There is limited evidence from randomized trials to support the administration of inactivated influenza vaccine in healthy children.6 This randomized study provides additional evidence of the efficacy of QIV against influenza (as confirmed by means of rt-PCR assay). The study was performed to provide direct evidence of the clinical benefit of the vaccine, especially in the prevention of moderate-to-severe influenza, an end point that captures the most clinically significant outcomes leading to health care consultations or hospitalization. The greatest value of vaccination is in the prevention of clinically significant disease rather than mild upper respiratory tract illness. Parents are most likely to seek medical help for children with a respiratory tract infection who have symptoms of lower respiratory tract disease, high temperature, or earache.16 Studies that do not differentiate these manifestations of influenza from mild illness cannot assess the effectiveness of the vaccine in attenuating illness and therefore may undervalue its benefit.

Our study showed QIV efficacy of 55% against influenza of any severity. This is similar to the estimates of the efficacy of TIV in other randomized trials: 43% (among children 6 months to 6 years of age),17 51% (among children 18 months to 6 years of age),18 and 56% (among children 3 to 9 years of age, against H1N1 disease),19 as well as an estimate of 48% from a meta-analysis of data for children of all ages.20 In our study, the efficacy of QIV was higher against moderate-to-severe disease (approximately 70% overall and in each of the two age groups). Most breakthrough cases in the QIV group were of mild severity. In a post hoc analysis, the QIV was associated with an 80% reduction in the rate of lower respiratory tract illness (the most common serious outcome of influenza) and a 70% reduction in the rate of body temperature above 39°C, as compared with the control vaccine.

Our study provided evidence that the QIV prevents influenza associated with the A/H1N1, A/H3N2, and B Victoria strains individually. Only two rt-PCR–confirmed cases associated with the B Yamagata virus were seen (both in the control group), precluding a meaningful estimate of the vaccine efficacy against that strain. However, the immune response to B Yamagata was as high as the response to the other strains, suggesting that the efficacy of the QIV against B Yamagata may be similar to the efficacy against the other strains. Vaccine efficacy is substantially reduced when the vaccine B strain is mismatched to the circulating strain.7-10 Only in the Philippines were both B lineages detected, reflecting the unpredictable geographic variability of influenza virus circulation. Introduction of the QIV is expected to result in a modestly lower incidence of influenza-related outcomes than that seen with TIV, with the net effect varying from one season to another.21 The true value of the QIV will be seen in years when the two B lineages are cocirculating or if there is a shift from one lineage to another between the time the vaccine is developed and the beginning of the influenza season.

Influenza in children results in increased outpatient visits, hospitalizations, and days missed from school.1-3,16,22,23 Among children with moderate-to-severe disease, the QIV, as compared with the control vaccine, was associated with 69% fewer medical visits, 75% fewer hospitalizations, 77% fewer absences from school, and 61% fewer parental absences from work. In all the study countries, the school year includes most of the peak influenza season. The age at which children begin day care or school varies considerably among countries, ranging from 3 to 7 years of age. The proportion of parents working outside the home is also variable. The estimate of the effect of vaccination with the QIV on school and workplace absenteeism is thus a broad approximation. In countries outside the study where children begin attending day care or school at an earlier age, a higher proportion of parents work outside the home, or both, the effect of vaccination on absenteeism may be greater than is indicated here.

The safety profile of the QIV was similar to that of hepatitis A vaccine, which we used as a control, except that pain at the injection site was reported more frequently in the QIV group. The experience of injection-site pain with the QIV as compared with TIV has been variable, with some studies suggesting similar levels of pain with the QIV and TIV and others suggesting a modestly higher level of pain with the QIV.24-27 A higher incidence of fever resulting from inclusion of a fourth strain was a theoretical concern because of the high incidence of fever observed with the TIV Fluvax (CSL) in Australia,28 which is believed to be due to a larger number of viral components in that vaccine than in other TIVs. However, in the current study, the incidence of fever was similar in the QIV and control groups and similar to the rate observed in previous studies of TIVs in children (in which fever was defined as a body temperature of 37.5°C or higher or 38°C or higher). 15,29 In the current study involving children residing mainly in tropical countries, the immunogenicity of the QIV was high, similar to that in a study of the same vaccine in children 3 to 17 years of age residing in Canada, Mexico, and the United States.24

A limitation of the study is that it was conducted during only one season and provides only a snapshot of the situation in that season. For example, the findings are limited by the low circulation of the B Yamagata lineage, as noted above. A major strength is that this was an individually randomized trial of an inactivated influenza vaccine in children 3 to 8 years of age. The study was conducted in three global regions and used both active and passive surveillance to identify cases of influenza, with analysis of more than 95% of samples from children with suspected cases. Other important strengths were the end points we selected and the use of an rt-PCR assay to confirm the presence of influenza virus. Selection of appropriate end points is a major challenge for influenza vaccine trials. We chose rt-PCR–confirmed influenza as the primary end point because rt-PCR assay has been shown to be associated with higher detection rates than conventional methods such as serologic testing and cell culture.13,30-33 As noted above, we included the prevention of moderate-to-severe influenza as an end point because we believe that the most important effect of influenza vaccination lies in the prevention of moderate-to-severe disease. Ideally, trials of vaccine efficacy would capture separately both the most severe cases (severe lower respiratory tract illness and serious complications) and cases that are less severe but nevertheless concern parents and have an effect on utilization of health care resources. Unfortunately, such trials would require the enrollment of impractically large numbers of participants. We therefore chose a dichotomous classification of influenza: mild and not mild (i.e., moderate-to-severe). We believe that this is a valid classification because it distinguishes between influenza that causes mild upper respiratory tract illness and low-grade fever from more severe illness that may have adverse clinical consequences and may increase the utilization of health care resources. Moreover, it is a practical classification with respect to the sample size needed for vaccine trials. Because of this relatively smaller sample size, however, the number of children in the study who had lower respiratory tract illness was small (10 children, all in the control group).

In conclusion, the QIV was shown to be efficacious in preventing influenza A and B in children 3 to 8 years of age. Given the problem of poor vaccine efficacy against mismatched B lineages, the QIV will be of greatest value during seasons in which both lineages are circulating or in the event that there is an unexpected shift from one lineage to another. The efficacy of the vaccine was higher against moderate-to-severe disease — a potentially important end point associated with the highest clinical, social, and economic burden — than against illness of any severity. These results highlight the potential clinical benefit of administering inactivated influenza vaccines in healthy children.