Role of T-regulatory cells in the response to hepatitis B vaccine in hemodialysis patients.

Human disease elicits a complex array of biological processes that results in long-term protective immunological memory to infectious agents. Chronic kidney disease is known to impair induction of sustained immunological memory to hepatitis B vaccine (HBVax) antigens. We asked the question: Does end-stage renal disease promote changes in subtypes of regulatory T (Treg) cells that correlate with diminished amnestic response to HBVax antigen compared to healthy controls? The study design and setting was a prospective observational cohort at a veterans affairs medical center.

Evaluation of potential genotoxicity of HIV entry inhibitors derived from natural sources.

AIDS is a global pandemic that has seen the development of novel and effective treatments to improve the quality of life of those infected and reduction of spread of the disease. Palmitic Acid (PA), which we identified and isolated from Sargassum fusiforme, is a naturally occurring fatty acid that specifically inhibits HIV entry by binding to a novel pocket on the CD4 receptor. We also identified a structural analogue, 2-bromopalmitate (2-BP), as a more effective HIV entry inhibitor with a 20-fold increase in efficacy.

Vaccination issues in patients with chronic kidney disease.

Infections are an important cause of morbidity and mortality among patients at all stages of chronic kidney disease. Prevention through vaccination remains the best strategy to minimize the adverse consequences associated with these infectious diseases in this, and all, populations. Unfortunately, patients with chronic kidney disease demonstrate inadequacies of specific immune-cell function that are required for generating a protective vaccine response.

Diverting T helper cell trafficking through increased plasticity attenuates autoimmune encephalomyelitis.

Naive T helper cells differentiate into functionally distinct effector subsets that drive specialized immune responses. Recent studies indicate that some of the effector subsets have plasticity. Here, we used an EAE model and found that Th17 cells deficient in the transcription factor BCL11B upregulated the Th2-associated proteins GATA3 and IL-4 without decreasing RAR-related orphan receptor γ (RORγt), IL-17, and GM-CSF levels.

Safety and immunogenicity of LC16m8, an attenuated smallpox vaccine in vaccinia-naive adults.

Introduction: LC16m8 is an attenuated cell culture-adapted Lister vaccinia smallpox vaccine missing the B5R protein and licensed for use in Japan.

Methods: We conducted a phase I/II clinical trial that compared the safety and immunogenicity of LC16m8 with Dryvax in vaccinia-naive participants. Adverse events were assessed, as were electrocardiography and laboratory testing for cardiotoxicity and viral culturing of the vaccination sites.

Ex vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency and the development of a thymic T cell lymphoma.

We have previously shown that in vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency (XSCID) results in sustained T cell reconstitution and sustained marking in myeloid and B cells for up to 4 years with no evidence of any serious adverse effects. The purpose of this study was to determine whether ex vivo γ-retroviral gene therapy of XSCID dogs results in a similar outcome. Eight of 12 XSCID dogs treated with an average of dose of 5.

IMVAMUNE: modified vaccinia Ankara strain as an attenuated smallpox vaccine.

Smallpox vaccines based on replicating vaccinia virus are known to elicit rare yet serious adverse events, particularly in human populations with immune deficiency, atopic dermatitis and at the extremes of age. A vaccine that induces protective immune responses equivalent to first-generation smallpox vaccines while reducing the risk for severe adverse events is critical for a national stockpile of smallpox vaccines. Modified vaccinia Ankara (MVA) has been proposed as an immediate solution for vaccination of high-risk individuals.

Comparison of the safety and immunogenicity of ACAM1000, ACAM2000 and Dryvax in healthy vaccinia-naive adults.

Currently, more than half of the world's population has no immunity against smallpox variola major virus. This phase I double-blind, randomized trial was conducted to compare the safety and immunogenicity of two clonally derived, cell-culture manufactured vaccinia strains, ACAM1000 and ACAM2000, to the parent vaccine, Dryvax. Thirty vaccinia-naïve subjects were enrolled into each of three groups and vaccines were administered percutaneously using a bifurcated needle at a dose of 1.

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime-protein boost HIV-1 vaccine in healthy human volunteers.

An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report on the induction of human immunodeficiency virus type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime-protein boost HIV-1 vaccine formulation, DP6-001, in a Phase I clinical trial. Robust cross-subtype HIV-1 specific T cell responses were detected in IFN-gamma ELISPOT assays.

The safety and tolerability of an HIV-1 DNA prime-protein boost vaccine (DP6-001) in healthy adult volunteers.

This report describes the safety observations following administration of a polyvalent DNA prime-protein boost HIV-1 vaccine formulated with adjuvant QS21. Local injection site reactions were the most common (65% of subjects), and included type IV delayed-type hypersensitivity (DTH) reactions at prior DNA inoculation sites in 12 of 28 (43%) subjects following protein vaccination. Systemic reactions revealed two cases of vasculitis temporally related to inoculation with recombinant Env protein+QS21 adjuvant.

Multifunctional T-cell characteristics induced by a polyvalent DNA prime/protein boost human immunodeficiency virus type 1 vaccine regimen given to healthy adults are dependent on the route and dose of administration.

A phase I clinical vaccine study of a human immunodeficiency virus type 1 (HIV-1) vaccine regimen comprising a DNA prime formulation (5-valent env and monovalent gag) followed by a 5-valent Env protein boost for seronegative adults was previously shown to induce HIV-1-specific T cells and anti-Env antibodies capable of neutralizing cross-clade viral isolates. In light of these initial findings, we sought to more fully characterize the HIV-1-specific T cells by using polychromatic flow cytometry. Three groups of participants were vaccinated three times with 1.

ACAM2000: a newly licensed cell culture-based live vaccinia smallpox vaccine.

Background: Due to concern over i) expiration of currently available calf-lymph vaccine (Dryvax); ii) calf lymph as a vaccine (bovine spongiform encephalopathy [BSE], other possible contaminations and animal welfare); and iii) use of variola as a weapon for bioterrorism, a new and safer vaccinia-based smallpox vaccine derived from new cell culture-based technology was proposed. Federally funded work by Acambis, Inc. resulted in FDA approval for ACAM2000 in August 2007.

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime-protein boost HIV-1 vaccine in healthy human volunteers.

An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report on the induction of Human Immunodeficiency Virus Type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime-protein boost HIV-1 vaccine formulation, DP6-001, in a Phase I clinical trial conducted in healthy adult volunteers of both genders. Robust cross-subtype HIV-1-specific T cell responses were detected in IFNgamma ELISPOT assays.

Clinical and immunologic responses to multiple doses of IMVAMUNE (Modified Vaccinia Ankara) followed by Dryvax challenge.

Smallpox vaccination with replication deficient vaccinia strains such as Modified Vaccinia Ankara (MVA) may induce protective immunity with improved safety and tolerability profiles compared with currently available smallpox vaccines. Ninety subjects were randomized equally to six groups in a partially blinded, randomized, controlled clinical trial. IMVAMUNE (MVA-BN, Bavarian Nordic A/S, Kvistgård, Denmark) vaccine or placebo was administered at Study Days 0 and 28 by subcutaneous or intramuscular injection and five groups were challenged with Dryvax at study Day 112.

Immunological memory after exposure to variola virus, monkeypox virus, and vaccinia virus.

We compared cellular and humoral immunity to vaccinia virus (VV) in individuals exposed to 3 different orthopoxviruses: 154 individuals previously vaccinated with VV, 7 individuals with a history of monkeypox virus infection, and 8 individuals with a history of variola virus infection. Among individuals vaccinated >20 years prior, 9 (14%) of 66 individuals demonstrated VV-specific interferon (IFN)- gamma enzyme-linked immunospot (ELISPOT) assay responses; 21 (50%) of 42 had lymphoproliferative (LP) responses, and 29 (97%) of 30 had VV-specific neutralizing antibodies. One year after monkeypox virus infection, 6 of 7 individuals had IFN- gamma ELISPOT responses, all had VV-specific LP responses, and 3 of 7 had VV-specific neutralizing antibodies.

Expression and function of TLR2, TLR4, and Nod2 in primary canine colonic epithelial cells.

The gut maintains a delicate balance between the downregulation of inflammatory reactions to commensal bacteria and the capacity to respond to pathogens with vigorous cellular and humoral immune responses. Intestinal epithelial cells, including colonic epithelial cells (CECs) possess many properties of cells of the innate immune system, in particular the ability to recognize and respond to microbial antigens. Recognition of microorganisms by CECs is based upon their recognition of signature molecules, called microbe-associated molecular patterns (MAMP), by pattern recognition receptors (PRR) including membrane toll-like receptors (TLR) and cytosolic Nod2, an intracellular counterpart of TLRs.

Identification of vaccinia CD8+ T-cell epitopes conserved among vaccinia and variola viruses restricted by common MHC class I molecules, HLA-A2 or HLA-B7.

Immunization with vaccinia virus results in long-lasting protection against smallpox and is an approach that has been successfully used to eliminate natural smallpox infections worldwide. Today, vaccinia virus is very important not only as a vaccine virus to protect human against smallpox, but also as an expression vector for immunization against other infectious diseases, such as HIV and cancer. In this article, we identify three new vaccinia human CD8+ T-cell epitopes conserved among vaccinia and variola viruses restricted by HLA-A2, HLA-B7, or HLA-B*3502, which belongs to the HLA-B7 supertype.

Severe papillomavirus infection progressing to metastatic squamous cell carcinoma in bone marrow-transplanted X-linked SCID dogs.

Canine X-linked severe combined immunodeficiency (XSCID) is due to mutations in the common gamma chain (gammac) gene and is identical clinically and immunologically to human XSCID, making it a true homologue of the human disease. Bone marrow-transplanted (BMT) XSCID dogs not only engraft donor T cells and reconstitute normal T-cell function but, in contrast to the majority of transplanted human XSCID patients, also engraft donor B cells and reconstitute normal humoral immune function. Shortly after our initial report of successful BMT of XSCID dogs, it soon became evident that transplanted XSCID dogs developed late-onset severe chronic cutaneous infections containing a newly described canine papillomavirus.

A live, attenuated recombinant West Nile virus vaccine.

West Nile (WN) virus is an important cause of febrile exanthem and encephalitis. Since it invaded the U.S.

Novel nutritional immune formula maintains host defense mechanisms.

Military combat and training stress induce immune changes that increase the risk of infection and ultimately influence soldiers' performance and readiness. Strenuous military training/assessment provides a uniform stress and the opportunity to evaluate nutritional strategies to minimize stress-induced immune changes that predispose soldiers to infection. Immunological changes and effects of a novel nutritional immune formula (NNIF) were examined prospectively in a double-blind, controlled study of 200 soldiers attending Special Forces Assessment and Selection School.

Correction of canine X-linked severe combined immunodeficiency by in vivo retroviral gene therapy.

X-linked severe combined immunodeficiency (XSCID) is characterized by profound immunodeficiency and early mortality, the only potential cure being hematopoietic stem cell (HSC) transplantation or gene therapy. Current clinical gene therapy protocols targeting HSCs are based upon ex vivo gene transfer, potentially limited by the adequacy of HSC harvest, transduction efficiencies of repopulating HSCs, and the potential loss of their engraftment potential during ex vivo culture. We demonstrate an important proof of principle by showing achievement of durable immune reconstitution in XSCID dogs following intravenous injection of concentrated RD114-pseudotyped retrovirus vector encoding the corrective gene, the interleukin-2 receptor gamma chain (gamma c).

Definitive toxicology and biodistribution study of a polyvalent DNA prime/protein boost human immunodeficiency virus type 1 (HIV-1) vaccine in rabbits.

A toxicity and immunogenicity study, evaluating the safety of a polyvalent DNA prime/protein boost HIV-1 vaccine (DP6-001), was examined in rabbits. Animals were primed with a cocktail of six different DNA plasmids expressing five HIV-1 env genes and one gag gene followed by boosting with five gp120 proteins homologous to the DNA vaccines. The vaccine was shown to be immunogenic as evident from the induction of high-titered anti-Env and anti-Gag antibodies.

Identification of murine poxvirus-specific CD8+ CTL epitopes with distinct functional profiles.

Murine T cell epitopes against vaccinia virus (VV) have not been characterized to date in part due to the large and complex genome of VV. We have identified and characterized two CD8+ T cell epitopes on the A47L (modified VV Ankara strain (MVA)-029) and J6R (MVA-043) proteins of VV that are Db and Kb restricted, respectively. Following i.