By Michael Howell
Scientists at Rocky Mountain Laboratory in Hamilton recently published the results of a study proving for the first time that a single dose of an experimental Ebola virus (EBOV) vaccine completely protects cynomolgus macaques against the current EBOV outbreak strain in West Africa, EBOV-Makona. The live-attenuated vaccine, VSV-EBOV, also called rVSV-ZEBOV, uses genetically engineered vesicular stomatitis virus (VSV) to carry an EBOV gene that has safely induced protective immunity in macaques. The vaccine is undergoing clinical trials on humans in Guinea.
According to the lead author of the report, Andrea Marzi, PhD, of NIAID’s Laboratory of Virology, the study on the macaques at RML showed that the vaccine was very effective and only a single dose of the vaccine is completely effective on the monkeys if given seven days before they are infected with the virus and when given three days before infection with the virus, two out of three survive.
Marzi said that the preliminary reports form clinical trials on humans underway in Guinea, where the Ebola virus is active, indicate that the vaccine is working on humans as well but may need to be taken at least 10 days prior to exposure to provide maximum protection.
“The important thing here is the news that the vaccine, which has been around for 10 to 15 years, is effective on the latest strain of the virus that is currently ravaging parts of West Africa,” said Marzi. Previous animal studies demonstrated that VSV-EBOV could successfully protect monkeys against the first EBOV strain recognized, Mayinga, in 1976, and against EBOV-Kikwit, a strain that emerged in Central Africa in 1995. This new study shows that certain immune responses induced by VSV-EBOV are similar against all three viruses. The scientists, from NIH’s National Institute of Allergy and Infectious Diseases Division of Intramural Research, concluded from these findings that VSV-EBOV likely would be equally protective against different EBOV strains.
Dr. Heinz Feldmann, currently Chief Virologist at RML, designed the rVSV-ZEBOV vaccine while working for the Public Health Agency of Canada in Winnipeg. He swapped the gene for a VSV surface protein with the one from Ebola, creating a ‘recombinant’ virus – one with a new combination of genes. The protein comes from the Zaire species of Ebola. It is the same vaccine being used in the human trials in Guinea.
Feldmann and immunologist Thomas Geisbert from Texas have worked for over a decade on development of the vaccine testing it on rodents and non-human primates. In a 2005 study in Nature Medicine, they showed that a single injection protected monkeys against lethal doses of Ebola, and that no animals developed fever or other symptoms of illness.
“Without these two and the work they did characterizing the virus over all these years we would not be where we are now using the vaccine in clinical trials,” said Marzi.
The Ebola virus is a BioSafety Level 4 pathogen and requires maximum containment. When RML built a BioSafety Level 4 lab in 2005, Feldmann took a job there and brought vials of Ebola virus with him from Canada when he came. Marzi, who worked with Feldmann in Canada, followed him to RML in 2008.
Dr. Marshall Bloom, Associate Director of Scientific Management at RML, recalls that, when they began discussions at RML about construction of a BioSafety Level 4 lab, they let people know that one of the goals was to develop new vaccines and diagnostic measures against serious viral infections like Ebola virus. Level 4 work began in the second half of 2009.
“Half a dozen years later we are testing a vaccine that is now being used successfully in West Africa,” said Bloom.
Knowing that a vaccine works is not the same as knowing how it works. One thing the scientists have discovered is that Ebola victims can make antibodies against the virus naturally, but that adaptive immune response can take several days – too late to beat an infection, as the virus normally kills in the second week after exposure.
The vaccine prompts immune cells to make antibodies against the antigens produced by the genetically-modified VSV – including the Ebola protein.
As Feldmann told biologist JV Chamary writing for Forbes magazine, “The immune response immediately recognizes that outer surface protein of Ebola because it has seen it before through the vaccine. The immune response kicks in very, very quickly, and can then eliminate or at least limit the infection to an extent that the person can survive.”
Besides studying the virus, Marzi also volunteered to go to Monrovia, Liberia in 2014, at the height of the epidemic there, to analyze Ebola test results from the ELWA3 hospital compound. Witnessing the profound, and at the time overwhelming, effects of the virus and knowing that a potential vaccine was on the horizon fueled her interest.
“When we got there, we realized how many people are deployed, and we thought it was worth asking the question quickly: ‘If there was a vaccine to give to those people, how long before their deployment would they need it to be safe?'” she said. “It was always an interesting scientific question. But participating in the effort brought it to the front of our minds.”
“Our experience in Liberia really underlined that we needed to get this done,” she said.
Marzi is very excited about the results of the latest clinical trials. She said that side effects appear to be about the same as many experience with a flu shot, a little soreness at the injection site and possibly a slight fever.
“It is awesome to see that this actually works and is now in human trials and that all the work was worth it,” she said.
But a lot of questions remain to be answered. Besides the question of how quick it can take effect, there is the question of how long a vaccination may remain effective. Marzi said that work on guinea pigs shows that the vaccine is effective for at least nine months and, judging from a related vaccine based on the same principle in macaques, it can last at least up to 13 months.
“With ongoing clinical trials in humans we have a chance to look into that,” she said.
This is a question that will take some time to answer.
Another exciting result of the work, according to Marzi, is that the technique used to create the Ebola vaccine using the VSV offers a platform that could be used in development of vaccines for other diseases such as Marburg, Lassa, Andes and Nika fevers.
The study results were published in Science: A Marzi et al. VSV-EBOV rapidly protects macaques against infection with the 2014/15 Ebola virus outbreak strain. Science DOI: 10.1126/science.aab3920 (2015).