How to prevent rubella epidemics and congenital rubella syndrome: lessons from 42 years of longitudinal epidemiology in Osaka Prefecture, Japan (1982-2023).

BACKGROUND: Despite the introduction of rubella-containing vaccine into routine immunization in 1977, rubella has not been eliminated in Japan. This study aimed to validate the immunization strategy and to highlight the crucial elements of elimination program. METHODS: We scrutinized cases of rubella and congenital rubella syndrome (CRS). Additionally, we analyzed the national vaccination coverage, seroprevalence, and number of maternal rubella-related spontaneous or artificial fetal deaths. RESULTS: The shift from selective to universal immunization significantly reduced rubella cases coupled with increased seroprevalence in children. However, rubella resurged in 2012-2013 and 2018-2019, which was virologically and serologically confirmed to be associated with imported rubella virus (RuV) and susceptible males. Although the disease burden of CRS may have been suppressed in the past by the large number of spontaneous or artificial fetal deaths, the incidence rate of CRS was comparable to that of the 1960s to 1980s. Cases of breakthrough infection and CRS were identified in females who were considered to have a history of single-dose vaccination. CONCLUSIONS: Even with universal immunization, future epidemics and severe outcomes cannot be prevented unless immunization gaps are closed. Furthermore, CRS and breakthrough infection are not completely prevented by single-dose vaccination, indicating the need for second-dose vaccination.

The Role of Human Mobility Flow in the Region-to-Region Spread of Respiratory Syncytial Virus Infection among Infants: An Infographic Analysis.

The region-to-region spread of human infectious diseases is considered to be dependent on the human mobility flow (HMF). However, it has been hard to obtain the evidence for this. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic in Japan 2020, the government has enforced countermeasures against COVID-19 nationwide, namely the restriction of personal travelling, universal masking, and hand hygiene. As a result, the spread of acute respiratory infections had been effectively controlled. However, COVID-19 as well as pediatric respiratory syncytial virus (RSV) infections were not well-controlled. The region-to-region spread of pediatric RSV infections in 2020-2021 was recognizable unlike those in 2018 and 2019. In this study, we investigated the correlation between the trend of regional reports of the pediatric RSV infections and the HMF based on cellular phone signal data. Upon closer examination of both epidemiological trend and HMF data, the spread of pediatric RSV infection from one region to another was logically explained by HMF, which would serve as the evidence of the dependence of regional transmission on HMF. This is the first solid evidence where this correlation has been clearly observed for the common respiratory infections. While social implementation of infection control measures has successfully suppressed the droplet-mediated respiratory infections, such as influenza, but not the airborne infections, it was suggested that the aerosol transmission and adult asymptomatic carrier were involved in the transmission of RSV akin to COVID-19.

Clinical perspectives of Treponema pallidum subsp. Endemicum infection in adults, particularly men who have sex with men in the Kansai area, Japan: A case series.

Bejel, caused by Treponema pallidum subsp. Endemicum (TEN), is a locally transmitted disease among children and juveniles in hot and dry regions. The number of adult cases of TEN infection outside of endemic areas has recently increased. We clinically examined five cases of TEN infection among adult cases previously reported in Japan. TEN infection mainly developed among young to middle-aged men who have sex with men (MSM). The clinical features of cases of TEN infection were similar to those of primary- and secondary-stage T. pallidum subsp. pallidum (TPA) infection. Genital lesions were common as the primary lesion. The clinical features and laboratory parameters of cases of TEN infection were similar to those of TPA infection. Most of the isolated strains had the A2058G mutation in 23S rDNA, which is responsible for resistance to macrolides. We also performed the systemic literature review of the TEN cases outside the endemic countries. The recent reported cases diagnosed with molecular methods shared the clinical features, occurred in young-to middle-aged sexually active persons in urban areas of developed countries and often accompanied with genital lesions, which were distinct from the classic description of bejel. This case series and the literature review provides important clinical insights and will contribute to the clinical detection of this rarely identified disease in developed countries. The surveillance of treponematoses, including TEN infection, using molecular diagnostic techniques is also warranted in developed countries, for the purpose of grasping the epidemic situation and control the local transmission.

Relationship between biochemical markers and measles viral load in patients with immunologically naive cases and secondary vaccine failure: LDH is one of the potential auxiliary indicators for secondary vaccine failure.

This study investigated the correlation between biochemical markers and viral load among 38 measles cases, including 15 immunologically naive patients and 23 patients with secondary vaccine failure (SVF). We examined four biochemical markers, namely, aspartate aminotransferase, alanine aminotransferase, C-reactive protein, and lactate dehydrogenase (LDH) and their relationship between virus genome copy numbers in peripheral blood mononuclear cells (PBMCs) and throat swabs as well as the concentration of measles-specific IgG. Although viral genome copies in both clinical specimens showed a significant correlation with specific IgG concentration, they had a higher correlation in PBMCs (Pearson's product-moment correlation coefficient, -0.662; p < .0001) than in throat swabs (Spearman's rank correlation coefficient, -0.443; p = .0078). The viral load in PBMCs also significantly correlated with LDH values (correlation coefficient, 0.360; p = .036). Thus, the serum LDH level might be a potential auxiliary indicator to distinguish immunologically naive patients with measles from those with SVF.

Iron-Utilization System in Vibrio vulnificus M2799.

Vibrio vulnificus is a Gram-negative pathogenic bacterium that causes serious infections in humans and requires iron for growth. A clinical isolate, V. vulnificus M2799, secretes a catecholate siderophore, vulnibactin, that captures ferric ions from the environment. In the ferric-utilization system in V. vulnificus M2799, an isochorismate synthase (ICS) and an outer membrane receptor, VuuA, are required under low-iron conditions, but alternative proteins FatB and VuuB can function as a periplasmic-binding protein and a ferric-chelate reductase, respectively. The vulnibactin-export system is assembled from TolCV1 and several RND proteins, including VV1_1681. In heme acquisition, HupA and HvtA serve as specific outer membrane receptors and HupB is a sole periplasmic-binding protein, unlike FatB in the ferric-vulnibactin utilization system. We propose that ferric-siderophore periplasmic-binding proteins and ferric-chelate reductases are potential targets for drug discovery in infectious diseases.

VuuB and IutB reduce ferric-vulnibactin in Vibrio vulnificus M2799.

Vibrio vulnificus, a pathogenic bacterium that causes serious infections in humans, requires iron for growth. Clinical isolate, V. vulnificus M2799, secretes a catecholate siderophore, namely, vulnibactin, to capture iron (III) from the environment. Growth experiments using a deletion mutant indicated that VuuB, a member of the FAD-containing siderophore-interacting protein family, plays a crucial role in Fe3+-vulnibactin reduction. IutB, a member of the ferric-siderophore reductase family, stands a substitute for VuuB in its absence. It remained unclear why V. vulnificus M2799 has two proteins with relevant functions. Here we biochemically characterized VuuB and IutB using purified recombinant proteins. Purified VuuB, a flavoprotein, catalyzed the reduction of Fe3+-nitrilotriacetic acid as its electron acceptor, in the presence of NADH as its electron donor and FAD as its cofactor. IutB catalyzed the reduction of Fe3+-nitrilotriacetic acid, in the presence of NADH, NADPH, or reduced glutathione as its electron donor. The optimal pH values and temperatures of VuuB and IutB were 7.0 and 37 °C, and 8.5 and 45 °C, respectively. On analyzing their ferric-chelate reductase activities, both VuuB and IutB were found to catalyze the reduction of Fe3+-aerobactin, Fe3+-vibriobactin, and Fe3+-vulnibactin. When the biologically relevant substrate, Fe3+-vulnibactin, was used, the levels of ferric-chelate reductase activities were similar between VuuB and IutB. Finally, the mRNA levels were quantified by qRT-PCR in M2799 cells cultivated under low-iron conditions. The number of vuuB mRNA was 8.5 times greater than that of iutB. The expression ratio correlated with the growth of their mutants in the presence of vulnibactin.

Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response.

The innate immune system senses RNA viruses by pattern recognition receptors (PRRs) and protects the host from virus infection. PRRs mediate the production of immune modulatory factors and direct the elimination of RNA viruses. Here, we show a unique PRR that mediates antiviral response. Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP ribose) polymerase (TIPARP), a Cysteine3 Histidine (CCCH)-type zinc finger-containing protein, binds to Sindbis virus (SINV) RNA via its zinc finger domain and recruits an exosome to induce viral RNA degradation. TIPARP typically localizes in the nucleus, but it accumulates in the cytoplasm after SINV infection, allowing targeting of cytoplasmic SINV RNA. Redistribution of TIPARP is induced by reactive oxygen species (ROS)-dependent oxidization of the nuclear pore that affects cytoplasmic-nuclear transport. BCL2-associated X protein (BAX) and BCL2 antagonist/killer 1 (BAK1), B-cell leukemia/lymphoma 2 (BCL2) family members, mediate mitochondrial damage to generate ROS after SINV infection. Thus, TIPARP is a viral RNA-sensing PRR that mediates antiviral responses triggered by BAX- and BAK1-dependent mitochondrial damage.

Bejel, a Nonvenereal Treponematosis, among Men Who Have Sex with Men, Japan.

Bejel, an endemic treponematosis caused by infection with Treponema pallidum subspecies endemicum, has not been reported in eastern Asia and the Pacific region. We report local spread of bejel among men who have sex with men in Japan. Spread was complicated by venereal syphilis.

Circulation of Distinct Treponema pallidum Strains in Individuals with Heterosexual Orientation and Men Who Have Sex with Men.

Human treponematosis is caused by various pathogenic Treponema pallidum subspecies, including T. pallidum subsp. pallidum, T. pallidum subsp. pertenue, T. pallidum subsp. endemicum, and Treponema carateum The global prevalence of syphilis has been increasing since the 2000s. Men account for more than 90% of the cases, with the majority being men who have sex with men (MSM). In Japan, the increase in the number of syphilis patients began in 2011, a 10-year delay from the global trend. In 2017, a total of 5,829 syphilis cases (3,934 men and 1,895 women) were reported, with an outstanding increase in cases among young adult women; the number reported for women age 15 to 20 years was 1,100. Hence, a molecular epidemiological study was conducted on circulating T. pallidum strains using two strain typing methods, the enhanced CDC method and sequencing-based molecular typing. Clinical specimens from 95 adults suspected of syphilis were collected from September 2013 to August 2017 in Osaka, Japan. T. pallidum DNA was detected in specimens from 25 males and 11 females, including seven MSM. The majority of the heterosexual patients (66.7% and 90.9% of males and females, respectively) were positive for 14d/f-SSR8. In contrast, the genotypes identified in the MSM group were significantly divergent. T. pallidum subsp. endemicum was notably identified in two MSM patients. Macrolide-sensitive or Nichols-like strains were significantly associated with the MSM group. These data suggest that distinct T. pallidum strains were circulating in the heterosexual and MSM groups. Our findings imply that independent factors may contribute to the increased syphilis prevalence in heterosexual and MSM populations.

Clinical value of enzyme immunoassay that detects rubella-specific immunoglobulin M immediately after disease onset.

A total of 300 patients with nucleic acid test-confirmed rubella, mostly adults, were investigated to determine the clinical value of a rubella-specific IgM test using an EIA kit. IgM titers increased after rash onset, the median IgM titer being significantly higher 3 days post-onset than on previous days (P < 0.0001). Similarly, the IgM-positive rate at 3 days post-onset (61.5%) was significantly higher than on previous days (P < 0.0001). This IgM test against rubella at 3 days or more post-disease onset provides the clinically relevant information.

Foodborne Outbreaks Caused by Human Norovirus GII.P17-GII.17-Contaminated Nori, Japan, 2017.

Seven foodborne norovirus outbreaks attributable to the GII.P17-GII.17 strain were reported across Japan in 2017, causing illness in a total of 2,094 persons. Nori (dried shredded seaweed) was implicated in all outbreaks and tested positive for norovirus. Our data highlight the stability of norovirus in dehydrated food products.

Current prevention and control of health care-associated infections in long-term care facilities for the elderly in Japan.

Residents of long-term care facilities for the elderly are vulnerable to health care-associated infections. However, compared to medical institutions, long-term care facilities for the elderly lag behind in health care-associated infection control and prevention. We conducted a epidemiologic study to clarify the current status of infection control in long-term care facilities for the elderly in Japan. A questionnaire survey on the aspects of infection prevention and control was developed according to SHEA/APIC guidelines and was distributed to 617 long-term care facilities for the elderly in the province of Osaka during November 2016 and January 2017. The response rate was 16.9%. The incidence rates of health care-associated infection outbreaks and residents with health care-associated infections were 23.4 per 100 facility-years and 0.18 per 1,000 resident-days, respectively. Influenza and acute gastroenteritis were reported most frequently. Active surveillance to identify the carrier of multiple drug-resistant organisms was not common. The overall compliance with 21 items selected from the SHEA/APIC guidelines was approximately 79.2%. All facilities had infection control manuals and an assigned infection control professional. The economic burdens of infection control were approximately US$ 182.6 per resident-year during fiscal year 2015. Importantly, these data implied that physicians and nurses were actively contributed to higher SHEA/APIC guideline compliance rates and the advancement of infection control measures in long-term care facilities for the elderly. Key factors are discussed to further improve the infection control in long-term care facilities for the elderly, particularly from economic and social structural standpoints.

High transmissibility of norovirus among infants and school children during the 2016/17 season in Osaka, Japan.

The number of person-to-person transmitted norovirus cases (n = 4,712) in school children in Osaka, Japan, during 2016/17 was the largest since 2012/13. Norovirus outbreaks were reported by 101 schools including 53 nursery schools (1,927 cases), 18 kindergartens (1,086 cases) and 30 elementary schools (1,699 cases). The dominant genotype among outbreaks was GII.P16-GII.2 (57.4%; 58/101), followed by GII.P2-GII.2 (8.9%; 9/101) and GII.P7-GII.6 (5.9%; 6/101). GII.4 was not detected despite dominance in previous years.

Global Spread of Norovirus GII.17 Kawasaki 308, 2014-2016.

Analysis of complete capsid sequences of the emerging norovirus GII.17 Kawasaki 308 from 13 countries demonstrated that they originated from a single haplotype since the initial emergence in China in late 2014. Global spread of a sublineage SL2 was identified. A new sublineage SL3 emerged in China in 2016.

Antiviral activity of acid beta-glucosidase 1 on enterovirus 71, a causative agent of hand, foot and mouth disease.

Enterovirus 71 (EV71) is a causative agent of hand, foot and mouth disease (HFMD). EV71 causes fever, rash, diarrhoea and, in some cases, acute encephalopathy/encephalitis, which can be fatal. No specific treatment is currently available for EV71 infection. Here, we conducted a cDNA library screen and identified acid ß-glucosidase 1 (GBA1; also known as ß-glucocerebrosidase) as an EV71 resistance factor. The anti-EV71 function of GBA1 was verified by gene transduction and knockdown experiments. Cerezyme, a molecular drug used to treat Gaucher's disease and having recombinant human GBA1 as the active ingredient, protected against EV71 infection. The anti-EV71 activity of GBA1 was bimodal: endogenous GBA1 restricted cell surface expression levels of scavenger receptor class B, member 2 (SCARB2), also known as lysosomal integral membrane protein 2 (LIMP-2), and exogenous recombinant GBA1 interfered with EV71 to interact with SCARB2 outside the cell. Thus, our findings suggest that GBA1 may represent a novel molecular target for the treatment of EV71 infection.

An infant with acute gastroenteritis caused by a secondary infection with a Rotarix-derived strain.

Rotavirus vaccines have been successful in controlling severe diarrhea and have decreased deaths of young children globally. Rotarix and RotaTeq are the two currently available live-attenuated rotavirus vaccines. The vaccine virus can grow in a recipient's gut and spread from the vaccinee to naïve individuals. The potential for the emergence of revertant viruses is a concern with live-attenuated vaccines. We identified a previously healthy infant with severe acute gastroenteritis that was positive for rotavirus in a non-endemic season. A whole genome sequencing revealed that all of the viral genome segments were highly similar to those of the Rotarix virus, with the exception of five amino acid mutations in viral genes that could be associated with virulence. The younger sibling of this patient was administered Rotarix before the onset of disease in this patient, although no gastrointestinal symptoms were reported. Epidemiological data, circumstantial evidence, and the genome analysis suggest that the vaccine virus was transmitted from the vaccinee to the patient. CONCLUSION: This is a severe acute gastroenteritis case most probably attributed to the secondary infection of Rotarix-related virus without underlying diseases. The importance of molecular surveillance of rotavirus infections is discussed. What is Known: • The live-attenuated rotavirus vaccines, Rotarix and RotaTeq, have been successful in controlling severe diarrhea and have decreased deaths of young children globally. • Attenuated vaccine virus can grow in a recipient's gut and spread to naïve individuals and may revert to cause secondary symptomatic infections. What is New: • This is the first report describing a Rotarix-associated secondary infection resulting in severe acute gastroenteritis in an infant without underlying diseases. • Amino acid mutations that might contribute to viral pathogenesis were identified by whole genome sequencing.

Conformational properties of the third variable loop of HIV-1AD8 envelope glycoprotein in the liganded conditions.

The conformational dynamics of the HIV-1 envelope glycoprotein gp120 and gp41 (Env) remains poorly understood. Here we examined how the V3 loop conformation is regulated in the liganded state using a panel of recombinant HIV-1NL4-3 clones bearing HIV-1AD8 Env by two experimental approaches, one adopting a monoclonal neutralizing antibody KD-247 (suvizumab) that recognizes the tip of the V3 loop, and the other assessing the function of the V3 loop. A significant positive correlation of the Env-KD-247 binding was detected between the liganded and unliganded conditions. Namely, the mutation D163G located in the V2 loop, which enhances viral susceptibility to KD-247 by 59.4-fold, had little effect on the sCD4-induced increment of the virus-KD-247 binding. By contrast, a virus with the S370N mutation in the C3 region increased the virus-KD-247 binding by 91.4-fold, although it did not influence the KD-247-mediated neutralization. Co-receptor usage and the susceptibility to CCR5 inhibitor Maraviroc were unaffected by D163G and S370N mutations. Collectively, these data suggest that the conformation of the liganded V3-loop of HIV-1AD8 Env is still under regulation of other Env domains aside from the V3 loop, including V2 and C3. Our results give an insight into the structural properties of HIV-1 Env and viral resistance to entry inhibitors by non-V3 loop mutations.

Zinc-finger antiviral protein mediates retinoic acid inducible gene I-like receptor-independent antiviral response to murine leukemia virus.

When host cells are infected by an RNA virus, pattern-recognition receptors (PRRs) recognize the viral RNA and induce the antiviral innate immunity. Toll-like receptor 7 (TLR7) detects the genomic RNA of incoming murine leukemia virus (MLV) in endosomes and mediates the antiviral response. However, the RNA-sensing PRR that recognizes the MLV in the cytosol is not fully understood. Here, we definitively demonstrate that zinc-finger antiviral protein (ZAP) acts as a cytosolic RNA sensor, inducing the degradation of the MLV transcripts by the exosome, an RNA degradation system, on RNA granules. Although the retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) RIG-I and melanoma differentiation-associated protein 5 detect various RNA viruses in the cytosol and induce the type I IFN-dependent antiviral response, RLR loss does not alter the replication efficiency of MLV. In sharp contrast, the loss of ZAP greatly enhances the replication efficiency of MLV. ZAP localizes to RNA granules, where the processing-body and stress-granule proteins assemble. ZAP induces the recruitment of the MLV transcripts and exosome components to the RNA granules. The CCCH-type zinc-finger domains of ZAP, which are RNA-binding motifs, mediate its localization to RNA granules and MLV transcripts degradation by the exosome. Although ZAP was known as a regulator of RIG-I signaling in a human cell line, ZAP deficiency does not affect the RIG-I-dependent production of type I IFN in mouse cells. Thus, ZAP is a unique member of the cytosolic RNA-sensing PRR family that targets and eliminates intracellular RNA viruses independently of TLR and RLR family members.

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.

Influenza vaccination during pregnancy and its usefulness to mothers and their young infants.

The current approach to protecting pregnant women from influenza infection and serious influenza-related complications is vaccination. It is, therefore, critical to evaluate the vaccine's safety, immunogenicity, and protection efficacy during pregnancy. However, because it is affected by previous influenza vaccination or infection, the efficacy of the seasonal trivalent inactivated influenza vaccine is difficult to evaluate in pregnant women. The A/H1N1pdm pandemic in 2009 provided us with the opportunity to evaluate the immunogenicity of the influenza vaccine unaffected by previous vaccinations or infections. Vaccination with inactivated influenza virus during pregnancy elicited neutralizing antibody titers that were sufficient and comparable to those of naturally infected individuals. Furthermore, post-pandemic surveys provided a wealth of definitive information on vaccine efficacy and safety. In addition, transplacental transfer of antibodies following vaccination protected newborn infants against influenza infection. With reports showing the effectiveness of influenza vaccine during pregnancy, it is suggested that influenza vaccination benefits both mothers and their young infants.