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Background Evidence is limited for influenza vaccine effectiveness (VE) against laboratory-confirmed influenza among young children. Using test-negative design (a modified case-control study) which minimizes confounding by health care-seeking behavior and misclassification of diseases, we aimed to monitor influenza VE among young children in Japan where all approved influenza vaccines are egg-propagated, inactivated formulations (IIV). Methods For seasons spanning 2013-14 to 2017-18 in Osaka and Fukuoka Prefectures, Japan, we employed prospective, active, and systematic recruitment of children aged Results We analyzed 4,614 subjects including 1,917 cases. VEs of IIV with 2 doses approximated 50%, ranging from 41% (95% confidence interval [CI]: 14 % to 60%) in 2016-17 season to 63% (95% CI: 45% to 76%) in 2017-18 season. Significant VEs were also shown for predominant circulating strains every season, irrespective of their antigenic match to vaccine strains (56% and 65% for A[H1N1]pdm, 37% and 50% for A[H3N2], and 60% for B[Yamagata]). Conclusions IIV provided modest and significant protection against laboratory-confirmed influenza in young Japanese children. Key messages Test-negative design is useful for monitoring influenza VE.

Supplemental Digital Content is available in the text, In young children, infrequent antigen exposure, which is partly characterized by fewer vaccinations, may be a factor impairing the immunogenicity of inactivated influenza vaccine. We assessed the effects of prior vaccinations on age-specific immune responses in Japanese children aged 6 months to 3 years, using data from a cohort study with 266 children who had received 2 doses (0.25 mL/dose for < 3 years old, 0.5 mL/dose for 3 years old) in the 2006/2007 season. Serological measures, primarily seroprotection rates, between previously vaccinated and vaccine-naïve children were compared within 1-year age strata. The seroprotection rate was defined in 2 ways as the proportion of subjects who achieved an antibody titer of 1:40 or 1:160. Multivariate logistic regression was also performed to estimate the independent effect of prior vaccination on seroprotection rate. After the first dose, seroprotection rates with the threshold of 1:40 in vaccine-naïve 1-year-olds remained low (28% for AH1, 26% for AH3, 2% for B), similar to those of 0-year-olds. In contrast, seroprotection rates in previously vaccinated 1-year-olds (77% for AH1, 86% for AH3, 18% for B) were significantly higher than those in vaccine-naïve 1-year-olds. These seroprotection rates for AH1 and AH3 were comparable with those in previously vaccinated 2- and 3-year-olds. Although seroprotection rates for B remained low in every age stratum even after the second dose, seroprotection rate in previously vaccinated 1-year-olds (50%) was similar to that in 3-year-olds. After adjustment for age, baseline antibody titer and experience of acute febrile respiratory illness in the preceding season, odds ratios showed a significant independent positive effect of prior vaccination on seroprotection rate for every strain. After the seroprotection threshold was changed from 1:40 to 1:160, the results of the effects of prior vaccinations on immunogenicity were similar or became more evident, which demonstrate the robustness of our findings. Our study found that prior vaccinations improved poor immunogenicity among young children, especially in 1-year-olds.

Four pediatric clinics in Fukuoka, Japan, collected 822 cases of nasopharyngeal specimens from patients with influenza-like symptoms from 1 October 2002 to 31 March 2003. Age distribution of these cases was 6 months to 15 years old and mean age was 5.98 years old. Two hundred seventy-eight cases were positive for influenza type A(H3N2) and 176 cases for type B. When compared with virus culture, the sensitivity of the rapid detection kits for type A(H3N2) was 89.4% by nasal swab and 78.8% by throat swab, while type B testing revealed 75.7% positive by nasal swab and 78.3% by throat swab. Comparison of sensitivity of rapid detection kits to virus culture from the onset of influenza-like illness showed testing at 6 h from onset yielded the highest sensitivity (89.3%) in A(H3N2) (p

Antigenicity of all the A(H3) viruses which we isolated from specimens collected in Sendai and Fukuoka, Japan in 2002–2003 influenza season was examined by hemagglutination inhibition test (HI) using the ferret antiserum against A/Panama/2007/99 (H3N2), the vaccine strain for the past three influenza seasons, provided by WHO Influenza Collaborating Center, Japan. All the viruses were isolated in MDCK cell system. From the beginning of the epidemic, we found that many isolated virus strains reacted with the standard antiserum more than 4- to 16-fold less than its homologous titer, in both cities. The number of isolation of such antigenic drifted viruses increased and dominated the isolates in this season. We show here the chronological appearance of such variants in this season. Furthermore, we performed genetic analyses on the HA genes of the isolates along with those of previous two consecutive seasons. Thus it was revealed that the isolates of this season make a clear cluster different from the cluster in the previous seasons, and the variants of 2002–2003 season make a different cluster from those of previous two seasons. Moreover, no difference was found in clusters which could explain the difference between these variants and nonvariants, and among variants isolated in four cities.

A series of studies were performed to investigate the ability of rapid antigen-detection kits in diagnosis of influenza. Clinical specimens were collected from a total of more than 3000 cases of influenza-like illness who visited out-patient clinics in Sendai and Fukuoka, Japan, during the 2001–2002 and 2002–2003 influenza seasons. Each clinical specimen was examined with a kit and virus isolation, and results were analyzed retrospectively by several points of interest: sensitivity of the kits based on the virus isolation and the sensitivity by type and subtype of influenza, kinds of specimens, the time course of influenza, and variation of sources of the specimens. Thus, the sensitivities of a kit were 83%, 52% and 58% in general for influenza A(H3N2), A(H1N1), and B, respectively, and those of another kit were 76%, 71%, and 62%, respectively, in 2001–2002 influenza season. The sensitivity using nasal swabs was better than that using throat swab, though only 5% up. Specimens tended to be less sensitive when collected shortly after the onset of illness, and the sensitivity seemed quite varied (17–92%) by source of specimens: staff who collect the specimens, and/or by population of the patients.

In Japan, the routine immunization program with oral polio vaccine (OPV) has been suspended since September 2012, when a program with 4 doses of inactivated monovalent polio vaccine (IPV) or quadrivalent vaccine against diphtheria, pertussis, and tetanus with IPV (DTaP-IPV) was introduced. The aim of this study was to examine the interchangeability among these 3 types of polio vaccines.We conducted a prospective cohort study at 5 pediatric clinics in Japan. A total of 153 infants were assigned to 1 of the 4 groups by considering the vaccination history of OPV and trivalent vaccine against DTaP. Eleven infants with a history of OPV received 3 doses of DTaP-IPV; 49 infants with a history of OPV and DTaP received 3 doses of IPV; 50 polio vaccine-naive infants received 2 doses of IPV followed by 2 doses of DTaP-IPV; and 43 polio vaccine-naive infants received 2 doses of DTaP-IPV followed by IPV. The immunogenicity after polio vaccination was evaluated among these 4 groups.After 2 doses of polio vaccination, more than 80% of the infants exhibited a neutralization antibody titer ≥1:8 for all Sabin strains and wild strains in all groups. After the third dose, the seroprotection proportion (i.e., a neutralization antibody titer ≥1:8) reached about 100%. After the fourth dose, a neutralization antibody titer exceeded the required protective levels (i.e., a neutralization antibody titer ≥1:8) considerably in all groups.Four doses of polio vaccines induced a sufficient level of immunity in Japanese infants, irrespective of vaccine combinations or order.

We studied the immunogenicity of trivalent-inactivated influenza vaccine. Subjects were 259 children under 4 years old who visited six pediatric clinics to undergo influenza vaccination. Age distribution was 64 aged1.0, 65 aged 1.0-1.9, 64 aged 2.0-2.9, and 66 aged 3.0-3.9 years, including subjects who had been previously vaccinated within the last three years, 0% (0/64) aged1.0, 26% (17/65) aged 1.0-1.9, 72% (46/64) aged 2.0-2.9, and 77% (51/66) aged 3.0-3.9 years old. Two doses of vaccine were given subcutaneously four weeks apart. Dosage was 0.l mL for children under 1 year old, while for children aged one year or older, dosage was 0.2mL, based on standard Japanese recommendations. To measure hemagglutination inhibition (HI) antibody titer, triplet sera were obtained before vaccination (S0), 4 weeks after the first vaccination (S1), and 4 weeks after the second vaccination (S2). The geometric mean of HI antibody titer, the response proportion (titer riseor =4-fold), and the achievement proportion (postvaccination titeror =1 : 40) were calculated by age group. Analysis of variance was used to estimate the independent effect of age and prevaccination titer on antibody increase. The geometric means of HI antibody titer were lower among the two younger age groups than among the two older age groups, regardless of vaccine strain or when blood samples were collected. The achievement proportion after 2 doses of vaccine in the1.0, 1.0-1.9, 2.0-2.9, 3.0-3.9 year age groups were 38%, 58%, 89%, and 85% against A (HI) ; 52%, 54%, 81%, and 73% against A (H3) ; and 23%, 49%, 67%, and 71% against B. Regarding the analysis of variance, prevaccination titer consistently indicated strong effects on antibody increase, regardless of vaccine strain or combination of paired sera. After two doses of vaccine (S2/S0), significant effects of age on antibody induction were shown against A (H1) and B (p = 0.000 and 0.002). Thus, the immunogenicity of trivalent-inactivated influenza vaccine was strongly influenced by prevaccination titer and age. Even two doses of vaccine did not induce a protective antibody level in about 50 to 80% of subjects among infants aged1.0 year, and 40 to 50% among children 1.0-1.9 year old.