Thursday, September 24, 2015

Progress in Developing a Vaccine against the Ebola Virus

Progress in Developing a Vaccine against the Ebola Virus
The recent spread of hemorrhagic fever (EHF) in areas of West Africa including Guinea, Sierra Leone and Liberia has placed considerable urgency on the need to develop an effective vaccine against the pathogen responsible for this horrific and highly contagious disease, the Ebola virus (EBOV).  To date, of the approximately 27,200 reported cases, there have been more than 11,100 deaths – a mortality rate of  40.8 percent.   EBOV is so infectious that a high incidence rate has also been reported among health care workers.  It needs to be kept in mind that the health care infrastructure of the countries affected has been severely compromised especially since these so-called, “low resource” countries have budgets inadequate to respond effectively to this challenge.

By way of background EBOV belongs to a class of viruses called filoviruses.   Filoviruses are single-stranded RNA viruses.  This class of viruses possesses a glycoprotein (GP) on its surface that could conceivably make a good candidate as an immunogen – a protein capable of eliciting an immune response.

Dr. Andrea Marzi at the Laboratory of Virology, Division of Intramural Research at the National Institute of Allergy and Infectious Diseases  at the National Institutes of Health in Hamilton Montana.and his colleagues  have helped develop a strategy for developing such a vaccine.  The strategy they employed can be outlined in the following way –
  • A live attenuated stomatitis virus was employed as a viral vector
  • Recombinant technology was employed to modify this virus so that it expresses the Ebola GP on its surface referred to as Viral Stomatitis Vector EBOV (VSV-EBOV)
  • This viral vector was then introduced into experimental animals – the rodent and macaque.

This approach was shown to be highly efficacious in both pre and post exposure vaccinations.  These results were so promising that phase 1 clinical trials in humans  were begun in several  worldwide locations. 

The following is in the author’s own words – “Complete and partial protection was achieved with a single dose given as late as 7 and 3 days before challenge, respectively.  This indicates that VSV-EBOV may protect humans against EBOV infections in West Africa with relatively short time to immunity, promoting its use for immediate public health responses.”

Wednesday, September 2, 2015

Tumor Suppressor p53 and the Clearance of Apoptotic Cells

Within the human body, with its complex array of highly differentiated organs and tissues, it is estimated that more than a billion cells die each day.  Most of these deaths arise from a natural process referred to as apoptosis – programmed cell death.  Since apoptosis is integral to the functioning of a healthy organism, its mechanism has been the focus of study for many years. 

In addition to the process of apoptosis, there also exists a mechanism for the efficient processing and clearance of the cellular debris that is a direct result of apoptosis.  Otherwise, the accumulation of released substances from dead cells could function as autoantigens and elicit an undesirable immune response against normal tissue resulting in autoimmune diseases.  In addition, chronic inflammation and developmental abnormalities could result from the buildup up cellular debris.  It has been established that the immune response to apoptotic cells involves the mobilization of phagocytic cells whose function is to engulf the dead or dying cells.  This process necessarily requires the expression of immune tolerance in order to prevent an autoimmune response.

The tumor suppressor  p53 protein has long been associated with the mechanism of apoptosis.  However, little has been established in regards to the putative role of p53 in the clearance of cellular debris that results from apoptosis.

Dr. Kyoung Wan Yoon and his colleagues from the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA have focused their research efforts on the elucidation of the role of p53 in the clearance of post apoptotic cells and the establishment of tolerance to self-antigens.

What they have shown is the following.  As a result of stress upon a cell that leads to p53-mediated apoptosis, p53 triggers the production of a protein product from the so-called “Death Domain1a (DD1a)” gene.  DD1a functions as a ligand that is instrumental in the binding of the apoptotic cell to the phagocytic immune cell that will eventually engulf the dead cell.  Once this engulfment occurs it subsequently triggers the binding of an inhibitory T cell that ensures tolerance to self-antigens; thereby, preventing untoward reactions that could lead to a disease state.

This kind of work is extremely valuable in furthering the understanding of the mechanism of self-tolerance.  Such knowledge may prove instrumental in determining the underlying mechanisms involved in auto-immune disease.