Safety of live attenuated influenza vaccine (LAIV) in children and adults with asthma: a systematic literature review and narrative synthesis

ABSTRACT

Introduction

Asthma is one of the most common chronic respiratory conditions worldwide and can be exacerbated by influenza. Findings from early trials demonstrated a higher risk of medically significant wheezing in otherwise healthy young children (aged 6 − 23 months) following administration of the Ann Arbor-backbone live attenuated influenza vaccine (LAIV-AA). In more recent years, several additional studies have investigated the safety of LAIV-AA in older children (2 − 17 years of age) and adults with asthma or prior wheezing, but these findings have not yet been systematically evaluated.

Areas covered

We conducted a systematic literature review to assess and synthesize the evidence from all available studies on the safety of LAIV-AA in people aged 2 − 49 years with a diagnosis of asthma or recurrent wheezing.

Expert opinion

Fourteen studies over 20 years, involving a total of 1.2 million participants, provided evidence that LAIV-AA was well tolerated with no safety concerns in individuals aged 2 − 49 years with a diagnosis of asthma or recurrent wheezing. These data can help inform guidelines for use of LAIV-AA in children and adults with a history of asthma or recurrent wheezing.

KEYWORDS:

• Adults
• asthma
• children
• live attenuated influenza vaccine
• safety
• wheeze

1. Introduction

Asthma is one of the most prevalent chronic respiratory conditions worldwide, affecting an estimated 339 million people globally [1]. Among children, asthma is the most common chronic disease, with an estimated 14% of all children globally having been diagnosed with asthma at some point in their lives [2,3]. Influenza can be associated with asthma complications as it can cause further inflammation of the airways and lungs, worsening asthma symptoms, and triggering acute asthma exacerbations [4]. Children with asthma have higher rates of influenza associated hospitalization compared with healthy children/children without asthma [5,6].

Vaccination remains the most effective method of preventing influenza [7,8], with public health and medical experts, along with stakeholder groups such as the United States (US) Advisory Committee on Immunization Practices (ACIP) and Canada’s National Advisory Committee on Immunization recommending that children and adults with asthma receive an annual influenza vaccine [4,9,10]. In the United Kingdom (UK), influenza vaccination is offered to everyone 6 months and older with severe asthma [11]. Influenza vaccination is effective in reducing the number and severity of respiratory infections and can prevent asthma exacerbations. Importantly, influenza vaccination demonstrated vaccine effectiveness of 59–78% for the prevention of asthma attacks leading to emergency visits and/or hospitalizations [12].

Live attenuated influenza vaccine (Ann Arbor-backbone; LAIV-AA), developed using master donor viruses type A and B (A/AA and B/AA), is approved for use in those aged 2–49 years of age in the US and multiple additional countries [13], and those aged 2–17 years of age in Europe [14]. An early pragmatic, randomized, placebo-controlled safety study of children aged 1–17 years found a significant increase in illnesses coded as reactive airway disease in children aged 18–35 months (risk ratio 4.06; 90% confidence interval: 1.29 to 17.86) [15]. Subsequently, in a randomized study of children aged 6–59 months without a recent episode of wheezing or severe asthma, prospectively defined medically significant wheezing was increased in children aged 6–23 months who received LAIV-AA compared with those who received inactivated influenza vaccine (IIV) [13,16]. This study also demonstrated a higher risk of hospitalization in children aged 6–11 months following administration of LAIV-AA [13].

As a result, clinical guidance via prescribing information and vaccination policy guidelines recommended against the use of LAIV-AA in children younger than 2 years of age, as well as individuals 2 years and older with a history of asthma or wheezing. Current US Food and Drug Administration (FDA) label warnings for use of LAIV-AA in the US note that children younger than 5 years of age with recurrent wheezing and persons of any age with asthma may be at increased risk of wheezing following the administration of LAIV-AA [13,17]. In the US ACIP recommendations, LAIV-AA is listed as a contraindication in children aged 2 − 4 years who have received an asthma diagnosis, or who have had a wheezing episode diagnosed by a healthcare provider in the preceding 12 months. Much like the FDA, the ACIP list asthma in persons aged 5 years or over as a precaution for the use of LAIV-AA [9].

Over the 8 years since the US approval, the safety and efficacy of LAIV-AA in children with a history of asthma or recurrent respiratory infections had been demonstrated [18,19]. As a result, children aged 2 − 17 years with a history of mild to moderate asthma or recurrent wheeze are within the EU indication. Use of LAIV-AA in children and adolescents with severe asthma or active wheezing are listed as a special precaution and warning because these individuals have not been adequately studied in clinical trials. Similar to the US, the EMA recommends that LAIV-AA should not be used in infants and toddlers below 24 months of age because of safety concerns regarding increased rates of hospitalization and wheezing in this population [14].

Following the significant use of LAIV-AA in children in recent years, a number of studies have investigated the safety of LAIV-AA in individuals with asthma or prior wheezing. Findings from these studies have not yet been reviewed as a whole. The aim of this systematic literature review was to assess the available evidence regarding the safety of LAIV-AA in individuals aged 2–49 years with a diagnosis of asthma (any severity) or recurrent wheezing.

2. Methods

This systematic literature review evaluated studies relating to the safety of LAIV-AA in children and adults aged 2–49 years. The systematic review has been registered with PROSPERO (https://www.crd.york.ac.uk/prospero/), ID CRD42020171839. Figure 1 shows the full methodology, including the search, screening, data collection, and narrative synthesis processes.

Figure 1. Full methodology of the systematic literature review, including the search, screening, data extraction, and narrative synthesis processes. LAIV, live attenuated influenza vaccine

2.1. Search strategy and eligibility criteria

The systematic literature search was conducted using the electronic databases PubMed and The Cochrane Database of Systematic Reviews. The following search terms were used: (‘Live attenuated influenza vaccine’ OR LAIV) AND ‘safety’ AND ‘asthma’ OR (‘respiratory sounds’ OR ‘respiratory’ AND ‘sounds’ OR ‘respiratory sounds’ OR ‘wheezing’ OR ‘respiratory’). There were no time restrictions applied to the search criteria.

Table 1 provides an overview of the eligibility criteria for this systematic literature review. Studies were excluded if they did not contain data on Ann Arbor LAIV.

Table 1. Eligibility criteria for studies to be included in the systematic literature review

Criteria
Population/participants/conditions	Children or adults (any sex), aged 2–49 years, with a diagnosis of asthma (any severity) or recurrent wheezing
Interventions or exposures	Vaccination with A/Ann Arbor- and/or B/AA-backbone LAIV-AA administered intranasally Any formulation (monovalent, bivalent, trivalent, or quadrivalent)
Comparisons or control groups	Placebo, trivalent or quadrivalent IIV, unvaccinated or intra-patient comparison
Outcomes of interest	Primary outcome measures:Incidence rates of clinical events in risk window Risk measures expressed as relative risk, odds ratio, incidence rate ratio, hazard ratio, relative incidence, or other appropriate measure Hospitalization rate in risk window Any relevant reactogenic respiratory outcome relating to vaccine safety (e.g. asthma exacerbation or wheezing within 180 days)
Setting	Primary care, inpatient, emergency, or outpatient visits in any country
Study design	Randomized controlled trials, observational studies, retrospective and prospective outcome studies
Language	English
Country	Any

IIV, inactivated influenza vaccine; LAIV, live attenuated influenza vaccine.

2.2. Study selection

Initially, study titles and abstracts were screened for eligibility and were excluded if they clearly did not meet the inclusion criteria. Thereafter, full texts of potentially relevant studies were obtained and reviewed independently by two reviewers to determine eligibility for inclusion. Studies containing duplicate information or not meeting the inclusion criteria upon further review were excluded. Ambiguous decisions were resolved after discussion with the authors.

2.3. Data extraction

Data were extracted into an Excel document to collate and summarize the study design and results. Data extracted included study design, setting, time period, participants, LAIV-AA formulation, comparator, outcome, events in the vaccinated and comparator groups, types of event measured, and key results. Any studies that did not contain data meeting the inclusion criteria during data extraction were subsequently excluded. Meta-analysis was not considered appropriate for this collection of studies due to the variability in outcomes measured, which included hazard ratios, relative risk, odds ratios, spirometry values, change in asthma control test scores, incidence of asthma exacerbation, and rates of adverse events. Hence, a narrative synthesis was performed.

2.4. Synthesis

A narrative synthesis was undertaken to synthesize the findings of the included studies. First, the results of each study were assessed systematically, highlighting the important characteristics (outcomes, age groups investigated, comparators etc.) and key results (safety and reactogenicity data). The studies were then grouped by key outcomes and findings in relation to age group and presented in tabular form. This allowed for comparison of studies with similar outcomes measured and to help identify any patterns. Studies with outcomes not repeated or measured in other studies could not be grouped and were assessed separately. The key implications of the studies were then summarized descriptively following the comparison of the study outcomes.

3. Results

The initial literature search identified 84 records, and from these, 28 full-text articles were assessed for eligibility (Figure 2). Fourteen articles were then excluded as they did not meet the eligibility criteria for the following reasons: no measures of asthma or wheezing (one article), did not report incidence rate/risk measure (four articles), insufficient data regarding safety of LAIV-AA with asthma (one article), duplicate data from other studies (four articles), participants not being within the age range (one article), no comparison for healthy controls (one article), LAIV-AA was not assessed (one article), and no results available as the article was a protocol (one article).

Figure 2. PRISMA flow diagram of systematic literature review search strategy and screening process. LAIV, live attenuated influenza vaccine; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses

A total of 14 studies were retained for the narrative synthesis of the systematic literature review. Detailed characteristics of the studies included in the review are presented in Table 2. Study design was diverse and included: randomized, non-randomized, retrospective, prospective, observational, and non-interventional analysis. The number of subjects with asthma or recurrent wheezing in the studies ranged substantially, from 48 [20] to 166,174 [21]. The included studies were conducted from 1997–1998 [20] to 2016–2017 [22], over 20 influenza seasons.

Table 2. Baseline characteristics and key results for included studies in the systematic literature review

Reference	Influenza season	Study design, including vaccine used vs control	Number of subjects (with asthma/recurrent wheeze) and age group	Type and definition of asthma/wheezing	Primary safety outcome	Key results
Redding et al. [20]	1997	Randomized double blind, placebo-controlled study. Intranasal LAIV3 vs intranasal placebo	48 9–17 years	Stable diagnosed moderate to severe asthma defined as FEV1 < 80% predicted after withholding albuterol for 8 hours	Spirometry values (FEV1)	No significant changes in FEV1 or asthma symptoms within each group post-vaccination and between LAIV3 and placebo groups No SAEs in either treatment group
Piedra et al. [30]	1998–2002	Non-randomized, community-based open-label trial. LAIV3 vs pre-vaccination period	11,096 2–18 years*	History of wheezing or mild, intermittent asthma Mild, intermittent asthma defined as those not using steroids, or bronchodilator therapy daily or every other day	Risk ratio of SAEs and MAARI	No significant increases in risk of healthcare utilization attributed to MAARI and asthma rates compared with pre-vaccination periods No SAEs attributed to LAIV3
Gaglani et al. [23]	1998–1999 and 2001 − 2002	Retrospective analysis of an open-label field trial. LAIV3 (for those without asthma), TIV (for those with asthma) vs reference period^†	2196 2–18 years*	Mild-intermittent asthma or reactive airways disease or intermittent wheezing Children with intermittent wheezing were defined as those with a history of asthma or reactive airways disease or wheezing who did not use steroids (oral or inhaled)	Risk ratio of MAARI during 0–14 and 0–42 days post-LAIV3 were compared with respective reference periods (before day 0 and after 14 or 42 days)	No increased risk for MAARI or asthma exacerbation post-vaccination in LAIV3 recipients with intermittent wheezing
Fleming et al. [18]	2002–2003	Phase III randomized, open-label study. Intranasal LAIV3 vs TIV	2229 6–17 years	Clinical diagnosis of asthma defined as an ICD9 diagnosis code of 493 plus 1 or more prescriptions for asthma medication within the previous 12 months	Incidence of asthma exacerbation (acute wheezing illness associated with hospitalization, unscheduled clinic visit, or new prescription)	No significant differences in incidence of asthma exacerbation post-vaccination between groups Percentage of subjects with reactogenicity events was similar between groups, except for runny nose/nasal congestion, which was significantly higher with LAIV3, and wheeze, which was significantly higher with TIV
Ambrose et al. [24]	2002–2003 and 2004–2005	Retrospective evaluation of 2 randomized, multinational trials. LAIV3 vs TIV	1940 2–5 years	Mild or moderate asthma or a history of wheezing Diagnosis based on investigator judgment	Rates and rate difference of wheezing endpoints	No significant differences in rates of wheezing, lower respiratory illness, and hospitalizations post-LAIV3 vs TIV The incidence of reactogenicity events was similar among LAIV3 and TIV In both studies, the incidence of runny/stuffy nose was generally higher post-LAIV, and the differences were significant after dose 2 in study 1 and dose 1 in study 2
Tennis et al. [25]	2007–2009	Retrospective evaluation of 4 cohorts of children. LAIV3 (formulation based on years studied) vs TIV	42,424^‡ 24–59 months	Asthma was identified based on claims diagnosis; for those with a single outpatient diagnosis, a claim for inhaled SABA was required. Recurrent wheezing was identified based on a claim for inhaled SABA in the prior 12 months with no asthma diagnosis	Type and number of hospitalizations or ED visits within 42 days post-vaccination	Among children with asthma, there was a trend toward fewer LAIV LAIV3 recipients having inhaled corticosteroid dispensed in the past 12 months compared with TIV recipients Among children with wheezing, the frequency of SABA and inhaled corticosteroid use were generally similar in both LAIV3 and TIV recipients No evidence of increased rates of ED visits or hospitalizations 42 days post-vaccination with LAIV3 compared with TIV
Ray et al. [26]	2007–2014	Retrospective case-centered analysis. Monovalent LAIV-AA, LAIV3 and LAIV4 (formulation based on years studied) vs IIV	154,994 2–17 years	History of asthma was defined as those who received at least 1 ICD9 diagnosis code for asthma (493.xx) any time prior to IIV/LAIV-AA immunization. Asthma severity was categorized into [1] current or recent, persistent asthma; [2] current or recent, not persistent asthma; or [3] remote history of asthma Diagnosis based on investigator judgment	Odds ratio of acute asthma exacerbations 1–14 days (risk), and 29–42 days (comparison), after immunization	LAIV-AA was associated with significantly lower odds of inpatient/ED visits for asthma exacerbation during the risk interval compared with IIV for all subgroups except those with a remote history of asthma only LAIV-AA was associated with significantly lower odds (P = 0.04) of asthma exacerbation compared with IIV among children with all asthma types and among those with current or recent, not persistent asthma
Nordin et al. [27]	2007–2016	Retrospective observational cohort study using a pre-post-guideline-controlled design. Guideline recommended Monovalent LAIV-AA, LAIV3 and LAIV4 (formulation based on years studied) cohort vs guideline IIV cohort	4771 2–17 years	Asthma defined as at least two asthma diagnoses (ICD9 diagnosis codes 493.xx) on different days at outpatient, ED, or inpatient visits in the 12 months prior to vaccination	Adjusted ratio of rate ratios of acute, medically attended lower respiratory events	No increase in lower respiratory events, primarily asthma exacerbations or wheezing, or hospitalization risk in the LAIV-AA guideline group vs the IIV group (increase of LAIV-AA use from 23% to 68% in children with asthma in the guideline group compared with an increase of LAIV-AA use of only 7% to 11% in the IIV control group)
Duffy et al. [31]	2008–2011	Retrospective observational cohort study. LAIV3 and monovalent LAIV-AA vs self-controlled risk interval method	11,761 2–49 years	For all cohorts, asthma was defined as any of the following in the previous 12 months: [1] a diagnosis of asthma (ICD-9 code 493.xx) for at least 2 clinic visits, or at least 1 ED visit, or at least 1 hospitalization; [2] for those over 5 years of age, definition also included at least 2 SABA medications dispensed; [3] at least 1 SABA and 1 other asthma medication dispensed. Recurrent wheezing was defined as a child younger than 5 years of age who had at least one of the following in the prior 12 months: [1] at least 2 visits for acute bronchiolitis, bronchitis not specified as acute or chronic, chronic bronchitis, other disease of the trachea or bronchi, wheezing, or other respiratory distress or insufficiency; [2] at least 2 SABA medications dispensed; [3] at least 1 SABA and at least 1 other asthma medication dispensed	Incidence rate ratio of lower respiratory tract events, including asthma exacerbation and wheezing	No significant differences in risk of having a healthcare visit for any reason post-vaccination days 1 to 14 compared with days 29 to 42 No significantly increased risk of lower/upper respiratory AEs or healthcare visits post-vaccination days 1 to 14 compared with days 29 to 42 in children 2–4 years with recurrent wheezing No increased risk of medically attended lower respiratory tract AEs (including asthma exacerbation or wheezing) in the 14 days post-vaccination
Tennis et al. [21]	2009–2010	Retrospective evaluation of 4 cohorts of children. LAIV3 (formulation based on years studied) vs TIV	166,174 24–59 months*	Asthma diagnosis and treatment within the previous 12 months, or recurrent wheezing (with a treatment occurring ≥1 time in the previous 12 months but no asthma diagnosis)	Frequency and type of ED visits or hospitalizations within 42 days post-vaccination	Among children with asthma or recurrent wheezing, hospitalizations and ED visits for lower respiratory conditions were not more frequent post-LAIV3 compared with post-TIV
Baxter et al. [28]	2013–2014	Prospective, non-randomized, observational cohort study. LAIV4 vs IIV and unvaccinated individuals	62,040^§ 2–49 years	History of wheezing or asthma (complementary analysis)	Hazard ratios of medically attended events and hospitalizations during periods at risk immediately after LAIV4 vaccination vs incidence rates during reference periods later in the follow-up period and vs rates in IIV and unvaccinated controls	Risk of any medically attended event not significantly increased with the LAIV4 group vs both the IIV and unvaccinated groups Among children with a history of asthma or wheezing, risk of wheezing post-vaccination was not higher with the LAIV4 group vs both the IIV and unvaccinated groups
Turner et al. [32]	2013–2014	Prospective, multicenter, open-label, phase IV intervention study. Cohort with egg allergy and asthma/recurrent wheeze vs cohort with egg allergy without asthma. Both vaccinated with LAIV3 (formulation based on years studied)	188 2–17 years*	Physicians diagnosis of asthma/recurrent wheeze. Those with a history of severe but stable asthma were not excluded	Primary outcome related to asthma: Incidence of delayed symptoms up to 72 hours post-vaccination, incidence of adverse events of non-allergic cause post-vaccination, change in nasal airway patency	No risk factors were identified for occurrence of an acute AE when assessed for the presence of physician-diagnosed asthma/recurrent wheeze or allergic rhinitis Children with recurrent wheeze or asthma were not more likely to experience AEs or wheeze/cough compared with those without asthma/wheezing within 72 hours post-LAIV3 Wheeze/cough was not more common in children receiving regular inhaled corticosteroids No SAEs were attributable to LAIV3
Caspard et al. [29]	2013–2015	Prospective, non-interventional cohort study. LAIV3/4 vs IIV and unvaccinated individuals	11,463 2–17 years	Diagnosis of asthma (LAIV3/4 and IIV recipients with asthma matched by use of oral steroid prescription and/or hospital admission in past 12 months)	Any hospitalization documented in the linked Hospital Episodes Statistics database within 42 days and up to 6 months post-vaccination	Up to 6 months, hospitalization incidences were lower after LAIV-AA than after IIV, no significant differences between hospitalizations post-LAIV3/4 compared with unvaccinated individuals No medically attended event of interest occurred at an increased rate post-LAIV3/4 vs IIV and unvaccinated controls
Turner et al. [22]	2016–2017	Prospective, multicenter, open-label, phase IV intervention study. LAIV4 vs baseline asthma control/symptoms	478 2–18 years	Current physician-diagnosed moderate to severe asthma and prescribed regular inhaled corticosteroids; children 2–5 years were also eligible if they had 2 or more exacerbations of wheezing in the previous year requiring oral steroids or hospitalization	Change in asthma control before and in the 4 weeks after LAIV4 as assessed by (c)ACT score or TRACK score, and by severity classification	No significant change in asthma control by child age or asthma severity, as assessed by age-appropriate questionnaires No associations between baseline asthma control and odds of asthma exacerbations The rate of acute AEs after immunization was in line with the reported rate of AEs described in the literature for the normal population

*Age group is for asthma and wheezing cohorts included in the review only, ^†Before day 0, after days 14 and 42, ^‡N is for seasons 1 and 2 for both LAIV-AA and TIV recipients in the asthma/recurrent wheezing cohort. ^§N is for total number in study; N for complementary analysis in those with a history of wheezing or asthma not stated.

(c)ACT, (Children’s) Asthma Control Test; AE, adverse event; ED, emergency department; FEV1, forced expiratory volume; ICD, International Classification of Diseases; IIV, inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; LAIV3, trivalent live attenuated influenza vaccine; LAIV4, quadrivalent live attenuated influenza vaccine; MAARI, medically attended acute respiratory illness; SABA, short-acting beta-agonist; SAEs, serious adverse events; SCRI, self-controlled risk interval; TIV, trivalent influenza vaccine; TRACK, Test for Respiratory and Asthma Control for Kids.

The method of comparison also varied within the studies; nine studies used IIV as a control [18,21,23–29], two used unvaccinated controls [28,29], three used a reference time period self-control (a specific time frame pre-vaccination or post-vaccination) [23,30,31], one used placebo [20], One used a cohort without asthma [32], and one used baseline asthma symptoms as the control [22]. The majority of studies (12; 86%) evaluated the safety of LAIV-AA in children and adolescents (aged 2–18 years), whereas only two were performed in adults aged 18–49 years [28,31].

The key results from the studies in terms of outcomes measured are presented in Table 2 with the study details. Notably, no studies found an increased risk of significant clinical outcomes measured post-vaccination with LAIV-AA in children and adolescents with a history of wheeze or asthma. Specifically, no significant differences in the risk of asthma exacerbations, wheezing, or healthcare utilization were identified in LAIV-AA recipients compared with the controls. In two studies, there was a higher incidence of a runny or stuffy nose in children following LAIV-AA [18,24]. LAIV-AA was associated with lower odds of inpatient or emergency department visits for asthma exacerbation compared with IIV [26] in one study, and in another, significantly higher incidences of wheezing were noted in those receiving inactivated trivalent influenza vaccine compared with trivalent LAIV-AA [18].

To aid further comparison, study findings are presented by risk ratio in Figure 3, and by type of outcome measured and age group in Table 3. Approximately 79% of studies evaluated medically attended acute/lower respiratory illness, hospitalizations, emergency department visits, and healthcare utilization, which were investigated across a wide range of age groups, from infants to adults. LAIV-AA was not associated with an increased risk for any of the measured outcomes in any age group investigated (Table 3). Figure 3 demonstrates the range of findings with no outcomes being statistically increased in LAIV-AA recipients versus controls.

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

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

Outcomes investigated	Findings	Age groups
Medically attended lower respiratory events	No increased risk with LAIV-AA compared with IIV [27],*[28], unvaccinated controls [28], or the self-controlled risk interval [31]	2–17 years [27] 2–49 years [28,31]
Hospitalizations/emergency department visits/healthcare utilization	No increased risk with LAIV-AA compared with IIV/TIV [18,21,24–29], a reference period [28], unvaccinated individuals [28,29], pre-vaccination [30] or the self-controlled risk interval [31] Hospitalization incidence lower after LAIV-AA than IIV [29]	2–17 years [26,27,29] 2–49 years [28,31] 24–59 months [21,25] 2–5 years [24] 6–17 years [18] 2–18 years [30]
Vaccine safety signals	No clinically meaningful safety signals associated with LAIV-AA [28]	2–49 years [28]
Wheezing	No increased risk with LAIV-AA compared with IIV [27,28], TIV [24], or unvaccinated controls [28]	2–17 years [27] 2–49 years [28] 2–5 years [24]
Acute asthma exacerbations	LAIV-AA was associated with lower odds of inpatient/emergency department visits for asthma exacerbation compared with IIV for all subgroups except those with a remote history of asthma only [26] No increased risk with LAIV-AA compared with TIV [18] or reference periods [23]	2–17 years [26] (This is for all age groups in the analysis except for those with remote asthma) 6–17 years [18] 2–18 years [23]
Serious adverse events	No serious adverse events attributable to LAIV-AA [20,30,32]	2–17 years [32] 2–18 years [30] 9–17 years [20]
Reactogenicity events	Incidence among LAIV-AA and TIV similar (apart from incidence of runny nose/nasal congestion, which was significantly higher with LAIV3 [18,24], and wheeze, which was significantly higher with TIV [18]	2–5 years [24] 6–17 years [18]
Medically attended acute respiratory illness	No increased risk with LAIV-AA compared with reference [23] and pre-vaccination periods [30]	2–18 years [23,30]
Change in FEV1	No significant changes within group after vaccination with LAIV-AA or between LAIV-AA and placebo groups [20]	9–17 years [20]
Change in asthma control	No significant changes after LAIV-AA compared with pre-vaccination [22]	2–18 years [22]

*Study was looking at LAIV-AA guidelines, the population was not all vaccinated with LAIV.

FEV₁, forced expiratory volume; IIV, inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; TIV, trivalent influenza vaccine.

There was no difference seen in the risk of an asthma associated event when comparing the outcomes measured in children and adults. In the two studies performed in adults aged 18 − 49 years, the outcomes investigated included medically attended lower respiratory events, hospitalizations [28,31], vaccine safety signals, and wheezing [28]. All other outcomes were only assessed in children aged 2–18 years.

4. Discussion

The results of this systematic literature review demonstrated that LAIV-AA was well tolerated in adults (18–49 years of age) and children (2–17 years of age) with a diagnosis of asthma or a history of recurrent wheezing. No safety concerns were associated with LAIV-AA in children and adolescents with asthma across a wide range of asthma-related outcomes investigated by the studies included in this review. Only runny nose/nasal congestion was associated with LAIV, which is a minor and well-known reactogenicity event associated with the intranasal replication of LAIV-AA [33].A strength of this review was the comprehensive approach, which allowed for a detailed assessment of all studies available to date despite methodological differences. A total of 471,802 participants with asthma or recurrent wheezing from the included studies were evaluated as part of this systematic review (in studies where N is specified for each treatment group; LAIV-AA participants N = 55,849, controls N = 356,753), which adds to the robustness of the findings. There was a wide range in the number of participants across the studies. The largest of which was from a US vertically integrated healthcare system which included 166,174 participants with asthma or recurrent wheezing, of whom 9,278 (6%) received LAIV-AA [21].

The 14 studies evaluated support the safety of LAIV-AA in individuals 2–49 years of age with asthma across a range of outcomes, and when compared with placebo, trivalent or quadrivalent IIV, reference periods, or unvaccinated or intra-patient controls, across 20 influenza seasons. Although two large studies investigated the safety of LAIV-AA in adults (total of 73,801 participants) [28,31], no data are available for adults older than 49 years of age.

As studies were primarily undertaken in persons with mild to moderate asthma or a history of recurrent wheezing (Table 2), this analysis provides reassurance of the safety of LAIV-AA in this population. However, given the limited data on the safety of LAIV-AA in children and adults with severe asthma, conclusions on the safety of LAIV-AA in this population will require further investigation before informed guidance for this population can be developed.

A limitation of this systematic review is the different methodologies and different outcomes used in the studies included. As a result, a formal meta-analysis could not be conducted. Treatment administration (LAIV, IIV, or no vaccine) was not controlled in the non-randomized studies, so observed differences between treatment groups may be confounded by differences between the groups at baseline. The included articles studied a range of different LAIV-AA formulations including monovalent, trivalent and quadrivalent. The solicited sides effects of these formulations have a high degree of homogeneity suggesting similar safety profiles regardless of valency. Despite these limitations, the overall results were consistent across studies in this review, providing confidence in the findings.

Several of the included studies recommended that the guidelines (specific to the US) for use of LAIV-AA in children with asthma or wheezing should be reconsidered in the light of the evidence demonstrating no additional risk compared with study controls. Duffy et al [31] stated that the precaution in the US guidance regarding increased risk of wheezing after LAIV-AA in those with intermittent or mild persistent asthma or children 2–4 years old with recurrent wheezing might not be warranted. Similarly, Piedra et al [30] suggested that expanding the current recommendations to include children with mild intermittent asthma should be considered. The UK has retained a recommendation against use of LAIV-AA in those with an acute asthma exacerbation in the previous 72 hours, as there are no available data on the safety of LAIV-AA vaccination in this setting (and such children should be offered IIV [34]). However, the study by Turner et al [22] provided evidence for the revised UK guidance for the 2019/20 influenza season that ‘children with asthma on inhaled corticosteroids may safely be given LAIV, irrespective of the dose prescribed.’

5. Conclusions

The evidence from this systematic literature review demonstrated that LAIV-AA was well tolerated in children and adults aged 2 − 49 years with mild to moderate asthma or recurrent wheeze, with no safety concerns or increased risk identified for any of the respiratory outcomes measured when comparing LAIV-AA with injectable influenza vaccines or non-vaccine controls.

6. Expert opinion

Although randomized controlled trials have demonstrated a higher risk of reactive airway disease and wheezing events in children 6 − 23 months following administration of LAIV-AA [13,15,16], multiple studies in individuals 2 − 49 years of age with asthma or a history of recurrent wheezing have shown no increased risk of significant adverse events following LAIV-AA. Fourteen studies that included a total of 471,802 participants with asthma or recurrent wheezing found no significant safety concerns or increased risk for any asthma-related outcomes measured. The evidence presented in the studies in this review may help inform clinical guidelines for the use of LAIV-AA in children and adults with mild to moderate asthma or recurrent wheeze [30,31]. Due to limited data, the safety of LAIV-AA in individuals with severe asthma or active wheezing has not been established.

When licensed and recommended vaccines already exist, newer vaccines, particularly those with a novel mechanism of action, face a high hurdle to demonstrate safety in specific subpopulations. It is not always possible to conduct the necessary studies prior to approval and thus data obtained post-licensure becomes particularly important. While prospective, double-blind, randomized studies remain the gold standard for evidence, high-quality, non-randomized studies can greatly contribute to our understanding of vaccine safety and effectiveness in the real world. When possible, such studies should be conducted in a consistent manner to enable pooling of data across studies; such harmonization would rely on explicit guidance from vaccine experts and policymakers regarding best practices.

Article highlights

• Influenza has been associated with asthma complications and exacerbations; vaccinating against influenza is effective in reducing the number and severity of respiratory infections and can prevent asthma exacerbation.

• Findings from early randomized controlled trials suggested a higher risk of wheezing in children aged 6–23 months following administration of LAIV. At that time, limited data were available in older children and adults with a history of asthma or recurrent wheezing. As a result, initial clinical guidance warned against the use of LAIV-AA in individuals with a history of asthma or recurrent wheezing.

• Since initial approval, multiple studies have been conducted evaluating the safety of LAIV-AA in individuals aged 2–49 years with a diagnosis of asthma or recurrent wheezing. This systematic literature review assessed and synthesized the available evidence regarding the safety of LAIV-AA in this population.

• No studies found an increased risk of significant asthma-related clinical outcomes measured post-vaccination with LAIV; including no significant differences in the risk of asthma exacerbations, wheezing, or hospitalizations in LAIV-AA recipients with a history of mild to moderate asthma or recurrent wheezing compared with controls. The only event increased after LAIV-AA was runny nose/nasal congestion.

• Gaps in the literature include a lack of data in individuals with active wheezing or diagnosed with severe asthma.

Declaration of interest

A Bandell and CS Ambrose are employees of and shareholders in AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgment(s)

India Wright, MSc and Talya Underwood MPhil (Cantab) performed the systematic literature review and provided medical writing support, and editorial support was provided by Rachael Cazaly, BSc, all of Core Medica, London, UK, supported by AstraZeneca according to Good Publication Practice guidelines (Link). The Sponsor was involved in the study design, collection, analysis, and interpretation of data, as well as data checking of information provided in the manuscript. However, ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors.

Additional information

Funding

This paper received writing support, funded by AstraZeneca.