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Large scale investigation of the clinical effectiveness of neuraminidase inhibitors for circulating influenza viruses are important along with the surveillance of virus susceptibility in vitro.The duration of fever and other influenza symptoms as markers of the clinical effectiveness of laninamivir octanoate hydrate (laninamivir) were investigated in the Japanese 2017/18 and 2018/19 influenza seasons and compared with the results of the previous six seasons.Influenza A(H1N1)pdm09, A(H3N2), and B were found in 14, 45, and 52 patients in the 2017/18 season and in 22, 62, and 0 in the 2018/19 season, respectively. The median duration of fever for B was significantly longer than for A(H1N1)pdm09 and A(H3N2) in the 2017/18 season (p = 0.0461) and for A(H3N2) than for A(H1N1)pdm09 in the 2018/19 season (p = 0.0290). However, the differences were subtle in both seasons for other symptoms, with no significant differences in their median duration in comparison of the circulating types/subtypes. Over the eight seasons with the previous six seasons added, the median durations of fever were consistently longer for B than for A, but the relation between the A subtypes was inconsistent. The median durations of fever were comparable over the eight seasons for the virus types/subtypes, as were the median durations of other symptoms. The percentage of febrile patients decreased in a similar pattern over the eight seasons for each type/subtype.The results confirmed that laninamivir has continued to be clinically effective against all types/subtypes of influenza viruses, with no safety issues.

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.

Although the virological and clinical efficacies of baloxavir for influenza and the post-treatment emergence of variant viruses have been reported in clinical trials, its efficacies have not been fully investigated in clinical settings. This prospective, observational investigator-initiated study was conducted during the 2019–2020 Japanese influenza season. In outpatients receiving baloxavir or oseltamivir, nasopharyngeal samples were obtained on day 1 before treatment and on the scheduled days 5 and 10 after treatment. RT-PCR and sequencing were performed to detect polymerase acidic protein (PA) E23X/I38X and neuraminidase (NA) H275Y variants in clinical and cultivated samples. Fever and illness-related symptoms were recorded using self-reporting diaries. Overall, 116 outpatients, 76 treated with baloxavir (34 under 12 years) and 40 with oseltamivir (32 under 12 years), were eligible. Of these, 91 were infected with A (H1N1)pdm09 (78.4%), of which 58 received baloxavir and 33 received oseltamivir. PA variants were detected in clinical (1.7%, 1/58; 3.8%, 1/26 for children under 12 years) and isolated (3.4%, 2/58; 3.8%, 1/26 for children under 12 years) samples obtained on day 5 after baloxavir treatment, but not on day 10. The isolation frequencies of A (H1N1)pdm09 on days 5 and 10 after baloxavir treatment were 5.2% (3/58) and 0.0% (0/58), respectively. Of the three viruses isolated on day 5, two (66.7%, 2/3) were PA I38 T/F variants with reduced baloxavir susceptibility. The isolation frequencies of A (H1N1)pdm09 on days 5 and 10 after oseltamivir treatment were 30.3% (10/33) and 6.1% (2/33), respectively. Only the two viruses isolated on day 10 were NA H275Y variants. The median duration of fever in baloxavir and oseltamivir recipients was 22.3 and 27.5 h, respectively. No patients with PA or NA variants showed prolonged durations of fever. Baloxavir was virologically effective for influenza in the clinical setting of the 2019–2020 Japanese season. Variant emergence after baloxavir treatment was limited to the early post-treatment stage.

We have evaluated a new immunochromatographic kit, "KBM LineCheck Flu AB", which had been developed for enhanced detection of influenza B viruses. Five strains of influenza A and B viruses were tested for reactivity and detection limits of the kit. Compared with the detection limits of commercially available kit of QuickNavi-Flu, "KBM LineCheck Flu AB" showed a nearly equal reactivity to influenza A viruses, but quadruple reactivity to 2 influenza B viruses. Also, "KBM LineCheck Flu AB" exhibited high specificity when tested in 130 influenza-negative culture specimens derived from 24 adult volunteers. Furthermore, "KBM LineCheck Flu AB" was clinically evaluated by using 866 specimens, including 190 nasal swabs, 201 nasal aspirations, 262 self-blown nasal discharges, and 213 pharyngeal swabs. Compared with the results of QuickNavi-Flu for influenza A, the test efficiency for the nasal swabs, the nasal aspirations, self-blown nasal discharges, and pharyngeal swabs were calculated to be 95.8%, 92.0%, 95.0%, and 94.8%, respectively. Whereas, as to influenza B, the test efficiency for the nasal swabs, the nasal aspirations, self-blown nasal discharges, and pharyngeal swabs was calculated to be 96.3%, 98.5%, 96.2%, and 93.4%, respectively. Similarly, compared with the results of influenza A viral culture, the test efficiency for the nasal swabs, the nasal aspirations, self-blown nasal discharges, and pharyngeal swabs was calculated to be 95.3%, 91.0%, 93.9%, and 92.5%, respectively. Regarding influenza B culture, the test efficiency for the nasal swabs, the nasal aspirations, self-blown nasal discharges, and pharyngeal swabs were calculated to be 95.8%, 97.5%, 95.1%, 91.5%, respectively. Overall, we concluded that the "KBM LineCheck Flu AB" is useful and suitable for diagnosis of influenza A and especially influenza B.

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.

Background/aimsTreatment with antiviral neuraminidase inhibitors suppresses influenza viral replication and antigen production, resulting in marked attenuation of mucosal immunity and mild suppression of systemic immunity in mice. This study investigated the effects of immunomodulator clarithromycin (CAM) supplementation on mucosal and systemic immunity in pediatric patients with influenza treated with neuraminidase inhibitors.MethodsA retrospective, non-randomized case series study was conducted among five treatment groups of 195 children aged 5.9±3.3 years infected with influenza A in 2008/2009 season. The five treatment groups were oseltamivir (OSV), zanamivir (ZNV), OSV+CAM, ZNV+CAM and untreated groups. Anti-viral secretory IgA (S-IgA) levels in nasal washes and IgG levels in sera were measured. The re-infection rate was analyzed among the same five treatment groups in the 2009/2010 season.ResultsTreatment of influenza with OSV and ZNV for 5 days attenuated the induction of anti-viral S-IgA in nasal washes and anti-viral IgG in serum, compared with the untreated group. The combination of CAM plus OSV or ZNV boosted and restored the production of mucosal S-IgA and systemic IgG. The re-infection rates in the subsequent season were significantly higher in the OSV and ZNV groups than the untreated, while CAM+OSV and CAM+ZNV tended to reduce such rate.ConclusionsCAM restored the attenuated anti-viral mucosal and systemic immunity and reduced the re-infection rate in the subsequent year in pediatric patients with influenza treated with OSV and ZNV.

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.