Deimmunization of flagellin for repeated administration as a vaccine adjuvant.

Flagellin, a protein-based Toll-like receptor agonist, is a versatile adjuvant applicable to wide spectrum of vaccines and immunotherapies. Given reiterated treatments of immunogenic biopharmaceuticals should lead to antibody responses precluding repeated administration, the development of flagellin not inducing specific antibodies would greatly expand the chances of clinical applications. Here we computationally identified immunogenic regions in Vibrio vulnificus flagellin B and deimmunized by simply removing a B cell epitope region. The recombinant deimmunized FlaB (dFlaB) maintains stable TLR5-stimulating activity. Multiple immunization of dFlaB does not induce FlaB-specific B cell responses in mice. Intranasally co-administered dFlaB with influenza vaccine enhanced strong Ag-specific immune responses in both systemic and mucosal compartments devoid of FlaB-specific Ab production. Notably, dFlaB showed better protective immune responses against lethal viral challenge compared with wild type FlaB. The deimmunizing B cell epitope deletion did not compromise stability and adjuvanticity, while suppressing unwanted antibody responses that may negatively affected vaccine antigen-directed immune responses in repeated vaccinations. We explain the underlying mechanism of deimmunization by employing molecular dynamics analysis.

Combination of Photodynamic Therapy and a Flagellin-Adjuvanted Cancer Vaccine Potentiated the Anti-PD-1-Mediated Melanoma Suppression.

Immune checkpoint inhibitors become a standard therapy for malignant melanoma. As immune checkpoint inhibitor monotherapies proved to have limited efficacy in significant portion of patients, it is envisaged that combination with other therapeutic modalities may improve clinical outcomes. We investigated the effect of combining photodynamic therapy (PDT) and TLR5 agonist flagellin-adjuvanted tumor-specific peptide vaccination (FlaB-Vax) on the promotion of PD-1 blockade-mediated melanoma suppression using a mouse B16-F10 implantation model. Using a bilateral mouse melanoma cancer model, we evaluated the potentiation of PD-1 blockade by the combination of peritumoral FlaB-Vax delivery and PDT tumor ablation. A photosensitizing agent, pheophorbide A (PhA), was used for laser-triggered photodynamic destruction of the primary tumor. The effect of combination therapy in conjunction with PD-1 blockade was evaluated for tumor growth and survival. The effector cytokines that promote the activation of CD8+ T cells and antigen-presenting cells in tumor tissue and tumor-draining lymph nodes (TDLNs) were also assayed. PDT and FlaB-Vax combination therapy induced efficacious systemic antitumor immune responses for local and abscopal tumor control, with a significant increase in tumor-infiltrating effector memory CD8+ T cells and systemic IFNγ secretion. The combination of PDT and FlaB-Vax also enhanced the infiltration of tumor antigen-reactive CD8+ T cells and the accumulation of migratory CXCL10-secreting CD103+ dendritic cells (DCs) presumably contributing to tumor antigen cross-presentation in the tumor microenvironment (TME). The CD8+ T-cell-dependent therapeutic benefits of PDT combined with FlaB-Vax was significantly enhanced by a PD-1-targeting checkpoint inhibitor therapy. Conclusively, the combination of FlaB-Vax with PDT-mediated tumor ablation would serve a safe and feasible combinatorial therapy for enhancing PD-1 blockade treatment of malignant melanoma.

Analysis of Adult Patients with Tinea Capitis in Southeastern Korea.

BACKGROUND: Tinea capitis is a cutaneous infection of dermatophytes and predominant in children. Although tinea capitis in Korea is controlled by oral antifungal medications and concerted public health initiatives, it's still a health issue. OBJECTIVE: To investigate changes in the epidemiological and mycological characteristics of adult patients with tinea capitis in southeastern Korea. METHODS: Using medical records from Kyungpook National University Hospital and Catholic Skin Clinic from 1989 to 2018, we retrospectively investigated the epidemiological and mycological characteristics of 266 adult patients (aged over 20) with tinea capitis. RESULTS: Among total 266 patients, 239 were KOH-positive. The annual incidence of tinea capitis ranged from 3 to 18 between 1989 and 2018. Of the total, 54 (20.30%) were male and 212 (79.70%) were female. Eighty patients (30.08%) were in their seventies, the most commonly affected age group. Of the remaining, 58 (21.80%) were in their sixties, and 41 (15.41%) in eighties. Among all, 77 (28.95%) visited the hospital in summer, 72 (27.07%) in spring, 64 (24.06%) in winter, and 53 (19.92%) in fall. Dermatophytes were cultured from 171 patients. Microsporum canis was the most common dermatophyte (42.48%), while Trichophyton rubrum was the second (15.79%). Of the 266 patients, 186 (69.92%) lived in urban areas and 80 (30.08%) in rural areas. CONCLUSION: The epidemiological and mycological characteristics of adult patients with tinea capitis were different from those of children in terms of annual incidence, sex distribution, and isolated dermatophytes. These results provide useful information for the treatment and prevention of tinea capitis.

Retrospective two-centre study on prepubertal children with Tinea capitis in Korea.

Tinea capitis is an infectious dermatological disorder caused by dermatophytes that occur primarily in children. It has recently been brought under effective control in Korea since the introduction of oral antifungal medications and the implementation of concerted public health initiatives. Therefore, its incidence rate has decreased considerably. We investigated changes in the epidemiological and mycological characteristics of tinea capitis patients under the age of 10 in Korea. Using medical records from Kyungpook National University Hospital and the Catholic Skin Disease Clinic from 1989 to 2018, we retrospectively investigated the characteristics of 786 patients with tinea capitis. Of the 786 patients, 744 were KOH-positive. The annual incidence of tinea capitis was decreased from 120 to less than 10 between 1989 and 2018. Overall, 446 (56.74%) were male and 340 (43.26%) were female, representing a ratio of 1:0.8. In terms of the seasonality of it, 276 (35.11%) visited hospital in winter, 193 (24.55%) in spring, 177 (22.52%) in fall and 140 (17.81%) in summer. Dermatophytes were cultured from 628 patients. Microsporum canis was the most common dermatophyte (73.16%), followed by Trichophyton verrucosum and Trichophyton rubum. Of the 786 patients, 577 (73.41%) lived in urban areas and 209 (26.59%) in rural areas. Changes in the epidemiological and mycological characteristics of children with tinea capitis were shown in incidence, sex distribution, seasonality and causative dermatophytes. The incidence of tinea capitis has fallen significantly in prepubertal children. Nevertheless, continuous surveillance is needed to prevent tinea capitis in Korea.

Low But Continuous Occurrence of Microsporum gypseum Infection in the Study on 198 Cases in South Korea from 1979 to 2016.

BACKGROUND: Microsporum gypseum has been isolated from South Korea since 1966. However, the incidence of M. gypseum infection is very low. OBJECTIVE: The aim of this study is to add massive data on M. gypseum to the literature and to provide useful information on clinical and mycological characteristics of M. gypseum. METHODS: We retrospectively analyzed data of 198 cases infected with M. gypseum from 1979 to 2016. The identification of M. gypseum was done with mycological examination using 15% KOH preparation and potato corn meal tween 80 agar culture media. RESULTS: The incidence of M. gypseum infection was very low in South Korea, showing a tendency to decrease. Out of 198 cases, men were 94 cases (47.5%) and women were 104 cases (52.5%). Mean age of all patients was 29.83 years old: 24.97 years old in men and 34.22 years old in women. M. gypseum infection occurred most frequently in September (16.7%) and August (16.2%). The most common clinical type of M. gypseum infection was tinea corporis (38.4%). CONCLUSION: M. gypseum infection shows very low incidence but still remains around us until recent years. We should keep in mind the characteristics of M. gypseum.

Skin Infection due to Trichophyton tonsurans Still Occurs in People in Korea but not as Outbreaks.

Since 1995, Trichophyton tonsurans has been one of the causative agents of dermatophytosis in Korea. Herein we evaluate 77 patients infected with T. tonsurans who visited an outpatient clinic between 2004 and 2014. Infections due to T. tonsurans were diagnosed by mycological examination, which included direct microscopic examination using 15% KOH and culture in potato dextrose agar complemented with 0.5% chloramphenicol. The annual prevalence of infection due to T. tonsurans was the highest in 2014 (15 cases) but remained constant in non-gladiators between 2004 and 2014. The ratio of male to female patients was 1:0.3. The spring season presented the highest incidence compared with other seasons, with 27 cases. The incidence of infections due to T. tonsurans among gladiators was highest in spring compared with the other seasons whereas the incidence in non-gladiators was the highest in the winter. The body site most commonly affected was the face. Tinea corporis was the most common subtype of dermatophytosis caused by T. tonsurans. Herein, we demonstrate that the prevalence of infection with T. tonsurans remain constant throughout the study period in Korea.

Increasing Prevalence of Trichophyton rubrum Identified through an Analysis of 115,846 Cases over the Last 37 Years.

Trichophyton rubrum is the most common dermatophyte in the world with the highest prevalence in Korea. There are few reports about epidemiological and mycological characteristics of T. rubrum based on long-term, large-scale studies. The purpose of this study was to investigate the clinical and epidemiological characteristics of T. rubrum infections in Korea. We retrospectively investigated with patients' records about the epidemiological and mycological status of 115,846 cases with T. rubrum infection that was mycologically diagnosed at Catholic Skin Disease Clinic from 1979 to 2013. Direct microscopy in 15% KOH solution and culture was done in each case. The annual incidence of patients with T. rubrum infection had been increasing during the period; and of 131,122 patients with dermatophytosis, 115,846 patients (88.35%) had T. rubrum infection. Disease was most prevalent among patients in their twenties in the 1970s and 1980s; in their thirties in the 1990s; in their forties in the 2000s; and in their fifties in the 2010s. The sex ratio was 1.5:1. T. rubrum infection was most commonly seen in summer and was found predominantly in patients living in urban areas. Toe webs were most frequently involved, followed by toenails and groin. This epidemiologic findings provide useful information for prevention of T. rubrum infection and future dermatophytosis prospects.

Decreasing incidence of Trichophyton mentagrophytes in Korea: analysis of 6,250 cases during the last 21-year-period (1992-2012).

Trichophyton mentagrophytes is the second common dermatophyte in Korea. However, few reports have been issued on the epidemiological and mycological characteristics of T. mentagrophytes in Korea based on long-term, large-scale study. The purpose of this study was to elucidate the epidemiological and mycological characteristics of T. mentagrophytes in Korea. During the 21-yr-period from 1992 to 2012, 6,250 patients with T. mentagrophytes were surveyed to determine annual incidence and the distribution of subjects by age, sex, season, involved sites, and place of residence. T. mentagrophytes infections were confirmed by fungal culture. In addition, the colony appearance of T. mentagrophytes was classified as granular, persicolor, powdery, or downy. Epidemiological analysis showed that annual incidence reached a peak in 2005, and then gradually decreased. T. mentagrophytes infection was most common in July, and was found predominantly in middle-aged adults, especially in those in their forties. Mycological analysis showed a powdery colony appearance was the most common, followed by persicolor and granular colonies. Toewebs were most frequently involved. This investigation on T. mentagrophytes provides insights into its incidence and characteristics.

Decreasing prevalence of Microsporum canis infection in Korea: through analysis of 944 cases (1993-2009) and review of our previous data (1975-1992).

Since 1957, Microsporum (M.) canis has been one of the common causative agents of dermatophytosis in Korea. We analyzed 944 patients infected with M. canis who attended outpatient clinic over a 17-year period (1993-2009). M. canis infections were diagnosed by mycological examinations, including direct microscopic examinations with 15% KOH and cultures on potato dextrose agar complemented with 0.5% chloramphenicol. Mycological examinations confirmed 164,903 cases of dermatophytosis, 944 (0.6%) of which were M. canis infections. The annual prevalence of patients with M. canis infection was the highest in 2002 (91 cases). Then, the prevalence of patients with M. canis infection markedly decreased until 2008 (15 cases). The ratio of male to female patients was 0.65:1, but the ratio in children under the age of 15 was 1.14:1 and was 0.20:1 in adults. Seasonally, 274 cases occurred in winter, showing higher incidence than in other seasons. There was a difference in the clinical forms of M. canis infections between children and adults; tinea (T.) capitis was the most common form in children, but T. corporis was the most common in adults. We demonstrate that the decreasing prevalence of M. canis infections over the study period has been noted in Korea.