Influenza is an acute respiratory illness associated with increased frequency of outpatient visits, missing school days and missing work days by parents. Children <2 years of age are at higher risk for developing the disease and its complication.1 This led The Advisory Committee on Immunization Practices, the American Academy of Pediatrics (AAP), the Canadian Pediatric Society, the Central European Vaccination Advisory Group and the World Health Organization to recommend universal influenza vaccination for all children between 6 and 23 months of age.2–6
There are 2 types of influenza vaccines approved for use in children: Live attenuated influenza vaccines (LAIV) and inactivated influenza vaccines (IIV). The choice depends upon several factors, such as age, comorbidities and safety profile.7
Current policies do not approve the use of LAIV in children <2 years of age and only recommend IIV.2,3,6,7 In the United States, LAIV was first licensed by the Food and Drug Administration in 2003 for immunization of healthy individuals aged 5–49 years. Subsequently, in 2007, the Food and Drug Administration extended the approval for children 2–5 years. This change was mainly based on 3 studies8–11 that included children <2 years of age. Canada and the United Kingdom have recently recommended LAIV over IIV in children >2 years of age due to a higher effectiveness to prevent influenza.3,12
Reasons for not approving the use of LAIV in children <2years of age are not clear and have not been studied systematically. Concerns are increased hospitalization rate and increased incidence of medically significant wheezing. These data are derived from a subgroup analysis by age, conducted in a single randomized controlled trials (RCT).11 This was a post hoc analysis and the authors of the RCT did not conduct an interaction test between the subgroups to conclude whether these results differed beyond chance. LAIV vaccines have been shown to have higher immunogenicity in children 1–5 years of age13 and higher efficacy in children <2 years of age,14 when compared with IIV. Additionally, recent trials suggest additional benefits of LAIV over IIV in children as young as 6 months.15
These data highlight the importance of systematically assessing the existing body of evidence about LAIV in this specific population. Therefore, we conducted this systematic review (SR) and meta-analysis.
MATERIALS AND METHODS
The reporting of this SR followed the guidance provided in the PRISMA statement.16
Following a predesigned protocol, we included RCTs that enrolled healthy children <2 years of age who received LAIV and evaluated its effectiveness and safety, compared with placebo or IIV (only seasonal vaccines). For safety outcomes, we searched for observational studies focusing on postmarketing studies, allowing us to detected rare adverse events.
Considering the existence of several SRs addressing a similar question, we decided to conduct an umbrella SR17 Using this approach, an expert reference librarian (L.J.P.) designed and conducted electronic search strategies (Table 1) with input from study investigators with expertize in conducting SR (M.H.M. and G.J.P.) to find eligible SRs as a source for RCTs. Subsequently, we updated the literature search of the included SRs to the present time to capture recent RCTs and observational studies. We searched the following electronic databases: Medline, EMBASE and Cochrane Library; through the OVID interface, we searched Web of Science, Scopus, PsycInfo and CINAHL from inception through February 2013. Additionally, 2 reviewers (G.J.P. and J.P.D.) reviewed the reference lists of the eligible primary studies, narrative reviews and queried experts.
Selection of Studies
We evaluated each systematic review using the Assessment of Multiple Systematic Reviews criteria,18 particularly emphasizing the quality and comprehensiveness of the search strategy. Inclusion and exclusion criteria were also considered.
Search output was uploaded into a web-based system (DistillerSR, Ottawa, Canada). Two reviewers working independently considered the potential eligibility of each abstract. Disagreements were considered eligible for the full text review. Eligible studies were reviewed in full text versions. If we could not obtain outcome data for the specific age group of interest, the study was excluded. We achieved near perfect agreement (kappa = 0.93) during this phase.
Data Extraction and Management
Data were extracted using a predesigned, piloted web-based extraction form. Working in duplicates, reviewers extracted the following descriptive data: full description of participants enrolled (age and health status), intervention (description of the vaccines, number of doses, etc.) and control characteristics (placebo or IIV description). We extracted the outcomes of interest focusing on patient important outcomes19 for the whole vaccination scheme and per each dose. Effectiveness measures were (1) laboratory-confirmed influenza, (2) medically-attended wheezing (MAW) and (3) hospitalization rate. Safety measures included the incidence of (1) acute otitis media, (2) cough, (3) fever, (4) pharyngitis, (5) rhinorrhea, (6) severe adverse events (SAE) and (7) death. SAEs were defined as any adverse event severe enough to require medical intervention, grade 2–4.20
We contacted corresponding authors of each study twice within 2 weeks via e-mail or by phone or mail when e-mail was not available to get additional information.
We used the Cochrane Risk of Bias assessment tool to evaluate the methodological quality of the included RCTs and the Newcastle-Ottawa scale for observational studies.
All the outcomes included in this review are dichotomous; therefore, we measured the effect size using the relative risk (RR) and 95% confidence interval (CI). The I2 statistic was used to measure inconsistency that was not attributable to chance.21 To pool data across studies, we used the random effects model to provide conservative estimates that incorporate uncertainty due to heterogeneity between studies.22 Analyses were performed using STATA version 12 software (StataCorp, College Station, TX).
Assessment of Publication Bias
The small number and heterogeneity of the trials made the assessment of publication bias unfeasible.23
Search Results and Study Description
The primary search strategies identified 479 potentially eligible SRs, 2 of those were finally selected.14,24 These SRs included 42 RCTs. We updated the search strategies of these 2 included SRs identifying 477 potentially eligible RCTs. Finally, 7 RCTs fulfilled our eligibility criteria and were included in the meta-analysis (Fig. 1). No unpublished studies were identified.
The included studies (Table 2) enrolled 6281 children with a mean age of 11 months (Range: 1.5–24 months). One of the included studies, Belshe et al11 (published in 2 publications Belshe et al11 and Belshe et al33), compared LAIV against IIV; the remaining RCTs compared LAIV against placebo.
The update of the search strategy identified 2 postmarketing retrospective studies comparing LAIV versus IIV. These studies included 495,227 patients. The characteristics of these studies are summarized in Table 2.
Three of the included RCTs had adequate randomization methods; all of them preserved randomization by concealing the allocation. All the RCTs included in the meta-analysis reported attrition during the follow up, with a mean of 7%. The overall risk of bias was considered low to moderate.
The included observational studies did not report matching participants based on clinical characteristics or adjusting their results accordingly. Table 3 summarizes the quality of the included studies.
We attempted to contact 6 authors of the included trials for additional information not reported in the published manuscripts or to clarify published data. We received 2 answers11,30 providing the required information.
Outcomes of Interest
LAIV Versus Placebo
Laboratory-confirmed influenza. We identified 1 multicenter trial that enrolled children aged 11 to <24 months27 evaluating this outcome. This trial showed that LAIV had a significant protective effect on the development of laboratory-confirmed influenza (RR = 0.36, 95% CI: 0.23–0.58, P < 0.05) with a a number needed to vaccinate of 17 (95% CI: from 11 to 33; Fig. 2). Other effectiveness measures were not assessed for this comparison.
Fever. A meta-analysis of 6 studies (10 comparison of doses) showed that children who received LAIV had an increased risk of developing fever compared with children who received placebo (RR = 1.16, 95% CI: 1.04–1.30, P < 0.05, I2 = 0.0%). The outcome was not related to the dose given (first, second or third). None of the included studies reported the occurrence of febrile seizures.
Acute otitis media. Using the pooled data from 3 studies, LAIV did not increase the risk of acute otitis media when compared with placebo (RR = 0.97, 95% CI: 0.35–2.70, P > 0.05, I2 = 0.0%).
Pharyngitis. Pharyngitis was reported in 2 studies. There was no increased risk of pharyngitis following vaccination (RR = 1.03, 95% CI: 0.79–1.34, P > 0.05, I2 =0.0%).
Rhinorrhea. We found 4 studies evaluating the development of rhinorrhea. Meta-analysis of these studies showed an increased risk for the development of rhinorrhea in children who received LAIV compared with placebo (RR = 1.18, 95% CI: 1.07–1.31, P < 0.05, I2 = 28.3%).
SAE. SAE were reported in 2 RCTs. Lum et al27 considered as SAE the following: gastroenteritis, convulsions, bronchospasm, pneumonia, pharyngitis, bronchitis and fever. The study did not specify if all of them were considered attributable to the vaccine. Vesikari et al30 reported 1 SAE in each arm. In the LAIV arm, a child developed a convulsion 2 days after the first dose of LAIV; this was considered as possibly related to vaccine. In the placebo arm, a child developed an upper respiratory tract infection with fever and otitis media beginning 3 days after receiving the first dose of placebo. According to these data, compare with placebo, LAIV did not increase the risk for SAE (RR = 0.80, 95% CI: 0.50–1.28, P > 0.05, I2 = 0.0%).
Death. Lum et al27 reported 2 deaths, 1 in each group. Neither 1 of deaths was attributed to LAIV by the study investigators.
LAIV versus IIV
One of the included studies (Belshe et al11,33) evaluated this comparison.
Laboratory-confirmed Influenza. The efficacy of the 2 vaccines was similar in terms of preventing laboratory-confirmed influenza through viral culture in children 6–11 months (RR = 0.76, 95% CI: 0.45–1.30, P > 0.05; Fig. 3).
Hospitalization. Hospitalization rate was assessed in the trial by Belshe et al11 as a post hoc analysis. This outcome was defined as hospitalization from any cause, regardless severity, etiology or association with the intervention, that occurred within the 180 days after the last dose of vaccine. Respiratory causes were reported more frequently. The study demonstrated that in children 6–11 months of age 6.1% (42/684) of the subjects assigned to the LAIV group and 2.6% (18/683) of the subjects assigned to the IIV group were hospitalized. This implied an increased risk of hospitalization for LAIV when compared with IIV (RR = 2.33, 95% CI: 1.36–4.01, P < 0.05).
On the other hand, among children 12–23 months of age, the differences in hospitalization rates were 3.2% (42/1308) in the LAIV group and 3.5% (45/1292) in the IIV group. This showed an RR of 0.92 (95% CI: 0.61–1.39, p>0.05) implying no statistically significant differences between the 2 interventions.33
For these 2 age groups combined (6–23 months), there was no statistically significant increase in hospitalization rate (RR = 0.92, 95% CI: 0.69–1.24, P > 0.05).
MAW. MAW was assessed up to 180 days after the administration of the last vaccination dose. It was defined as the presence of wheezing on physical examination conducted by a health provider with a prescription for a daily bronchodilator, respiratory distress or hypoxemia. In children 6–23 months of age, there was a statistically significant increase in MAW with LAIV compared with IIV (5.9% versus 3.8%; P = 0.002).33
SAE. For the whole population (children 6–59 months—8352 children), Belshe et al11 reported 136 SAE in the LAIV group and 124 in the IIV group. In chidren 6–11 months of age, they reported 44 SAE in the LAIV arm and 23 in IIV arm. A small proportion of SAE (6 in LAIV and 5 in IIV) was considered by the investigators who were unaware of treatment assignments to be potentially related to the vaccines. For children 6–23 months of age, 55 SAE were reported for the LAIV group (1308 children) and 41 for IIV group (1292 children). No information was reported to whether these were considered to be related to vaccination.33
Death. Two deaths unrelated to the interventions were reported by the same trial11; 1 in each group (1 because of foreign body aspiration and 1 because of house fire). The age of these children was not reported. No other safety outcomes were reported in children <2 years of age.
Evidence From Observational Studies
We found 2 postmarketing evaluations that assessed the safety of LAIV use in children <2 years of age in 3 consecutive seasons (2007–2008, 2008–2009 and 2009–2010). All outcomes were assessed over the 42 days after vaccination. The observational studies had clear limitations particularly as it pertains to ascertainment of exposure (type of vaccination) which can be inaccurate when derived from administrative codes.
The pooled estimates for the 3 seasons did not show an increased rate of any cause emergency department visit or hospitalization in children who received LAIV (compared with those who received IIV, RR = 0.74, 95% CI: 0.43–1.25, P > 0.05, I2 = 66.1%; Fig. 4).
No lower respiratory tract illness cases were reported during seasons 2007–2008 or 2008–2009. On the other hand, during season 2009–2010, the rate of asthma and pneumonia was higher in those children who received LAIV compared with IIV.
We conducted a systematic review and meta-analysis to assess the efficacy and safety of LAIV in children <2 years of age. We found that LAIV is capable of reducing the incidence of laboratory-confirmed influenza in this population, when compared with placebo with RR of 0.36 and number needed to vaccinate of 17. Compared with the estimate obtained in a Cochrane systematic review for IIV (RR = 0.55, number needed to vaccinate of 28),14 LAIV seems to be more or as effective.
Although LAIV only appears to increase the incidence of minor side effects when compared with placebo (fever and rhinorrhea), safety concerns still exist. Evidence derived from a single study suggests a possible increase in hospitalization rate (post hoc analysis) and MAW. Evidence from observational studies did not show an increased rate of hospitalization or emergency deparment visits (composite endpoint) in children who received LAIV compared with those who received IIV; these studies had key methodological limitations.
The evidence about this topic is sparse and heterogeneous. Studies included several vaccine characteristics, doses and variable matching between the vaccine composition and circulating strains; these are factors that can significantly affect the results.
Limitations and Strengths
The strengths of this review relate to the measures undertaken to reduce the effect of bias and error: predefined protocol-driven procedures, duplicate review and attempts to contact authors for missing data. The systematic reviews on which we relied to identify older studies were quite comprehensive and rigorous (according to the Assessment of Multiple Systematic Reviews assessment).18
On the other hand, the body of evidence has key limitations. Although there are many studies that evaluated LAIV in children and some of them enrolled children <2 years of age, there were only 6 published studies assessing LAIV versus placebo exclusively in children <2 years. Most of these studies were published during the 1990s. Of them, only 1 study evaluated efficacy. This fact seems even more surprising considering that a SR published in 2012 only found 1 study evaluating the comparison IIV versus placebo in this age group,14 the current recommended intervention.
The only available trial that compared LAIV versus IIV enrolled a small percentage of children with asthma. We decided to include this study because we considered this proportion to be sufficiently small and because there was no other source of evidence. Furthermore, the hospitalization analysis in that study was conducted post hoc and defined hospitalization as “any cause hospitalization”; a suboptimal outcome definition that cannot be directly attributed to the effect of the vaccine.
Implications for Practice and Research
Universal influenza vaccination of children 6–23 months has been recommended by Advisory Committee on Immunization Practices,7 AAP,2 Canadian Paediatric Society3 and Central European Vaccination Advisory Group5 and World Health Organization.6 Vaccination has proved to be the most effective strategy for preventing influenza and related mortality and complications.7 The implementation of this recommendation had clear challenges. In previous seasons (2000–2001, 2001–2002 and 2004–2005), there was a shortage of IIV in the United States.34–36 Current recommendations of universal influenza vaccination will continue to increase demand for IIV; which may lead to similar shortages in the future. Additionally, a response to an influenza pandemic is another scenario that necessitates an alternative for IIV. In these situations, the potential adverse effects that may be greater with LAIV in children <2 years, would be greatly outweighed by the benefits. Additional options for this population, such as LAIV, are extremely needed.
Additionally, LAIV has shown to be protective for strains not included in the vaccine in children9 even when a single dose was administered during an outbreak.37 Also, it was more effective when compared with IIV in mismatched seasons (54.4%, 95% CI: 41.8–64.5 fewer cases in LAIV compared with IIV) in children 2–7 years of age.33 Finally, the fact that LAIV is administrated intranasally implies the generation of mucosal immunity38 and an easy and painless approach.
Even when LAIV is more expensive than IIV (US$17.30 per dose vs. US$8.25–13.65),40 studies have shown that the increased efficacy may result in decreased healthcare and societal costs for children 24–59 months of age (parental work days lost, school/daycare days missed). In this analysis, LAIV had a net total cost savings of US$45.80 per child, relative to IIV.40
It is clear that more evidence is needed to recommend LAIV in children <2 years of age with high confidence. Based on the information presented here, we can conclude that the use of LAIV may be a suitable option under specific circumstances. Potential harms would have to be outweighed by potential higher efficacy and cost effectiveness. When more evidence on this topic becomes available, an updated cost effectiveness analysis will be necessary. Lastly, LAIV administration that does not require trained personnel makes it highly desirable in underserved areas or areas with limited availability of healthcare workers.
It is worthy to highlight the new quadrivalent LAIV that contains 4 strains of influenza viruses (2A, 2B) and can provide additional protection against B strains. Considering the previously known efficacy of LAIV and the expanded strain coverage of the quadrivalent LAIV, the latter should become a target for future safety and efficacy studies in younger children. From what we learned from the published literature of LAIV, stratification of results based on history of asthma and other relevant comorbidities is paramount.
Currently, we believe that the lack of approval for the use of LAIV in children <2 years of age made by World Health Organization, Centers for Disease Control and Prevention, AAP and Canadian Pediatric Society should be taken cautiously. Perhaps it should be considered as relative rather than an absolute dissaproval (based on vaccine availability) or as a weak (conditional) recommendation against the use of LAIV in children <2 years of age.41,42 Shared decision making that involves parents is encouraged in this setting.
LAIV is highly effective in children <2 years of age compared with placebo and is at least as effective compared to IIV. The safety profile of LAIV is reasonable although evidence is sparse. LAIV may be considered as an option in this age group particularly during seasons with vaccine shortage and during a pandemic response.
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