HIV Clinical Research Sites to Join Pediatric Tuberculosis Vaccine Study

From the National Institutes of Health:

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.

From the National Institutes of Health:

January 30, 2012

Looking Inside Viruses

Since the discovery of the microscope, scientists have tried to visualize smaller and smaller structures to provide insights into the inner workings of human cells, bacteria and viruses. Now, researchers have developed a new way to see tiny structures within viruses.

Computer reconstruction of a virus shell (gray) and inner structure (magenta). In the background, a cryo-electron micrograph of viral particles with inner structures bubbling from radiation damage.

Conventional cryo-electron microscopy (cryo-EM) has allowed researchers to image the surface of viruses in great detail. But scientists hadn't been able to clearly visualize structures inside viruses. Cryo-EM procedures use radiation, and higher doses damage viruses, destroying the very structures researchers would like to view.

A team led by Dr. Alasdair Steven of NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and Dr. Lindsay Black at the University of Maryland Medical School was studying a type of virus that infects bacteria and so might one day be used to combat pathogens. Past studies showed that the virus, called ϕKZ, contains a cylindrical protein structure called the inner body. Those studies, however, used disrupted viruses. The inner body can't be distinguished from the DNA that surrounds it in intact viruses using conventional cryo-EM.

In the January 13, 2012, issue of Science, the researchers described how they were able to turn the problem of radiation damage into an asset. They realized that the proteins inside the virus are more sensitive than DNA to radiation damage. After recording images of the virus with low doses of radiation, they used higher doses. As the inner structure deteriorated, it appeared as a cylinder of bubbles. The team was able to superimpose the images and, using 3-D computer reconstruction, clearly visualize the viral structure. The investigators call their technique bubblegram imaging.

Based on the shape and position of the inner body, the researchers believe that it helps organize DNA into its compact structure. In the future, bubblegram imaging may yield further insights into the inner workings of viruses and suggest strategies for developing novel therapies.

The scientists anticipate other uses for bubblegram imaging as well. For example, it could be used to visualize the interactions of proteins with DNA in human cells.

“This new cryo-EM procedure renders previously invisible proteins visible and, thus, will provide new understanding of cell biology,” Steven says.

From the National Institutes of Health:

January 30, 2012

Manganese May Prevent Toxin Damage

A new study suggests that manganese, an essential nutrient, may prevent the deadly effects of Shiga toxin. The finding may lead to cheap, effective treatments for dangerous foodborne Shigella or E. coli infections, which currently affect millions worldwide.

Shiga toxin (green) in the intestine. Image by S. Schuller, Wellcome Images. All rights reserved by Wellcome Images.

Foodborne illness is often caused by bacteria that contaminate raw foods. To healthy people, most of these bacteria are harmless. Infections by bacterial strains that carry Shiga toxin, however, can lead to dangerous complications, including severe bloody diarrhea, kidney failure and even death. Shiga toxin is a protein produced by certain strains of Shigella and E. coli bacteria. When cells of the digestive tract take up Shiga toxin, it interferes with cellular functions and the cells die.

Ordinarily, dangerous proteins taken up by the cell are routed via a compartment called the endosome to the lysosome, where they're destroyed. Shiga toxin, however, escapes this route by leaving the endosome and traveling through the Golgi apparatus to the cell's protein production machinery. Once there, the toxin halts protein production and kills the cell.

In earlier research, scientists directed by Dr. Adam Linstedt of Carnegie Mellon University found that Shiga toxin uses a specific cellular protein, called GPP130, to bypass the cell's defenses and avoid destruction. GPP130 ordinarily moves between the endosome and the Golgi apparatus. However, manganese disrupts this movement and causes the cell to break down GPP130. Linstedt and his colleagues reasoned that because manganese could divert GPP130, it might also affect Shiga toxin. Their work, funded by NIH's National Institute of General Medical Sciences (NIGMS), appeared in the January 20, 2012, issue of Science.

Curious about the connection between GPP130 and Shiga toxin, the researchers broke the GPP130 protein into pieces. They found that Shiga toxin binds directly to one section of the GPP130 protein. This binding allows Shiga toxin to avoid destruction in the lysosome by piggybacking a ride on GPP130 as it leaves the endosome to travel to the Golgi.

When the scientists added manganese to the mix, GPP130 was destroyed by the cell. Without GPP130, Shiga toxin couldn't escape from the endosome and instead moved to lysosomes for destruction.
The researchers next pretreated mice with several doses of manganese, and then gave the mice lethal doses of Shiga toxin. All the mice without pretreatment died within 4 days. All those pretreated with higher doses of manganese survived. This pretreatment experiment may not directly translate to clinical use. However, with further research, the scientists hope to find a manganese treatment that can be used as a preventative measure or at disease onset to prevent Shiga toxin-related death.

“While Shiga toxin infection affects people in the developed world, it affects far more people in the developing world. An inexpensive, accessible treatment—not a designer drug—is the ideal solution,” says Linstedt.
These findings point toward an inexpensive, life-saving treatment for millions worldwide. However, because excess manganese can cause serious side effects, more work must be done to determine if manganese can be safe and effective for use in humans.

—by Lesley Earl, Ph.D.

Welcome!

Welcome to my new GERMS blog!  I decided to name the blog as a tribute to Judith Miller, Stephen Engelberg, and William Broad, who, about 10 years ago, wrote a book of the same title that scared the bejabbers out of me!

Miller, et. al. made me aware of a world of unseen, silent killers and how these were being harnessed to produce biological weapons.  The authors made reference to Richard Preston, who has also written some scary fiction and non-fiction about viruses and bacteria.  And how could I not mention Tom Clancy's Rainbow Six?

One cannot talk about biological weapons without mentioning naturally occurring pathogens.  Some of these have received a great deal of press coverage, while others have received none.  In some cases, pathogens have received very little press coverage because treatment is very simple.  There is a TV star who has been quietly working in Haiti to de-worm children.  It is such a simple procedure, but it makes such a difference in the lives of the children affected!

I hope that this forum can serve as a resource for alleviating human suffering from infectious diseases, especially the ones that are so easily prevented!

Jon