PDF
ePub
Citation
Print
INTRODUCTION
Influenza is a highly infectious disease that can cause complications leading to serious morbidity and mortality in young children. Primary viral pneumonia, secondary bacterial pneumonia, croup, myositis, toxic shock, Reye syndrome, and acute encephalopathy have been reported in children with influenza infections.123) Annual vaccination is the most effective strategy for preventing influenza infections, and influenza vaccination is believed to have reduced the incidence of laboratory-confirmed influenza, its associated complications, hospitalizations, and deaths.34)
The inactivated trivalent influenza vaccine, which has been used consistently since 1978, contains purified and inactivated materials from 3 viral strains; that is, 2 influenza A strains and one influenza B strain.5) The safety and tolerability of trivalent inactivated influenza vaccines have been evaluated in previous studies.67)
In Korea, the current recommendation is to vaccinate children of ≥6 months of age every year. The vaccine coverage rate is much higher for young children than it is for adolescents. Although both split influenza vaccines and subunit influenza vaccines are used for children, limited data are available regarding their efficacy and safety in children in Asia, including Korea. Previous studies have compared the immunogenicity and reactogenicity of split vs. subunit influenza vaccine in Korean children of ≤35 months.8) Therefore, the first aim of this study was to compare the immunogenicities and reactogenicities of these 2 types of influenza vaccines in children of ≥36 months. The second aim of this study was to investigate the immunogenicity and reactogenicity of the influenza vaccines commonly used in Korean children and adolescents.
MATERIALS AND METHODS
1. Study design
Our study was carried out in 2 non-randomized cohorts of children in an open-label trial at 6 hospitals from October 2008 to December 2008, after a protocol was approved by the Institutional Review Board (IRB) of each hospital (Korea University Ansan Hospital IRB No. AS0219). Written informed consent was obtained from all parents and from the participants of >7 years of age at the time of enrollment.
Subjects enrolled in the study were 36 months to <18 years of age. Children who were allergic to influenza vaccines or egg protein, had developed acute febrile illness within 24 hours of vaccination, were on immune-suppressant medication (including corticosteroids), had a history of transfusion within 6 months, and had any condition that might interfere with the evaluation were excluded. All subjects were divided into 2 age groups (36 to <72 months and 72 months to <18 years) to compare the immunogenicity according to age as it has been reported in previous studies that children under 6 years have lower seroprevalence rates.91011)
All subjects were observed for 30 minutes following vaccine administration to check for immediate local and/or systemic reactions. Each subject (or their guardian) filled out a diary card and recorded any local (pain, redness, swelling, petechiae, ecchymosis, edema, abscess) and/or systemic reaction (axillary temperature of ≥37.5°C, fever, shivering, headache, myalgia, arthralgia, fatigue, malaise) that occurred during 7 days following the vaccination. Any serious adverse event that occurred between the vaccination day and 30th day post-vaccination and any medication taken during the study period were recorded. Venous blood samples were obtained from all subjects on days 0 and 30.
2. Vaccines
The 2 vaccines used in the study were Vaxigrip® (a split influenza vaccine; Aventis Pasteur MSD, Lyon, France) and SK Influenza Trivaccine® (a subunit influenza vaccine, Agripal S1; Chiron Vaccines, Siena, Italy). Both vaccines contained A/Brisbane/59/2007 (H1N1) strain (IVR-148), A/Uruguay/716/2007 (H3N2) strain (NYMCX-175C), and B/Florida/4/2006 strain. The vaccines were injected intramuscularly into the deltoid muscle at a single dose of 0.5 mL.
3. Antibody studies
The antibody titers of the H1N1, H3N2, and B virus strains were determined using the hemagglutination inhibition (HI) test. The HI test is based on the ability of specific anti-influenza antibodies to inhibit the hemagglutination of chicken red blood cells by influenza virus hemagglutinin. The sera to be tested were previously treated in order to eliminate nonspecific inhibitors and the anti-species hemagglutinin. The titer was expressed as the reciprocal of the highest dilution of serum that completely inhibited hemagglutination. For evaluation purposes, a titer of 40 was considered to be protective.1213)
The HI titers to strains H1N1, H3N2, and B were measured using A/Brisbane/59/2007 IVR-148 (H1N1), A/Uruguay/716/2007 NYMCX-175C (H3N2), and B/Florida/4/2006, respectively. The immunogenicities of the 2 studied vaccines were assessed on the bases of the frequency of seroconversion on day 30, the proportion of subjects seroprotected on days 0 and 30, and the increase in geometric mean titer of anti-HI antibodies between days 0 and 30, defined as the geometric mean titer ratio. Seroconversion was defined as a change from a pre-vaccination titer of <10 to a post-vaccination titer of ≥40, or a ≥4-fold rise in titer in those with an initial anti-HI antibody titer of ≥10. Seroprotection was defined as a titer of ≥40.12)
The following serological assessments were considered for each strain in the subjects: 1) the number of seroconversions, or a significant increase in the anti-hemagglutinin antibody titer of >40%; 2) a mean geometric increase of >2.5; and 3) the proportion of subjects achieving an anti-HI antibody titer of 1:40 to be >70%.14)
RESULTS
1. Subjects
Among the 202 children enrolled in the study, half received the split vaccine and the other half received the subunit vaccine. Five subjects were excluded from the immunogenicity study owing to a failure to obtain paired blood samples from them. Therefore, in total, 197 (98 in split vaccine group and 99 in subunit vaccine group) paired blood specimens (days 0 and 30) were obtained for antibody assessment (Table 1).
Table 1
Demographic characteristics
2. Immunogenicity
The seroprotection and seroconversion rates were compared between the 98 children in the split vaccine group and 99 children in the subunit vaccine group. Both vaccines induced increases in these rates in a large proportion of the subjects (Table 2).
Table 2
Comparison of immunogenicity between split and subunit influenza vaccine
In both the split and subunit vaccine group, similar seroprotection rates (anti-HI antibody titers ≥40) were achieved against the H1N1, H3N2, and B strain (95.9%, 94.9%, 96.9% vs. 96.0%, 90.9%, 87.9%). The seroconversion rates in both the split and subunit vaccine groups showed no significant differences (32.7%, 75.5%, 52.0% vs. 40.4%, 61.6%, 49.5%).
3. Immunogenicity according to age group
The seroprotection and seroconversion rates for the 2 vaccines were also separately assessed in 2 age groups (36 to <72 months and 72 months to <18 years). Both rates for the split vaccine and subunit vaccine were similar in both age groups.
In the age group of 36 to <72 months, the seroprotection rates against the H1N1, H3N2, and B strains were not very different between the 2 vaccine groups. However, the H1N1 seroconversion rate was higher in the subunit vaccine group than in the split vaccine group (53.1% vs. 20.6%) (Table 3).
In the age group of 72 months to <18 years, the split vaccine and subunit vaccine did not show differences in both the seroprotection rate and seroconversion rate for the 3 strains. Both vaccines showed high seroprotection rates against the H1N1, H3N2, and B strains, but relatively low seroconversion rates for all 3 (Table 4).
Table 3
Comparison of immunogenicity between split and subunit influenza vaccine according to age group: 36 to <72 months
Values are presented as number (%) or 95% confidence interval.
Abbreviations: GMT, geometric mean titer; HAI Ab, hemagglutination inhibiting antibody.
*P<0.05, compared by vaccine groups for HAI Ab and GMT in ages 36 to <72 months; P<0.05, compared for pre to post change by vaccine groups for seroconversion number in ages 36 to <72 months.
Table 4
Comparison of immunogenicity between split and subunit influenza vaccine according to age group: 72 months to <18 years
Values are presented as number (%) or 95% confidence interval.
Abbreviations: GMT, geometric mean titer; HAI Ab, hemagglutination inhibiting antibody.
*P<0.05, compared by vaccine groups for HAI Ab and GMT in ages 72 months to <18 years; P<0.05, compared for pre to post change by vaccine groups for seroconversion number in ages 72 months to <18 years.
4. Reactogenicity
The 197 vaccinated subjects were evaluated for local and systemic reactions. The overall proportion of local reactions (occurring 30 minutes to 7 days after vaccine administration) was higher in the split vaccine group than in the subunit vaccine group (n=62 vs. 42; 63.3% vs. 42.4%). The local reactions consisted mainly of pain, erythema, induration, and petechiae, but were not serious in both groups. Systemic reactions (occurring 30 minutes to 7 days after vaccine administration) were also more prevalent in the split vaccine group than in the subunit vaccine group (n=42 vs. 29; 42.9% vs. 29.3%). The intensity of most systemic reactions was also mild for both vaccines. With regard to the reactogenicity difference between the 2 age groups, children of 72 months to <18 years had more frequent elicitations of systemic reactions with both vaccines (Table 5).
Table 5
Local and systemic reactions by vaccine type and age group
DISCUSSION
Influenza is a cause of morbidity and mortality in children, and vaccination has proven to be an effective method for preventing this disease and its complications. In the results obtained from this study, we found that both the split and subunit influenza vaccines showed effective immunogenicity and safety in Korean children and adolescents. Furthermore, by age group, children of 72 months to <18 years showed higher rates of systemic side effects and lower seroconversion rates. Both types of vaccines meet all 3 criteria set by the Committee for Medicinal Products for Human Use for all 3-virus strains in the vaccine.14)
For both the split and subunit vaccines, the seroconversion rate was relatively low compared with the high seroprotection rate. The probable reason for the lower seroconversion rate is a high pre-vaccination antibody titer, since a high titer of preexisting homologous antibodies may mask the antibody fold increase. Such high pre-vaccination antibody titer probably resulted from either the high vaccination coverage of Korean children compared with that in other countries or the high morbidity of influenza in Korea.15) This correlated with the lower seroconversion rates seen in the children of older age.
The immunogenicity of the split vaccine in children has already been confirmed in previous studies.16) However, there is limited comparative data on the clinical effects of split and subunit vaccines in children. In previous adult studies, split vaccines showed greater clinical effectiveness in younger adults than in adults aged >50 years,17) but in other studies in Europe,1819) there was no difference in effectiveness in the elderly. In a study by Kim et al.,8) the immunogenicity of the split vaccine was found to be superior to that of the subunit vaccine in children <3 years of age in a given flu season. In our present study, we confirmed that the split vaccine also exhibited better immunogenicity in children and adolescents of 36 months to 18 years of age. This difference in immunogenicity might be due to the manufacturing process. Differences in the influenza antigen variety may affect its efficacy.
Usually, the hemagglutinin titer of 1:40 has been known to correlate with a 50% reduction in contracting influenza. However, this is based on adult studies, and previous studies have shown that this might not effectively reflect the protective level for children.1213) Black et al.20) reported that a cutoff value of 1:330 would predict an 80% rate of protection. On the basis of this criterion, we compared the seroprotection rates of the split and subunit vaccines, whereupon no significant difference between the 2 vaccine groups and the 2 age groups were found.
With regard to the local adverse effects, the subunit vaccine elicited less side effects than the split vaccine. The differences in the concentrations of nonviral compounds (e.g., ovalbumin and endotoxin) may lead to different post-vaccination reactogenicity profiles. The contents of total protein and matrix protein are lower in the subunit vaccines than in the split vaccines.21) In previously reported studies, Korean children tended to show higher rates of local side effects than the children in European and US studies, for which the incidence was commonly reported as 20–30%.22) In our study, 37.5–67.2% of the vaccinated children reported at least one of the local reactions indicated on the diary card, and 23.5–53.1% reported systemic signs/symptoms. However, no serious reactions were reported in our study. The Fluarix® clinical study showed a high frequency of local reactions (15–52.6%) in subjects of 3 to <18 years of age. These results are in accord with the findings of our study.23)
The limitation of our study is that it was open and non-randomized. Most of the clinical studies conducted so far have used inactivated split vaccines and enrolled children ≥3 years old. More comparative studies like the present one are needed to demonstrate the efficacy and safety of trivalent inactivated subunit influenza vaccines in children.
In conclusion, both the split and subunit influenza vaccines that are commonly used in Korean children and adolescent were immunogenic and well tolerated. However, each of the vaccines showed different immune responses and side effects depending on the child's age. Children in the older age group showed lower seroconversion rates and elicited local and systemic adverse events more frequently. Whether these observations are true in other ethnicities and with other vaccines needs confirmation through further clinical experience and a well-designed randomized prospective study.
XML Download