NIH-funded HIV clinical research sites to join pediatric tuberculosis vaccine study

Several U.S. government-funded HIV/AIDS clinical research sites in Africa will join other collaborators in an ongoing clinical trial testing an investigational tuberculosis (TB) vaccine in infants at risk for TB infection. "We are pleased to be able to tap into our existing HIV/AIDS clinical research infrastructure to help test promising investigational vaccines against TB," said NIAID Director Anthony S. Fauci, M.D. The sites are funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The Phase II proof-of-concept study is testing the safety and effectiveness of an investigational booster TB vaccine developed by Aeras, a Rockville, Md.-based nonprofit organization focused on developing vaccines and other products to prevent TB, and Crucell N.V., a biopharmaceutical company based in the Netherlands.

The trial began in October 2010 and is now ongoing at three sites in Kenya, South Africa and Mozambique. It is sponsored by Aeras and receives funding from Aeras, Crucell and the European and Developing Countries Clinical Trials Partnership.

The trial, which will enroll HIV-uninfected infants ages 16 weeks to 26 weeks, is testing the AERAS-402/Crucell Ad35 candidate TB vaccine as a booster immunization to the current bacille Calmette-Guérin (BCG) TB vaccine. In countries where TB is highly endemic, the World Health Organization (WHO) recommends that all infants receive the BCG vaccine at birth. It is not routinely administered to infants in the United States. The BCG vaccine, first administered to humans in 1921, is the only licensed TB vaccine and reduces the risk of some forms of TB in children. However, it provides limited protection against adult pulmonary TB, the contagious and most common form of TB.

To allow for increased enrollment, the study is now being expanded to include up to six NIAID-supported clinical trial sites in sub-Saharan Africa. The first of these sites to join the trial is the Perinatal HIV Research Unit at the Chris Hani Baragwanath Hospital in Soweto, South Africa. The site is a member of several NIAID-funded clinical trials networks, including the HIV Vaccine Trials Network (HVTN), the HIV Prevention Trials Network (HPTN) and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT). The HPTN is largely funded by NIAID with additional funding by the National Institute on Drug Abuse and the National Institute of Mental Health, all part of the NIH. IMPAACT is funded by NIAID and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, also part of the NIH.

Additional IMPAACT sites are expected to participate in the clinical trial when the next stage of enrollment opens in several months.

The AERAS 402/Crucell Ad35 vaccine is being given as a booster immunization to healthy infants who received the BCG vaccine at birth to determine if the investigational vaccine can increase protection against TB. The recombinant vaccine uses a live, non-replicating adenovirus (Ad35) to deliver three specific Mycobacterium tuberculosis antigens designed to stimulate the immune system and protect against TB. The vaccine does not contain live TB and cannot cause vaccinated infants to become infected with TB. The investigational vaccine had an acceptable safety profile in previous clinical trials among healthy adults and infants, as well as among HIV-infected adults and adults with latent TB.
The study was approved by ethics committees at each participating site as well as by national regulatory authorities in each of the participating countries. Additionally, an independent data and safety monitoring board regularly reviews the study data to ensure the protection of the study participants. Informed consent by a parent or legally authorized representative is required to enroll an infant into the study. The study is expected to be completed in 2015.
According to the WHO, in 2010 TB sickened 8.8 million people and killed 1.4 million people worldwide. It is a leading cause of death among people who are also infected with HIV. In Africa, there were an estimated 2.3 million TB cases and 254,000 TB deaths in 2010.

For more information about clinical trial NCT01198366 visit clinicaltrials.gov. For more information about tuberculosis, see the NIAID Tuberculosis Web portal.

NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

Permalink | Leave a comment  »

A pilot-scale membrane bioreactor (MBR) was installed and operated for one year at a Swiss hospital. It was fed an influent directly from the hospital’s sanitary collection system. To study the efficiency of micropollutant elimination in raw hospital wastewater that comprises a complex matrix with micropollutant concentrations ranging from low ng/L to low mg/L, an automated online SPE-HPLC-MS/MS analytical method was developed. Among the 68 target analytes were the following: 56 pharmaceuticals (antibiotics, antimycotics, antivirals, iodinated X-ray contrast media, antiinflamatory, cytostatics, diuretics, beta blockers, anesthetics, analgesics, antiepileptics, antidepressants, and others), 10 metabolites, and 2 corrosion inhibitors. The MBR influent contained the majority of those target analytes. The micropollutant elimination efficiency was assessed through continuous flow-proportional sampling of the MBR influent and continuous time-proportional sampling of the MBR effluent. An overall load elimination of all pharmaceuticals and metabolites in the MBR was 22%, as over 80% of the load was due to persistent iodinated contrast media. No inhibition by antibacterial agents or disinfectants from the hospital was observed in the MBR. The hospital wastewater was found to be a dynamic system in which conjugates of pharmaceuticals deconjugate and biological transformation products are formed, which in some cases are pharmaceuticals themselves.

Permalink | Leave a comment  »

SENP1 prevents crucial gene-activator STAT5 from becoming trapped in nucleus

MD Anderson News Release 01/27/12

When SUMO grips STAT5, a protein that activates genes, it blocks the healthy embryonic development of immune B cells and T cells unless its nemesis breaks the hold, a research team led by scientists at The University of Texas MD Anderson Cancer Center reports today in Molecular Cell.

"This research extends the activity of SUMO and the Sentrin/SUMO-specific protease 1 (SENP1) to the field of immunology, in particular the early lymphoid development of T and B cells," said the study's senior author, Edward T. H. Yeh, M.D., professor and chair of MD Anderson's Department of Cardiology.

SUMO proteins, also known as the small ubiquitin-like modifiers or Sentrin, attach to other proteins in cells to modify their function or to move them within a cell. SENP1 is one of a family of six proteins that snips SUMO off of SUMO-modified proteins. SUMOylation (SUMO modification) of proteins has been implicated in development of cancer, heart and neurodegenerative diseases, among others.

The team first analyzed the role of SENP1 in the development of lymphoids in mice and found it is heavily expressed in precursor cells, the early stages of B and T cell development.

Working with genetically modified mice they developed that lack SENP1 gene expression, Yeh and colleagues found the mouse embryos had severe defects in their T and B cells, white blood cell lymphocytes that identify and fight infection.

SUMO pins STAT5 in the nucleus
Subsequent experiments led them to STAT5, a transcription factor known to play critical roles in the development and function of immune cells. Transcription factors work in the cell nucleus, activating gene expression by connecting to a gene's promoter region.

"STAT5 works in a cycle, moving from the cytosol of a cell into the nucleus to activate genes and then back out to the cytosol," Yeh said. "We found that when STAT5 is SUMOylated in the nucleus it gets trapped there when there's no SENP1 to remove SUMO."

The team found that SUMO muscles in on two other signaling events that govern STAT5 activity - phosphorylation and acetylation.

SUMO inhibits STAT5 signaling
STAT5 is activated in the cell cytosol when the JAK tyrosine kinase attaches a phosphate group at a specific site on the STAT5 protein. This transformed STAT5 crosses the nuclear membrane into the nucleus to transcribe genes.

The team found that SUMO attaches to STAT5 close to its phosphorylation site and that cells lacking SENP1 have increased SUMOylation and decreased phosphorylation.

SUMOylation vs. acetylation
In addition to phosphorylation, acetylation of STAT5 has been shown to be essential for STAT5 to cross the nuclear membrane into the nucleus to enhance gene transcription. Yeh and colleagues found that SUMO competes directly with acetyl groups for the same binding site, inhibiting acetylation.

"Without SENP1 to remove SUMO, STAT5 can't be acetylated or phosphorylated and can't be recycled for use again," Yeh said. "We discovered that SENP1 controls lymphoid development through regulation of SUMOylation of STAT5."

Since Yeh's lab discovered SUMOylation in 1996, SUMO has been found to alter the function of thousands of proteins.

Yeh is hosting the 6th International Conference SUMO, Ubiquitin, UBL Proteins: Implications for Human Diseases Feb. 8-11 in the Dan L. Duncan Building at MD Anderson. Yeh organizes the meeting every other year.

"There used to be so little known about SUMO. Now, a protein is assumed to be SUMOylated until proved otherwise," Yeh said.

Co-authors with Yeh are lead author Thang Van Nguyen, Ph.D., and Hong Dou of MD Anderson's Department of Cardiology; Pornpimon Angkasekwinai, Ph.D., and Chen Dong, Ph.D., of MD Anderson's Department of Immunology; Feng-Ming Lin, Ph.D., Long-Sheng Lu, M.D., Ph.D., and Jinke Cheng, D.V.M., of the Texas Heart Institute/St. Luke's Episcopal Hospital in Houston; and Y. Eugene Chin, Ph.D., of Brown University School of Medicine and Rhode Island Hospital.

Nguyen developed this project as a graduate student in The University of Texas Graduate School of Biomedical Sciences, a joint operation of MD Anderson and The University of Texas Health Science Center at Houston. Angkasekwinai also is affiliated with Thammasat University in Pathumthani, Thailand.

This research was funded by a grant from the National Cancer Institute and a fellowship to Nguyen from the Vietnam Education Foundation. 01/27/12

Permalink | Leave a comment  »