Few viruses are more feared than Ebola virus, the deadly microbe that periodically attacks African villages and kills up to 90 percent of those it infects. Although other viral diseases claim more lives each year, the ruthless efficiency and nightmarish symptoms of Ebola virus make a vaccine against this killer an important goal of scientists. Now, as described in the November 30 issue of Nature, a team of researchers led by scientists from the National Institutes of Health (NIH) has developed a novel vaccine that prevents Ebola virus infection in monkeys. All four vaccinated monkeys were completely protected from a lethal dose of the virus. This study describes the first primate model of immune protection against Ebola virus, a model that may allow scientists to rationally design a vaccine that prevents this dreaded disease in humans.
"Doctors have essentially been helpless against Ebola virus," says Gary Nabel, M.D., Ph.D., director of the Dale and Betty Bumpers Vaccine Research Center (VRC) at the NIH and a lead author of the study. "We have not known if immunity to the virus exists or what parts of the immune response are important. Our studies show that animals can launch an effective immune response against Ebola virus, and we can use knowledge of this response to design a vaccine that protects non-human primates from infection. Although much more work needs to be done, we hope this moves us closer to new vaccines and treatments for Ebola and other viruses."
Ebola virus kills quickly, giving the body little time to launch an effective immune response. Infected individuals suffer severe pain, high fever and extensive internal bleeding. Although the virus periodically strikes humans, scientists do not know where it resides in nature between outbreaks.
"Ebola is a difficult virus because currently available antiviral drugs have no proven effect on it and we do not know its natural reservoir, making environmental control impossible. A vaccine is therefore the best hope for protecting humans from infection, and this study makes some key advances toward realizing that goal," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), which funds the VRC along with the National Cancer Institute (NCI). NIAID, NCI and the NIH Office of AIDS Research spearhead the Center.
Dr. Nabel and colleagues had previously tested genetic Ebola vaccines strands of DNA containing genes that encode Ebola virus proteins for their ability to induce immune responses in rodents and to protect against disease. Unlike traditional vaccines, typically made from viral proteins, DNA vaccines more closely mimic virus infection because they enter a cell and use that cell's machinery to manufacture new viral proteins. Researchers believe this strategy might better trick the immune system into thinking a real virus infection has occurred.
Previously, Dr. Nabel's laboratory and a second research team independently showed a DNA vaccine could protect mice and guinea pigs from a specially adapted Ebola virus strain lethal to rodents. An effective human vaccine, however, must protect against three known fatal Ebola virus strains Zaire, Sudan and Ivory Coast. Ebola Zaire is the form of virus associated with the most human deaths.
To ensure that a multi-strain vaccine would not weaken the immune response to the Zaire strain, a team of scientists led by VRC research fellow Nancy Sullivan, Ph.D., and Dr. Nabel combined genes encoding surface proteins from the Sudan, Zaire and Ivory Coast Ebola viruses. Working with researchers from the Centers for Disease Control and Prevention's high-containment or biosafety level 4 facility, Dr. Nabel's team compared this vaccine to the one tested previously in rodents. The new vaccine produced an immune response equally powerful to that of the original vaccine in protecting guinea pigs from the Zaire strain.
The scientists then turned to boosting the anti-Ebola virus immune response by using a weakened form of a different virus, adenovirus, to make an Ebola virus protein from the Zaire strain. Adenoviruses typically cause respiratory diseases, but the researchers used a modified form that can enter cells without reproducing or causing disease. Such viruses have been used in other studies to boost immune responses in mice. Dr. Nabel's team attached the Ebola Zaire virus surface protein gene to the DNA of the weakened adenovirus, and tested this new booster vaccine in mice. The vaccine produced a more vigorous immune response than that observed with the multi-strain DNA vaccine, and it increased the amount of antibodies and T cells directed against the Ebola virus protein.
Armed with this promising new vaccine, the researchers tested a novel prime-boost immunization strategy on eight monkeys. Four monkeys received the three-strain Ebola virus DNA vaccine and then were injected with the Ebola-adenovirus booster. The other four monkeys received placebo immunizations. All four vaccinated monkeys launched strong anti-Ebola immune responses and survived a subsequent exposure to lethal doses of Ebola Zaire virus. Three of these monkeys showed no sign of viral infection, whereas a slight, temporary increase in Ebola virus in the blood of one of the vaccinated monkeys disappeared after one week. More than six months after infection, the four monkeys remained symptom-free with no detectable virus in the blood.
The researchers are continuing their efforts. "We of course want to test the multivalent vaccine for effectiveness against all three strains of Ebola virus," says Dr. Sullivan, "but we also need to look more closely at the immune response induced by these vaccines so we can nail down what is needed for protection." By studying the mechanism of protection induced by the vaccine, they can determine what combination of antibodies, helper T cells and killer T cells defend the monkeys against infection. They then hope to use this information to rationally design new vaccines and antiviral treatments for humans.
Last week, the Ugandan Ministry of Health was reporting cumulative figures of 337 cases, including 121 deaths.