How an Ebola vaccine candidate activates our immune system
In 2016, a clinical phase I trial on a potential vaccine against the dreaded Ebola virus was successfully completed. The tested vaccine “rVSV-ZEBOV” proved to be safe and effective. In a further trial, DZIF scientists from the University Medical Center Hamburg-Eppendorf (UKE) have now shown in detail how our immune systems react to the vaccine for the first time. This is an important step on the path to licensing a vaccine.
“Alongside antibodies, Ebola specific T cells are developed after the vaccination. Numerous immunotransmitters are also released after contact to the Ebola glycoprotein,” explains Christine Dahlke, DZIF scientist at the UKE Hamburg-Eppendorf and first author of the current trial. The extensive data showed that stronger immune responses are induced by administering the highest dose of 20 million PFU (plaque forming units). This is an important aspect for the scheduled licensing process which is due to be completed by the company MSD this year. The acquired immune response induced by the vaccine protects humans by developing antibodies as well as Ebola specific T cells which, for example, recognise and eliminate infected cells. While antibody responses can be detected quickly in the serum, the investigations for Ebola specific T cells are far more complex and extensive.
Rapid development of a vaccine against Ebola
When the WHO declared the Ebola epidemic an international public health emergency in 2014, the German Center for Infection Research had already been working on an Ebola vaccine. Since November 2014, the vaccine “rVSV-ZEBOV” has been tested in four independent clinical phase I trials. One of them was conducted at the UKE in Hamburg-Eppendorf, led by DZIF Professor Marylyn Addo. She and all other involved scientists are participants of a WHO founded expert consortium called VEBCON, which the aims at rapid and coordinated clinical Ebola vaccine testing. Now, only about two years later, the vaccine candidate is almost ready for licensing by the American authority FDA. However, up to now, it has not been clear which immune responses against Ebola are induced. “Initially, we knew that specific antibodies are developed against the virus and that these are still detectable after six months,” explains Marylyn Addo. It is likely that these antibodies substantially contribute to the vaccine protection.
However, what the scientists did not yet know was to what degree the other arm of our acquired immune system, the so-called T cells, are involved. Are Ebola specific T cells developed in response to the vaccination? And how does the immune system react to Ebola virus proteins? Are transmitters activated? Does the immune system still become activated after three to six months, when it recognises Ebola proteins?
Current study
The research team led by Addo has now closed the knowledge gap using the samples that had been collected from 30 healthy trial subjects of the clinical phase I trial in Hamburg. In Hamburg, three different doses of rVSV-ZEBOV were tested (ten trial subjects per dose group). The scientist created a so-called immuneprofile which details the acquired immune responses with regard to the different doses.
“Trial participants who received the vaccine in the highest administered dose developed T cells that specifically targeted the Ebola glycoprotein used in the vaccine,” explains Christine Dahlke. In an Ebola infection, these T cells are able to recognise infected cells and induce cell death, so-called apoptosis. Additionally, a cascade of signal molecules and transmitters were activated, which activate immune cells and therefore inhibit viral replication in infected people. “This knowledge about the exact mechanisms of defence in different doses is very important for finding the ideal dose and will have an effect when the vaccine is used,” explains Dahlke. The scientists are confident that their investigations will make a contribution to doctors being better armed in the next outbreak.
Background
rVSV-ZEBOV is an attenuated, genetically modified vesicular stomatitis virus (VSV) that carries an Ebola virus surface protein called glycoprotein. The development of the vaccine was supervised by the WHO through VEBCON. The German Center for Infection Research supported the preparation of the trials at the UKE in Hamburg and in Gabon and provided initial funding. The Federal Ministry of Health (BMG) and the British Wellcome Trust provided the funding for the clinical trial preparation and implementation. The Canadian Health Authority donated the vaccine candidate to the WHO, which then made it available for these trials.
