key: cord-0682759-twyiiac6 authors: Shinjoh, Masayoshi; Furuichi, Munehiro; Kobayashi, Hisato; Yamaguchi, Yoshio; Maeda, Naonori; Yaginuma, Mizuki; Kobayashi, Ken; Nogayama, Taisuke; Chiga, Michiko; Oshima, Mio; Kuramochi, Yuu; Yamada, Go; Narabayashi, Atsushi; Ookawara, Ichiro; Nishida, Mitsuhiro; Tsunematsu, Kenichiro; Kamimaki, Isamu; Shimoyamada, Motoko; Yoshida, Makoto; Shibata, Akimichi; Nakata, Yuji; Taguchi, Nobuhiko; Mitamura, Keiko; Takahashi, Takao title: Trends in effectiveness of inactivated influenza vaccine in children by age groups in seven seasons immediately before the COVID-19 era date: 2022-04-11 journal: Vaccine DOI: 10.1016/j.vaccine.2022.04.033 sha: 4b5e68bfbe20b7a146c5080c435a092509ecdeae doc_id: 682759 cord_uid: twyiiac6 BACKGROUND: We have reported the vaccine effectiveness of inactivated influenza vaccine in children aged 6 months to 15 years between the 2013/14 and 2018/19 seasons. Younger (6-11 months) and older (6-15 years old) children tended to have lower vaccine effectiveness. The purpose of this study is to investigate whether the recent vaccine can be recommended to all age groups. METHODS: The overall adjusted vaccine effectiveness was assessed from the 2013/14 until the 2020/21 season using a test-negative case-control design based on rapid influenza diagnostic test results. Vaccine effectiveness was calculated by influenza type and by age group (6–11 months, 1–2, 3–5, 6–12, and 13–15 years old) with adjustments including influenza seasons. RESULTS: A total of 29,400 children (9347, 4435, and 15618 for influenza A and B, and test-negatives, respectively) were enrolled. The overall vaccine effectiveness against influenza A, A(H1N1)pdm09, and B was significant (44% [95% confidence interval (CI), 41–47], 63% [95%CI, 51–72], and 37% [95%CI, 32–42], respectively). The vaccine was significantly effective against influenza A and B, except among children 6 to 11 months against influenza B. The age group with the highest vaccine effectiveness was 1 to 2 years old with both influenza A and B (60% [95%CI, 55–65] and 52% [95%CI, 41–61], respectively). Analysis for the 2020/21 season was not performed because no cases were reported. CONCLUSIONS: This is the first report showing influenza vaccine effectiveness by age group in children for several seasons, including immediately before the coronavirus disease (COVID-19) era. The fact that significant vaccine effectiveness was observed in nearly every age group and every season shows that the recent vaccine can still be recommended to children for the upcoming influenza seasons, during and after the COVID-19 era. Immunizing children with the influenza vaccine is effective for both direct protection (reducing an individual's chance of infection) and indirect protection (decreasing transmission to others) [1] [2] [3] [4] . Thus, the influenza vaccine is recommended widely, and routine annual influenza vaccination has been recommended for children aged ≥6 months without contraindications by the Center for Disease Control's Advisory Committee on Immunization Practices [5] . In Japan, immunization with influenza vaccine is not included in routine immunizations, and is a voluntary immunization. Thus, children have no duty to receive this vaccination. The overall vaccine coverage rate in Japan remained low at approximately 30%, 60%, and 40% for children aged 1, 2-12, and 13-15 years, respectively [6] . A two-dose regimen is recommended for all children aged 6 months to 12 years old regardless of recent immunization histories, and a single dose is recommended only for children 13 years and older in Japan [7] . In the United States, children who previously received ≥2 total doses of influenza vaccine ≥4 weeks apart before July 1 of the season require only one dose for the season, and others require two [8] . Dose volumes of 0.25 ml and 0.5 ml are recommended for children 6 months to 2 years old and for children 3 years old and over, respectively, similar to the United States. Although children aged 6-11 months are included in the recommended group, the vaccine effectiveness (VE) for this specific age group has not been proved recently. Our series of VE studies since the 2013/14 season [7, [9] [10] [11] [12] [13] demonstrated that vaccines in younger (6-11 months) and older (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) years old) children tended to be less effective. We showed significant VE against influenza A in the 2018/19 season for children aged 6-11 months (63% [95% confidence interval (CI), 15-84]) [7], but the VE for this age was not statistically significant against either influenza A and B in other seasons (95%CI of the odds ratio included 1.0). In one of our studies in the five-season analysis (2013/14-2017/18) [13] , all age groups (1-2, 3-5, 6-12 years old) except 6-11 months showed significant VE for both influenza A and B. The small sample size in this age group in the dose analysis (none, once, or twice) may be one of the reasons for this result. The purpose of this study was to measure the VE for preventing influenza by age group to investigate whether the recent vaccine can be recommended to all age groups of children, including 6-11 months and 6-15 years old, using the data on several seasons immediately before and during the COVID-19 era, including unreleased analysis for the 2019/20 season and dose (once or twice) analysis for 6 months to 12 years old. As previously reported, we used a test-negative case-control design based on rapid influenza diagnostic test (RIDT) results to assess the VE. We enrolled children who were 6 months to 15 years old with a fever of ≥38°C who were suspected of having influenza and had received an RIDT at one of our outpatient clinics at 20 hospitals in the north (Gunma, Tochigi), middle (Saitama, Tokyo, Chiba), and south (Kanagawa, and Shizuoka) Kanto region in Japan between the 2013/14 and 2020/21 seasons (November 1-March 31). The data were obtained from the database that we used in our recent VE studies, including the risk analysis study [7, [9] [10] [11] [12] [13] [14] . Cases and controls were defined as RIDT-positive and RIDT-negative patients, respectively. Medical interviews and/or medical records from the Maternal and Child Health Handbooks provided by local governments were the source of vaccine information. Patients who had already been prescribed any anti-influenza viral drugs prior to the visit were excluded. All patients were enrolled during the period of influenza each season (December-March). Total number of lifetime doses of the vaccine was not investigated. To analyze the VE for preventing hospitalization, cases and controls were defined as RIDT-positive and RIDT-negative hospitalized patients, respectively. The method for calculation is similar to that used in previous studies [12, 13, 19, 20] . VE was defined as "1-odds ratio (OR)," and OR was calculated as follows: (Number of influenza-positives among vaccinated patients × number of influenza-negatives among unvaccinated patients) / (number of influenza-negatives among vaccinated patients × number of influenza-positives among unvaccinated patients). Adjustments to the VE are explained in "Statistical analyses" below. The VE for preventing influenza A(H1N1)pdm09 was also analyzed in three hospitals where ImunoAce Flu and Linjudge FluA/pdm were utilized. We recorded the number of vaccine doses per patient (none, one, or two) and compared the VE among them. Because a single dose is recommended only for children ≥13 years old, as explained above, this analysis was performed only among children aged 6 months to 12 years old including the sub-analysis for 6 months to 2 years old (for 0.25 ml/dose), and 6 months to 5 years (for young children). Statistical analyses were performed using the SPSS 26.0 or 27.0 software program (IBM, Chicago, USA) and the BellCurve for Excel for Windows software program (Social Survey Research Information Co., Ltd., Tokyo, Japan). p < 0.05 was considered statistically significant. Binary logistic regression methods were used to analyze the VE. Confounding factors, such as sex, age (0-15 years old), comorbidity (yes or no), colder or warmer area (northern, middle, or southern area), month of onset, and season were entered in the analysis by the forced entry method. In the 2019/20 season, the adjusted VE for preventing influenza A illness was 44% (95%CI, 35%-52%, n=3290) ( Table 2 ). The overall adjusted VE for seven seasons for preventing influenza A illness was 44% (95%CI, 41%-47%, n=24,419) and 48% (95%CI, 44%-51%, n=13,806) for all participants and those who visited 12-48 h after onset only, respectively. Significant adjusted VE for preventing influenza A illness was shown for all age groups. The highest adjusted VE was 60% (95% CI, 55%-65%, n=6611) for children aged 1-2 years old. Significant adjusted VE was also shown among the children aged 6-11 months (36% [95% CI, 10-55], n=1210). Adjusted VE was 55% (95% CI, 42%-66%, n=1136) and 44% (95% CI, 41%-47%, n=20,851) for inpatients and outpatients, respectively. The former, which indicated the adjusted VE for preventing hospitalization, was higher but was not statistically significant (Breslow-Day test, p = 0.3972). Significant adjusted VE for preventing influenza A hospitalization was shown for all age groups between 1 and 12 years old ( Table 2) . The influenza vaccine was significantly effective in all seven seasons. Among them, relatively higher adjusted VE (more than 50%) was observed in 2013/14, 2015/16, and 2017/18 seasons. There was no significant difference in the VE between participants with and without underlying diseases (Breslow-Day test, p = 0.180), and between one and two doses (see "Twice compared with once" at the bottom of Table 2 ). Only three hospitals used Linjudge FluA/pdm to detect A(H1N1)pdm09 [18] ( Table 3 ). The overall adjusted VE for seven seasons for preventing influenza A(H1N1)pdm09 illness was 63% (95% CI, 51%-72%, n=1603) and 60% (95% CI, 38%-74%, n=589) for all participants and those who visited 12-48 h after onset only, respectively ( Table 3) . Significant adjusted VE for preventing influenza A(H1N1)pdm09 illness was shown for all age groups except 6-11 months and 13-15 years, in which the number of enrollees was insufficient. The highest adjusted VE was 79% (95% CI, 63%-88%, n=567) for children aged 1-2 years old. In the 2019/20 season, the adjusted VE for preventing influenza B illness was 29% (95% CI, 5%-46%, n=2405) ( The vaccine was significantly effective against influenza A and B in all age groups, except among In most of our previous data, the VE for children 6-11 months has not been investigated statistically [7, [9] [10] [11] [12] [13] . Although the VE is not high, the children in this age group were also protected by IIV in the present study. This suggests that recent IIV should be recommended for all children, including infants aged 6-11 months. Interestingly, the adjusted VE was the highest in the 1-2-year-old groups against all influenza subtypes (influenza A, A(H1N1)pdm09, and B for 60%, 79%, and 52%, respectively). One of the explanations is immaturity of the immune system in the children aged 6-11 months. Also, both vaccinated and unvaccinated older children tended to have a similar level of immunity at baseline, because of the possible prior history of immunization or influenza itself [9] . In other words, both vaccinated and unvaccinated older children tended to have a similar antibody titer at baseline. In fact, the pre-seasonal titers of serum hemagglutination inhibition (HAI) antibodies increased with age during childhood against almost all influenza types every season according to the national surveillance data [6] . Similar to our report, the VE among children aged 1-2 years was higher (63%) than the VE among children aged 2-5 years (45%-57%) in a prospective, non-randomized, observational study [21] . In contrast, according to a recent report in Australia, the adjusted VE analyzed by a matched case-control study increased with age among children 6 months to 4 years [22] . However, it is difficult to compare the VE with the previously published data because we could not exclude the effect of infection history or previous immunization, maternal immunization during pregnancy, dose-effect (once or twice), and difference in analyzed season and methodology. The adjusted VE for preventing hospitalization was significant in influenza A as seen in adults [19, 20] . Similar to overall VE against influenza A, the VE in younger children (1-2 years [13] , and that only the two-dose regimen is effective in children aged 6 months to 12 years in one of our related hospitals [27] . In a systematic review, the VE was higher for fully vaccinated children than for partially vaccinated children, especially those aged 6 to 23 months [25] . Similarly, another report showed that the adjusted VE against any influenza was 51% (95% CI 44-57) and 41% (95% CI 25-54) among fully and partially vaccinated children aged 6 months to 8 years, respectively [26] . We speculate that the VE related to vaccine dose depends on many factors, including history of immunization and influenza infection [22] , seasons, and vaccine mismatch. Thus, the two-dose regimen can be recommended, especially for younger children. combined the seasonal data. However, we always adjusted the data by season. We believe that this combined but adjusted data may lead to an answer to the question, "Is IIV effective overall?" In conclusion, during the recent seven seasons immediately before the COVID-19 era, IIV was effective against both influenza A and B in all age groups of children, except for influenza B in infants aged 6-11 months. The highest VE was observed among 1-2 year olds in both influenza A and B. Also, the vaccine is effective in preventing hospitalization with influenza A for children aged 1-12. As approximately half of children are not immunized every year in Japan [6] , IIV should be recommended to children of all age groups to reduce both influenza illness and influenza hospitalization. This work was supported by JSPS KAKENHI, Japan (Grant Number JP20K10546). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The overall adjusted vaccine effectiveness was assessed from the 2013/14 until the 2020/21 season using a test-negative case-control design based on rapid influenza diagnostic test results. Vaccine effectiveness was calculated by influenza type and by age group (6-11 months, 1-2, 3-5, 6-12, and 13-15 years old) with adjustments including influenza seasons. A total of 29,400 children (9347, 4435, and 15618 for influenza A and B, and test-negatives, respectively) were enrolled. 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The authors are also grateful for the participation of the subjects and the clinical and laboratory personnel at each hospital.