patients with chronic medical conditions who are athigh risk of influenza-related complications, because the efficacy and safety of LAIV has notbeen established in these individuals.[2]LAIV offers a number of advantages over TIV
and, because of these, the WHO is focusing efforts on expanding the production of LAIV aspart of the global pandemic influenza action plan
(GAP) to increase global pandemic influenza
preparedness.[61] A live influenza A/H1N1 monovalent vaccine was among the first vaccines to beapproved for the prevention of influenza causedby the 2009 pandemic influenza A/H1N1 virus.[62,63]
The advantages of LAIV, as identified by theWHO, include the needle-free mode of administration, which could potentially ‘‘facilitate mass
immunization and be safer’’, the intranasal modeof delivery, which is ‘‘expected to elicit a similar
immune response to natural infection’’ and theadministration of a live replicating vaccine which‘‘might induce a broader immune response’’.[11]Other advantages identified were the speed atwhich LAIV could be produced (within 1 year vs
1–2 years for TIV), the higher number of doses
which could be obtained per egg (30–50 times morethan TIV) and the straightforward technology.[11]In addition, the average capital investment costrequired to create the capacity to produce one
dose of seasonal influenza vaccine per year was
lowest ($US0.20) for LAIV compared with otheregg-based or cell-culture based vaccines, including cell culture-based LAIV,[64] which is currently
being investigated in a proof-of-concept trial.[65]These advantages were all thought to be particularly attractive for resource-poor countries.[11]Although the WHO GAP focused on the advantages of the production and use of LAIV in apandemic influenza setting, the majority of benefits associated with its use in this setting also
apply in the seasonal influenza setting.
LAIV is an intranasally administered seasonal
influenza vaccine that contains three live, geneticª 2011 Adis Data Information BV. All rights reserved.

1617

reassorted viruses.[6] Originally approved in aformulation that required freezing, it has now
been replaced by a refrigerator-stable formulation (section 1).[16] In phase III trials, LAIV was
not always associated with high rates of seroconversion, particularly in older children andadults, and in subjects who were seropositive fora particular influenza strain at baseline (section 4).
Despite the low (or inconsistent) rates of seroconversion seen in most of the trials reviewed in
section 4, LAIV demonstrated efficacy in protecting against seasonal influenza infection invarious clinical trials (section 2).
One of the most likely reasons for LAIV efficacy in the absence of a serum antibody responseis the CMI response elicited by the vaccine.[48]In an exploratory immunogenicity study conducted in young children aged 6 to <36 months,
seroconversion rates ranged from 20% to 70%,
depending on influenza viral strain. However,strong CMI responses were seen in LAIV recipients in this study and, unlike TIV, which
generally only elicited CMI responses in subjects
with detectable levels of pre-existing antibody
against influenza virus,[31] LAIV, at the recommended dose, generated responses in young children with no detectable HI assay titres at baseline(section 4.7).
Furthermore, in a field efficacy study conducted on the basis of these results, it was shownthat CMI played a significant role in protection
against community-acquired influenza infection,and further analysis indicated that the majority ofchildren with ‡100 SFCs/106 PBMCs could beconsidered seroprotected against clinical influenza(section 4.7).[31] Because of this, it was proposedthat this may represent a target for protection in
future influenza vaccine development. However,further investigation is required.
Mucosal (nasal) response was also proposed
to be involved in the mechanism of action of
LAIV. In a subgroup of young children participating in one of the key immunogenicity studies,
seropositive LAIV recipients were 4.5 times more
likely to develop a mucosal immune responsethan a seroresponse, indicating that mucosal immune response may be the only indication of a
vaccine take in seropositive children (section 4.2). Of
Drugs 2011; 71 (12)1618interest, results of a challenge study demonstrated
that the presence of post-vaccination serum HI
antibody or nasal wash IgA antibody to H1N1
antigen in young children was correlated withsignificant protection from H1N1 challenge, as
indicated by lower rates of viral shedding in thesechildren than in those with no post-vaccination
serum HI antibody or nasal wash IgA antibody
detected (section 4.5).
Further immunogenicity studies indicated thatthe rate of viral shedding after LAIV administration may decrease with increasing age, andthat it might be higher in subjects who were seronegative/serosusceptible to a particular influenza
viral strain at baseline than in those who wereseropositive for that strain (section 4.5). Viral
shedding is the process by which infectious vaccine viruses may be cultured from nasal secretions
after vaccine administration, meaning that there
is a theoretical possibility that infectious viruses
may be transmitted to non-vaccinated individuals.[43] However, despite the high rate of viral
shedding (80%) seen in young children aged
9–36 months who attended daycare in a doubleblind, randomized trial (section 4.5), the rate
(1.01–1.75%) and probability (0.58–2.87%, depending on the number of LAIV-vaccinated children
in the group) of viral transmission to other daycare attendees who received placebo was low(section 4.6). Of note, the one case of confirmed
transmission observed in this study did not leadto influenza illness (section 4.6). Results of another viral shedding study discussed in section 4.5
confirmed that there was a theoretical risk of
LAIV virus transmission from children to adults
or other children, or from adults to children.[43]This conclusion was based on a comparison ofshed virus titres observed in the study. However,
the risk of transmission was thought to be highly
unlikely after 5–7 days post-vaccination, and theactual amount of transferred virus (i.e. pickedup from droplets on counter surfaces, etc.) was
expected to be lower than the quantity actually
recovered from the mucosa.[43] These results support the current CDC recommendation for LAIV
recipients to avoid contact with severely (but notless severely) immunosuppressed patients for atleast 7 days after vaccination.[2,43]ª 2011 Adis Data Information BV. All rights reserved.

Carter & Curran

Although the cross immunogenicity of LAIV
has not been formally assessed, an HI antibody
response was elicited to an H3N2 viral strain that
was antigenically different to the one contained in
the vaccine (and became the major cause of influenza that season) after LAIV administration in
one of the key immunogenicity studies conductedin young children (section 4.8). In this study,
cross-reactive antibodies to the variant H3N2
strain were seen in 98% of LAIV recipients.
Seroresponse rates elicited by LAIV did not
significantly differ from those elicited by TIV inchildren with HIV infection (section 4.4.1). In
contrast, LAIV did not appear to be immunogenic in adults with HIV infection in terms ofseroresponse rates (section 4.4.2). In addition,
results of these studies demonstrated that LAIV
did not affect HIV replication in HIV-infectedsubjects in terms of changes in plasma HIV RNA
levels or CD4 cell counts. However, because of
the potential risks associated with administrationof a live vaccine to immuncompromised patients,
the manufacturer’s US prescribing information
recommends careful consideration of the risks
and benefits before deciding to use LAIV in suchpatients.[12]Other immunogenicity studies showed that theimmunogenic response to LAIV in young healthy
children was not affected by concomitant administration with the MMR and varicella vaccinesor OPV, and that the immunogenic response to
the MMR and varicella vaccines or OPV was notaffected by concomitant administration with
LAIV (section 4.9).
The efficacy of LAIV in adults was investigatedin two randomized, double-blind, multicentre
studies (section 2.2). In a placebo-controlled study
conducted in healthy working adults, there wasno significant difference between LAIV and placebo in the incidence of febrile illnesses occurring
during the peak influenza outbreak period (primary endpoint) [section 2.2.1].[32] However, LAIV
was significantly more effective than placebo interms of other endpoints, including the numberof febrile illnesses meeting the criteria for URTIs
or severe febrile illnesses, which were thought
to be have more specificity for true influenza
illnesses.[32] LAIV was also associated with a
Drugs 2011; 71 (12)Intranasal Live Attenuated Influenza Vaccine: A Review

reduction in work absenteeism and healthcare
provider use (section 2.2.1).[32] Moreover, theduration of illness was shorter in the LAIV population than in the placebo population and there
was less antibacterial or over-the-counter drug
use in LAIV recipients with febrile illness (primary endpoint) or febrile upper respiratory tract
illness.[32] Given that antibacterials are not effective against viral illnesses, the lower antibacterial
use in LAIV recipients indicates that LAIV vaccination may actually help to control the emergence of antimicrobial resistance.[32]In a placebo- and active-comparator study,
conducted in adults in a ‘real-world’ setting, LAIV
significantly reduced the incidence of symptomatic,laboratory-confirmed influenza compared withplacebo (primary endpoint) [section 2.2.2].[33] However, TIV was associated with a 50% greater reduction in the primary endpoint than LAIV inthis study.[33] Because LAIV must ‘infect to protect’,[10] it is possible that the difference in vaccine
efficacy demonstrated in this study was related to
an inability of LAIV to infect, potentially becauseof HI antibodies which may be present because ofprior exposure to similar viral influenza strains.[33]However, this does not appear to be a limitation in young children, who are less likely thanadults (or older children) to have had previous
exposure to influenza viruses.[10] In randomized,
double-blind, multicentre studies conducted inchildren aged £71 months, LAIV was effective inpreventing culture-confirmed influenza caused byviral strains that antigenically matched those in
the vaccine and/or in preventing culture-confirmed
influenza caused by any viral strain (each a primary endpoint in two trials) [section 2.1.1]. In
addition, the absolute efficacy of LAIV in preventing culture-confirmed influenza caused byantigenically matching viral strains was up to89% (primary endpoint in one trial). The vaccine
was effective in both study years of each of thetrials, even in years when the circulating strains of
H3N2 virus did not match those contained inseasonal vaccines, including those contained in
LAIV.
LAIV also demonstrated statistical superiority
over TIV in protecting against antigenicallymatching vaccine influenza strains (primaryª 2011 Adis Data Information BV. All rights reserved.

1619

endpoint), or against any influenza viral strain
in healthy young children aged 6–59 months
participating in a randomized, double-blind,multinational study (section 2.1.3). Furthermore,
LAIV was statistically more effective than TIV inpreventing against culture-confirmed influenza
illness caused by antigenically matching (primary
endpoint of both trials) and/or mismatching viralstrains in children with recurrent RTIs, and inchildren or adolescents with asthma (section 2.1.3).
Although it appeared that the relative efficacy of
LAIV compared with TIV might be higher in older
compared with younger children with recurrent
RTIs,[20] the discrepancy was thought to be caused
by a difference between the two age groups in theincidence of influenza A/H3N2 versus A/H1N1
and B, and no such difference was shown whendata were analyzed by strain in each age group.[29]Not only did LAIV provide direct immunity inclinical trials, but the vaccine also appeared toprovide indirect (herd) protection to the community, as demonstrated by the lower rates ofschool absenteeism, medically attended acuterespiratory illness and fever or influenza-like illness seen in intervention areas than in comparison areas in three large community-based studies(section 2.3).
LAIV was generally well tolerated in clinical
trials, with most adverse events being mild tomoderate in severity (section 3). Runny nose/
nasal congestion was the most commonly occurring LAIV-associated adverse event in all age
groups. Study discontinuations due to adverse
events were infrequent, and vaccine-related serious adverse events were not seen in most age
groups.
However, LAIV was associated with an increased incidence of medically attended asthma
events in children aged 18–35 months in a large
safety analysis,[38] and an active-comparator trial
conducted on the basis of these results demonstrated a higher incidence of medically significant
wheezing in children aged <24 months receiving
LAIV than in those receiving TIV (section 3.1.3).[19]In addition, more children aged 6–11 months
with a history of wheezing were hospitalized in
the LAIV than in the TIV group in the activecomparator study.[19] In addition, it was noted
Drugs 2011; 71 (12)Carter & Curran

1620

that LAIV recipients aged 6–11 months had asignificantly higher rate of hospitalization fromany cause than TIV recipients (section 3.1.2). Basedon these results, LAIV is not approved for use
in children <2 years of age.[12] In addition, themanufacturer’s US prescribing information statesthat LAIV should not be used in asthmatic subjects
or children aged <5 years with recurrent wheezing
unless the benefits outweigh the risks.[12] In addition, use in subjects with severe asthma or active
wheezing is not recommended (section 5).[12]In conclusion, LAIV is a trivalent, seasonal
influenza vaccine that is nasally administered andis effective and well tolerated in children, adolescents and adults. LAIV was more effective than
TIV in children, although this advantage was notseen in studies in adults. In the US, LAIV is indicated for the active immunization of healthy
subjects aged 2–49 years against influenza diseasecaused by virus subtypes A and type B containedin the vaccine.
Disclosure
The preparation of this review was not supported by any
external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity
to comment on this article. Changes resulting from comments
received were made by the author on the basis of scientific andeditorial merit.

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Correspondence: Natalie J. Carter, Adis, a Wolters Kluwer
Business, 41 Centorian Drive, Private Bag 65901, Mairangi
Bay, North Shore 0754, Auckland, New Zealand.
E-mail: demail@adis.co.nz

Drugs 2011; 71 (12)