YEARS IN THE MAKING, EBOLA BUBBLES TO THE SURFACE
Bubbling under the surface for years like a volcano packing heat, Ebola erupts into a stark reality for the world health community.
First appearring in 1976, Ebola is a classified “Category A” potential bioterrorism agent. With an incubation period of up to 21 days (early symptoms mimick the everyday flu), it is entirely possible that infected individuals board planes, unknowingly carrying the virus around the world. Given the threat, developing vaccines and treatments is an urgent priority.
The World Health Organization (WHO) has confirmed 932 deaths through August 6th, mostly in Liberia, Sierra Leone, and Guinea. In total over 1,700 cases have been reported. WHO has pledged $100 million to help bring the current outbreak under control.
In this issue, we will learn how Ebola causes its destruction and the therapeutics and discuss vaccines in development for the virus.
TINY VIRUS, BIG PROBLEM
Seven proteins, a long single strand of RNA, and a lipid membrane make up the intelligent, yet calamitous Ebola virus. How does a handful of proteins and genetic material wreak such havoc? White blood cells called macrophages become infected during an integral part of the immune process; Ebola disrupts the body’s defenses against foreign invaders.
Macrophages normally release signaling molecules to alert and activate other white blood cells to help fight infection. Simply put, Ebola inhibits macrophages from doing their job. The virus stealthily evades the immune system and spreads to the lining of blood vessels before moving to liver and kidney tissue. Infected endothelial cells (the cells that line blood vessels) become leaky, giving rise to the gruesome hemorrhaging characteristic of infection.
MARKET WATCH: EBOLA THERAPEUTICS
Unlicensed antibody therapy Zmapp takes the path less traveled when used to treat two Ebola patients on US soil.
Mapp Biopharmaceuticals (San Diego, CA) developed Zmapp while working on antibody cocktails to fight Ebola. The serum has yet to reach even a basic Phase I human trial—as is the case with all except one potential Ebola therapeutic. The basic idea behind Zmapp is for its antibodies to neutralize Ebola by binding to the virus and preventing it from entering the target cells. Therapeutic antibodies are typically produced in Chinese hamster ovary (CHO) cells, but Zmapp’s antibodies are produced in tobacco plants.
An RNA interference (RNAi) drug developed by Tekmira Pharmaceuticals (Vancouver, British Columbia) is targeting Ebola by silencing its genes. The drug demonstrated efficacy bycontrolling the virus in non-human primates and began human safety testing in January of 2014. An elevated inflammatory response to the drug caused the FDA to impose a clinical hold on the TKM-Ebola Phase I study. Tekmira is currently preparing a Complete Response to the Agency and Tekmira hopes to resume testing by Q4 2014.
Duplicating a drug used to treat other viruses (such as herpes and hepatitis), BioCryst (Durham, North Carolina) is developing an inhibitor to an enzyme that Ebola uses to make copies of its genetic material. Since the inhibitor has a chemical structure similar to the building blocks that make up RNA, Ebola unknowingly incorporates these inhibitors into its growing RNA strand. The secret—once incorporated the RNA strand cannot grow any longer, thus stopping Ebola replication. BioCryst’s drug is still in preclinical development.
Novartis’ blockbuster leukemia drug, Gleevec, just might have crossover potential as an Ebola drug. Both Gleevec and the related drug Tasigna inhibit an enzyme called Bcr-Abl that is overactive in certain types of leukemia. Ebola uses a related enzyme called cAbl1 to help its reproduction. Gleevec and Tasigna appear to inhibit viral replication of Ebola-infected cells in the lab via the enzyme pathway.
MARKET WATCH: EBOLA VACCINES
The premise behind vaccines is straightforward: induce an immune response by injecting the patient with a killed or weakened virus—both traditional vaccine preparations.
Ebola may necessitate a different strategy: a DNA vaccine.
How do DNA vaccines work? Inject a viral gene (that provides the recipe to make a particular viral protein) into a patient so that their own cells manufacture that viral protein. The viral protein is unable to cause disease, but is able to elicit an immune response. That response makes memory B-cells which act as sentries that watch out for particular pathogens to appear, and then quickly wipe them out.
The advantages of DNA vaccines:
- They likely induce a more robust immune response.
- They can protect against multiple viral strains at once.
- They are much more transport stable than protein or virus-based vaccines, which takes acute importance considering their intended deployment in developing countries; they will be less dependent on refrigeration in order to maintain efficacy.
The development of DNA vaccines has been elusive due to inefficient delivery methods. However, Inovio Pharmaceutical (Blue Bell, PA, and San Diego, CA) has a DNA vaccine program that holds promise of demonstrated efficacy in preclinical mice testing models. Inovio has developed an electroporation-based delivery system: injection of a vaccine into skin or muscle followed up with short, controlled electrical pulses which significantly increases the tissue’s abililty to take up the DNA vaccine. Perhaps this delivery method could be employed for an Ebola DNA vaccine?
GlaxoSmithKline’s recent acquisition of Okairos, a Swiss biotech with a DNA-based Ebola vaccine in its preclinical development portfolio, is also jumping on the Ebola bandwagon.