Effectiveness of seasonal influenza vaccines in children – a systematic review and meta-analysis

Abstract

Influenza virus causes an acute respiratory tract infection, which results in considerable morbidity and mortality worldwide (1,2). Influenza A genus is classified into many different serotypes; H1N1 and H3N2 notably cause disease in humans. Population groups at particular risk of influenza include children, pregnant women, the elderly, and patients with co-morbidities (3). Prevention of influenza is a major health issue worldwide, but providing protection by vaccination is challenging because each season the disease is caused by different strains of the virus. Current recommendations for influenza vaccination include people over the age of 65, pregnant women, people with chronic respiratory illness, and those in long-stay residential care homes (4). Influenza vaccines are not typically recommended for use in healthy children. Vaccination of healthy children aged from 6 to 24 months has been advocated in the USA, since 2004, which has gradually included children up to 59 months, and the current recommendation is to vaccinate all children from 6 months up to 19 years – with particular emphasis on children under the age of 5 or with chronic illnesses (5). No influenza vaccines have been approved for use in children younger than 6 months (6).

There are two types of vaccine available – live and inactivated, both of which can be used in children. They contain three different virus strains: two influenza A (H1N1-like and H3N2-like) and one influenza B, which have to be administered annually. Live vaccines are administered via an intranasal spray, whereas inactivated vaccines are injected, either intramuscularly or intradermally. Inactivated influenza vaccines contain killed virus, which makes them safer for use in pregnant women and those with underlying medical conditions; they cannot induce mild signs and symptoms of influenza like live vaccines. Vaccines can be adjuvanted to improve their immunogenicity (7). Inactivated influenza vaccines have been successfully adjuvanted and their safety and immunogenicity proven for use in children (8). It has also been hypothesized that vaccinating children against influenza has indirect benefits, such as reducing influenza-related morbidity and mortality in the elderly population (9). This study aimed to assess which vaccines were most appropriate for use in healthy children from 6 months to 18 years of age, by critically and systematically reviewing the evidence on their efficacy and effectiveness and performing meta-analysis of the available information.

Methods

Search of the literature

We aimed to identify all randomized control trials (RCTs) and cohort or case-control studies investigating the effectiveness or efficacy of influenza vaccines in reducing the incidence of influenza-like illness (ILI) or laboratory-confirmed influenza in children. In order to achieve this we searched Ovid MEDLINE (In-Process & Other Non-Indexed Citations and Ovid MEDLINE 1946 to Present), Embase + Embase Classic (1947 to present), the Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index of Nursing and Allied Health Literature (CINAHL), World Health Organisation Library Information System (WHOLIS), Latin American and Caribbean Health Sciences Literature (LILACS), and Global Health Library (1910 to December 2011) using different combinations including the following search terms: influenza vaccines, attenuated vaccines, live vaccines, vaccination, human influenza, child, preschool-child, infant, influenza-like illness, hospitalization.

After elimination of duplicates, results of searches from all databases combined identified 2105 potentially relevant articles. The titles and abstracts were screened and studies measuring only the safety or immunogenicity of vaccines were excluded, and so were the studies on pandemic influenza vaccines, studies assessing efficacy or effectiveness of vaccines in adults and children with asthma, and review articles. This process left 122 articles that required a more detailed evaluation, 92 of which did not fulfill the inclusion criteria. The number of studies that met all of the inclusion criteria was 30 (Figure 1).

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Figure 1

A summary of the literature review.

Results

The retained 30 studies comprised 19 RCTs (10-28), 9 cohort studies (29-37), and 2 case-control studies (38,39). There were 9 studies that assessed the efficacy of live vaccines, 8 of which were RCTs (11-14,20,22,26,27) and 1 was cohort study (31). Eight studies evaluated the effectiveness of live vaccines: 4 RCTs (10,19,24,25) and 4 cohort studies (30,31,34,35). Thirteen studies assessed the efficacy of inactivated vaccines: 7 RCTs (13,14,16-18,21,28), 4 cohort studies (32,33,36,37), and 2 case-control studies (38,39). Eight studies assessed the effectiveness of inactivated vaccines: 5 RCTs (15-17,23,24) and 3 cohort studies (29,32,36). The results were expected to show higher efficacy (which was assessed against proven influenza infection) than effectiveness (which would be measured against any cause of respiratory illness).

Discussion

This review showed a high efficacy of influenza vaccines against influenza infection, but a considerably lower effectiveness. There was a slight difference in favor of live vaccines in efficacy, but hardly any in effectiveness. Two studies demonstrated the efficacy of live vaccines in children under 2 years of age (22,27), which was an important contribution to available information on this age group. Expectedly, both live and inactivated vaccines were more efficacious against infection with strains of influenza virus that were antigenically similar to strains contained in the vaccine (22,26-28), highlighting the need for good strain-matching for the vaccines that are being delivered in large programs. Adjuvanted inactivated vaccines showed efficacy almost as good as that of live vaccines, although this result came from only one study (28). These conclusions are in line with previously conducted systematic reviews on influenza vaccines (41), suggesting that there is a growing agreement about the key technical indicators, and that the future research challenges will be more focused on achieving more equitable impact of the available preventive interventions (42).

This report has several limitations. We performed meta-analyses of the studies that were matched for the type of vaccine (live or inactivated), antigen used (similar or any), and analysis used (per protocol or intention to treat). Still, studies that were grouped together varied in study designs, case definitions, and age ranges applied (Supplementary material(supplementary material)). Moreover, we excluded several papers in Russian (43-49), because it was not possible for us to assess full text articles and we already felt that we had enough evidence. For a more in depth review, we could also consider wider aspects of influenza vaccination, such as the cost-effectiveness and safety of implementing vaccination programs for different age groups, the effect that vaccination may have on reducing absence from school and parents’ absence from work, and acceptability of vaccine to providers and end-users. There have been studies researching the indirect beneficial effect that vaccinating children has on morbidity and mortality from influenza in the elderly (9), which could be another interesting research area.

In many studies, there was a lack of information on the composition of the vaccine used and its matching to the circulating strains of influenza viruses for that season. This is vital as it inevitably will have a significant effect on the efficacy of vaccines. Influenza vaccines will not have effect against antigenically dissimilar viruses. There are also some limitations imposed by the nature of research available in the area of influenza vaccines. There were no studies that directly compared live and inactivated vaccines, although such studies would allow an analysis of the efficacy and effectiveness of the vaccines in a comparable context. There was a considerable heterogeneity in the outcome definitions used in the studies, particularly with reference to ILI definitions. Studies also differed according to methods of collecting data on ILIs; in some studies cases were diagnosed by general practitioners or pediatricians on visits to a clinic and in others according to parental reports of symptoms.

The main strength of this review, compared to other relevant literature, is that it summarized the available information on this issue and provided an evidence base from which further research could be conducted. It exposed differences in the quality and methodological approaches to studies, such as the definition of outcomes and study designs and gaps in information provided for certain age groups. It strengthened the existing knowledge, providing a summary of the data on the effect of live and inactivated vaccines in preventing influenza in children, in whom it showed comparable results to healthy adults. Areas for future research have also been highlighted, such as the direct comparison of the efficacy of live and inactivated vaccines, more systematic research into benefits of each type of vaccine for different age groups, and the need for a wider evidence base supporting potentially promising adjuvanted inactivated influenza vaccines (50).

Acknowledgments

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