Phase 2 Randomized Trial of the Safety and Efficacy of MHAA4549A, a Broadly Neutralizing Monoclonal Antibody, in a Human Influenza A Virus Challenge Model.

MHAA4549A, a human monoclonal antibody targeting the hemagglutinin stalk region of influenza A virus (IAV), is being developed as a therapeutic for patients hospitalized with severe IAV infection. The safety and efficacy of MHAA4549A were assessed in a randomized, double-blind, placebo-controlled, dose-ranging study in a human IAV challenge model. One hundred healthy volunteers were inoculated with A/Wisconsin/67/2005 (H3N2) IAV and, 24 to 36 h later, administered a single intravenous dose of either placebo, MHAA4549A (400, 1,200, or 3,600 mg), or a standard oral dose of oseltamivir. Subjects were assessed for safety, pharmacokinetics (PK), and immunogenicity. The intent-to-treat-infected (ITTI) population was assessed for changes in viral load, influenza symptoms, and inflammatory biomarkers. MHAA4549A was well tolerated in all IAV challenge subjects. The 3,600-mg dose of MHAA4549A significantly reduced the viral burden relative to that of the placebo as determined by the area under the curve (AUC) of nasopharyngeal virus infection, quantified using quantitative PCR (98%) and 50% tissue culture infective dose (TCID50) (100%) assays. Peak viral load, duration of viral shedding, influenza symptom scores, mucus weight, and inflammatory biomarkers were also reduced. Serum PK was linear with a half-life of ∼23 days. No MHAA4549A-treated subjects developed anti-drug antibodies. In conclusion, MHAA4549A was well tolerated and demonstrated statistically significant and substantial antiviral activity in an IAV challenge model. (This study has been registered at ClinicalTrials.gov under identifier NCT01980966.).

Differential expression of CD26 on virus-specific CD8(+) T cells during active, latent and resolved infection.

The hallmark of effective establishment of immune memory is the long-term memory cell that persists in the absence of antigen. To explore its characteristics, we investigated the differences between a resolved successful immune response, such as after influenza (flu) vaccination, and the state of chronic infection with persistent antigen, such as with cytomegalovirus (CMV), Epstein-Barr virus (EBV) or human immunodeficiency virus (HIV), which leads to defective T-cell memory. Immunophenotypic analyses using multi-parameter flow cytometry and tetramer technology identified a unique pattern of CD26(high) expression among influenza-specific CD8(+) T cells, but not among CD8(+) T cells specific for CMV, EBV (three different epitopes) or HIV. The median percentage of CD8(+) T cells expressing CD26 was 95.5% for influenza, but for cells specific for CMV, EBV and HIV it was 10.5%, 12%-19%, and 13.2%, respectively. These findings suggest that expression of CD26(high) may be a characteristic of a memory cell. CD26(high) expression correlates with expression of CD127, a marker of memory cells. Furthermore, CD26(high) cells can produce interleukin-2. These findings offer insight into the dynamics of T-cell differentiation, and they may offer a specific marker of a successfully developed memory CD8(+) T cell, that of CD26(high). This marker has the potential to be useful in studies of immune responses to infectious agents, and to new vaccine candidates.

Postnatal stem/progenitor cells derived from the dental pulp of adult chimpanzee.

BACKGROUND: Chimpanzee dental pulp stem/stromal cells (ChDPSCs) are very similar to human bone marrow derived mesenchymal stem/stromal cells (hBMSCs) as demonstrated by the expression pattern of cell surface markers and their multipotent differentiation capability. RESULTS: ChDPSCs were isolated from an incisor and a canine of a forty-seven year old female chimpanzee. A homogenous population of ChDPSCs was established in early culture at a high proliferation rate and verified by the expression pattern of thirteen cell surface markers. The ChDPSCs are multipotent and were capable of differentiating into osteogenic, adipogenic and chondrogenic lineages under appropriate in vitro culture conditions. ChDPSCs also express stem cell (Sox-2, Nanog, Rex-1, Oct-4) and osteogenic (Osteonectin, osteocalcin, osteopontin) markers, which is comparable to reported results of rhesus monkey BMSCs (rBMSCs), hBMSCs and hDPSCs. Although ChDPSCs vigorously proliferated during the initial phase and gradually decreased in subsequent passages, the telomere length indicated that telomerase activity was not significantly reduced. CONCLUSION: These results demonstrate that ChDPSCs can be efficiently isolated from post-mortem teeth of adult chimpanzees and are multipotent. Due to the almost identical genome composition of humans and chimpanzees, there is an emergent need for defining the new role of chimpanzee modeling in comparative medicine. Teeth are easy to recover at necropsy and easy to preserve prior to the retrieval of dental pulp for stem/stromal cells isolation. Therefore, the establishment of ChDPSCs would preserve and maximize the applications of such a unique and invaluable animal model, and could advance the understanding of cellular functions and differentiation control of adult stem cells in higher primates.

PCB concentrations in shrimp from major import markets and the United States.

Currently, environmental studies describing levels of polychlorinated biphenyls (PCBs) in imported shrimp are limited, particularly studies of aquaculture shrimp. In the present study, we measured concentrations of the 209 PCB congeners in 84 uncooked, warm-water shrimp samples from the United States and 14 other countries in three continents. Total PCB and dioxin-like PCB (DL-PCB) levels were not significantly different between wild-caught and farm-raised shrimp, and the distribution of total PCB levels did not vary considerably by country of origin although significant differences were observed in some cases. Regional trends in both total PCB and DL-PCB concentrations were observed, with the highest concentrations measured in shrimp from North America followed by Asia and then South America. The lower chlorinated homologues (i.e., mono-, di-, and tri-PCBs) generally comprised a greater fraction of the total levels measured in farm-raised shrimp and shrimp from Asia and South America whereas higher chlorinated homologues (i.e., hepta-, octa-, nona-, and deca-PCBs) contributed more to levels in wild-caught shrimp and shrimp from North America. Estimated daily intake of PCBs associated with shrimp consumption ranged from 2 pg/kg/d (shrimp from South America) to 15 pg/kg/d (shrimp from North America). Results from the present study were comparable to other studies conducted recently and demonstrate that exposure to PCBs from consumption of farm-raised and wild-caught shrimp imported from different regions are not likely to pose any health risks.

Antigen-specific CD4+ T cells recognize epitopes of protective antigen following vaccination with an anthrax vaccine.

Detection of antigen-specific CD4+ T cells is facilitated by the use of fluorescently labeled soluble peptide-major histocompatibility complex (MHC) multimers which mirror the antigen specificity of T-cell receptor recognition. We have used soluble peptide-MHC class II tetramers containing peptides from the protective antigen (PA) of Bacillus anthracis to detect circulating T cells in peripheral blood of subjects vaccinated with an anthrax vaccine. PA-specific HLA class II-restricted T lymphocytes were isolated which displayed both TH1- and TH2-like characteristics, indicating heterogeneity of the lymphocyte lineage within the CD4+ response. Presentation of antigen to these T-cell clones by HLA-matched antigen-presenting cells exposed to the intact PA protein confirmed that the identified epitopes are indeed naturally processed by the human immune system. Specific tetramer-derived T-cell profiling may be useful for monitoring helper CD4+ T-cell responses to anthrax vaccination.