The efficacy and safety of intralesional Candida vaccine versus topical diphencyproprobenone in immunotherapy of verruca vulgaris: A randomized comparative study.

Various therapeutic options are available for verruca. While physical destruction may be associated with scarring, immunotherapy may be effective in treating warts through stimulating body immune response. The objective of the study was to compare the efficacy, safety, and outcome of Candida antigen vs diphencyprone (DPCP) in the treatment of warts. Fifty patients were randomly assigned to receive either intralesional Candida antigen every 3 weeks or weekly DPCP application. Both treatments were applied only to the mother wart. Lesions' clearance and associated side effects were observed up to 4 weeks after treatment. Two blinded physicians evaluated photos of warts before and 4 weeks after the end of treatment. Both modalities granted wart clearance and/or improvement with no statistically significant difference; however, Candida antigen was significantly better in clearing adjacent untreated warts (p = 0.046). Fewer side effects were observed among the Candida antigen group. The response was duration associated in the Candida groups only. Intralesional Candida antigen injection and DPCP treatments for warts yielded improvement with superiority of Candida injection in eradicating distant lesions and fewer side effects. A shorter wart duration may be associated with a better therapeutic response with Candida antigen.

Comparative Study of Intralesional Vitamin D3 Injection and Candida Albicans Antigen in Treating Plantar Warts.

BACKGROUND: Warts, or verrucae, are mucosal human papilloma virus (HPV) infections that are very challenging to treat. OBJECTIVE: To compare the safety and efficacy of intralesional injection of vitamin D3 versus intralesional injection of candida albicans antigen for plantar warts. METHODS: Forty patients were included in the study and were divided into two groups (A&B) with 20 patients each. Group A received intralesional vitamin D3 while Group B received intralesional Candida antigen. Injection was done every 3 weeks until clearance of warts or a maximum of three treatments. RESULTS: Nine patients showed complete clearance in group A (45%), while 6 patients (30%) showed partial response and no response in 5 patients (25%) of group (A). As for group (B), complete clearance of the treated warts was observed in 8 patients (40%), partial response in 6 patients (30%) while no response was observed in 6 patients (30%). No superiority of one treatment to the other was observed nor was any statistical significance in both groups’ responses noted. CONCLUSION: Treatment of multiple warts by intralesional injection of candida antigen or vitamin D3 is safe and effective, with good cure rates, has an excellent safety profile, with minimal recurrences and statistically equivalent. J Drugs Dermatol. 2021;20(5):546-549. doi:10.36849/JDD.5264.

The Pathogenesis of Aspergillus fumigatus, Host Defense Mechanisms, and the Development of AFMP4 Antigen as a Vaccine.

Aspergillus fumigatus is one of the ubiquitous fungi with airborne conidia, which accounts for most aspergillosis cases. In immunocompetent hosts, the inhaled conidia are rapidly eliminated. However, immunocompromised or immunodeficient hosts are particularly vulnerable to most Aspergillus infections and invasive aspergillosis (IA), with mortality from 50% to 95%. Despite the improvement of antifungal drugs over the last few decades, the therapeutic effect for IA patients is still limited and does not provide significant survival benefits. The drawbacks of antifungal drugs such as side effects, antifungal drug resistance, and the high cost of antifungal drugs highlight the importance of finding novel therapeutic and preventive approaches to fight against IA. In this article, we systemically addressed the pathogenic mechanisms, defense mechanisms against A. fumigatus, the immune response, molecular aspects of host evasion, and vaccines' current development against aspergillosis, particularly those based on AFMP4 protein, which might be a promising antigen for the development of anti-A. fumigatus vaccines.

Intralesional Measles, Mumps, and Rubella Vaccine Versus Intralesional Candida Antigen in the Treatment of Common and Plantar Warts.

BACKGROUND: Intralesional immunotherapy has been effectively used in the treatment of warts; however, comparative studies between different antigens are limited. OBJECTIVE: To evaluate the efficacy and safety of intralesional measles, mumps, and rubella (MMR) vaccine compared with intralesional Candida antigen for the treatment of multiple common and plantar warts. METHODS: Sixty-eight adult patients with multiple common and plantar warts were randomly assigned into two groups, each containing 34 patients. The first group received intralesional MMR vaccine, while the second group received intralesional Candida antigen. Each treatment was injected into the largest wart at 2-week intervals until complete clearance or for a maximum of 5 sessions. RESULTS: The overall therapeutic response was higher in the Candida antigen group (73.5%) compared with the MMR group (67.7%); however, the difference was not statistically significant. Complete clearance of common warts was higher in the Candida antigen group, while that of plantar warts was higher in the MMR group. Adverse effects were transient and well tolerated in both groups. No recurrence was detected during the 6-month follow-up period. CONCLUSION: Intralesional MMR and intralesional Candida antigen showed comparable efficacy and safety in the treatment of common and plantar warts.

Intralesional Antigen Immunotherapy in the Treatment of Periungual Warts.

BACKGROUND: Intralesional immunotherapy using different types of antigens is considered an effective and safe treatment option for different types of warts. However, there are few studies that illustrate the use of these antigens in the treatment of periungual warts as a distinct type of warts. OBJECTIVE: To evaluate the efficacy and safety of three antigens: measles, mumps, rubella (MMR) vaccine, Candida antigen, and purified protein derivative (PPD) in the treatment of periungual warts. METHODS: The study included 150 patients who were randomly assigned to 3 groups with 50 patients in each. Each agent was injected intralesionally at a dose of 0.1 mL into the largest wart at 2-week intervals until complete clearance or for a maximum of 5 sessions. RESULTS: Complete clearance of warts was observed in 70%, 80%, and 74% in PPD, Candida antigen, and MMR vaccine groups, respectively. There was no statistically significant difference regarding the therapeutic response between the 3 studied groups. Adverse effects were transient and insignificant in the 3 groups. No recurrence of the lesions was reported in any of the studied groups. CONCLUSIONS: Intralesional antigen immunotherapy seems to be an effective therapeutic option for the treatment of periungual warts.

Role of mannose binding lectin in response to candida antigen immunotherapy of warts.

BACKGROUND: Warts is the commonest cutaneous manifestation of human papillomavirus (HPV) infection. Intralesional Candida antigen immunotherapy is used for wart treatment. AIM: To identify the role of mannose binding lectin (MBL) in susceptibility to HPV infection and to explore the relationship between MBL and response to intralesional Candida antigen immunotherapy of wart. PATIENTS AND METHODS: A case-control study was enrolled with 96 participants; 48 wart cases and 48 healthy controls. MBL serum level assay baseline and after six settings of intralesional candida antigen injection was done by ELISA technique. MBL2 gene exon 1 codon 54 polymorphism was detected by using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). RESULTS: A statistically significant difference in MBL serum level between wart cases and controls was found. An association between MBL2 exon1 codon 54 polymorphism and susceptibility to HPV infection and development of warts was proved. Carriage of genotype AB was more frequent wart cases (95.8%) than in controls (20.8%). No statistical significance association could be found between the therapeutic response to Candida antigen immunotherapy in wart cases and MBL as regards its serum level and genotypes. CONCLUSIONS: MBL play an important role in host defense against HPV infection.

Complement component 3c and tumor necrosis factor-α systemic assessment after Candida antigen immunotherapy in cutaneous warts.

BACKGROUND: Cutaneous warts are the commonest benign lesion produced by human papillomavirus. Lesions often regress spontaneously yet have a high rate of recurrence. They impair patients' quality of life and carry the potential risk of cancer. Nowadays, Candida antigen immunotherapy has become an encouraging therapeutic modality for warts. We tried to assess the role of the complement pathway and T helper 1 immune response in clinical response to Candida antigen immunotherapy via complement component 3c (C3c) and tumor necrosis factor (TNF)-α, respectively. METHODS: A total of 44 patients with cutaneous warts were enrolled in the study. Patients were injected with Candida antigen at 2-week interval until complete clearance of the lesion or for a maximum of 5 sessions. Blood samples were collected before initiation and after completion of immunotherapy. C3 and C4 were measured using an automated turbidimetric method. Mannose-binding lectin (MBL), C3c, and TNF-α were measured using enzyme-linked immune sorbent assay. RESULTS: A total of 56.4%, 17.9%, and 25.7% of the patients showed complete, partial, and no response to immunotherapy, respectively. Lesions on the dorsum of the foot and sole showed significant clearance (p value = 0.037). All patients had no deficient C3, C4, and MBL serum levels. C3c and TNF-α serum levels were significantly higher in non-responder group (p value < 0.001 and < 0.001, respectively). C3c and TNF-α serum levels were strongly correlated in all the studied patients (r = 0.8, p value < 0.001). CONCLUSIONS: Candida antigen immunotherapy is an effective therapeutic modality for cutaneous warts. C3c and TNF-α serum levels were higher in patients who failed to respond to immunotherapy. CLINICAL TRIAL REGISTRY NUMBER: NCT04399577 , May 2020 "retrospectively registered".

A Combination of Polybacterial MV140 and Candida albicans V132 as a Potential Novel Trained Immunity-Based Vaccine for Genitourinary Tract Infections.

Recurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs) represent major healthcare problems with high socio-economic impact worldwide. Antibiotic and antifungal prophylaxis remain the gold standard treatments for RUTIs and RVVCs, contributing to the massive rise of antimicrobial resistance, microbiota alterations and co-infections. Therefore, the development of novel vaccine strategies for these infections are sorely needed. The sublingual heat-inactivated polyvalent bacterial vaccine MV140 shows clinical efficacy for the prevention of RUTIs and promotes Th1/Th17 and IL-10 immune responses. V132 is a sublingual preparation of heat-inactivated Candida albicans developed against RVVCs. A vaccine formulation combining both MV140 and V132 might well represent a suitable approach for concomitant genitourinary tract infections (GUTIs), but detailed mechanistic preclinical studies are still needed. Herein, we showed that the combination of MV140 and V132 imprints human dendritic cells (DCs) with the capacity to polarize potent IFN-γ- and IL-17A-producing T cells and FOXP3+ regulatory T (Treg) cells. MV140/V132 activates mitogen-activated protein kinases (MAPK)-, nuclear factor-κB (NF-κB)- and mammalian target of rapamycin (mTOR)-mediated signaling pathways in human DCs. MV140/V132 also promotes metabolic and epigenetic reprogramming in human DCs, which are key molecular mechanisms involved in the induction of innate trained immunity. Splenocytes from mice sublingually immunized with MV140/V132 display enhanced proliferative responses of CD4+ T cells not only upon in vitro stimulation with the related antigens contained in the vaccine formulation but also upon stimulation with phytohaemagglutinin. Additionally, in vivo sublingual immunization with MV140/V132 induces the generation of IgG and IgA antibodies against all the components contained in the vaccine formulation. We uncover immunological mechanisms underlying the potential mode of action of a combination of MV140 and V132 as a novel promising trained immunity-based vaccine (TIbV) for GUTIs.

Combined bivalent human papillomavirus vaccine and Candida antigen versus Candida antigen alone in the treatment of recalcitrant warts.

BACKGROUND: The burden of human papillomavirus (HPV) infection and HPV-associated diseases is consistently growing worldwide. Several combination therapies are being tested nowadays for the treatment of recalcitrant warts, with promising results. AIMS: To evaluate the potential therapeutic role of combined bivalent HPV vaccine (Cervarix) and Candida antigen versus candida antigen alone in the treatment of multiple recalcitrant warts. PATIENTS/METHODS: Forty patients with recalcitrant warts were enrolled into this study. They were divided into two groups (A and B), each including 20 patients. Patients in the group (A) received intralesional Candida antigen injection alone for five sessions at 2-week intervals. Patients in the group B received combined treatment of bivalent recombinant HPV vaccine and intralesional Candida antigen. Candida antigen was administered as in the group A, while Cervarix vaccine was given intramuscularly at 0, 1, and 6 months as scheduled. Follow-up was made monthly for 6 months to detect any possible recurrence. RESULTS: Eight patients (40%) in the group (A) showed complete clearance of warts after intralesional Candida antigen injection alone, while 14 patients (70%) in the group (B) showed complete regression of warts after the combined therapy. No significant side effects were reported in both groups, and no recurrence was detected. CONCLUSION: Bivalent human papillomavirus vaccine combined with Candida antigen is a promising, effective, and safe modality for the treatment of multiple recalcitrant warts.

Protection of mice against experimental cryptococcosis using glucan particle-based vaccines containing novel recombinant antigens.

Meningitis due to Cryptococcus neoformans is responsible for upwards of 180,000 deaths worldwide annually, mostly in immunocompromised individuals. Currently there are no licensed fungal vaccines, and even with anti-fungal drug treatment, cryptococcal meningitis is often fatal. Our lab previously demonstrated vaccination with recombinant cryptococcal proteins delivered in glucan particles (GPs) protects mice against an otherwise lethal infection. The aim of the present study was to discover additional cryptococcal antigens affording vaccine-mediated protection. Sixteen proteins, each with evidence of extracellularity, were selected for in vivo testing based on their abundance in protective alkaline extracts of an acapsular C. neoformans strain, their known immunogenicity, and/or their high transcript level during human infection. Candidate antigens were recombinantly expressed in E. coli, purified and loaded into GPs. BALB/c and C57BL/6 mice received three subcutaneous injections of GP-based vaccine, and survival was assessed for 84 days following a lethal orotracheal challenge with strain KN99. As with our six published GP-vaccines, we saw differences in overall protection between mouse strains such that BALB/c mice typically demonstrated better survival than C57BL/6 mice. From these studies, we identified seven new proteins which, when administered as GP-vaccines, protect BALB/c and/or C57BL/6 mice against cryptococcal infection. With these results, we expand the pool of novel protective antigens to eleven proteins and demonstrate the potential for selection of highly transcribed extracellular proteins as vaccine targets. These screens highlight the efficacy of GP-subunit vaccines and identify promising antigens for further testing in anti-cryptococcal, multi-epitope vaccine formulations.

Intralesional vitamin D3 versus Candida antigen immunotherapy in the treatment of multiple recalcitrant plantar warts: A comparative case-control study.

Intralesional immunotherapy is one of the therapeutic tools of warts. Intralesional Candida antigen was reported as successful treatment of warts. Topical and intralesional vitamin D have been used recently for wart treatment. We aim to evaluate the efficacy and safety of intralesional injection of vitamin D3 in treatment of multiple recalcitrant plantar warts in comparison with intralesional Candida antigen. Sixty patients were divided into three groups: Group I received intralesional vitamin D3, Group II intralesional Candida antigen, and Group III intralesional saline (control group). Injection was done every 3 weeks until clearance of warts or a maximum of three treatments. There was a statistically significant more reduction of warts numbers after treatment in Group I than in the other groups (p < .05). Group I showed better clinical response than Group II (p = .021). In both Groups I and II, clinical response was less favorable in patients with longer disease duration (p = .026). There was also limitation as it is a small study population. Intralesional vitamin D3 injection in multiple recalcitrant plantar warts is a simple, safe, cost effective treatment modality with minimal side effects, and superior results compared with intralesional injection of Candida antigen.

Clinical outcomes in ocular pythiosis patients treated with a combination therapy protocol in Thailand: A prospective study.

Ocular pythiosis is the second most common form of human pythiosis, and the rates of evisceration/enucleation in Thailand are 55-79%. This prospective study was conducted to evaluate treatment outcomes of the combination therapy protocol and the potential use of serum (1→3)-ß-glucan (BG) and Pythium insidiosum-specific antibody (Pi-Ab) as an aid to diagnosis and monitoring of ocular pythiosis. Thirty patients were enrolled in the study and 14 (non-globe salvage) required evisceration/enucleation. The globe salvage group was significantly younger, and first ocular surgeries were performed significantly sooner than in the non-globe salvage group. Serum BG and Pi-Ab levels were similar among the 2 groups over time. In vitro susceptibility testing of antifungal agents revealed relatively high minimum inhibitory concentrations and lack of synergistic effect. Serum BG and Pi-Ab would not be useful in diagnosis and monitoring of ocular pythiosis. Until effective antimicrobial agents are discovered, ocular surgeries are still the mainstay therapy in Thailand.

Peripheral blood toll-like receptor 4 correlates response to candida immunotherapy of warts.

Human papilloma virus infection may be self-limiting; however, some cases may spread. There are no factors predicting the prognosis of such infections. The present study aimed to evaluate the significance of TLR4 expression in predicting the response of warts to candida immunotherapy. A total of 60 patients with different types of warts were included in the present study. A total volume of 2 ml venous blood was collected and real-time polymerase chain reaction was used to determine expression of TLR4. Patients were subjected to intralesional injection of Candida antigen into the largest wart at 2-week intervals until complete clearance or for a maximum of six sessions. Of the total 58 patients available for analysis of study results, 44 patients (75.9%) showed complete resolution with better response in younger ages. The TLR4 expression in patients with complete and partial response was significantly higher than that in patients who had no response (p = .006). Among our patients, 48.3% showed no side effects, 44.8% showed local reactions, and 6.9% showed systemic side effects. Only four patients showed recurrence after 6 months. Using receiver operating characteristic curve analysis, at cutoff of expression level >12 is accompanied by 100% specificity of TLR4 in predicting treatment response to candida immunotherapy. Candida immunotherapy is an effective warts treatment, especially in young patients. Higher PMBC TLR4 levels can predict response to candida immunotherapy.

A Large Case-series of Successful Treatment of Patients Exposed to Mold and Mycotoxin.

PURPOSE: The goal of this study was to present the results of treatment of 100 chemically sensitive and chronically mold-exposed patients, who continued to be disabled even after decontamination of their houses or work places or they were physically removed from their sources of mold. METHODS: Molds were identified, serum anti-mold immunoglobulin G antibodies were measured, patients were skin-tested, immunologic abnormalities were recorded, and objective neurologic tests were performed in a subset of patients. FINDINGS: Patient sensitivities and exposures were confirmed by measuring serum immunoglobulin G anti-mold antibodies, intradermal skin testing, and trichothecene toxin breakdown products in the urine. Patients were positive (44%-98%) for individual molds. Abnormalities in T and B cells were found in >80% of patients. Respiratory signs were present in 64% of all patients, and physical signs and symptoms of neurologic dysfunction were present in 70%. Objective autonomic nervous system test results were abnormal in almost 100% of patients tested. Objective neuropsychological evaluations were conducted in 46 of the patients who exhibited symptoms of neurologic impairment and showed typical abnormalities in short-term memory, executive function/judgment, concentration, and hand/eye coordination. Patients (N = 100) with documented mold exposure were divided into 3 groups: (1) those who improved easily, with mold avoidance and antigen injections; (2) those who improved after desensitization to their mold antigens plus additional mycotoxin antigens; and (3) those who had their regular mold antigens, additional mycotoxin antigens, along with regimens that included sauna, oxygen therapy, and nutrients. Approximately 85% of all patients cleared completely; 14% had partial improvement, and 1% remained unchanged. IMPLICATIONS: Exposure to molds has been increasingly recognized as a major reason for patients presenting with multiple organ symptoms that could not otherwise be explained. Early diagnosis and appropriate treatment could be very successful.

Preclinical safety and immunological efficacy of Alternaria alternata polymerized extracts.

INTRODUCTION: Alternaria alternata is a widespread fungi whose allergy is a risk factor for asthma development. The use of a polymerized allergen extract (allergoid) may be safer than native extract based treatments while maintaining efficacy. The objective of this study was to characterize biochemically and immunochemically a new Alternaria alternata allergoid. METHODS: Characterization of native and allergoid extracts was performed by determination of protein content, protein and allergenic profile, biological potency, identification of Alternaria allergens, and Alt a 1 quantification. Safety was evaluated in toxicological assays (Ames test, limit test, and fish embryo acute toxicity test in zebrafish, and maximum tolerated dose and Dose-range finding study in rats). Efficacy was evaluated as the capacity to induce IgG antibodies that block IgE-binding to the allergen and cytokine induction (IFN-γ, IL-4, IL-6, IL-10, and TNF-α) in PBMC from atopic donors. RESULTS: Protein and antigenic profiles showed significant modification of the depigmented allergoid with respect to the native extract, inducing a lower IgE binding capacity. Alt a 1, Alt a 3, Alt a 6, and Alt a 8 allergen sequences were identified in the polymer. No toxicological nor genotoxicity effects were observed. The polymer induced IgG antibodies that blocked human IgE binding epitopes, and it induced higher IL-10 levels and similar levels of the other cytokines than native extract in PBMC. CONCLUSIONS: This new A. alternata allergoid could be an effective immunotherapy treatment leading to cytokine stimulation and inducing synthesis of IgG antibodies able to block IgE binding to the allergen. In addition, no toxicological effect was observed, and it may be safer than native extract due to its lower IgE binding capacity and cytokine induction that suggest tolerance induction via T cell shift to Treg (IL-10).

Vaccination with Recombinant Cryptococcus Proteins in Glucan Particles Protects Mice against Cryptococcosis in a Manner Dependent upon Mouse Strain and Cryptococcal Species.

Development of a vaccine to protect against cryptococcosis is a priority given the enormous global burden of disease in at-risk individuals. Using glucan particles (GPs) as a delivery system, we previously demonstrated that mice vaccinated with crude Cryptococcus-derived alkaline extracts were protected against lethal challenge with Cryptococcus neoformans and Cryptococcus gattii The goal of the present study was to identify protective protein antigens that could be used in a subunit vaccine. Using biased and unbiased approaches, six candidate antigens (Cda1, Cda2, Cda3, Fpd1, MP88, and Sod1) were selected, recombinantly expressed in Escherichia coli, purified, and loaded into GPs. Three mouse strains (C57BL/6, BALB/c, and DR4) were then vaccinated with the antigen-laden GPs, following which they received a pulmonary challenge with virulent C. neoformans and C. gattii strains. Four candidate vaccines (GP-Cda1, GP-Cda2, GP-Cda3, and GP-Sod1) afforded a significant survival advantage in at least one mouse model; some vaccine combinations provided added protection over that seen with either antigen alone. Vaccine-mediated protection against C. neoformans did not necessarily predict protection against C. gattii Vaccinated mice developed pulmonary inflammatory responses that effectively contained the infection; many surviving mice developed sterilizing immunity. Predicted T helper cell epitopes differed between mouse strains and in the degree to which they matched epitopes predicted in humans. Thus, we have discovered cryptococcal proteins that make promising candidate vaccine antigens. Protection varied depending on the mouse strain and cryptococcal species, suggesting that a successful human subunit vaccine will need to contain multiple antigens, including ones that are species specific.IMPORTANCE The encapsulated fungi Cryptococcus neoformans and Cryptococcus gattii are responsible for nearly 200,000 deaths annually, mostly in immunocompromised individuals. An effective vaccine could substantially reduce the burden of cryptococcosis. However, a major gap in cryptococcal vaccine development has been the discovery of protective antigens to use in vaccines. Here, six cryptococcal proteins with potential as vaccine antigens were expressed recombinantly and purified. Mice were then vaccinated with glucan particle preparations containing each antigen. Of the six candidate vaccines, four protected mice from a lethal cryptococcal challenge. However, the degree of protection varied as a function of mouse strain and cryptococcal species. These preclinical studies identify cryptococcal proteins that could serve as candidate vaccine antigens and provide a proof of principle regarding the feasibility of protein antigen-based vaccines to protect against cryptococcosis.

Yeast Expressing Gp43 Protein as a Vaccine Against Paracoccidioides brasiliensis Infection.

Paracoccidioidomycosis (PCM) represents the most frequent systemic mycosis in Latin American. The disease is caused by the pathogenic thermally dimorphic fungus Paracoccidioides brasiliensis, and is initially characterized by pulmonary lesions, which can subsequently disseminate to other organs, resulting in secondary injuries. Although its high incidence, there is no commercially available vaccine against fungal diseases. A novel strategy, using Saccharomyces cerevisiae yeast as a vehicle for immunization against PCM, was recently successfully described. Herein, we describe strategies for the construction of the suitable S. cerevisiae vaccine, and protocols of administration and evaluation of the efficacy of the vaccine against experimental PCM.

Uveitis Following Treatment of Verruca Vulgaris with Intralesional Candida Antigen.

This is a first literature report of a case of uveitis along with severe systemic symptoms following verruca vulgaris treatment with intralesional Candida antigen. We believe the Candida injection was causative.