Characteristics of Moyamoya Disease Based on National Registry Data in Japan.

Background and Purpose- A public registration system for intractable diseases was started in Japan in 1972 to investigate the etiology and pathogenesis of intractable diseases while reducing out-of-pocket medical expenses on patients. The goal of this study was to investigate the epidemiology and clinical characteristics of Moyamoya disease using data from applications submitted to this system between 2004 and 2008. Methods- In addition to demographic factors such as onset age and family history, we evaluated clinical presentation type, imaging findings, clinical symptoms, and functioning in activities of daily living (ADL). Results- Of 3859 cases for which applications were submitted, 2545 were confirmed to meet the diagnostic criteria after data cleansing. Onset age showed a bimodal distribution, and Moyamoya disease had a higher incidence in women than in men. The presence of occlusion and infarction in the proximal region of the anterior cerebral artery was more frequent in pediatric cases than adult cases. Our findings also indicated that 23% of patients required assistance with ADL. Cerebral infarction (odds ratio [OR], 12.5; 95% CI, 3.55-44.66), seizure (OR, 7.44; 95% CI, 1.29-42.96), and sensory disorders (OR, 5.23; 95% CI, 1.15-23.75) were identified as significant predictors of impaired ADL in pediatric cases 3 years after the initial application. Moderate ADL function (OR, 11.59; 95% CI, 5.29-25.39) and intellectual disabilities (OR, 4.38; 95% CI, 1.58-12.17) at the time of the application were identified as significant prognostic factors in adults. Conclusions- The results of this study indicated that characteristics of Moyamoya disease such as onset type, symptoms, and imaging abnormalities differ with onset age. Prognostic analyses suggested that pediatric cases with good ADL but with infarct type onset, seizure, or sensory disorders might have a subsequent decline in ADL.

Improved survival rate by temperature control at compression sites in rat model of crush syndrome.

BACKGROUND: Crush syndrome (CS) has been reported in disasters, terrorist incidents, and accidents, and the clinical and pathologic picture has gradually been clarified. Few lethal and reproducible animal models of CS with use of a quantitative load are available. A new model is needed to investigate pathologic and therapeutic aspects of this injury. MATERIALS AND METHODS: Using a device built from commercially available components, both hindlimbs of anesthetized rats were respectively compressed for 6 h using 3.6-kg blocks. The effects of trunk warming alone without compressed hindlimbs (Group A), non-warming at room temperature (Group B), whole-body warming including compressed hindlimbs (Group C), or warming of compressed hindlimbs alone (Group D) during compression were examined. Survival rates were compared and hematological and histologic analyses were performed at specific time points after compression release. RESULTS: Limb or whole-body warming significantly worsened the survival of rats. We found a much lower survival rate of 0%-10% in animals, in which the hindlimbs were warmed during compression (Groups C and D) at 12 h after compression release, compared with 90%-100% in animals without warming of the hindlimbs (Groups A and B). Groups C and D showed significantly enhanced hyperkalemia at ≥4 h after compression release and all blood samples from dead cases showed hyperkalemia (>10 mEq/L). CONCLUSIONS: We developed a new lethal and reproducible rat CS model with a quantitative load. This study found that warming of compressed limbs worsened the survival rate and significantly enhanced hyperkalemia, apparently leading to cardiac arrest.

Prognostic Factors in Prostate Cancer Associated with Ulcerative Colitis.

Ulcerative colitis (UC) has been associated with increased prostate cancer (PCa) risk. However, the mechanisms underlying UC and increased PCa risk remain unclear, and research on this topic is scarce in Japan. We have investigated whether UC is associated with PCa risk in the Japanese population and the risk factors related to PCa among older UC patients. This retrospective single-center cohort study was conducted between January 2010 and April 2022. A total of 68 cases were analyzed, and 9 cases of PCa were observed (13.2%). PCa occurred more frequently in the adult-onset group (8/40, 20.0%) than in the older-onset group with UC (1/28; 3.57%). No significant differences were observed between immunosuppressive therapies and PCa in patients, excluding those with pancolitis-type UC. PCa occurred more frequently in the pancolitis type, and the biologics group had no PCa cases, but the difference was not statistically significant (p = 0.07). This study suggests that pancolitis type and UC onset in middle-aged patients may be risk factors and found that biologics potentially suppress PCa development.

Risk Factors Associated With Perioperative Skeletal Muscle Loss in Patients With Colorectal Cancer.

BACKGROUND/AIM: Postoperative changes in body composition, especially loss of muscle mass, often occur in gastrointestinal cancer patients. Few studies have reported perioperative changes in the body composition of patients with colorectal cancer. Therefore, this study aimed at clarifying changes in body composition during the perioperative period and identifying risk factors for skeletal muscle mass loss in patients with colorectal cancer. PATIENTS AND METHODS: This prospective observational study included 148 patients who underwent robot- or laparoscopic-assisted surgery for colorectal cancer. RESULTS: The rate of change in body composition at discharge was -6.25% for body fat, with a higher rate of decrease than that for skeletal muscle mass (-3.30%; p=0.0006) and body water mass (-2.66%; p=0.0001). Similarly, even at one month postoperatively, body fat mass (-8.05%) was reduced at a greater rate than skeletal muscle mass (-2.02% p=0.0001) and body water mass (-1.33% p=0.0001).The site-specific percent change in limb skeletal and trunk muscle mass at discharge was the greatest in the lower extremities at -5.37%, but one month after surgery, the upper extremities had the greatest change at -4.44%. The Prognostic Nutritional Index (PNI) influenced skeletal muscle mass loss at discharge [odds ratio (OR)=2.6; 95% confidence interval (CI)=1.30-5.58], while diabetes (OR=4.1; 95%CI=1.40-12.43) and ileostomy (OR=6.7; 95%CI=1.45-31.11) influenced skeletal muscle loss one month postoperatively. CONCLUSION: Preoperative and postoperative nutritional guidance/intervention and body part-specific rehabilitation should be provided to prevent skeletal muscle mass loss in patients with low PNI, diabetes, and those undergoing ileostomy.

The Movement Disorder Society Criteria: Its Clinical Usefulness in Multiple System Atrophy.

Objective In 2022, Wenning et al. proposed the Movement Disorder Society Criteria (MDS Criteria) for the Diagnosis of Multiple System Atrophy (MSA). These criteria were expected to provide useful alternatives to the second consensus statement. We examined trends in these diagnostic criteria. Methods We used patient data registered with the Hokkaido Rare Disease Consortium for Multiple System Atrophy, which has been recruiting patients with MSA through medical facilities in Hokkaido since November 2014. Patients were evaluated according to the MDS criteria based on neurological examinations and imaging findings at three separate times: the first evaluation, the time of enrollment (diagnosis), and the most recent evaluation (final evaluation). Results The MDS criteria were examined in 68 of 244 patients enrolled between November 2014 and July 2022. At the initial evaluation, the classifications were as follows: clinically established (n=27; 39.7%); clinically probable (n=13; 19.1%); possible prodromal (n=12; 17.6%); and negative (did not meet criteria (n=16; 23.5%). At the time of diagnosis, the classifications were as follows: clinically established (n=45; 66.2%); clinically probable (n=12; 17.6%); possible prodromal (n=4; 5.9%); and negative (n=7; 10.3%). At the final evaluation, the classifications were as follows: clinically established (n=52; 76.5%); clinically probable (n=9; 13.2%); possible prodromal (n=2; 2.9%); and negative (n=5; 7.4%). Conclusions We were able to clarify the changes in the criteria values and transition of patients due to the clarification of imaging and supportive findings in the MDS criteria.

Insufficient preparedness of primary care practices for pandemic influenza and the effect of a preparedness plan in Japan: a prefecture-wide cross-sectional study.

BACKGROUND: Cases of emerging infectious diseases, including H5N1 influenza, H7N9 influenza, and Middle East Respiratory Syndrome, have been reported in recent years, and the threat of pandemic outbreaks persists. In Japan, primary care is the frontline against emerging infectious diseases in communities. Although the importance of pandemic preparedness in primary care has been highlighted previously, few studies have thus far investigated the preparedness among primary care practices (PCPs) or differences in the preparedness of different institutional settings. We examined PCP preparedness and response to the 2009 influenza pandemic in Japan, and explored the role of a pandemic preparedness plan during the pandemic. METHODS: We used a survey questionnaire to assess how well individual PCPs in Okinawa, Japan, were prepared for the 2009 influenza pandemic. The questionnaire was mailed to all eligible PCPs (N = 465) in Okinawa, regardless of their institutional setting. In addition, we assessed the differences in the preparedness of clinics and hospitals and determined whether the national preparedness plan affected individual preparedness and response. Data were analyzed using descriptive and logistic regression analyses. RESULTS: A total of 174 (37.4%) PCPs responded to our survey. In general, high-level personal protective equipment (PPE) such as N95 masks (45.4%), gowns (30.5%), and eye protection (21.3%) was stocked at a low rate. Clinic-based PCPs were significantly less prepared than hospital-based PCPs to provide N95 masks (OR 0.34), gowns (OR 0.15), and eye protection (OR 0.18). In addition, only 32.8% of PCPs adopted an adequate business continuity plan (BCP). After controlling for institutional setting, reading the national preparedness plan was significantly associated with establishment of a BCP (OR 5.86), and with knowledge of how to transfer a swab specimen to a local medical laboratory (OR 5.60). CONCLUSIONS: With regard to PPE availability, PCPs (especially clinic-based PCPs) were not adequately prepared for the influenza pandemic. Awareness of the national pandemic preparedness plan is likely to promote prefecture-wide implementation of BCPs and surveillance activity.

Hospital Management and Public Health Role of National Hospitals after Transformation into Independent Administrative Agencies.

The development of medical care, technological advances, and the ageing of society have led to rising medical costs. As a result, there is a demand to improve the efficiency of healthcare delivery systems, including public healthcare institutions, in order to ensure the sustainability of healthcare functions. In 2004, as part of national civil service reform in Japan, national hospitals were merged in order to form the National Hospital Organization (NHO). The NHO used new public management methods and was required to be self-financing and to maintain critical functions under a five-year management plan. The objective of this study was to examine whether the NHO was able to maintain its key function in the national infrastructure in terms of management. An analysis of the business conditions of the NHO was performed based on the financial statements from FY 2004 to FY 2018 using evaluation indexes. In the first and second periods, the NHO achieved its targeted management improvements. However, since FY 2014, even with the utmost restrictions on capital investment, the profits have not increased, and the free cash flow has been negative. Our results suggest that further organizational reforms are needed in order to sustain the NHO infrastructure in the long term and to withstand health crisis management during periods such as the COVID-19 pandemic.

Improving the Accuracy of Diagnosis for Multiple-System Atrophy Using Deep Learning-Based Method.

Multiple-system atrophy (MSA) is primarily an autonomic disorder with parkinsonism or cerebellar ataxia. Clinical diagnosis of MSA at an early stage is challenging because the symptoms change over the course of the disease. Recently, various artificial intelligence-based programs have been developed to improve the diagnostic accuracy of neurodegenerative diseases, but most are limited to the evaluation of diagnostic imaging. In this study, we examined the validity of diagnosis of MSA using a pointwise linear model (deep learning-based method). The goal of the study was to identify features associated with disease differentiation that were found to be important in deep learning. A total of 3377 registered MSA cases from FY2004 to FY2008 were used to train the model. The diagnostic probabilities of SND (striatonigral degeneration), SDS (Shy-Drager syndrome), and OPCA (olivopontocerebellar atrophy) were estimated to be 0.852 ± 0.107, 0.650 ± 0.235, and 0.858 ± 0.270, respectively. In the pointwise linear model used to identify and visualize features involved in individual subtypes, autonomic dysfunction was found to be a more prominent component of SDS compared to SND and OPCA. Similarly, respiratory failure was identified as a characteristic of SDS, dysphagia was identified as a characteristic of SND, and brain-stem atrophy was identified as a characteristic of OPCA.

Serological responses in humans to the smallpox vaccine LC16m8.

In response to potential bioterrorism with smallpox, members of the Japanese Self-Defense Forces were vaccinated with vaccinia virus (VACV) strain LC16m8, an attenuated smallpox vaccine derived from VACV strain Lister. The serological response induced by LC16m8 to four virion-surface proteins and the intracellular mature virus (IMV) and extracellular enveloped virus (EEV) was investigated. LC16m8 induced antibody response against the IMV protein A27 and the EEV protein A56. LC16m8 also induced IMV-neutralizing antibodies, but unlike the VACV strain Lister, did not induce either EEV-neutralizing antibody or antibody to EEV protein B5, except after revaccination. Given that B5 is the only target for EEV-neutralizing antibody and that neutralization of both IMV and EEV give optimal protection against orthopoxvirus challenge, these data suggest that immunity induced by LC16m8 might be less potent than that deriving from strain Lister. This potential disadvantage should be balanced against the advantage of the greater safety of LC16m8.

Airport quarantine inspection, follow-up observation, and the prevention of pandemic influenza.

INTRODUCTION: After a report of H1N1 novel influenza in Mexico and North America, Japan conducted onboard quarantine inspections from late April 2009. The detection rate in border quarantine inspection is low due to incubation period and thus inspection is considered to be ineffective in blocking the entry of influenza. However, little is known about the concomitant effects of such inspection, such as increased traceability, upon secondary transmission. METHODS: Epidemiological data were collected from the web sites of the Department of Health, Labor, and Welfare of Japan and the National Institute of Infectious Diseases of Japan. The number of weekly patients with H1N1 pandemic influenza in eight districts of Japan was summarized. The number of patients who passed through quarantine inspection at the airports was also calculated. A person with overseas travel history was defined as a person who had a flight only from the United States, Canada, or Mexico and passed through the quarantine inspection (according to the quarantine policy of the Japanese government). The numbers were adjusted for the population of each district and expressed as the number of patients per one million people. RESULTS: Despite Kanto district having the largest population, the number of patients with H1N1 novel influenza was relatively small. The total number of cases in each district correlated inversely to the percentage of cases with airport quarantine inspection. DISCUSSION: Quarantine inspection at the airports, follow-up observation by local authorities, and overall concomitant efforts may have contributed to secondary infection control in Japan.

Developing an electronic health record for intractable diseases in Japan.

Because intractable diseases result from unidentifiable causes and are very difficult to treat, they require a lifelong epidemiology database. Japan does not use global unique identifiers, such as social security numbers, so we conducted a feasibility study regarding an electronic health record (EHR). An EHR can be used as a lifelong database and reduce conventional administrative work. However, it will be necessary to develop additional tools to overcome issues specific to Japan before an EHR can be implemented.

Effect of Serial Passage on the Pathogenicity and Immunogenicity of Vaccinia Virus LC16m8 Strain.

The phenotype of an attenuated live vaccine depends on gene mutation achieved by, for example, many passages in cultured cells. Viral clones with preferable phenotypes are selected and the causative genetic mutation(s) are later identified. LC16m8 is an example of a highly attenuated smallpox vaccine that was developed and licensed in Japan in the 1970s. LC16m8 was obtained by the passaging of Lister strain, with indicators of small plaque formation and temperature sensitivity as virus phenotypes. This strain can replicate in mammalian cells and provides robust cellular and humoral immunity, as well as long-term immune memory. Recent studies using proteome-wide antigen arrays have revealed that antibody production against LC16m8 and other VACVs differs largely among individuals. Moreover, associations between SNPs in immune-related genes and immune outcomes have been increasingly found. These results lead to predicting adverse events of a vaccine, which is a purpose of vaccinomics. Studies on VACV will continue to contribute to the understanding of host-pathogen interactions and to development of a vaccine for other infectious and non-infectious diseases. Here, we review studies of VACV, including our recent research on LC16m8, with a focus on the phenotype and genotype, and we discuss future research directions.

Multiple system atrophy in Hokkaido, Japan: a prospective registry study of natural history and symptom assessment scales followed for 5 years.

OBJECTIVES: Multiple system atrophy (MSA) is a refractory neurodegenerative disease, but novel treatments are anticipated. An accurate natural history of MSA is important for clinical trials, but is insufficient. This regional registry was launched to complement clinical information on MSA. SETTING: Patient recruitment started in November 2014 and is ongoing at the time of submission. The number of participating facilities was 66. Postal surveys were sent to medical facilities and patients with MSA in Hokkaido, Japan. PARTICIPANTS: After obtaining written consent from 196 participants, 184 overview surveys and 115 detailed surveys were conducted. PRIMARY AND SECONDARY OUTCOME MEASURES: An overview survey evaluated conformity to diagnostic criteria and a detailed survey implemented an annual assessment based on the Unified Multiple System Atrophy Rating Scale (UMSARS). RESULTS: At the time of registration, 58.2% of patients were diagnosed with cerebellar symptoms predominant type MSA (MSA-C) and 29.9% were diagnosed with parkinsonism predominant type MSA (MSA-P). UMSARS Part Ⅳ score of 4 or 5 accounted for 53.8% of participants. The higher the UMSARS Part Ⅳ score, the higher the proportion of MSA-P. At baseline, levodopa was used by 69 patients (37.5%) and the average levodopa dose was 406.7 mg/day. The frequency of levodopa use increased over time. Eleven cases changed from MSA-C to MSA-P during the study, but the opposite was not observed. Information about survival and causes of death was collected on 54 cases. Half of deaths were respiratory-related. Sudden death was recorded even in the group with UMSARS Part Ⅳ score of 1. CONCLUSIONS: This study is the first large-scale prospective MSA cohort study in Asia. MSA-C was dominant, but the use of antiparkinsonian drugs increased over the study period. Changes from MSA-C to MSA-P occurred, but not vice versa.

Effect of photocrosslinkable chitosan hydrogel and its sponges to stop bleeding in a rat liver injury model.

This study examined the hemostatic efficacy of photocrosslinkable chitosan hydrogel-mixed photocrosslinked chitosan sponges (PCM-S) after hepatic injury in rats. The left lobe of the liver was penetrated with a dermal punch to produce a penetrating wound in heparinized and nonheparinized rats. Treated rats either had PCM-S applied into the wound and then were immediately ultraviolet irradiated, or they had TachoComb (TC) inserted into the wound. Blood loss, hemostasis, and survival were quantified after the hepatic injury. Measurements on serum alanine aminotransferase in nonheparinized rats and hemoglobin concentrations and histologic examinations in heparinized rats were performed to assess hepatic function. Although the hemostatic effect in the PCM-S-treated nonheparinized rats was identical to that of the TC-treated group, PCM-S-treatment has higher hemostatic effect in heparinized rats. No adverse events related to the use of PCM-S were detected in blood and histologic examinations.

Photocrosslinkable chitosan hydrogel can prevent bone formation in both rat skull and fibula bone defects.

UV light irradiation to a photocrosslinkable chitosan (Az-CH-LA) resulted in an insoluble and flexible hydrogel within 30 s. The purpose of this study was to evaluate the ability of the photocrosslinkable chitosan to inhibit bone formation in the bone defects. A 5-mm-diameter defect was made in the rat calvarium, and then photocrosslinkable chitosan was implanted and irradiated with UV for 30 s. Furthermore, a 2-mm defect was made in the fibula of a rat hind leg, and then photocrosslinkable chitosan was implanted and irradiated with UV. Bone formations in the rat skull and fibula defects with photocrosslinkable chitosan hydrogel were significantly prevented for 8 weeks. Thus, the chitosan hydrogel has an inhibitory effect on bone formation.

Coatings of low-density lipoprotein and synthetic glycoconjugates as substrata for hepatocytes.

Asialoglycoprotein (ASGP) receptors expressed on rat hepatocytes interact with glycoproteins containing galactose or N-acetylgalactosamine residues at the nonreducing termini of oligosaccharide chains to mediate endocytosis, and cholesterol transport protein with apolipoprotein B (LDL, low-density lipoprotein) in plasma interacts with LDL receptors and heparinoids in the extracellular matrix. We developed novel techniques to prepare galactose- and LDL-immobilized culture plates, using galactose-tagged polystyrene (galactose-carrying polystyrene [GalCPS]: N-p-vinylbenzyl-O-beta-D-galactopyranosyl-[1-->4]-D-gluconamide) and poly(2-acrylamide-2-methyl-1-propanesulfonate) (PAPS), respectively. Hepatocytes adhered well to plates coated with either GalCPS or LDL, and therefore the GalCPS- and LDL-coated plates were examined as specific substrata for culturing hepatocytes. These cultures promoted the formation of three-dimensional, multicellular aggregates with regulation of excess proliferation of non-parenchymal cells. Furthermore, the LDL coating resulted in higher albumin synthesis and an identical level of lactate dehydrogenase (LDH) compared with cells cultured on collagen- and GalCPS-coated plates. Thus, the two culture systems described here, and especially the LDL-coated plates, have potential for the development of a hybrid artificial liver.

Fragmin/protamine microparticle-coated matrix immobilized cytokines to stimulate various cell proliferations with low serum media.

Fragmin/protamine microparticles (F/P MPs) have been shown to bind to culture plates, thereby retaining heparin-binding cytokines. Most protocols for in vitro cultures of human microvascular endothelial cells (hMVECs), human dermal fibroblast cells (hDFCs), and hematopoietic cell line (TF-1) include high fetal bovine serum (FBS) (10%) medium as a nutritional supplement. Growth rates of those cells on the F/P MP-coated plates were higher in low FBS (1%) medium containing fibroblast growth factor (FGF)-2 (for hMVECs and hDFCs) and interleukin (IL)-3/granulocyte-macrophage colony-stimulating factor (for TF-1 cells) than without coating. The cytokines in low FBS medium were shown to be immobilized on the F/P MP-coated plate and released into the culture medium with a half releasing time of 4-5 days. Furthermore, those cells grew well on each cytokine-preimmobilized F/P MP-coated plate in low FBS medium. Thus, the F/P MP-coated matrix with adequate heparin-binding cytokines may provide biomaterials for controlling cellular growth and differentiation.

Accelerated wound healing in healing-impaired db/db mice by autologous adipose tissue-derived stromal cells combined with atelocollagen matrix.

Adipose tissue-derived stromal cells (ATSCs) have recently gained widespread attention as a potential alternate source to bone marrow-derived mesenchymal stem cells with a proliferative capacity and a similar ability to undergo multilineage differentiation. In this study, we evaluated the effectiveness of freshly isolated autologous ATSCs-containing atelocollagen matrix with silicon membrane (ACMS) on wound healing of diabetic (db/db) mice. Cultured ATSCs from (db/db) mice secreted significant amounts of growth factors and cytokines, which are suitable for wound repair. Two full thickness round skin defects were made on the backs of healing-impaired db/db mice. Freshly isolated autologous ATSCs-containing ACMS or ACMS alone were applied to the wounds. Twelve mice were treated and then killed at 1 or 2 weeks (n = 6 each). Histologic sections of the wounds were prepared at each time period after treatment. Histologic examination demonstrated significantly advanced granulation tissue formation, capillary formation, and epithelialization in diabetic healing-impaired wounds treated with autologous ATSCs-containing ACMS, compared with mice treated with ACMS alone. These results suggested that transplantation of autologous ATSCs-containing ACMS significantly accelerated wound healing in diabetic healing-impaired db/db mice.

Clinical and immunological response to attenuated tissue-cultured smallpox vaccine LC16m8.

CONTEXT: The attenuated, tissue-cultured, third-generation smallpox vaccine LC16m8 was administered to vaccinia-naive infants in Japan during the 1970s without serious adverse events. It is a good candidate for use as part of a prevention plan for bioterrorism. OBJECTIVE: To assess the immunogenicity and frequency of adverse events of LC16m8 vaccine in unvaccinated and previously vaccinated adults. DESIGN, SETTING, AND PARTICIPANTS: Between 2002 and 2005 we vaccinated and revaccinated 1529 and 1692 adults, respectively, in the Japan Self-Defense Forces with LC16m8 vaccine, given intraepidermally using a bifurcated needle. Vaccinees were examined 10 to 14 days after vaccination to determine if they had developed a major skin reaction ("take"). Neutralizing antibody responses among 200 participants were assessed using a plaque-reduction neutralization test 30 days postvaccination. We monitored vaccinees for adverse events for 30 days postvaccination. MAIN OUTCOME MEASURES: Documentation of a vaccine take, presence of neutralizing antibody response, and frequency of adverse events. RESULTS: The proportions of take in vaccinia-naive and previously vaccinated individuals were 1443 of 1529 (94.4% [95% confidence interval {CI}, 93.2%-95.9%] and 1465 of 1692 (86.6% [95% CI, 85.0%-88.2%]), respectively. Seroconversion or an effective booster response among the individuals with take was elicited in 37 of 41 (90.2% [95% CI, 81.2%-99.3%]) vaccinia-naive participants and in 93 of 155 (60.0% [95% CI, 52.3%-67.7%]) previously vaccinated participants. One case of allergic dermatitis and another of erythema multiforme, both of which were mild and self-limited, were suspected to be caused by vaccination. No severe adverse events were observed. CONCLUSION: Administration of an attenuated tissue-cultured smallpox vaccine (LC16m8) to healthy adults was associated with high levels of vaccine take and seroconversion in those who were vaccinia-naive and yielded an effective booster response in some previously vaccinated individuals.

Profiling of the antibody response to attenuated LC16m8 smallpox vaccine using protein array analysis.

Concerns about bioterrorism and outbreaks of zoonotic orthopoxvirus require safe and efficacious smallpox vaccines. We previously reported the clinical efficacy and safety profiles of LC16m8, a live, attenuated, cell culture-derived, smallpox vaccine, examined in over 3000 healthy Japanese adults with various vaccination histories. In this study, serum of approximately 200 subjects pre and post LC16m8 vaccination were subjected to a vaccinia virus-specific protein array to evaluate the proteome-wide immunogenicity. The relationships between antigen-specific antibodies and plaque reduction neutralization titers were analyzed. LC16m8 induced antibodies to multiple vaccinia antigens in primary-vaccinated individuals and yielded effective booster responses in previously vaccinated individuals, demonstrating similar antibody profiles to those reported for other vaccinia virus strains. Several immunodominant antigens were indicated to be important for neutralization of the intracellular mature virion. The similarity of antibody profiles between LC16m8 and other smallpox vaccine strains supports the immunogenicity and protective efficacy of LC16m8.