The problem: establishing efficacy of a promising Ebola vaccine
2014-2016 saw the biggest Ebola outbreak in history. With the death toll climbing, the race was on to develop and test a vaccine that could halt its spread. One of the most promising vaccines, originally developed by the Public Health Agency of Canada, was granted permission for use in clinical trials in Africa, Europe, the United States and Canada to test its safety and efficacy. However, the number of new cases began to decline before some of the trials started. This meant that efficacy could only be evaluated in one phase three clinical trial. That left some unanswered questions: researchers had good evidence that the vaccine worked, but the exact mechanisms were still unknown. Crucially, it was unclear how long the vaccine could be expected to provide protection in those who received it.
Getting a picture of the immune response – and side effects
The vaccine is based on the vesicular stomatitis virus, genetically engineered to contain a protein from the Zaire strain of the Ebola virus. Over 16, 000 volunteers have received the shot as part of controlled trials. In a study conducted in Guinea during the west African outbreak, the vaccine was shown to be up to 100 % effective using a “ring vaccination” method; this means vaccinating the patient’s close contacts as well as the contacts of those close contacts. In 2015, VSV-EBOVAC got to work using cutting-edge technologies to analyse samples taken from volunteers before and after vaccination during the early clinical trials. This gave them excellent data on the type and strength of the immune responses triggered, as well as the kind of side effects that could be expected.
When a vaccine is administered it leaves its own plasma signature, which is the telltale sign in the blood of vaccine-induced immune activity. VSV-EBOVAC researchers were able to single out the rVSV∆G-ZEBOV-GP plasma signature. They now know more about how antibodies elicited by the vaccine in the body bind to viral glycoproteins, the rod-like proteins that dot the membrane of the virus. The researchers studied the neutralising properties of the antibodies, as well as their affinity and avidity, or how strongly and they bind to the virus.
They also made significant headway in determining the durability of immunity. They found that the antibody responses to rVSV∆G-ZEBOV-GP were shown to be going strong at least one year after immunisation, and VSV-EBOVAC’s follow-on project, VSV-EBOPLUS, later confirmed immunity up to two years (that project will soon be able to confirm if protection is conferred for up to five years). These immune responses were sustained across dose ranges and settings – as well as across gender, age and ethnicity – which is good news in countries where booster campaigns pose practical challenges.
They identified, too, the cytokines and chemokines that could be red flags for adverse reactions such as (self-limiting) arthritis, and showed that the occurrence of this side effect is associated with increased antibody responses over time. Another important discovery was that pre-existing antibodies against the virus didn’t affect the response to the vaccine.
Researchers also studied the response to vaccination using transcriptomics and metabolomics, which quantify, respectively, the messenger RNAs and the metabolites in blood, allowing the identification of characteristic transcriptomic and metabolomics signatures of the rVSV∆G-ZEBOV-GP vaccine.
Filling the translational gap, from the lab to local campaigns
The VSV-EBOVAC project can now provide public-health planners and workers with practical information related to how the vaccine works. It fills a translational gap between R&D in the lab and the response to the major Ebola outbreak that started in the east of the Democratic Republic of Congo in summer 2018. As part of the response to this Ebola outbreak, thousands of people were immunised with rVSV∆G-ZEBOV-GP (around 200,000 in the first year of the outbreak alone), and the data from the project has produced crucial clinical evidence that will speed up licensing. Some of the data have been published open access in important scientific journals and made available to other Ebola-related projects through the Central Ebola+ Information repository The project partners are hopeful it will help researchers studying other haemorrhagic fever disease strains establish safety and efficacy in the development of vaccines.
Speed and access
The project was made up of partners from different disciplines. The speed at which the work could be carried out was cited as one of the key benefits of working in an IMI-funded consortium. Researchers had direct access to the vaccine developer industry partner, another major advantage of IMI-funded projects, and the industry gained access to academic knowledge and skills unavailable in house. For the larger pharmaceutical industry partner, validating the most promising Ebola vaccine candidate for one of the world’s most high-profile, urgent and terrifying diseases was considered very positive for the public perception of the company. University partners also felt participation elevated their profile. As with all IMI projects, one of the key benefits is how the project allowed them to form new networks and partnerships, with SMEs working alongside academia and industry to get to know the context in which each operates, create new spin-off projects and seek funding opportunities.
The vaccine has been granted “Breakthrough Therapy Designation” by the FDA, and PRIority MEdicines (PRIME) status by the European Medicines Agency, and it is being used to support the 2018 outbreak control in the Democratic Republic of Congo. VSV-EBOPLUS is the follow-on phase of VSV-EBOVAC. Also funded by IMI, this project allows the project partners to extend follow up of clinical trials of the rVSV∆G-ZEBOV-GP vaccine to five years and to conduct clinical trials in children. They are refining the plasma signature and digging much deeper into the innate immune responses, and will soon be able to confirm if vaccine-induced antibody titers remain strong at five years after immunisation.
The VSV-EBOVAC project is part of IMI’s Ebola+ programme.
Achievements & News
How exactly does our immune system respond to vaccination? In the first study of its kind, scientists from IMI’s VSV-EBOVAC project, studying a promising Ebola vaccine, set out to find out which immune cells get activated early on, which inflammatory markers are released after that, and how this early activity later impacts the production of antibodies against the Ebola virus.### In the process, they discovered a unique signature of a promising Ebola vaccine candidate which could not only help predict adverse reactions and the effectiveness of this vaccine, but also inform the development of vaccines for other diseases as well. ‘These findings are important and indeed ground-breaking,’ said Claire-Anne Siegrist of the University of Geneva, the project's scientific coordinator. ‘No signature for this vaccine or any other Ebola vaccine has been previously identified. On a clinical level, this plasma signature can serve as a biological clue (biomarker) to anticipate and determine common side effects and the ability of our bodies to produce protective antibodies against the Ebola virus.’ The findings, which were published in the prestigious journal Science Translational Medicine, wouldn’t have been possible without IMI, she added. ‘The public-private nature of the project was tremendously important in achieving these results. In addition to academic partners, representatives of the vaccine manufacturers played a very important role in the study.’
Earlier this summer, researchers announced in The Lancet that an Ebola vaccine developed with Merck had shown 100% effectiveness in a Phase III clinical trial of over 7 000 people in Guinea. This is one of the potential vaccines being developed for the disease, and researchers say that work must continue.###
IMI’s VSV-EBOVAC project is studying in detail the signatures of immune responses elicited in humans by the VSV-ZEBOV vaccine using cutting-edge technologies combining in-depth human immune, transcriptomics and metabolomics profiling in relation to safety and immunogenicity.
One of the outstanding questions – which VSV-EBOVAC hopes to answer once enough time has elapsed since the Phase I trial, started in November 2014 – is how long the immunisation remains effective.
Many believe that the Merck vaccine should be used to protect those at high risk in areas still affected by Ebola. However, it may take months for approval by authorities.
The timing means that these vaccines under development are unlikely to have much of an impact on the current epidemic. However, these vaccines have been developed at unprecedented speed, and the work being done lays down techniques that could be used in similar fast-moving epidemics.
- To find out more, read the Horizon Magazine article
ParticipantsShow participants on map
Universities, research organisations, public bodies, non-profit groups
- Academisch Ziekenhuis Leiden, Leiden, Netherlands
- Centre de Recherches Medicales de Lambaréné, Lambaréné, Gabon
- Department of Health, Leeds, United Kingdom
- Eberhard Karls Universitaet Tuebingen, Tuebingen, Germany
- Eidgenossisches Departement Fur Verteidigung, Bevolkerungsschutz Und Sport, Bern, Switzerland
- Emory University Non Profit Corp, Atlanta, Georgia, United States
- Goeteborgs Universitet, Gothenburg, Sweden
- Sclavo Vaccines Association, Siena, Italy
- Universita Degli Studi Di Siena, Siena, Italy
- Universite De Geneve, Genève 4, Switzerland
- University of Oxford, Oxford, United Kingdom
Small and medium-sized enterprises (SMEs) and mid-sized companies (<€500 m turnover)
- Bioprotection Systems Corporation, Ames, United States
- Microbiotec SRL, Siena, Italy
|EU funding in €
|Academisch Ziekenhuis Leiden
|Bioprotection Systems Corporation
|Centre de Recherches Medicales de Lambaréné
|Department of Health
|Eberhard Karls Universitaet Tuebingen
|Emory University Non Profit Corp
|Sclavo Vaccines Association
|Universita Degli Studi Di Siena
|University of Oxford
|3 887 260