Ebola Finally Meets Its Match

The headlining Ebola crisis of last summer devastated West Africa, marking the largest outbreak since the discovery of the disease in 1976. The glaring lack of a treatment or vaccine caused the virus to quickly spread within Guinea, Sierra Leone, and Nigeria. A small number of infected healthcare workers were able to receive an experimental antibody known as Zmapp (Mapp Biopharmaceuticals, San Diego, CA) in the U.S last year, with eight out of the ten surviving. Zmapp—and other potential Ebola treatments—are now in clinical trials, even as the outbreak has begun to wane.

Enter rVSV-ZEBOV (NewLink Genetics, Ames, IA; Merck, Kenilworth, NJ), an Ebola vaccine that appears to be both safe and highly effective. So, how exactly does the Ebola vaccine work? Let’s take a look into the world of vaccines.

Training The ImmunE System

The principle behind vaccination is simple: by exposing an individual to an inactivated or otherwise harmless form of an infectious agent, you can “train” their immune system to recognize the pathogen by activating memory B-cells and in some cases, memory T-cells.

If the person is subsequently exposed to the actual pathogen, their immune system will immediately spring into action, recognizing the old target and going through their rehearsed game plan. Without vaccination or prior exposure to a particular pathogen, the immune system can take several weeks to ramp up its response. The speed at which Ebola is fatal underscores the need for a safe and effective vaccine to prevent such devastating outbreaks in the first place.

Fighting The Good Fight

While the premise behind all vaccines is similar—expose the patient to an inactivated pathogen to induce a protective immune response—the delivery platforms vary considerably.

Whole pathogen vaccines are made when the entire pathogen itself has been killed or attenuated (weakened). Attenuated vaccines may be more effective than killed vaccines at inducing a strong immune response, because they more closely mimic a natural infection. Common attenuated vaccines include the measles and mumps vaccines.

Pathogen subunits are vaccines that contain just one or a few proteins from the virus (or a toxin from a bacterium) in lieu of the whole pathogen. In some cases—as determined by clinical studies—these antigens alone are sufficient to induce an immune response. A subunit vaccine on the market today is Merck’s Gardasil against the human papilloma virus (HPV).

DNA vaccines are even smaller—they consist of a segment of DNA (a gene) encoding a pathogen protein, and are used in place of injecting the whole pathogen or pathogen subunit. The idea is to induce a patient’s muscle cells to take up the plasmid and make the viral protein (antigen). While DNA vaccines have yet to hit the market, many are effective at inducing an immune response in animals. One key challenge for this type of vaccine lies in delivery—getting a patient’s muscle cells to take up sufficient quantities of the antigen-encoding DNA. Inovio Pharmaceuticals (San Diego, CA) is developing an electroporation system that uses pulses of electricity to increase the uptake of injected DNA vaccines, aiming to battle HPV, hepatitis C, HIV, and influenza.

The One-Two-Three Punch: rVSV-ZEBOV

The experimental Ebola virus vaccine, dubbed rVSV-ZEBOV, combines elements of all three platforms listed above. The prefix “rVSV” stands for recombinant vesicular stomatitis virus (VSV); ZEBOV indicates the Zaire strain of Ebola virus—the strain that caused the 2014 outbreak.

rVSV-ZEBOV was created using genetic engineering techniques to splice the gene for the Ebola glycoprotein into VSV. VSV normally infects cattle—so it is considered safe to humans—but underwent further modification to make it even safer. The only Ebola gene transferred is the glycoprotein, thus there is no chance of contracting Ebola with the recombinant (genes from VSV and Ebola recombined) virus.

Why does the vaccine use the Ebola glycoprotein? This protein, normally present on the surface of the virus, is used by Ebola to enter target cells in the human body. The glycoprotein binds to cells that line the blood vessels, contributing to the massive hemorrhaging associated with Ebola infections. Using the glycoprotein as the vaccine antigen causes the patient to produce antibodies that bind to the glycoprotein, preventing it from infecting target cells and reducing hemorrhaging. Combining the Ebola glycoprotein with VSV closely mimics a natural infection, so it does a very good job of stimulating the immune system—without the attendant dangers of an actual infection. VSV is easily eliminated from the human body within a few days.

rVSV-ZEBOV testing In The Ring

In order to get a new vaccine approved, manufacturers must first demonstrate safety and efficacy. As with new drug approvals, this is typically a lengthy process, often taking up to a decade. Safety is first tested in healthy volunteers, and then individuals at risk for contracting the infectious disease are given the vaccine candidate. The at-risk individuals are followed for a period of time—typically a few years—to see if they are less likely to contract the disease than those in the control group (who did not receive the vaccine).

Since Ebola outbreaks tend to be infrequent and unpredictable, the traditional model of testing is difficult to complete. Merck used a “ring vaccination” approach: anyone in contact with the Ebola victims received the vaccine as soon as contact had been established—creating a “ring” of vaccinated people around one infected person. Another group of contacts were not given the vaccine until three weeks after the initial exposure. Each group contained approximately 2000 people. Among those given the vaccine immediately, no cases of Ebola were reported, whereas the control group reported 16 cases. The effectiveness of the vaccine shows in the math, giving hope to perhaps one day controlling—or even eradicating—the disease.

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