Immune response profiles from humans experimentally exposed to Phlebotomus duboscqi bites.

Introduction: Cutaneous leishmaniasis is a neglected vector-borne parasitic disease prevalent in 92 countries with approximately one million new infections annually. Interactions between vector saliva and the human host alter the response to infection and outcome of disease. Methods: To characterize the human immunological responses developed against saliva of Phlebotomus duboscqi, a Leishmania major (L. major) vector, we repeatedly exposed the arms of 14 healthy U.S volunteers to uninfected P. duboscqi bites. Blood was collected a week after each exposure and used to assess total IgG antibodies against the proteins of P. duboscqi salivary gland homogenate (SGH) and the levels of IFN-gamma and IL-10 from peripheral blood mononuclear cells (PBMCs) stimulated with SGH or recombinant sand fly proteins. We analyzed skin punch biopsies of the human volunteer arms from the insect bite site and control skin site after multiple P. duboscqi exposures (four volunteers) using immunohistochemical staining. Results: A variety of immediate insect bite skin reactions were observed. Late skin reactions to insect bites were characterized by macular hyperpigmentation and/or erythematous papules. Hematoxylin and eosin staining showed moderate mononuclear skin infiltrate with eosinophils in those challenged recently (within 2 months), eosinophils were not seen in biopsies with recall challenge (6 month post bites). An increase in plasma antigen-specific IgG responses to SGH was observed over time. Western Blot results showed strong plasma reactivity to five P. duboscqi salivary proteins. Importantly, volunteers developed a cellular immunity characterized by the secretion of IFN-gamma upon PBMC stimulation with P. duboscqi SGH and recombinant antigens. Discussion: Our results demonstrate that humans mounted a local and systemic immune response against P. duboscqi salivary proteins. Specifically, PduM02/SP15-like and PduM73/adenosine deaminase recombinant salivary proteins triggered a Th1 type immune response that might be considered in future development of a potential Leishmania vaccine.

A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic Escherichia coli CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G).

INTRODUCTION: Enterotoxigenic E. coli (ETEC) is a leading cause of diarrhea in travelers as well as for children living in low- to middle-income countries. ETEC adhere to intestinal epithelium via colonization factors (CFs). CFA/I, a common CF, is composed of a polymeric stalk and a tip-localized minor adhesive subunit, CfaE. Vaccine delivery by the transcutaneous immunization of dscCfaE was safe but was poorly immunogenic in a phase 1 trial when administered to volunteers with LTR(192G) and mLT. To potentially enhance the immunogenicity of CfaE while still delivering via a cutaneous route, we evaluated the safety and immunogenicity of two CfaE constructs administered intradermally (ID) with or without mLT. METHODS: CfaE was evaluated as a donor strand-complemented construct (dscCfaE) and as a chimeric construct (Chimera) in which dscCfaE replaces the A1 domain of the cholera toxin A subunit and assembles non-covalently with the pentamer of heat-labile toxin B (LTB). Subjects received three ID vaccinations three weeks apart with either dscCfaE (1, 5, and 25 µg) or Chimera (2.6 and 12.9 µg) with and without 0.1 µg of mLT. Subjects were monitored for local and systemic adverse events. Immunogenicity was evaluated by serum and antibody-secreting cell (ASC) responses. RESULTS: The vaccine was well-tolerated with predominantly mild and moderate local vaccine site reactions characterized by erythema, induration and post-inflammatory hyperpigmentation. High rates of serologic and ASC responses were seen across study groups with the most robust responses observed in subjects receiving 25 µg of dscCfaE with 0.1 mcg of LT(R192G). CONCLUSION: Both ETEC adhesin vaccine prototypes were safe and immunogenic when co-administered with mLT by the ID route. The observed immune responses induced with the high dose of dscCfaE and mLT warrant further assessment in a controlled human infection model.

A first in human clinical trial assessing the safety and immunogenicity of transcutaneously delivered enterotoxigenic Escherichia coli fimbrial tip adhesin with heat-labile enterotoxin with mutation R192G.

Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea among travelers and pediatric populations worldwide. The tip-localized adhesin of colonization factor antigen (CFA)/I fimbriae was engineered as a donor strand complemented variant (dscCfaE) and delivered via transcutaneous immunization. Preclinical vaccine testing demonstrated safety, immunogenicity and efficacy. A series of open-label dose-escalating phase 1 studies evaluated a 3-dose (days 0, 21, 42) regimen via a transcutaneous skin patch. A total of forty-six subjects were enrolled into one of four vaccine dose levels (10, 50, 250, or 1250 µg) co-administered with single-mutant heat-labile enterotoxin (LTR(192G)). At the 50 µg dose level, ten subjects received the dscCfaE vaccine without LT(R192G). The vaccine was well tolerated with mild local vaccine site reactions characterized by an erythematous papular rash and pruritus, which were less frequent and reactive in the group not receiving LT(R192G). The frequency of responses to dscCfaE were moderate, whereas anti-toxin responses (serum IgA/IgG) ranged from 75 to 100% across groups that received LT(R192G). Antigen-specific antibody-secreting cell responses were elicited at all dose levels, but were generally low. Follow-on studies will optimize construct and route of delivery and assess efficacy in an ETEC challenge study.

A grading system for local skin reactions developed for clinical trials of an intradermal and transcutaneous ETEC vaccine.

BACKGROUND: Trials assessing the safety of novel vaccine candidates are essential in the evaluation and development of candidate vaccines. Immunogenicity and dose-sparing features of vaccination approaches which target skin and associated tissues have garnered increased interest; for enteric vaccines, cutaneous vaccination has been of particular interest. Cutaneous vaccine site reactions are among the most common and visible vaccine related adverse events (AEs) when skin routes are used. Regulatory guidelines governing classification of severity focus on functional impact but are insufficient to characterize a spectrum of skin reaction and allow for comparisons of routes, doses and products with similar local cutaneous AEs. OBJECTIVES: Our group developed a grading scale to evaluate and compare cutaneous vaccine site reactions ahead of early-phase clinical trials of intradermal (ID) and transcutaneous immunization (TCI) with enterotoxigenic E.coli (ETEC) vaccine candidates (adhesin-based vaccine co-administered with LTR192G). We reviewed existing methods for characterizing the appearance and severity of local vaccine site reactions following TCI and ID vaccination and devised a standardized vaccine site appearance grading scale (VSAGS) for use in the clinical development of novel ETEC vaccine candidates which focused on pathophysiologic manifestation of skin findings. RESULTS: Available data from published reports revealed erythematous papules and pruritus were the most common local AEs associated with TCI. Frequency of reactions varied notably across studies as did TCI vaccination methodologies and products. ID vaccination commonly results in erythema and induration at the vaccine site as well as pigmentation changes. There was no published methodology to characterize the spectrum of dermatologic findings. CONCLUSION: ID and TCI vaccination are associated with a largely predictable range of cutaneous AEs. A grading scale focused on the appearance of cutaneous changes was useful in comparing cutaneous AEs. A standardized grading scale will facilitate documentation and comparison of cutaneous AEs.

Enfuvirtide and cutaneous injection-site reactions.

Enfuvirtide belongs to a newer class of antiretroviral (ARV) agents called fusion inhibitors for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Enfuvirtide blocks attachment, binding, and entry of the viral capsid into the host CD4+ cell. Administration is only available subcutaneously in a twice-daily regimen particularly for those patients who have previously failed more than one ARV regimen. Common side effects of enfuvirtide administration include fatigue, insomnia, nausea, and diarrhea; however, injection-site reactions are the most common side effect and present in nearly all individuals undergoing treatment. The spectrum of cutaneous manifestations ranges from little to no reaction to cysts, nodules, induration, or sclerodermalike lesions. These reactions are mostly variants of iatrogenically induced hypersensitivity and are self-limited.

Squamous cell carcinoma of the anal canal.

Squamous cell carcinoma of the anal canal (SCCAC) is an increasing concern in the human immunodeficiency virus (HIV)-positive population in the highly active antiretroviral therapy (HAART) era. A discussion of the epidemiology, risk factors, clinical presentation, diagnosis, and treatment of SCCAC is presented.

Anetoderma: a case report and review of the literature.

Anetoderma is a rare benign dermatosis caused by a loss of mid-dermal elastic tissue resulting in well-circumscribed areas of pouchlike herniations of flaccid skin. Anetoderma is classically categorized as either primary (idiopathic) or secondary (following an inflammatory dermatosis in the same location). We report a case of primary anetoderma (PA) occurring in a human immunodeficiency virus 1 (HIV-1)-infected man. We review the clinical presentation, possible etiologies, associated conditions, and limited treatment options of this disease.

Cutaneous myiasis.

UNLABELLED: Myiasis is the infestation of living tissue by the larvae of flies in the order Diptera. Cutaneous involvement is the most common type of myiasis. Cutaneous myiasis can be subdivided into furuncular, migratory, and wound myiasis. Each subtype is reviewed with discussion of the larvae involved, presenting signs and symptoms, clinical differential diagnoses, and treatment. Preventive measures are also described. LEARNING OBJECTIVES: At the conclusion of this learning activity, participants should be familiar with the causal agents, clinical manifestations, and treatment of human cutaneous myiasis.

Primary cutaneous endometriosis of the umbilicus: a case report.

Cutaneous endometriosis is a rare condition, especially in patients without a history of abdominal or pelvic surgery or known preexisting endometriosis. Most cases present with cyclic pain and bleeding at the site of an umbilical cutaneous nodule correlating with menses. We present an atypical case of primary cutaneous endometriosis of the umbilicus without a prior history of abdominal or pelvic surgery and without cyclic pain or bleeding.

Atypical cutaneous presentation of Waldenström macroglobulinemia: an extensive erythematous patch mimicking an angiosarcoma.

Waldenström macroglobulinemia (WM) is an immunoglobulin M-producing lymphoproliferative disorder in elderly individuals. Cutaneous manifestations of WM are rare and typically consist of plaques or nodules. We describe a case of a man with WM who presented with an extensive erythematous patch on the scalp that clinically mimicked an angiosarcoma.

Pyoderma gangrenosum occurring near an arteriovenous dialysis shunt.

Pyoderma gangrenosum (PG) is an uncommon cutaneous disease of unknown etiology. In 50 percent of affected patients, PG is associated with systemic disease including inflammatory bowel disease, arthritis, and hematologic malignancies.(1) Diagnosis of PG is based on clinical presentation, histopathology and on the exclusion of other diseases that can produce clinically similar lesions, e.g. infection, vasculitis, malignancy, collagen vascular diseases, diabetes, and trauma. Four variants of PG have been described: ulcerative, pustular, bullous, and vegetative.(2) We report a woman with renal failure who developed PG in the absence of any obvious triggering trauma in a distinctive unilateral crop just distal to an arteriovenous dialysis shunt.

Cutaneous onchocerciasis in an American traveler.

A case report of cutaneous onchocercias acquired during travels to Africa is presented. The salient epidemiologic, clinical, diagnostic, and therapeutic aspects are reviewed. Clinical and laboratory differences between onchocerciasis patients who are inhabitants of endemic areas and those who are occasional visitors to such areas are discussed. Parasitic infections, including onchocerciasis, should be considered in the differential diagnosis of pruritic eruptions in patients with a history of foreign travel to Africa, Central and South America.