Virological and clinical outcomes in outpatients treated with baloxavir or neuraminidase inhibitors for A(H3N2) influenza: A multicenter study of the 2022-2023 season.

While clinical trials have illuminated both the virological and clinical efficacy of baloxavir for influenza and post-treatment viral resistance, these aspects warrant further study in real-world settings. In response, we executed a prospective, observational study of the Japanese 2022-2023 influenza season. A cohort of 73 A(H3N2)-diagnosed outpatients-36 treated with baloxavir, 20 with oseltamivir, and 17 with other neuraminidase inhibitors (NAIs)-were analyzed. Viral samples were collected before and after administering an antiviral on days 1, 5, and 10, respectively. Cultured viruses were amplified using RT-PCR and sequenced to detect mutations. Fever and other symptoms were tracked via self-reporting diaries. In the baloxavir cohort, viral detection was 11.1% (4/36) and 0% (0/36) on day 5 and day 10, respectively. Two isolates from day 5 (5.6%, 2/36) manifested I38T/M-substitutions in the polymerase acidic protein (PA). For oseltamivir and other NAIs, viral detection rates were 60.0% (12/20) and 52.9% (9/17) on day 5, and 16.7% (3/18) and 6.3% (1/16) on day 10, respectively. No oseltamivir-resistant neuraminidase mutations were identified after treatment. Median fever durations for the baloxavir, oseltamivir, and other NAI cohorts were 27.0, 38.0, and 36.0 h, respectively, with no significant difference. Two patients harboring PA I38T/M-substitutions did not exhibit prolonged fever or other symptoms. These findings affirm baloxavir's virological and clinical effectiveness against A(H3N2) in the 2022-2023 season and suggest limited clinical influence of post-treatment resistance emergence.

No association between inactivated influenza vaccination and influenza viral load at diagnosis among young Japanese children: An observational study of the 2013/2014 through 2017/2018 influenza seasons.

BACKGROUND: The association between inactivated influenza vaccination and viral load in young children remains unclear. METHODS: During the 2013/2014 to 2017/2018 influenza seasons in Japan, children under 6 years of age with pre-defined influenza-like illness and influenza-positive status by real-time RT-PCR were recruited at pediatric clinics for this observational study. Influenza viral load was measured for the most predominant subtype/lineage in each season. Using median dichotomized viral load as an outcome, a multilevel logistic regression model was applied to estimate the multivariable adjusted odds ratio (MOR) and 95% confidence interval (CI) for higher viral load. RESULTS: A total of 1,185 influenza-positive children were analyzed. The median log10 viral load copy number (copies per milliliter) was 5.5 (interquartile range, 4.6 to 6.1) and did not differ by vaccination status: 5.5 for unvaccinated, 5.7 for one dose, and 5.5 for two doses (p = 0.67). The MOR of vaccinated (one or two doses) versus unvaccinated children was 1.19 (95% CI: 0.86-1.64). Other factors showing significant associations with higher viral load were positive results for A(H1N1)pdm09 and A(H3N2) in comparison with B/Yamagata. The respective MORs were 3.25 (95% CI: 2.28-4.64) and 1.81 (95% CI: 1.32-2.49). Significantly elevated MORs against higher viral load were also observed for higher body temperature at influenza diagnosis and shorter duration from fever onset to specimen collection. CONCLUSION: No association was observed between inactivated-influenza vaccination and viral load at influenza-positive diagnosis. Influenza subtype/lineage, body temperature, and time elapsed since fever onset were significantly associated with viral load.

Duration of fever and other symptoms after the inhalation of laninamivir octanoate hydrate: A study of the 2017/18 and 2018/19 seasons and comparison with the 2011/12 to 2016/17 Japanese influenza seasons.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The results confirmed that laninamivir has continued to be clinically effective against all types/subtypes of influenza viruses, with no safety issues.

Influence of Prior Influenza Vaccination on Current Influenza Vaccine Effectiveness in Children Aged 1 to 5 Years.

BACKGROUND: Although annual influenza vaccination is an important strategy used to prevent influenza-related morbidity and mortality, some studies have reported the negative influence of prior vaccination on vaccine effectiveness (VE) for current seasons. Currently, the influence of prior vaccination is not conclusive, especially in children. METHODS: We evaluated the association between current-season VE and prior season vaccination using a test-negative design in children aged 1-5 years presenting at nine outpatient clinics in Japan during the 2016/17 and 2017/18 influenza seasons. Children with influenza-like illness were enrolled prospectively and tested for influenza using real-time RT-PCR. Their recent vaccination history was categorized into six groups according to current vaccination doses (0/1/2) and prior vaccination status (unvaccinated = 0 doses/vaccinated = 1 dose or 2 doses): (1) 0 doses in the current season and unvaccinated in prior seasons (reference group); (2) 0 doses in the current season and vaccinated in a prior season; (3) 1 dose in the current season and unvaccinated in a prior season; (4) 1 dose in the current season and vaccinated in a prior season; (5) 2 doses in the current season and unvaccinated in a prior season, and (6) 2 doses in the current season and vaccinated in a prior season. RESULTS: A total of 799 cases and 1196 controls were analyzed. The median age of the subjects was 3 years, and the proportion of males was 54%. Overall, the vaccination rates (any vaccination in the current season) in the cases and controls were 36% and 53%, respectively. The VEs of the groups were: (2) 29% (95% confidence interval: -25% to 59%); (3) 53% (6% to 76%); (4) 70% (45% to 83%); (5) 56% (32% to 72%), and (6) 61% (42% to 73%). The one- and two-dose VEs of the current season were significant regardless of prior vaccination status. The results did not differ when stratified by influenza subtype/lineage. CONCLUSION: Prior vaccination did not attenuate the current-season VE in children aged 1 to 5 years, supporting the annual vaccination strategy.

Virological and clinical outcomes in outpatients treated with baloxavir or oseltamivir: A Japanese multicenter study in the 2019-2020 influenza season.

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.

Prior vaccinations improve immunogenicity of inactivated influenza vaccine in young children aged 6 months to 3 years: A cohort study.

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.

Immunogenicity study to investigate the interchangeability among three different types of polio vaccine: A cohort study in Japan.

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-naïve 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.

[Evaluation of a new immunochromatographic kit for enhanced detection of influenza B virus].

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.

Immunomodulator clarithromycin enhances mucosal and systemic immune responses and reduces re-infection rate in pediatric patients with influenza treated with antiviral neuraminidase inhibitors: a retrospective analysis.

BACKGROUND/AIMS: Treatment 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. METHODS: A 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. RESULTS: Treatment 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. CONCLUSIONS: CAM 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.

[Immunogenicity of trivalent-inactivated influenza vaccine among children less than 4 years old].

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 aged <1.0, 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) aged <1.0, 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 rise > or =4-fold), and the achievement proportion (postvaccination titer > or =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 the <1.0, 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 aged <1.0 year, and 40 to 50% among children 1.0-1.9 year old.