Incidence of Mumps Deafness in Japan, 2005-2017: Analysis of Japanese Insurance Claims Database.

BACKGROUND: Mumps deafness causes serious problems, and incidence data are needed to identify its disease burden. However, such data are limited, and the reported incidence is highly variable. Nationwide studies in Japan with a large age range are lacking. METHODS: This was a retrospective observational investigation of the 2005-2017 mumps burden using employment-based health insurance claims data. Data were analyzed for 5,190,326 people aged 0-64 years to estimate the incidence of mumps deafness. RESULTS: Of 68,112 patients with mumps (36,423 males; 31,689 females), 102 (48 males; 54 females) developed mumps deafness-an incidence of 15.0 per 10,000 patients (1 in 668 patients). Fifty-four (52.9%) patients had mumps deafness in childhood (0-15 years), and 48 (47.1%) had mumps deafness in adolescence and adulthood (16-64 years); most cases occurred in childhood, the peak period for mumps onset. The incidence of mumps deafness per 10,000 patients was 73.6 in adolescence and adulthood, 8.4 times higher than the incidence of 8.8 in childhood (P < 0.001). In childhood, the incidence of mumps deafness was 7.2 times higher among 6-15-year-olds (13.8; 95% CI, 10.2-18.2) than among 0-5-year-olds (1.9; 95% CI, 0.6-4.5), and this difference was statistically significant (P < 0.001). No sex difference was observed. CONCLUSIONS: The incidence of mumps deafness per 10,000 patients aged 0-64 years was 15.0 (1 in 668 patients). A secondary risk of deafness following mumps virus infection was identified not only for children, but also for adolescents and adults.

Mumps-Related Disease Burden in Japan: Analysis of JMDC Health Insurance Reimbursement Data for 2005-2017.

BACKGROUND: Mumps vaccination coverage is low in Japan, partly because of its voluntary nature. Although pediatric cases of mumps virus infection are captured by the National Epidemiological Surveillance of Infectious Diseases program under the Infectious Disease Law, there are currently no data regarding the occurrence of mumps and its complications in adults. METHODS: We investigated the annual incidence rates of mumps and its complications based on health insurance reimbursement data for 5,209,660 individuals aged 0-64 years for 2005-2017, obtained from JMDC Inc., to estimate the mumps-related disease burden during this period. RESULTS: There were three mumps outbreaks (2006, 2010, and 2016) during 2005-2017. The annual incidence of mumps was highest in individuals aged 0-5 years (808-3,792 per 100,000 persons), followed by those aged 6-15 years (658-2,141 per 100,000 persons). The incidence of mumps was higher in females than in males (male/female ratio, 0.90). Among mumps-related complications, the overall incidence (per 1,000 mumps cases) was highest for orchitis (6.6), followed by meningitis (5.8), deafness (1.3), pancreatitis (0.5), and encephalitis (0.3). No cases of oophoritis were noted. The overall incidence of mumps-related complications was 2.5 times higher in males than in females. CONCLUSIONS: This study revealed the disease burden due to mumps and its complications in Japan during 2005-2017. These data suggest the need for mumps-prevention measures in adolescents and adults, as well as in children.

[Relationship between Echovirus Epidemics and Incidence of Aseptic Meningitis following Mumps Vaccination Based on Previous Japanese Reports: Possibility of Misclassification of Echovirus Infection in Previous Reports].

OBJECTIVES: In Japan, the vaccination for mumps has been on a voluntary basis since 1993 because of safety concerns arising from the high incidence of aseptic meningitis associated with Japanese mumps vaccine strains. However, recent reports on the voluntary mumps vaccination have described the decreased incidence of postvaccination aseptic meningitis for unknown reasons. To explore the underlying reason for this decrease, we analyzed the influence of echoviruses, the most common causative viruses for community-acquired aseptic meningitis, on the previously reported incidence of aseptic meningitis following mumps vaccination. METHODS: We used available data on the yearly number of cases of echovirus detection from the Infectious Agents Surveillance Reports issued by the National Institute of Infectious Diseases as well as previously reported nationwide data on the incidence of postvaccination aseptic meningitis. RESULTS: The incidence of postvaccination aseptic meningitis tended to be higher during the period of an echovirus epidemic and lower during the period without such as epidemic. CONCLUSIONS: The present ecological trend analysis suggests the influence of echovirus epidemics on the previous reported incidence of aseptic meningitis following mumps vaccination. It is necessary to carry out a differential diagnosis of echovirus infection to identify the true causative viruses in aseptic meningitis following mumps vaccination.

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.

Effects of a Public Subsidy Program for Mumps Vaccine on Reducing the Disease Burden in Nagoya City, Japan.

Nagoya City initiated a public subsidy program for mumps vaccination using either the Torii or Hoshino strains in August 2010. To determine the effects of the program, we used publicly available information from Nagoya City to investigate the changes in immunization rates and numbers of patients who developed post-immunization adverse reactions, including post-vaccinal aseptic meningitis, in the 7 years since its initiation. We also investigated the numbers of mumps patients reported by sentinel sites in a national database during this period. The immunization rate in one-year-old children increased from 24.3% before the program to 91.0% after 7 years. The mean numbers of reported mumps cases per sentinel site in one-year-old to preschool children-the age groups targeted by the program- were 12.9 in the 7 years before the program and 4.93 in the 7 years after initiation of the program, showing a significant decrease of 1/2.6 (p = 0.01). The number of vaccinations during the 6.5-year period was 140,316, with only one case of aseptic meningitis reported (0.7 cases/100,000 vaccinations). No other serious adverse reactions were observed. The present findings demonstrate that the public subsidy program in Nagoya City is an effective and safe measure against mumps in children.

A web-based survey of erection hardness score and its relationship to aging, sexual behavior, confidence, and risk factors in Japan.

INTRODUCTION: Erection hardness is an elemental component of men's sexual quality of life that can be easily measured by the Erection Hardness Score (EHS). However, there are few published data regarding EHS, and there is little understanding of its relationships to aging, men's sexual behavior, sexual confidence, and risk factors in Japan. AIM: To assess EHS and how it correlates to aging, sexual behaviors, sexual self-confidence, and risk factors in a Japanese population database. METHODS: A web-based cross-sectional nationwide survey conducted between March and May 2009 in Japan. MAIN OUTCOME MEASURES: EHS, lifestyle factors, comorbidities, general health, sexual confidence, frequency of sexual behaviors, and attitudes toward treatment of erectile dysfunction (ED). RESULTS: A total of 7,710 men with a mean age of 39.3 ± 13.0 years participated in this survey. In 6,528 participants who were not using phosphodiesterase type 5 inhibitors, 3,540 (54.2%) had EHS ≤ 3 and 1,196 (18.3%) had EHS ≤ 2. We found a significant age-dependent decrease in EHS, sexual confidence, and frequency of sexual activities. Sexual confidence was strongly associated with higher EHS but was also associated with older age groups, presence of offspring, awareness of better general health, and greater frequency of sexual activity. In age-adjusted multivariate logistic regression, risk factors for a lower EHS (defined as EHS ≤ 2) were heavy smoking, which was defined as more than two packs per day (odds ratio [OR], 1.7) or a history of metabolic syndrome (OR, 1.4), hypertension (OR, 1.2), and diabetes mellitus (OR, 1.4). CONCLUSIONS: EHS correlates to various elements, such as aging, sexual behaviors, sexual confidence, and ED-related risk factors, and can be a valuable tool in clinical practice for monitoring and treating ED and thereby improving the quality of life for men and their sexual partners. Kimura M, Shimura S, Tai T, Kobayashi H, Baba S, Kano M, and Nagao K. A web-based survey of Erection Hardness Score and its relationship to aging, sexual behavior, confidence, and risk factors in Japan. Sex Med 2013;1:76-86.

Profiling characteristics of men who use phosphodiesterase type 5 inhibitors based on obtaining patterns: data from the nationwide Japanese population.

INTRODUCTION: Worldwide, certain subsets of men bypass healthcare provider (HCP) interactions and obtain phosphodiesterase type 5 inhibitors (PDE5i) from uncontrolled sources. AIM: To stratify men who are PDE5i users based on their obtaining patterns and investigate the characteristics that differentiate these groups. METHODS: A Web-based observational study conducted between March and June 2009 in Japan. MAIN OUTCOME MEASURES: We stratified the reported obtaining patterns into three categories: men who had a prescription for PDE5is from HCP, those who obtained PDE5is from friends, and those who purchased PDE5is via the Internet. Logistic regressions were conducted to determine independent predictors for each obtaining patterns. Erection function was evaluated by erection hardness score (EHS). RESULTS: Of 7,710 total recruited subjects, 1,144 men (14.8%) reported PDE5i use within the past year. Among 1,144 men, 625 men (54.6%) were prescribed PDE5i from HCP, whereas 267 men (23.4%) obtained PDE5i from friends and 252 men (22.0%) purchased PDE5i via the Internet. In a multivariable regression analyses, men being prescribed PDE5i from HCP were more likely to live in a northern area of Japan (OR 0.98), have a lower rate of smoking (OR 0.77), and have an awareness of ED (OR 3.04). In contrast, men who obtained PDE5i from friends were more likely to live in a southern area (OR 1.02), to have higher rate of alcohol intake and smoking (OR 1.20, OR 1.45), and lower awareness of ED (OR 0.39). Men purchasing PDE5i via the Internet were more likely to consider themselves to be in worse health (OR 0.85) and to have lower awareness of ED (OR 0.62). CONCLUSIONS: Our results could help to identify men who may bypass HCP interactions. These findings could aid in the targeting of public service announcements designed to encourage men to avoid obtaining uncontrolled PDE5i and consult with HCPs to protect their health.

Comparison between Sendai virus and adenovirus vectors to transduce HIV-1 genes into human dendritic cells.

Immuno-genetherapy using dendritic cells (DCs) can be applied to human immunodeficiency virus type 1 (HIV-1) infection. Sendai virus (SeV) has unique features such as cytoplasmic replication and high protein expression as a vector for genetic manipulation. In this study, we compared the efficiency of inducing green fluorescent protein (GFP) and HIV-1 gene expression in human monocyte-derived DCs between SeV and adenovirus (AdV). Human monocyte-derived DCs infected with SeV showed the maximum gene expression 24 hr after infection at a multiplicity of infection (MOI) of 2. Although SeV vector showed higher cytopathic effect on DCs than AdV, SeV vector induced maximum gene expression earlier and at much lower MOI. In terms of cell surface phenotype, both SeV and AdV vectors induced DC maturation. DCs infected with SeV as well as AdV elicited HIV-1 specific T-cell responses detected by interferon gamma (IFN-gamma) enzyme-linked immunospot (Elispot). Our data suggest that SeV could be one of the reliable vectors for immuno-genetherapy for HIV-1 infected patients.

Influence of glycosylation on the efficacy of an Env-based vaccine against simian immunodeficiency virus SIVmac239 in a macaque AIDS model.

The envelope glycoprotein (Env) of human immunodeficiency viruses (HIVs) and simian immunodeficiency viruses (SIVs) is heavily glycosylated, and this feature has been speculated to be a reason for the insufficient immune control of these viruses by their hosts. In a macaque AIDS model, we demonstrated that quintuple deglycosylation in Env altered a pathogenic virus, SIVmac239, into a novel attenuated mutant virus (delta5G). In delta5G-infected animals, strong protective immunity against SIVmac239 was elicited. These HIV and SIV studies suggested that an understanding of the role of glycosylation is critical in defining not only the virological properties but also the immunogenicity of Env, suggesting that glycosylation in Env could be modified for the development of effective vaccines. To examine the effect of deglycosylation, we constructed prime-boost vaccines consisting of Env from SIVmac239 and delta5G and compared their immunogenicities and vaccine efficacies by challenge infection with SIVmac239. Vaccination-induced immune responses differed between the two vaccine groups. Both Env-specific cellular and humoral responses were higher in wild-type (wt)-Env-immunized animals than in delta5G Env-immunized animals. Following the challenge, viral loads in SIVmac239 Env (wt-Env)-immunized animals were significantly lower than in vector controls, with controlled viral replication in the chronic phase. Unexpectedly, viral loads in delta5G Env-immunized animals were indistinguishable from those in vector controls. This study demonstrated that the prime-boost Env vaccine was effective against homologous SIVmac239 challenge. Changes in glycosylation affected both cell-mediated and humoral immune responses and vaccine efficacy.

Induction of Gag-specific T-cell responses by therapeutic immunization with a Gag-expressing Sendai virus vector in macaques chronically infected with simian-human immunodeficiency virus.

Recent prophylactic vaccine trials inducing virus-specific CD8+ T-cell responses have shown control of primary infections of a pathogenic simian-human immunodeficiency virus (SHIV) in macaques. In the chronic phase, therapeutic immunization replenishing virus-specific CD8+ T-cells is likely to contribute to sustained control of virus replication. In this study, we have administered a recombinant Sendai virus (SeV) vector into five rhesus macaques that had received prophylactic vaccinations and had controlled SHIV replication for more than 1 year after challenge. Our results indicate that virus-specific CD8+ T-cell responses can be expanded and broadened by therapeutic immunization with SeV vectors in the chronic phase after prophylactic vaccine-based control of primary immunodeficiency virus infections.

Loss of virus-specific CD4(+) T cells with increases in viral loads in the chronic phase after vaccine-based partial control of primary simian immunodeficiency virus replication in macaques.

Virus-specific cellular immune responses play an important role in the control of immunodeficiency virus replication. However, preclinical trials of vaccines that induce virus-specific cellular immune responses have failed to contain simian immunodeficiency virus (SIV) replication in macaques. A defective provirus DNA vaccine system that efficiently induces virus-specific CD8(+) T-cell responses has previously been developed. The vaccinated macaques showed reduced viral loads, but failed to contain SIVmac239 replication. In this study, macaques that showed partial control of SIV replication were followed up to see if or how they lost this control in the chronic phase. Two of them showed increased viral loads about 4 or 8 months after challenge and finally developed AIDS. Analysis of SIV-specific T-cell levels by detection of SIV-specific gamma interferon (IFN-gamma) production revealed that these two macaques maintained SIV-specific CD8(+) T cells, even after loss of control, but lost SIV-specific CD4(+) T cells when plasma viral loads increased. The remaining macaque kept viral loads at low levels and maintained SIV-specific CD4(+) T cells, as well as CD8(+) T cells, for more than 3 years. Additional analysis using macaques vaccinated with a Gag-expressing Sendai virus vector also found loss of viraemia control, with loss of SIV-specific CD4(+) T cells in the chronic phase of SIV infection. Thus, SIV-specific CD4(+) T cells that were able to produce IFN-gamma in response to SIV antigens were preserved by the vaccine-based partial control of primary SIV replication, but were lost with abrogation of control in the chronic phase.

Cytotoxic T lymphocyte-based control of simian immunodeficiency virus replication in a preclinical AIDS vaccine trial.

Recently, encouraging AIDS vaccine trials in macaques have implicated cytotoxic T lymphocytes (CTLs) in the control of the simian human immunodeficiency virus SHIV89.6P that induces acute CD4(+) T cell depletion. However, none of these vaccine regimens have been successful in the containment of replication of the pathogenic simian immunodeficiency viruses (SIVs) that induce chronic disease progression. Indeed, it has remained unclear if vaccine-induced CTL can control SIV replication. Here, we show evidence suggesting that vaccine-induced CTLs control SIVmac239 replication in rhesus macaques. Eight macaques vaccinated with DNA-prime/Gag-expressing Sendai virus vector boost were challenged intravenously with SIVmac239. Five of the vaccinees controlled viral replication and had undetectable plasma viremia after 5 wk of infection. CTLs from all of these five macaques rapidly selected for escape mutations in Gag, indicating that vaccine-induced CTLs successfully contained replication of the challenge virus. Interestingly, analysis of the escape variant selected in three vaccinees that share a major histocompatibility complex class I haplotype revealed that the escape variant virus was at a replicative disadvantage compared with SIVmac239. These findings suggested that the vaccine-induced CTLs had "crippled" the challenge virus. Our results indicate that vaccine induction of highly effective CTLs can result in the containment of replication of a highly pathogenic immunodeficiency virus.

Protective efficacy of an AIDS vaccine, a single DNA priming followed by a single booster with a recombinant replication-defective Sendai virus vector, in a macaque AIDS model.

We previously demonstrated the excellent protective efficacy of DNA priming followed by Gag-expressing Sendai virus (SeV) boosting (DNA prime/SeV-Gag boost vaccine) against a pathogenic simian-human immunodeficiency virus (SHIV89.6PD) infection in macaques. Here we show that we established a practical, safer AIDS vaccine protocol, a single DNA priming followed by a single booster with a recently developed replication-defective F deletion SeV-expressing Gag, and show its protective efficacy against SHIV89.6PD infections.

Primary replication of a recombinant Sendai virus vector in macaques.

An efficient antigen expression system using a recombinant Sendai virus (SeV) has been established recently and its potential to induce resistance against immunodeficiency virus infections in macaques has been shown. SeV replication has been well characterized in mice, the natural host, but not in primates, including humans. Here, primary SeV replication was investigated in macaques. After intranasal immunization with a recombinant SeV expressing simian immunodeficiency virus Gag protein, SeV-Gag, robust gag expression was observed in the nasal mucosa and much lower but significant levels of gag expression were observed in the local retropharyngeal and submandibular lymph nodes (LN). Expression peaked within a week and lasted at least up to 13 days after immunization. SeV-Gag was isolated from nasal swabs consistently at day 4 but not at all at day 13. Gag expression was undetectable in the lung as well as in remote lymphoid tissues, such as the thymus, spleen and inguinal LN, indicating that the spread of the virus was more restricted in macaques than in mice. SeV-specific T cells were detectable in SeV-immunized macaques at day 7. Finally, no naive macaques showed significant levels of anti-SeV antibodies in the plasma, even after living in a cage together with an acutely SeV-infected macaque for 5 weeks, indicating that SeV transmission from SeV-infected macaques to naive ones was inefficient. None of the SeV-immunized macaques displayed appreciable clinical manifestations. These results support the idea that this system may be used safely in primates, including humans.