Risk of herpes zoster according to past history in the general population: The Japanese Shozu herpes zoster study.

Immunity is known to persist after vaccination for varicella zoster virus, but the duration of immunity in patients who develop herpes zoster (HZ) remains unknown. To investigate the association between a past history of HZ and its occurrence in the general population. The Shozu HZ (SHEZ) cohort study included data for 12 299 individuals aged ≥50 years with information on their HZ history. Cross-sectional and 3-year follow-up studies were carried out to analyze the associations between a history of HZ (yes <10 years, yes ≥10 years, no) and the proportion of positive varicella zoster virus skin test results (erythema diameter ≥5 mm) and the risk of HZ after adjusting for potential confounding factors including age, sex, body mass index, smoking status, sleep duration, and mental stress. The incidences of positive skin test results were 87.7% (470/536) for individuals with a history of HZ <10 years ago, 82.2% (396/482) for those with a history of HZ ≥10 years, and 80.2% (3614/4509) for those with no history of HZ. The multivariable odds ratios (95% confidence intervals) of erythema diameter ≥5 mm were 2.07 (1.57-2.73) and 1. 39 (1.08-1.80) for individuals with a history <10 years and ≥10 years ago, respectively, compared with no history. The corresponding multivariable hazard ratios of HZ were 0.54 (0.34-0.85) and 1.16 (0.83-1.61), respectively. A past history of HZ <10 years ago may reduce the occurrence of HZ.

Predictors of herpes zoster severity and immune responses according to pain trajectories: A community-based prospective cohort study.

The authors aimed to identify determinants of the clinical course of herpes zoster and immunological responses, focusing on pain trajectories. This prospective community-based cohort study involved the analysis of responses to a valid pain survey provided by 375 patients diagnosed with herpes zoster based on clinical symptoms and virus identification by polymerase chain reaction. The authors analyzed most patients for humoral/cell-mediated immune response against varicella-zoster virus at the onset and 3 months post-onset. Six months post-initial visit, patients self-reported pain on a scale of 0 (no pain) to 5 (extremely strong pain) at up to 18 time points. Moreover, the pain trajectories were traced using group-based trajectory modeling. Subsequently, the authors used analysis of covariance to explore predictors and the humoral/cell-mediated immune response according to the pain trajectories. In addition, humoral/cell-mediated immune responses were assessed among each trajectory using paired t tests. Amon the five identified trajectories, two were isolated that particularly developed postherpetic neuralgia, with or without severe acute pain. Cancer therapy and corticosteroid use before herpes zoster onset specifically predicted postherpetic neuralgia without severe acute pain. In contrast, prescription of nonsteroidal anti-inflammatory drugs was uniquely associated with postherpetic neuralgia accompanied by severe acute pain. The aforementioned trajectories with postherpetic neuralgia showed increased antibodies and decreased cell-mediated immunity compared with those without postherpetic neuralgia. The authors could successfully distinguish between postherpetic neuralgia trajectories with and without severe acute pain. The identified key predictors and immunological responses against varicella-herpes zoster contribute further evidence to our understanding of the clinical features of herpes zoster and postherpetic neuralgia.

Longitudinal changes in cell-mediated immunity after varicella-zoster virus skin test in the general population; Shozu Herpes Zoster Study: SHEZ study.

Varicella-zoster virus-specific cell-mediated immunity has been associated with the onset and severity of herpes zoster (HZ), and the administration of the HZ vaccine enhanced the immunity. However, limited data is available on the duration of cell-mediated immunity enhancement by soluble antigen of varicella-zoster virus (VZV) skin test. A prospective, community-based cohort study was conducted in Shozu County, Kagawa Prefecture, Japan. Repeated VZV skin tests containing inactivated VZV antigen and blood tests were performed on 365 subjects aged 60 years and older at baseline, 1, 2, and 3 years later. The differential immunity indices of VZV over time for cell-mediated and humoral immunity were evaluated. VZV skin test reaction and ELISpot counts increased significantly at 1, 2, and 3 years later compared to the baseline. However, humoral immunity indices did not change materially over time. Soluble antigen by VZV skin test enhanced VZV-specific cell-mediated immunity, and it persisted for at least 1 year. In addition, the inoculation with inactivated antigens every year by VZV skin test continued to enhance VZV-specific cell-mediated immunity after 2 and 3 years.

The association of family history of herpes zoster and the risk of incident herpes zoster: the SHEZ Study.

BACKGROUND: We investigated whether family histories of herpes zoster (HZ) are associated with the risk of incident HZ in a Japanese population. METHODS: A total of 12,522 Japanese residents aged ≥50 years in Shozu County participated in the baseline survey between December 2008 and November 2009 (the participation rate = 72.3%). They were interviewed at baseline by research physicians regarding the registrants' history of HZ. A self-administered questionnaire survey was conducted to evaluate the potential confounding factors. 10,530 participants without a history of HZ were followed up to ascertain the incidence of HZ during 3-years follow-up until the end of November 2012 with Japanese nationals. We estimated hazard ratios (HRs) of incident HZ according to first-degree family histories using the Cox proportional hazard regression after adjusting for age, sex, and other potential confounding factors. RESULTS: Compared to no HZ history of each family member, a history of brother or sister was associated with a higher risk of incident HZ while histories of father and mother were not. The multivariable HR (95%CI) of incident HZ for a history of brother or sister was 1.67 (1.04-2.69). When comparing to no family histories of all first-degree relatives, the multivariable HRs (95%CIs) were 1.34 (0.77-2.34) for a history of brother or sister alone, but 4.81 (1.78-13.00) for a history of mother plus brother or sister. As for the number of family histories, the multivariable HRs (95%CIs) were 1.08 (0.76-1.54) for one relative (father, mother, or brother or sister) and 2.75 (1.13-6.70) for two or more relatives. CONCLUSION: Family histories of mother plus brother or sister and two or more first-degree relatives were associated with a higher risk of incident HZ.

Risk of Herpes Zoster in Relation to Body Mass Index Among Residents Aged ≥50 Years: The Shozu Herpes Zoster Study.

BACKGROUND: The impact of body mass index on incidence of herpes zoster is unclear. This study investigated whether body mass index was associated with a history of herpes zoster and incidence during a 3-year follow-up, using data from a prospective cohort study in Japan. METHODS: In total, 12,311 individuals were included in the cross-sectional analysis at baseline, of whom 1,818 with a history of herpes zoster were excluded from the incidence analysis, leaving 10,493 individuals. Body mass index (kg/m2) was classified into three categories (underweight: <18.5; normal: 18.5 to <25; and overweight: ≥25). To evaluate the risk of herpes zoster, we used a logistic regression model for prevalence and a Cox proportional hazard regression model for incidence. RESULTS: Being overweight or underweight was not associated with herpes zoster prevalence at baseline. The multivariate hazard ratios of herpes zoster incidence for overweight versus normal-weight groups were 0.67 (95% confidence interval, 0.51-0.90) in all participants, and 0.57 (95% confidence interval, 0.39-0.83) in women, with no significant difference for men. CONCLUSION: Being overweight was associated with a lower incidence of herpes zoster than being normal weight in older Japanese women.

Infectivity assay for detection of SARS-CoV-2 in samples from patients with COVID-19.

Since the coronavirus disease 2019 (COVID-19) outbreak, laboratory diagnosis has mainly been conducted using reverse-transcription polymerase chain reaction (RT-PCR). Detecting the presence of an infectious virus in the collected sample is essential to analyze if a person can transmit infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there have been no quantitative investigations conducted for infectious SARS-CoV-2 in clinical samples. Therefore, in the present study, a rapid and simple focus-forming assay using the peroxidase-antiperoxidase technique was developed to quantify infectious SARS-CoV-2 titers in 119 samples (n = 52, nasopharyngeal swabs [NPS]; n = 67, saliva) from patients with COVID-19. Furthermore, the study findings were compared with the cycle threshold (Ct) values of real-time RT-PCR. The infectious virus titers in NPS samples and Ct values were inversely correlated, and no infectious virus could be detected when the Ct value exceeded 30. In contrast, a low correlation was observed between the infectious virus titers in saliva and Ct values (r = -0.261, p = 0.027). Furthermore, the infectious virus titers in the saliva were significantly lower than those in the NPS samples. Ten days after the onset of COVID-19 symptoms, the infectious virus was undetectable, and Ct values were more than 30 in NSP and saliva samples. The results indicate that patients whose symptoms subsided 10 days after onset, with Ct values more than 30 in NSP and saliva samples, were less likely to infect others.

Virus Neutralization by Human Intravenous Immunoglobulin Against Influenza Virus Subtypes A/H5 and A/H7.

PURPOSE: Highly pathogenic avian influenza viruses are a threat to human health. Although donor populations have not experienced pandemic, they have been immunized by natural infections and/or vaccinations of influenza viruses such as A/H1N1, A/H3N2, and B. Therefore, it is considered that human intravenous immunoglobulin (IVIG) derived from healthy donors does not include IgG against avian influenza viruses. However, cross-reactivity has not been evaluated yet. In this study, cross-reactivity against the avian influenza virus A/H5N1, A/H7N1, A/H7N2, A/H7N7, A/H7N9, and A/H10N9 was evaluated. MATERIALS AND METHODS: Several lots of IVIG derived from healthy donors in Japan were tested for virus neutralization using single- or multi-cycle virus neutralizing (S-VN or M-VN) assays that evaluate the infection-step associated with HA or the infection and propagation steps associated with HA and NA, respectively. In addition, anti-NA activities were evaluated by inhibiting the enzymatic activity in NAI assays. RESULTS: IVIG lots showed high neutralizing activities against three A/H5N1 strains in M-VN assays, whereas activities in S-VN assays were unstable. In addition, A/H7N2 was also neutralized in S-VN and M-VN assays, with higher activity in M-VN than in S-VN assays. A/H7N1 was neutralized in S-VN and M-VN assays. In contrast, weak or no activity against A/H7N7, A/H7N9, and A/H10N9 was observed in S-VN and M-VN assays. NAI assay results show that IVIG lots had inhibitory activities against N1 and N2; however, N2 activities differed depending on the strain. In contrast, no activities were observed against N7 and N9. CONCLUSION: These results suggest that IVIG lots have neutralizing activity against avian influenza viruses during the virus propagation step, except for one strain, although no or weak activity was observed during the infection step.

Juice of Citrullus lanatus var. citroides (wild watermelon) inhibits the entry and propagation of influenza viruses in vitro and in vivo.

Vaccines and various anti-influenza drugs are clinically used to prevent and treat influenza infections. However, with the antigenic mismatch of vaccines and the emergence of drug-resistant viral strains, new approaches for treating influenza are warranted. This study focused on natural foods as potential candidates for the development of new treatment options for influenza infections. The screening of plants from the Cucurbitaceae family revealed that the juice of Citrullus lanatus var. citroides (wild watermelon) had the strongest ability to inhibit the replication of influenza virus in Madin-Darby canine kidney cells. The results of a time-of-addition assay indicated that wild watermelon juice (WWMJ) inhibits the adsorption and late stages of viral replication, suggesting that WWMJ contains multiple constituents with effective anti-influenza activity. A viral adsorption analysis showed that WWMJ reduces the amount of viral RNA in the cells at 37°C but not at 4°C, confirming that WWMJ inhibits viral entry into the host cells at 37°C. These results suggest that a mechanism other than the inhibition of viral attachment is involved in the anti-influenza action of WWMJ, which is perhaps responsible for a reduction in internalization of the virus. Administration of WWMJ into the nasal mucosa of BALB/c mice infected with the A/PR/8/34 mouse-adapted influenza virus was seen to significantly improve the survival rate. The findings of this study, therefore, demonstrate the anti-influenza potential of WWMJ in vitro and in vivo, thereby suggesting the candidature of WWMJ as a functional food product that can be used to develop anti-influenza agents and drugs.

Comprehensive Analysis of Antibodies Induced by Vaccination with 4 Kinds of Avian Influenza H5N1 Pre-Pandemic Vaccines.

Four kinds of avian-derived H5N1 influenza virus, A/Vietnam/1194/2004 (Clade 1), A/Indonesia/5/2005 (Clade 2.1), A/Qinghai/1A/2005 (Clade 2.2), and A/Anhui/1/2005 (Clade 2.3), have been stocked in Japan for use as pre-pandemic vaccines. When a pandemic occurs, these viruses would be used as vaccines in the hope of inducing immunity against the pandemic virus. We analyzed the specificity of antibodies (Abs) produced by B lymphocytes present in the blood after immunization with these vaccines. Eighteen volunteers took part in this project. After libraries of Ab-encoding sequences were constructed using blood from subjects vaccinated with these viruses, a large number of clones that encoded Abs that bound to the virus particles used as vaccines were isolated. These clones were classified into two groups according to the hemagglutination inhibition (HI) activity of the encoded Abs. While two-thirds of the clones were HI positive, the encoded Abs exhibited only restricted strain specificity. On the other hand, half of the HI-negative clones encoded Abs that bound not only to the H5N1 virus but also to the H1N1 virus; with a few exceptions, these Abs appeared to be encoded by memory B cells present before vaccination. The HI-negative clones included those encoding broadly cross-reactive Abs, some of which were encoded by non-VH1-69 germline genes. However, although this work shows that various kinds of anti-H5N1 Abs are encoded by volunteers vaccinated with pre-pandemic vaccines, broad cross-reactivity was seen only in a minority of clones, raising concern regarding the utility of these H5N1 vaccine viruses for the prevention of H5N1 pandemics.

Anti-Influenza Virus Activity of Adlay Tea Components.

Our previous study showed anti-influenza virus activity in adlay tea prepared from adlay seeds, naked barley seeds, soybean, and cassia seeds. In this study, we evaluated the anti-influenza virus activity of each component of this tea and analyzed their active ingredients. Each component was roasted and extracted in hot water; the extracts were tested for antiviral activity and their mechanisms of action were studied. All the tea components showed antiviral activity against the H1N1 and H3N2 influenza subtypes and against influenza B. The viral stages inhibited by the components were virus adsorption and replication in proliferative process, suggesting that the action mechanisms of the components might differ from those of oseltamivir acid. Of the tea components, soybean showed the strongest activity. Therefore, we analyzed its active ingredients by liquid chromatography quadruple time-of-flight mass spectrometry (LC/qTOF-MS) and daidzein and glycitein were detected as active ingredients. Here, anti-influenza virus action of glycitein was the first report.

Sleep Shortage Is Associated With Postherpetic Neuralgia Development Through Hyperesthesia and Acute Pain Intensity: A Community-Based Prospective Cohort Study.

OBJECTIVES: There have been no community-based studies investigating the association between sleep duration and postherpetic neuralgia (PHN) development. The aim of the current study was to examine the association of sleep with herpes zoster (HZ) incidence and PHN. METHODS: In total, 12,329 residents (ages 50 to 103 years) of Shozu County, Japan, participated in our study from December 2009 to November 2010 and were followed up for 3 years. At baseline, the participants completed self-administered health questionnaires, including those on usual sleep duration. Three dermatologists diagnosed HZ on the basis of clinical symptoms and virus identification testing by polymerase chain reaction and serological tests, and evaluated pain using a modified Zoster Brief Pain Inventory survey form via telephone. We used a Cox proportional hazard regression model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident HZ and PHN. We also performed mediation analysis to examine whether hyperesthesia and acute pain intensity mediated the association between sleep shortage and chronic pain intensity. RESULTS: During follow-up, 400 cases of HZ were identified. Of these, 55 participants developed PHN. Sleep duration was not associated with HZ incidence. Sleep shortage increased the risk for PHN (HR 2.02 [95% CI: 1.06 to 3.85]). Hyperesthesia and acute pain intensity mediated the association between sleep shortage and chronic pain intensity (indirect/total effect ratio = 50% mediation). CONCLUSIONS: Sleep shortage was associated with increased risk for PHN, and hyperesthesia and acute pain intensity appeared to mediate this association. Sleep shortage may be a novel risk factor for PHN.

Cytokine production in whole-blood cultures following immunization with an influenza vaccine.

A clinical trial of a quadrivalent split influenza vaccine was performed in the 2014/15 season. Sixty-four subjects aged 6 months to 18 years were enrolled in order to investigate the relationship between cellular and humoral immune responses. Subjects were categorized into two groups by measuring neutralizing antibodies: non-primed naïve/primed or seroconverted/non-seroconverted groups. Whole-blood cultures were stimulated with the H1N1 split antigen before immunization and one month after the first and second immunizations for subjects < 13 years and before and one month after the first dose for those ≥ 13 years in order to investigate cytokine production. Significant amounts of IL-2, IL-12, IL-13, MCP-1, MIP-1ß, and TNF-α were detected from one month after the first dose in the naïve group. In addition to these cytokines, the production of IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-17, G-CSF, and IFN-γ was enhanced one month after the second dose. No significant increase was noted in the primed group, except in the production of IL-10. In seroconverted subjects, the production of IL-2, IL-4, IL-8, IL-10, G-CSF, MCP-1, TNF-α, and IFN-γ increased one month after the first dose, which was earlier than in the naïve group, whereas no significant cytokine response was noted in subjects without seroconversion. Subjects ≥ 13 years were primed and the production of G-CSF, IL-4, and IL-1ß increased in subjects with seroconversion. Whole-blood cultures were also stimulated with the H3N2 split antigen and similar cytokine profiles were obtained. Many cytokines and chemokines, including inflammatory cytokines, were produced in seroconverted, but not non-seroconverted subjects.

Three Types of Broadly Reacting Antibodies against Influenza B Viruses Induced by Vaccination with Seasonal Influenza Viruses.

We analyzed the antibody (Ab) repertoire against influenza B viruses induced by vaccination with seasonal influenza viruses in one individual who had never been vaccinated until 2009. The vaccine used in this study comprised B/Massachusetts/2/2012 (Yamagata lineage), A/Texas/50/2012 (H3N2), and A/California/7/2009 (H1N1). One month after the subject received two vaccinations, blood (200 ml) was obtained and peripheral mononuclear cells were prepared, and a large Ab library was constructed using phage display technology. The library was screened with HA-enriched fraction of B/Massachusetts/2/2012 and B/Brisbane/60/2008 (Victoria lineage) virus, and a total of 26 Abs that potentially bound to hemagglutinin (HA) molecules were isolated. Their binding activities to six influenza B viruses, three of Yamagata lineage and three of Victoria lineage, and two influenza A viruses, H1N1 and H3N2, were examined. The Abs showed cross-reactivity at three different levels. The first type bound to all Yamagata lineage viruses. The second type bound to both Yamagata and Victoria lineage viruses. The third type bound to both influenza A and B viruses. These results indicate that common epitopes exist on HA molecules of influenza virus at various levels, and humans have capability to produce Abs that bind to such common epitopes.

Inhibition of influenza virus replication by adlay tea.

BACKGROUND: The present study was conducted aiming to examine the antiviral activity of adlay tea and its components against influenza viruses. We further aimed to clarify the mechanism by which these components regulate virus replication. RESULTS: Adlay tea at a concentration suitable for drinking inhibited the multiplication of influenza viruses. Moreover, our results suggest that individual components of the tea had antiviral activities against the influenza A/PR/8/34 virus. Adlay tea inhibited multiplication of the H1N1, H3N2 and B types of influenza virus, including oseltamivir-resistant viruses. In addition, adlay tea inhibited influenza infection during the periods of virus adsorption to the cell and virus replication. Adlay tea did not suppress hemagglutination inhibition or cell fusion, although it slightly inhibited virus binding to Malin Darby canine kidney cells. Furthermore, our findings suggest that the antiviral compounds included in adlay tea were ingredients other than polyphenols and that there were several types of effective compounds in adlay tea inhibiting several steps of viral replication. CONCLUSION: The results of the present study demonstrate that adlay tea had antiviral effects against influenza viruses. Our findings with respect to adlay tea suggest that the polyphenols might have a small influence on its antiviral activity and that other ingredients might have more influence. © 2017 Society of Chemical Industry.

Analysis of the glycoproteins of Seoul orthohantavirus strain B1 associated with fusion activity.

We analyzed two virus variants (S1 and L1) from Seoul orthohantavirus strain B1. Strain B1 produces large opaque plaques when plated on Vero E6 cell monolayers. However, although the L1 variant produced the large opaque plaques common to the strain, the variant S1 produced small clear ones on Vero E6 cells. Five days after Vero E6 cells were infected with the S1 variant, polykaryons formed spontaneously. However, the cells infected with the L1 variant did not show the formation of syncytia. An analysis of the pH dependency of the cell fusion demonstrated that the L1 variant could induce cell fusion, but only at a pH that was 0.2 units lower than the pH at which the S1 variant induced it. Sequencing of the M genome segment of the two virus variants revealed amino acid substitutions at 4 positions in the Gn and Gc gene products of the S1 variant. Two of these substitutions occurred in the extracellular domain of Gn and changed the charge of the protein. Our findings suggest that these amino acid substitutions caused the S1 variant Gn protein to induce fusion at an elevated pH.

Associations of Perceived Mental Stress, Sense of Purpose in Life, and Negative Life Events With the Risk of Incident Herpes Zoster and Postherpetic Neuralgia: The SHEZ Study.

In the present population-based prospective study, we examined the associations of psychosocial factors with the incidence of herpes zoster (HZ) and postherpetic neuralgia (PHN). Data were collected from 12,359 participants (≥50 years of age) who answered a self-completed health questionnaire in the Shozu County of Kagawa Prefecture in Japan. During a 3-year follow-up between December 2008 and November 2012, HZ and PHN were diagnosed in 400 and 79 subjects, respectively. We used Cox regression analysis to estimate hazard ratios of incident HZ and PHN according to psychosocial factors, adjusting for age, sex, histories of HZ, cancer, and diabetes, smoking and drinking habits, and time from disease onset to treatment. Men with high levels of mental stress were twice as likely to be at risk for incident HZ. The risk of incident HZ was approximately 60% lower among men and women who reported a high sense of purpose in life. Women who experienced negative life events-particularly changes in their work, living environment, and relationships-had a 2- to 3-fold higher risk of incident PHN. Psychosocial factors such as perceived mental stress, sense of purpose in life, and negative life events may contribute to the development of HZ and PHN in the general population.

Neutralizing activities against seasonal influenza viruses in human intravenous immunoglobulin.

Influenza viruses A/H1N1, A/H3N2, and B are known seasonal viruses that undergo annual mutation. Intravenous immunoglobulin (IVIG) contains anti-seasonal influenza virus globulins. Although the virus-neutralizing (VN) titer is an indicator of protective antibodies, changes in this titer over extended time periods have yet to be examined. In this study, variations in hemagglutination inhibition (HI) and VN titers against seasonal influenza viruses in IVIG lots over extended time periods were examined. In addition, the importance of monitoring the reactivity of IVIG against seasonal influenza viruses with varying antigenicity was evaluated. A/H1N1, A/H3N2, and B influenza virus strains and IVIG lots manufactured from 1999 to 2014 were examined. The HI titer was measured by standard methods. The VN titer was measured using a micro-focus method. IVIG exhibited significant HI and VN titers against all investigated strains. Our results suggest that the donor population maintains both specific and cross-reactive antibodies against seasonal influenza viruses, except in cases of pandemic viruses, despite major antigen changes. The titers against seasonal influenza vaccine strains, including past strains, were stable over short time periods but increased slowly over time.

BK-UM in patients with recurrent ovarian cancer or peritoneal cancer: a first-in-human phase-I study.

BACKGROUND: BK-UM (CRM197) is a mutant form of diphtheria toxin and a specific inhibitor of heparin-binding epidermal growth factor-like growth factor (HB-EGF). We assessed the safety, pharmacokinetics, recommended dose, and efficacy of BK-UM in patients with recurrent ovarian cancer (OC) or peritoneal cancer (PC), and measured HB-EGF levels in serum and abdominal fluid after BK-UM administration. METHODS: Eleven patients with advanced or recurrent OC or PC were enrolled and treated with BK-UM via the intraperitoneal route. The dose was escalated (1.0, 2.0, 3.3, and 5.0 mg/m2) using a 3 + 3 design. RESULTS: Eight of 11 patients completed treatment. No dose-limiting toxicity (DLT) was experienced at dose levels 1 (1.0 mg/m2) and 2 (2.0 mg/m2). Grade 3 transient hypotension as an adverse event (defined as a DLT in the present study) was observed in two of four patients at dose level 3 (3.3 mg/m2). Treatment with BK-UM was associated with decreases in HB-EGF levels in serum and abdominal fluid in seven of 11 patients and five of eight patients, respectively. Clinical outcomes included a partial response in one patient, stable disease in five patients, and progressive disease in five patients. CONCLUSIONS: BK-UM was well tolerated at doses of 1.0 and 2.0 mg/m2, with evidence for clinical efficacy in patients with recurrent OC or PC. A dose of 2.0 mg/m2 BK-UM is recommended for subsequent clinical trials. TRIAL REGISTRATION: This trial was prospectively performed as an investigator-initiated clinical trial. The trial numbers are UMIN000001002 and UMIN000001001, with registration dates of 1/30/2008 and 2/4/2008, respectively. UMIN000001001 was registered as a trial for the continuous administration of BK-UM after UMIN000001002 .

Relationship between cell-mediated immunity to Varicella-Zoster virus and aging in subjects from the community-based Shozu Herpes Zoster study.

Age-related declines in cell-mediated immunity (CMI) are associated with the incidence and severity of Herpes Zoster (HZ) infection. However, the level of Varicella-Zoster virus (VZV)-specific CMI associated with disease onset is unclear. This study aimed to examine factors associated with VZV-specific CMI, as measured by an interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay, in a Japanese cohort. The study enrolled 365 subjects aged 60 years and over, all of whom were taking part in the Shozu Herpes Zoster (SHEZ) study and had undergone four sets of blood and intradermal reaction tests during a 3 year follow-up period. The VZV-specific immunity profile of each subject was assessed, and linear mixed effects models were constructed to analyze IFN-γ ELISPOT results in association with a combination of factors. The model that best explained the IFN-γ ELISPOT results was selected using the Akaike Information Criteria. The best-fit model consisted of age group as the only explanatory fixed-effect variable. The model showed that VZV-specific CMI, quantified as numbers of spots on the ELISPOT assay, among subjects aged 70-79 was on average 10.30 points lower than that among subjects aged 60-69. There was no statistically significant difference between subjects aged 70-79 and those aged 80-89. Age was the only factor significantly associated with the level of VZV-specific CMI, as measured by the IFN-γ ELISPOT assay. These results may represent an important step towards quantifying the relationship between VZV-specific CMI and the onset of HZ. J. Med. Virol. 89:313-317, 2017. © 2016 Wiley Periodicals, Inc.

[Results of Booster Vaccination in Children with Primary Vaccine Failure after Initial Varicella Vaccination].

In October 2014, the varicella vaccination policy in Japan was changed from a single voluntary inoculation to two routine inoculations. This paper reports the results of booster vaccination in children who did not show seroconversion after initial vaccination (i.e., primary vaccine failure : PVF) over a 7-year period prior to the introduction of routine varicella vaccination. Between November 2007 and May 2014, 273 healthy children aged between 1.1 and 14.5 years (median : 1.7 years) underwent varicella vaccination. Before and 4 to 6 weeks after vaccination, the antibody titers were measured using an immune adherence hemagglutination (IAHA) assay and a glycoprotein-based enzyme-linked immunosorbent assay (gpELISA). In addition, side reactions were examined during the four-week period after vaccination. Children who did not show IAHA seroconversion (PVF) were recommended to receive a booster vaccination, and the measurement of antibody titers and an assessment of side reactions were performed after the booster dose. In May 2015, a questionnaire was mailed to each of the 273 participants to investigate whether they had developed varicella and/or herpes zoster after vaccination. After initial vaccination, the IAHA seroconversion rate was 75% and the mean antibody titer (Log2) with seroconversion was 4.7, while the gpELISA seroconversion rate was 84% and the mean antibody titer (Log10) with seroconversion was 2.4. Among children with PVF, 54 received booster vaccination within 81 to 714 days (median : 139 days) after the initial vaccination. After booster vaccination, the IAHA seroconversion rate was 98% and the mean antibody titer (Log2) with seroconversion was 5.8. Both the seroconversion rate and the antibody titer were higher compared with the values after the initial vaccination (p < 0.01). After booster vaccination, the gpELISA seropositive rate was 100% and the mean positive antibody titer (Log 10) was 3.6 ; similar results were obtained for the IAHA assay, with a significantly higher, antibody response than that after the initial vaccination (p < 0.01). Side reactions were generally minor, including fever (≥ 37.5 degrees C), rash at the injection site, and rash at other sites. There were no significant differences in the incidences of side reactions between the initial and booster vaccinations. A total of 185 participants responded to the questionnaire (response rate : 68%), and the period between receiving the initial vaccination and their response to the questionnaire ranged from 1.0 to 7.5 years (median : 4.0 years). The prevalence of breakthrough varicella after the initial vaccination was 17% among seroconverters who did not receive booster vaccination and 14% among non-seroconverters who received booster vaccination, showing no significant difference between the two groups. In conclusion, there are no safety issues regarding the administration of a booster vaccination to children with PVF after an initial varicella vaccination, and,a good antibody response can be expected.