The Ann Arbor strain LAIV has been evaluated in multiple randomized controlled studies in children with a medical history of wheezing and asthma. The first study evaluated the effect on pulmonary function, as measured by spirometry, in children aged 9 years and older with moderate to severe asthma. In this small study (N
48), no changes in pulmonary function were detected after vaccination with LAIV versus placebo [9
Subsequently, three large, randomized, TIV-controlled studies were conducted in children with a history of asthma or wheezing to further characterize the clinical outcomes after receipt of LAIV. Collectively, these studies included 4,169 children aged 2–17 years who were diagnosed with asthma or had a medically confirmed history of wheezing. All of the studies were prospectively designed to evaluate the effect of LAIV on asthma exacerbations and/or wheezing. The first study by Fleming et al. compared LAIV and TIV in 2,229 children aged 6–17 years with a clinical diagnosis of asthma [7
]. The study demonstrated that children who received LAIV experienced 35% fewer cases of culture-confirmed influenza illness, with asthma exacerbation rates, mean peak expiratory flow rate findings, asthma symptom scores, or nighttime awakening scores that were similar to TIV recipients.
The current analysis provides the data from two studies regarding the safety and efficacy of LAIV in children aged 2–5 years with a history of asthma or wheezing. Similar to the results observed by Fleming et al., there were no statistically significant increases in wheezing, LRI, or hospitalization among children receiving LAIV versus TIV. The type and incidence of REs and AEs observed in this study were consistent with those observed after vaccination with LAIV and TIV in other studies of young children. As expected, a higher rate of runny nose/nasal congestion was observed among LAIV recipients; this difference also likely explains the few unsolicited AEs that were increased among LAIV recipients (rhinorrhea and upper respiratory tract infection). These findings are supported by the results of a large, nonrandomized study of LAIV conducted over 4 years that included 2,196 healthy children aged 18 months to 18 years with a history of intermittent wheezing or asthma and found no increased risk for medically attended acute respiratory illness or asthma after vaccination with LAIV [10
In the original analysis of Belshe et al.’s study [4
], a post hoc trend toward an increased rate of all-cause hospitalization was observed among children aged 6–47 months, but not among those aged 48–59 months with a history of any prior wheezing. Following additional review of the data, officials at the U.S. Food and Drug Administration concluded that, for children ≥24 months of age who received LAIV, “there was little influence of history of wheezing on hospitalization and the rates of hospitalization were either similar to or actually higher in the TIV arm” and stated that the relationship of history of wheezing to a potential risk of all-cause hospitalization was likely “a statistical blip” [11
]. Additionally, no such trend was observed in Ashkenazi et al.’s study [8
]. The current analysis, which incorporates data from two distinct studies, provides a more comprehensive view of the safety of LAIV in young children with asthma or a history of wheezing.
Because LAIV vaccination entails nasopharyngeal replication of attenuated influenza viruses, some may raise concern regarding the long-term effects on airway function. However, it is rhinovirus-induced wheezing in the first 2–3 years of life, and not illness due to influenza, that has been correlated with allergic sensitization and subsequent asthma pathogenesis [12
]. Furthermore, a recent study demonstrated that allergic sensitization to aeroallergens precedes rhinovirus-induced wheezing, and viral wheeze did not lead to subsequent allergic sensitization [14
]. The current analysis, the study by Fleming et al., and multiple additional studies conducted in young children without asthma demonstrate that LAIV vaccination in children 2 years of age and older is not associated with subsequent wheezing or lower respiratory illness [7
]. In fact, in children aged 6–17 years with asthma, there was an 18% reduction (p
0.02) in wheezing in the 15 days after vaccination in LAIV versus TIV recipients [7
It should be noted that the safety of Ann Arbor strain LAIV has not been extensively studied among severe asthmatics (e.g., individuals currently requiring therapy with oral glucocorticosteroids or high-dose inhaled glucocorticosteroids) or individuals with recent active wheezing within the 7 days before vaccination. Additionally, the high rates of postvaccination wheezing in both treatment groups also highlight the difficulty of using non-controlled, passively collected surveillance data to evaluate vaccine safety in children with asthma or a history of wheezing [16
Both studies analyzed demonstrated fewer cases of culture-confirmed influenza illness among LAIV versus TIV recipients in the original overall study populations [4
]. The current analysis demonstrates consistent results among the cohorts of children with a history of asthma/wheezing, with one analysis reaching statistical significance despite the small study population. These data support the conclusion that Ann Arbor strain LAIV continues to provide a high level of protection against influenza illness in young children with asthma or a history of wheezing. The efficacy of the vaccine in this subset of children is important because annual vaccination against seasonal influenza is generally recommended in this population.
Strengths of the current analysis include the randomization of study subjects to LAIV versus TIV that provided two treatment groups with similar baseline characteristics, the prospective collection of history of asthma and wheezing at enrolment, and the prospective definitions of the wheezing endpoints. The analysis also benefits from the ability to analyze children of similar age from two separate studies conducted in different influenza seasons. The primary limitation of the current analysis is the post hoc definition of the study cohorts, but this was addressed in part by the analysis of the three subpopulations that varied based on the severity and recency of wheezing illness. Additionally, the identification of subjects with a diagnosis of asthma or history of wheezing relied on investigator judgment; there was no validation of investigator assessments. However, the proportions of subjects with prior receipt of inhaled and systemic corticosteroids help to validate that the identified children had significant wheezing disease.
In conclusion, in the European Union and Canada, LAIV is currently approved for use among children aged 2–17 years, including those with mild to moderate asthma or a history of wheezing. The results of the current analysis and previous studies support the safety and efficacy of Ann Arbor strain LAIV in these populations.