Nationwide epidemiologic study of norovirus-related hospitalization among Japanese older adults.

BACKGROUND: Older adults are vulnerable to hospitalization or death from norovirus infection, but the actual disease burden remains unknown. Therefore, we conducted a nationwide survey to estimate the number of inpatients with norovirus gastroenteritis and associated deaths among Japanese older adults. METHODS: We performed a nationwide two-step query targeting 4184 hospital departments selected from 17,575 departments using stratified random sampling according to the number of beds. We asked each department to complete a mail-back questionnaire on the annual numbers of inpatients with infectious gastroenteritis and associated deaths between administrative years 2012 and 2014, and the implementation status of norovirus infection testing. In a second query, we investigated the annual number of inpatients with norovirus gastroenteritis and associated deaths in departments that had reported infectious gastroenteritis inpatients in the first query. Clinical information was collected for inpatients with norovirus gastroenteritis in administrative year 2014. RESULTS: Norovirus testing for patients hospitalized for acute gastroenteritis was routinely conducted in 16% of the responding departments. Although half the departments responded that some acute gastroenteritis inpatients received such testing but others did not. In this situation, numbers of inpatients with norovirus gastroenteritis in Japan were estimated as 31,800 (95% CI: 25,700-37,900) in administrative year 2012, 21,600 (95% CI: 17,700-25,500) in administrative year 2013, and 15,700 (95% CI: 12,900-18,500) in administrative year 2014. The estimated number of associated deaths was approximately 600 in each administrative year. Factors associated with death included higher age, living in long-term care facilities, underlying illnesses such as chronic respiratory diseases, and complications such as aspiration pneumonia. CONCLUSIONS: The actual number of norovirus inpatient would be higher than the estimated here due to the low rate of routinely implemented norovirus testing. Considering Japan's rapidly aging society and the disease burden of norovirus infection among Japanese older adults, it is important to protect this high-risk population from norovirus infection.

Nationwide Survey of Pediatric Inpatients With Hand, Foot, and Mouth Disease, Herpangina, and Associated Complications During an Epidemic Period in Japan: Estimated Number of Hospitalized Patients and Factors Associated With Severe Cases.

BACKGROUND: Severe pediatric cases of hand, foot, and mouth disease (HFMD), herpangina (HA), and associated complications caused by enterovirus 71 (EV71) infection have brought substantial public health impact in Asia. This study aimed to elucidate the epidemiology of these pediatric cases in Japan. METHODS: A nationwide survey was conducted using stratified random sampling of hospital pediatric departments. We estimated the number of inpatients with HFMD, HA, and associated complications between April 1 and September 30, 2010, during which EV71 was circulating predominantly. Factors associated with severe cases with ≥7 days of admission, sequelae, or outcome of death were analyzed using multivariate logistic regression. RESULTS: During the 6-month epidemic period, the number of pediatric inpatients aged <15 years was about 2,900 (estimated cumulative incidence of hospitalized cases: 17.0 per 100,000 population). Severe cases were significantly associated with younger age. Compared to patients ≥5 years of age, the odds ratios (ORs) for <1 year of age and 1 to <3 years of age were 5.74 (95% confidence interval [CI], 2.14-15.4) and 2.94 (95% CI, 1.02-8.51), respectively. Elevated ORs for hyperglycemia (plasma glucose level of ≥8.3 mmol/L) on admission (OR 3.60; 95% CI, 0.94-13.8) were also observed. CONCLUSIONS: Disease burden of pediatric inpatients with HFMD, HA, and associated complications in Japan was described for the first time. During an EV71 epidemic, younger age and, suggestively, hyperglycemia may have been critical factors requiring more careful treatment.

Protective Effect of Maternal Influenza Vaccination on Influenza in Their Infants: A Prospective Cohort Study.

Background: Infants <6 months of age are too young to receive influenza vaccine, despite being at high risk for severe influenza-related complications. Methods: To examine the effectiveness of maternal influenza vaccination in preventing influenza in their infants, we conducted a prospective cohort study of 3441 infants born at participating hospitals before the 2013-2014 influenza season. At the time of recruitment, their mothers completed a questionnaire about influenza vaccination status for the 2013-2014 season. A follow-up survey was conducted after the end of the 2013-2014 season to collect information regarding influenza diagnosis and hospitalization among infants. Results: During the 2013-2014 influenza season, 71 infants (2%) had influenza diagnosed, and 13 infants (0.4%) were hospitalized with influenza. Maternal influenza vaccination (especially prenatal vaccination) decreased the odds of influenza among infants. The effectiveness of prenatal vaccination was 61% (95% confidence interval, 16%-81%), whereas that of postpartum vaccination was 53% (-28%-83%). Although maternal influenza vaccination was also associated with a decreased odds of influenza-related hospitalization among infants, vaccine effectiveness (73%) did not reach statistical significance, owing to the limited number of infants hospitalized because of influenza. Conclusions: The present findings indicated that pregnant women and postpartum women should receive influenza vaccination to protect their infants.

Immunogenicity and Efficacy of A/H1N1pdm Vaccine Among Subjects With Severe Motor and Intellectual Disability in the 2010/11 Influenza Season.

BACKGROUND: While the immunogenicity and effectiveness of seasonal influenza vaccines among subjects with severe motor and intellectual disability (SMID) are known to be diminished, the efficacy of the A/H1N1pdm vaccine has not been evaluated. METHODS: We prospectively evaluated 103 subjects with SMID (mean age, 41.7 years) who received trivalent inactivated influenza vaccine during the 2010/11 influenza season. The hemagglutination inhibition (HI) antibody titer was measured in serum samples collected pre-vaccination (S0), post-vaccination (S1), and end-of-season (S2) to evaluate subjects' immunogenicity capacity. Vaccine efficacy was assessed based on antibody efficacy and achievement proportion. RESULTS: The proportions of seroprotection and seroconversion, and the geometric mean titer (GMT) ratio (GMT at S1/GMT at S0) for A/H1N1pdm were 46.0%, 16.0%, and 1.8, respectively-values which did not meet the European Medicines Evaluation Agency criteria. The achievement proportion was 26%. During follow-up, 11 of 43 subjects with acute respiratory illness were diagnosed with type A influenza according to a rapid influenza diagnostic test (RIDT), and A/H1N1pdm strains were isolated from the throat swabs of 5 of those 11 subjects. When either or both RIDT-diagnosed influenza or serologically diagnosed influenza (HI titer at S2/HI titer at S1 ≥2) were defined as probable influenza, subjects with A/H1N1pdm seroprotection were found to have a lower incidence of probable influenza (odds ratio, 0.31; antibody efficacy, 69%; vaccine efficacy, 18%). CONCLUSIONS: In the present seasonal assessment, antibody efficacy was moderate against A/H1N1pdm among SMID subjects, but vaccine efficacy was low due to the reduced immunogenicity of SMID subjects.

Impact of genotype-specific herd immunity on the circulatory dynamism of norovirus: a 10-year longitudinal study of viral acute gastroenteritis.

Human norovirus is a major cause of viral acute gastroenteritis worldwide. However, the transition of endemic norovirus genotypes remains poorly understood. The characteristics of natural immunity against norovirus are unclear because few studies have been performed in the natural infection setting. This prospective 10-year surveillance study of acute gastroenteritis in the province of Osaka, Japan, revealed that norovirus spread shows temporal, geographic, and age group-specific features in the humans. Genogroup II genotype 4 (GII.4) was detected in most sporadic pediatric cases, as well as in foodborne and nursing home outbreaks, respectively. The dominant genotypes in outbreaks at childcare facilities and schools shifted every season and involved GI, GII.2, GII.3, GII.4, and GII.6. Evidence at both the facility and individual levels indicated that genotype-specific herd immunity lasted long enough to influence the endemic norovirus genotype in the next season. Thus, norovirus circulates through human populations in a uniquely dynamic fashion.

Factors impacting antibody kinetics, including fever and vaccination intervals, in SARS-CoV-2-naïve adults receiving the first four mRNA COVID-19 vaccine doses.

To evaluate the antibody response following the initial four doses of mRNA vaccines (BNT162b2 or mRNA-1273) in SARS-CoV-2-naïve healthy adults and investigate factors influencing antibody titer increases, this prospective cohort study was conducted in Japan from March 2021. The study included participants who received either the 1st and 2nd doses (n = 467), 3rd dose (n = 157), or 4th dose (n = 89). Blood samples were collected before and up to 6 months after each dose, and anti-receptor-binding domain antibody levels were measured. Multivariate analysis (usin multiple linear regression or linear mixed models) revealed several factors significantly associated with higher post-vaccination antibody levels, including mRNA-1273 vaccine (after the 1st and 2nd dose), male gender (after the 3rd and 4th doses), younger age (after the 1st and 2nd dose), non-smoking status (after the 2nd dose), non-use of immunosuppressive agents (after the 1st dose), higher pre-vaccination antibody titers (after the 2nd, 3rd, and 4th doses), and higher post-vaccination fever (after the 2nd and 4th doses). Furthermore, longer intervals since the last dose were significantly associated with higher antibody levels after the 3rd and 4th doses. These findings provide valuable insights for optimizing vaccination strategies.

Serum immunoglobulin G subclass levels and estimated clinical severity caused by possible influenza A (H1N1) pdm 2009 infection.

The clinical severity of the 2009 pandemic H1N1 influenza (H1N1 pdm09) was thought to be related to the difference between the amount of viral load and condition of the host immune response. We investigated the role of serum levels of IgG and its subclasses in clinical severity using the data from 45 child inpatients suffering from bronchitis or mild pneumonia caused by possible H1N1 pdm09 (pH1N1 pdm09) infection. After selecting parameters for serum IgG subclasses and logarithmically transformed urinary beta-2 microglobulin/creatinine (b2MG/Cr) values and admission duration, we performed path analysis using a mean covariance structure equation analysis to investigate the relationship between the clinical severity and the foregoing selected parameters. Total path analyses using a Bayesian method revealed that the estimated clinical severity caused by pH1N1 pdm09 was positively associated with maximal respiration rates, admission duration, and log urinary b2MG/Cr levels, whereas negatively associated with serum IgG, IgG1, IgG2, and IgG3 levels, duration of neuraminidase inhibitor therapy in outpatient clinics, and age. Serum IgG and its subclasses (IgG1-IgG3) reduced estimated clinical severity in children with pH1N1 pdm09 infection.

Early therapy with neuraminidase inhibitors for influenza A (H1N1) pdm 2009 infection.

BACKGROUND: Neuraminidase inhibitors have been reported to decrease mortality in patients infected with influenza A (H1N1) pdm 2009 (H1N1 pdm09), but it is not clear whether they are effective against H1N1pdm09 in apparently healthy children. METHODS: The effect of early treatment with neuraminidase inhibitors on 70 otherwise healthy children with possible H1N1 pdm09 (pH1N1pdm09) infection was investigated. The children were simultaneously treated with a neuraminidase inhibitor (oseltamivir or zanamivir) and maoto, a Japanese traditional herbal medicine, which had been reported to be effective against seasonal influenza. Clinical severity was assessed using patient history, namely the worst values for clinical vital signs and laboratory data on admission. After refining these parameters with univariate, decision tree and multiple regression analysis, mean covariance structure equation analysis was used to investigate the association of estimated clinical severity to the selected parameters. RESULTS: Total path analysis using a Bayesian method indicated that the estimated clinical severity of pH1N1pdm09 was positively associated with maximum body temperature, pulse rate, respiration rate, duration necessary for defervescence, admission duration and log urinary ß2-microglobulin/creatinine level, and negatively associated with age and the presence and duration of treatment with the neuraminidase inhibitor in the outpatient clinic. CONCLUSIONS: This study provides the first clinical evidence that early treatment with neuraminidase inhibitors in outpatient clinic decreased the estimated clinical severity of pH1N1pdm09 in apparently otherwise healthy pediatric inpatients.

Incidence and risk factors for norovirus-related diarrhea in Japanese geriatric intermediate care facilities: A prospective cohort study.

AIM: The risk of developing infectious diarrhea among elderly residents at Japanese geriatric intermediate care facilities is unclear. We investigated the incidence rate and risk factors of norovirus-related diarrhea at such facilities. METHODS: This prospective cohort study followed 1727 residents from November 2018 to April 2020 at 10 geriatric intermediate care facilities in Osaka, Japan regarding the occurrence of diarrhea. Resident data were collected from their medical records using structured forms at two to three of the following three time points: at recruitment, if they developed diarrhea, and when they left the facility. Residents who developed diarrhea were tested using rapid diagnostic tests for norovirus. Cox proportional hazard model was employed to hazard ratios (HRs) with 95% confidence intervals (CIs) to estimate the risk factors for norovirus-related diarrhea. RESULTS: During the study period, 74 residents developed diarrhea, 13 of whom were norovirus positive. The incidence rate of norovirus-related diarrhea was 10.11 per 1000 person-years (95% CI: 4.61-15.61). In terms of risk factors, people with care-needs level 3 were at a higher risk for developing norovirus-related diarrhea (adjusted HR [aHR] = 7.35, 95% CI: 1.45-37.30). Residents with hypertension (aHR = 3.41, 95% CI: 1.05-11.04) or stroke (aHR = 8.84, 95% CI: 2.46-31.83), and those who walked with canes (aHR = 16.68, 95% CI: 1.35-206.52) also had a significantly higher risk for norovirus-related diarrhea. CONCLUSIONS: Throughout the study period, the incidence of development of diarrhea was low. Care-needs level 3, stroke, hypertension and use of a cane were identified as risk factors for norovirus-related diarrhea in Japanese geriatric intermediate care facilities. Geriatr Gerontol Int 2023; 23: 179-187.

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.

Antibody responses after BNT162b2 vaccination in Japanese geriatric intermediate care facilities.

Background: To evaluate antibody responses against the primary series of vaccination of severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2] vaccines in the staff and residents of Japanese geriatric intermediate care facilities. Methods: All subjects (159 staff and 96 residents) received two doses of the BNT162b2 mRNA vaccine 3 weeks apart. Baseline data of subject were collected using a structured form. Serum samples were collected three times: before vaccination, 3 weeks after the first dose, and 4 weeks after the second dose, and anti-receptor binding domain of the spike protein of SARS-CoV-2 [anti-RBD] IgG was measured using two immunoassays. Results: After the second dose, geometric mean titers [GMT] of anti-RBD with both the Abbott and Roche assay were significantly lower in residents than staff (2282 AU/mL vs. 8505 AU/mL, and 258 U/mL vs. 948 U/mL, respectively). Multivariate analysis of characteristics affecting antibody responses (≥1280 AU/mL for Abbott and > 210 U/mL for Roche) showed lower odds ratios [ORs] for older age (adjusted OR per 10 year increase [aOR] = 0.62, 95 % confidence interval [95 %CI]; 0.38-1.02), steroid usage (aOR = 0.09, 95 %CI; 0.01-0.60) and regular nonsteroidal anti-inflammatory drugs [NSAIDs] usage (aOR = 0.16, 95 %CI; 0.03-0.88). Conclusions: Elderly people and steroid and NSAID users had lower antibody responses following the second vaccine dose.

IgG3 deficiency and severity of 2009 pandemic H1N1 influenza.

BACKGROUND: The severity of the 2009 pandemic H1N1 influenza (H1N1 pdm 09) in immune deficient children is unknown. The aim of the present study was to investigate this in a case of complete IgG3 deficiency complicated by pneumonia and asthma attack. METHODS: The clinical parameters of the IgG3 deficiency patient were compared with those of four control patients using 95% confidence intervals. These control patients were selected from 71 patients admitted due to pneumonia or bronchitis caused by H1N1 pdm 09, and were chosen according to age, absence of pretreatment with oseltamivir before admission, presence of a past history of asthma, use of antibiotics, and combination of inhalation of a beta2 agonist and treatment with i.v. methylprednisolone for asthma attack. RESULTS: The IgG3 deficiency patient had significantly longer duration of admission and period of oseltamivir, with a significantly decreased pulse oxygen saturation and increased maximum serum C-reactive protein, creatine kinase and urinary excretion of ß2-microglobulin/creatinine, compared with the controls (P < 0.05). CONCLUSIONS: Complete IgG3 deficiency is possibly associated with severity of the clinical course of pneumonia and asthma attack in children suffering from H1N1 pdm 09.

[Characterization of a nonspecific inhibitor found in human sera raised against the 2006/07 influenza vaccine strain A/Hiroshima/52/2005 (H3N2) virus].

The serology of influenza viruses typically uses hemagglutination inhibition (HI) or the neutralization test (NT). However, the sera of many humans and animals contain nonspecific inhibitors of hemagglutinin that must be inactivated or removed from the serum before use in the HI assay. Any nonspecific inhibitor in human serum is typically inactivated by pre-treatment with receptor-destroying enzyme (RDE). However, during the 2006/07 influenza circulating season, we observed that influenza vaccine strain A/Hiroshima/52/ 2005 (H3N2) exhibited susceptibility to an RDE-resistant inhibitor in human serum. We report herein on a preliminary characterization of this inhibitor, including the development of a novel inhibitor-inactivating technique for pre-treatment of human serum to be used for HI with the A/Hiroshima/52/2005 (H3N2) virus.

Annual trends in adverse events following mumps vaccination in Japan: A retrospective study.

BACKGROUND: In Japan, a monovalent mumps vaccine is provided on a voluntary basis. Due to public concerns over post-vaccination aseptic meningitis, the vaccination coverage is not high enough. The present study investigated the incidence of adverse events, including aseptic meningitis, after Torii strain-derived mumps vaccination. METHODS: This retrospective, observational study used data collected by a vaccine manufacturer regarding adverse events following mumps vaccinations at medical institutions between 1992 and 2018. In addition, the number of Torii strain-derived mumps vaccines shipped each year was obtained. The incidence (per 100,000 doses) and 95% confidence intervals (CIs) were calculated for all adverse events and each adverse event, categorized as aseptic meningitis, encephalitis, mumps, mumps complications, and others. RESULTS: During the study period, 8,262,121 mumps vaccine doses were shipped, and 688 subjects reported adverse events. The incidence for all adverse events (per 100,000 doses) was 8.33, and the incidence was 4.19 for aseptic meningitis, 0.33 for encephalitis, 0.80 for mumps, 0.25 for mumps complications, and 3.78 for others. The incidence of aseptic meningitis (per 100,000 doses) was 7.90 (95% CI: 5.61-10.18) between 1998 and 2000 but declined by half, to 3.91 (2.46-5.36), between 2001 and 2003. The most recent incidence (per 100,000 doses) of aseptic meningitis, for the period 2016 to 2018, was 2.78 (1.94-3.62). CONCLUSION: The incidence of post-vaccination aseptic meningitis has declined significantly since 2001, and the incidence has remained stable at fewer than 3 cases per 100,000 doses since 2010. Multiple factors might have contributed to the decline in aseptic meningitis incidence, including (i) lowered misclassification of aseptic meningitis resulting from echovirus infection; (ii) changes in the vaccine manufacturing process in 2000; and (iii) publication in 2008 of the recommendation for vaccination of children at 1 year of age.

Kinetics of anti-SARS-CoV-2 antibody titer in healthy adults up to 6 months after BNT162b2 vaccination measured by two immunoassays: A prospective cohort study in Japan.

BACKGROUND: Although several assays are used to measure anti-receptor-binding domain (RBD) antibodies induced after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination, the assays are not fully comparable in practice. This study evaluated the immunogenicity of the BNT162b2 mRNA vaccine in healthy adults using two immunoassays. METHODS: This prospective cohort study included SARS-CoV-2-naïve adults, predominantly healthcare workers, aged 20-64 years, who received two BNT162b2 vaccine doses between March and May 2021. Blood samples were collected before the first vaccination (S0), before the second vaccination (S1), 4 weeks after the second vaccination (S2), and 6 months after the second vaccination (S3). anti-RBD antibodies were measured using the Architect SARS-CoV-2 IgG II Quant (Abbott Laboratory) and Elecsys anti-SARS-CoV-2 S (Roche Diagnostics) assays. RESULTS: Among the 385 participants, the geometric mean antibody titers (GMTs) on the Architect assay (AU/mL) were 7.5, 693, 7007, and 1030 for S0, S1, S2, and S3, respectively. The corresponding GMTs on the Elecsys assay (U/mL) were 0.40, 24, 928, and 659, respectively. The GMT ratio (S3/S2) was 0.15 on the Architect and 0.71 on the Elecsys assay. The correlation between antibody titers measured with the two assays were strong at all time points after vaccination (Spearman's correlation coefficient: 0.74 to 0.86, P < 0.01 for all). GMT was significantly lower in the older age group after vaccination (P < 0.01), with no significant differences according to sex. Seroprotection (≥5458 AU/mL on the Architect assay and ≥ 753 U/mL on the Elecsys) at each time point was 0 %, 1 %, 67 %, and 1 % on the Architect assay and 0 %, 1 %, 62 %, and 43 % on the Elecsys, respectively. CONCLUSIONS: Two BNT162b2 vaccine doses resulted in adequate anti-RBD antibody response, which varied by age. As the two assays showed different kinetics, the results of single immunoassays should be interpreted with caution.

Interleukin-15 is critical in the pathogenesis of influenza a virus-induced acute lung injury.

Highly pathogenic influenza A viruses cause acute severe pneumonia to which the occurrence of "cytokine storm" has been proposed to contribute. Here we show that interleukin-15 (IL-15) knockout (KO) mice exhibited reduced mortality after infection with influenza virus A/FM/1/47 (H1N1, a mouse-adapted strain) albeit the viral titers of these mice showed no difference from those of control mice. There were significantly fewer antigen-specific CD44(+) CD8(+) T cells in the lungs of infected IL-15 KO mice, and adoptive transfer of the CD8(+) T cells caused reduced survival of IL-15 KO mice following influenza virus infection. Mice deficient in beta(2)-microglobulin by gene targeting and those depleted of CD8(+) T cells by in vivo administration of anti-CD8 monoclonal antibody displayed a reduced mortality rate after infection. These results indicate that IL-15-dependent CD8(+) T cells are at least partly responsible for the pathogenesis of acute pneumonia caused by influenza A virus.

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.

Development of an immunochromatographic assay specifically detecting pandemic H1N1 (2009) influenza virus.

The pandemic caused by a new type of influenza virus, pandemic H1N1 (2009) influenza virus A (AH1pdm), has had a major worldwide impact. Since hemagglutinin (HA) genes are among the most specific genes in the influenza virus genome, AH1pdm can be definitively diagnosed by viral gene analysis targeting the HA genes. This type of analysis, however, cannot be easily performed in clinical settings. While commercially available rapid diagnosis kits (RDKs) based on immunochromatography can be used to detect nucleoproteins (NPs) of influenza A and B viruses in clinical samples, there are no such kits that are specific for AH1pdm. We show here that an RDK using a combination of monoclonal antibodies against NP can be used to specifically detect AH1pdm. The RDK recognized AH1pdm virus isolates but did not recognize seasonal H1N1 and H3N2 and influenza B viruses, indicating that the specificity of the RDK is 100%. A parallel comparison of RDK with a commercial influenza A/B virus kit revealed that both types of kits had equal sensitivities in detecting their respective viruses. Preliminary evaluation of clinical samples from 5 individuals with PCR-confirmed human AH1pdm infection showed that the RDK was positive for all samples, with the same detection intensity as that of a commercial influenza A/B virus kit. This RDK, together with a new vaccine and the stockpiling of anti-influenza drugs, will make aggressive measures to contain AH1pdm infections possible.

Combined administration of (L)-cystine and (L)-theanine enhances immune functions and protects against influenza virus infection in aged mice.

Cell-mediated and humoral immune responses are attenuated with aging. Intracellular glutathione (GSH) levels also decrease with aging. Previously, we have reported that combined administration of (L)-cystine and (L)-theanine enhances antigen-specific IgG production, partly through augmentation of GSH levels and T helper 2-mediated responses in 12-week-old mice. These findings suggest that combined administration of (L)-cystine and (L)-theanine to aged mice improves immune responses via increase of GSH synthesis. Here, we examined the effects of combined administration of (L)-cystine and (L)-theanine on antigen-specific antibody production and influenza virus infection in aged mice. Combined administration of these amino acids for 14 days before primary immunization significantly enhanced the serum antigen-specific IgM and IgG levels in 24-month-old mice. Furthermore, 13-month-old mice co-treated with these amino acids orally for 10 days had significantly lower lung viral titers than controls at 6 days after influenza virus infection. In addition, this co-treatment also significantly prevented the weight loss associated with infection. Enhancement of anti-influenza-virus IgG antibodies by combined administration of (L)-cystine and (L)-theanine was seen 10 days after infection. The significantly elevated serum interleukin-10/interferon-gamma ratio and gamma-glutamylcysteine synthetase mRNA expression, which is the rate-limiting enzyme of GSH synthesis, in the spleen 3 days after infection may have contributed to the observed beneficial effects. These results suggest that combined administration of (L)-cystine and (L)-theanine enhances immune function and GSH synthesis which are compromised with advanced age, and may become a useful strategy in healthy aging.

Comparison of immunogenicity between candidate influenza A(H3N2) virus vaccine strains in Japan: A randomized controlled trial using a monovalent vaccine of A/Saitama/103/2014 (CEXP-002) and A/Hong Kong/4801/2014 (X-263).

BACKGROUND: For the 2017-18 influenza season, A/Saitama/103/2014 (CEXP-002) (Saitama strain) was antigenically more similar to prior circulating strains than A/Hong Kong/4801/2014 (X-263) (Hong Kong strain) in a ferret model and was selected as the A(H3N2) vaccine virus strain in Japan. However, the Saitama strain grew poorly, and the Japanese government switched to the Hong Kong strain, raising public concerns of poor effectiveness. To enhance understanding of the correlation between antigenicity in experimental models and immunogenicity, as a surrogate measure of vaccine effectiveness, in the human population, we compared the immunogenicity of specially-prepared single dose monovalent influenza A(H3N2) vaccines containing the Saitama or the Hong Kong strain. METHODS: A randomized controlled trial of 100 healthy adults aged 20-64 years (n = 50/group) was conducted. Virus neutralization assay was performed on sera from days 0 (pre-vaccination) and 21 (post-vaccination). Geometric mean titer (GMT), mean fold rise (MFR), seroconversion proportion (SCP), and seroprotection proportion (SPP) were calculated for vaccine strains and a representative circulating A(H3N2) virus strain (A/Osaka/188/2017). RESULTS: For the Hong Kong strain, post-vaccination GMT was significantly higher in the Hong Kong vaccine recipients (1:546 vs 1:260, p < 0.01), but MFR, SCP, and SPP were similar for both vaccine groups. For the Saitama strain, post-vaccination GMT (1:116 vs 1:61, p = 0.01) and SPP (86% vs 68%, p = 0.03) were significantly higher in the Hong Kong vaccine recipients, but MFR and SCP were similar for both vaccine groups. Against A/Osaka/188/2017, post-vaccination GMT and MFR were similar in both vaccine groups, but SCP (32% vs 4%, p < 0.01) and SPP (28% vs. 6%, p < 0.01) were significantly higher in the Hong Kong vaccine recipients. CONCLUSION: The Hong Kong vaccine induced better or equivalent immunogenicity in comparison to the Saitama vaccine. Our trial showed that antigenic similarity in experimental models does not necessarily correlate with immunogenicity in the human population. CLINICAL TRIAL REGISTRATION: UMIN000029293.