April 6, 2017
The French National Institute of Health and Medical Research (Inserm), the US National Institutes of Health (NIH) and the London School of Hygiene & Tropical Medicine (LSHTM), in collaboration with health authorities in Guinea and Liberia, are launching a large clinical trial of candidate Ebola vaccines under the aegis of the PREVAC international consortium (Partnership for Research on Ebola VACcination).
This trial seeks to identify vaccination regimens that hold the most promise to protect people from Ebola virus disease in order to prevent or quickly control a future outbreak. More than 5,000 adults and children living in countries at the epicenter of the 2014-16 West Africa Ebola epidemic will be enrolled. An additional site in Sierra Leone is also being planned. The PREVAC trial results from a research partnership that involves Inserm, NIH, LSHTM, and the West African Clinical Research Consortium.1 The pharmaceutical companies Janssen Vaccines & Prevention B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, Bavarian Nordic and Merck Sharp & Dohme, Corp (MSD outside USA and Canada), are supplying the experimental vaccines being tested in the PREVAC trial.
The trial will compare three experimental Ebola vaccination strategies with placebo regimens. It will be conducted in two stages, the first stage to take place in Guinea and Liberia. In Guinea, the trial is being conducted under the sponsorship of Inserm with the support of NIH and in collaboration with the Guinean authorities, and involves a partnership with the non-governmental organization ALIMA (The Alliance for International Medical Action). The NIH is sponsoring the trial based in Liberia, under its collaboration with the Liberia Ministry of Health in the Partnership for Research on Ebola Virus in Liberia (PREVAIL). Pending confirmation of funding, LSHTM will sponsor the planned site in Sierra Leone working with the University of Sierra Leone’s College of Medicine and Allied Health Sciences, which would conduct the study.
In its first stage, the trial will evaluate one of the three strategies, a prime-boost vaccination combining two different vaccines (one made by Janssen and the other by Bavarian Nordic) compared with a similar placebo regimen. Enrollment into this stage in Guinea and Liberia began on 27th March and 3rd April 2017, respectively. In a second stage, which is expected to start in the second half of 2017, the trial will evaluate all three vaccination strategies, including two additional strategies involving the Merck Sharp & Dohme, Corp vaccine.
On 29 March 2016, the Director-General of the World Health Organization (WHO) announced the end of the Public Health Emergency of International Concern caused by the Ebola outbreak.2 At the end of this epidemic, although important advances have been achieved, several questions remain regarding the durability of the immune response of candidate vaccines under development. PREVAC trial will evaluate the rapidity, intensity and duration of the immune responses generated by the various vaccination strategies, and the safety and tolerability of the various vaccines, particularly in children.
According to Yves Levy, Inserm Chairman and CEO; Anthony S. Fauci, Director of the National Institute of Allergy and Infectious Diseases at NIH; and Peter Piot, Director of the LSHTM: “We, Inserm, NIH, and LSHTM, have designed and launched this unique international research partnership with our colleagues from the West African countries most affected by Ebola virus disease to answer remaining questions regarding the safety and immunogenicity of candidate Ebola vaccine strategies and thereby enable us to better fight future Ebola outbreaks.”
The first stage of the PREVAC study will evaluate a prime-boost strategy that includes the Janssen and Bavarian Nordic experimental vaccines:
- Ad26.ZEBOV administered as a first dose followed 8 weeks later by MVA-BN-Filo as a booster dose.3 This vaccination strategy will be compared to an identical regimen in terms of dosage and duration, but made up of two placebos.
The second stage of the PREVAC study will evaluate all three strategies: the one used in the first stage, and two different regimens involving the experimental Merck Sharp & Dohme, Corp vaccine:
- rVSV∆G-ZEBOV-GP4 administered as a first dose followed 8 weeks later by a booster dose of the same vaccine
- rVSV∆G-ZEBOV-GP administered as a first dose followed 8 weeks later by an inert placebo
Each of these vaccination strategies will be compared to an identical regimen in terms of dosage and duration, but made up of two placebos.
PREVAC in Brief
Currently, there is no approved vaccine to prevent Ebola virus disease, although some vaccines are at late stages of development. To better prepare for Ebola outbreaks and help contain them in future, it is essential to pursue research on vaccination strategies to prevent Ebola virus disease.
PREVAC (Partnership for Research on Ebola VACcination), is a research consortium that brings together the health authorities of three countries in West Africa—Guinea, Liberia and Sierra Leone—and their international partners, the National Institute of Health and Medical Research (Inserm) in France, the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID/NIH) in the United States, and the London School of Hygiene & Tropical Medicine (LSHTM) in the United Kingdom. Additional partners in the consortium include the NGO field partner Alliance for International Medical Action (ALIMA). The pharmaceutical companies Janssen Vaccines & Prevention B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, Bavarian Nordic and Merck Sharp & Dohme, Corp (MSD outside USA and Canada), are supplying the experimental vaccines being tested in the PREVAC trial.
The PREVAC trial is a Phase 2 clinical trial being conducted in West Africa. It is a randomised trial that aims to compare three experimental Ebola vaccination strategies with placebos in order to determine whether these strategies are safe and able to trigger a durable immune response that can protect against Ebola virus disease. In the first stage, the trial intends to enroll up to 600 participants 12 years or older. In the second stage, the trial intends to enroll 4,900 participants: 3,500 healthy adults aged 18 years or older, and 1,400 children aged 1-17 years. The study will initially be conducted at two sites in Guinea (Conakry/Landréah and Maferinyah) and one site in Liberia (Monrovia), with an additional site in Sierra Leone awaiting confirmation.
The main objectives of the PREVAC Ebola vaccine trial are as follows:
- To further explore the safety of three Ebola vaccination strategies and their ability to trigger a protective and durable immune response against Ebola virus
- To assess these vaccination strategies in the general population and in important groups, such as children, for which there is only limited information available
- To obtain information on the duration of the immune response induced by the vaccines
In Guinea, two vaccination centres have been established, one in Conakry (in an urban area) and the other in Maferinyah (in a rural area). Liberia has one vaccination site in Monrovia.
According to Yazdan Yazdanpanah, PREVAC Principal Investigator, “Our challenge is to identify one or more safe, effective and durable vaccines in order to prevent or control the next Ebola outbreak, for both adults and children.”
"ALIMA's medical teams were at the front line in caring for patients with Ebola virus disease in Guinea. Today we know that this virus may reappear at any time. We therefore want to continue to support the population by pursuing the search for a vaccine capable of protecting the population from future epidemics," says Solenne Barbe, Programme Manager for ALIMA.
After the enrollment period, the participants will be followed up frequently at regular visits for at least 12 months. Teams of physicians, researchers and anthropologists will work in partnership in the field to ensure that the trial runs smoothly, and to answer questions from study participants and potential volunteers. Study staff will monitor participants’ health, record any side effects, and obtain blood samples at follow-up visits after the vaccinations.
An independent Data and Safety Monitoring Board (DSMB) will closely monitor safety and immune response information throughout the trial. Children under the age of 12 years will not be enrolled initially. The DSMB will first examine data in children ages 12 to 17 years to determine if it is safe to expand the trial to children ages five to 11 years. After another review of safety data, the DSMB will consider whether vaccination of children ages one to four years can begin.
There is no risk to participants in this trial of becoming infected with Ebola by the study vaccines. The vaccines being tested are not live Ebola virus. They contain a single gene coding for a single protein from the Ebola virus. This protein cannot cause infection. The principle is the same as for many other existing vaccines.
Additional information about the trial can be found on ClinicalTrials.gov under the identifier NCT02876328 and in the Questions and Answers below.
How does a preventive vaccine work?
Preventive vaccination usually involves administering an attenuated or inactivated form of an infectious agent (or one or more of the agent’s components) to a healthy individual. The objective is to trigger an immune response that involves the development of “memory” cells of the immune system that can immediately recognise the pathogen if it subsequently infects the individual.
1The WACRC—established in 2015 by scientific leaders in Liberia, Guinea, and Sierra Leone, and now also including Mali—conducts collaborative research to prevent or help respond to future outbreaks of Ebola and other infectious diseases and thereby advance health preparedness and security in this sub-region of West Africa.
3The Ad26.ZEBOV vaccine was developed by Janssen Vaccines & Prevention B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, and the MVA-BN-Filo vaccine was developed by Bavarian Nordic A/S. This investigational Ebola vaccine regimen was developed in a collaborative research program with the National Institutes of Health (NIH). Additional funders who have supported development of this vaccine regimen include Europe’s Innovative Medicines Initiative (IMI), and the Biomedical Advanced Research and Development Authority (BARDA), an office within the U.S. Department of Health and Human Services.
4The rVSV ∆G-ZEBOV-GP vaccine was developed by the Public Health Agency of Canada. The vaccine was licensed to NewLink Genetics, and on 24 November 2014, Merck Sharp & Dohme Corp. (MSD outside USA and Canada) and NewLink Genetics Corp. entered into a worldwide and exclusive licensing agreement in which Merck Sharp & Dohme Corp assumes responsibility for research, development, manufacture and distribution of the experimental vaccine. The Canadian and US Governments, among others, have contributed financial support.
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PREVAC—Partnership for Research on Ebola VACcination
In June 2015, during the West Africa Ebola outbreak, scientific leaders from Liberia, Sierra Leone and Guinea formed a research partnership—the West African Clinical Research Consortium—to conduct collaborative research and advance public health in this sub-region of West Africa. PREVAC (Partnership for Research on Ebola VACcination) is an international collaboration that stems from the WACRC and currently includes the health authorities in Guinea, Liberia and Sierra Leone and their international sponsors, the French National Institute of Health and Medical Research (Inserm) and the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health (NIAID/NIH), and the London School of Hygiene & Tropical Medicine (LSHTM). Other consortium partners include the NGO field partner The Alliance for International Medical Action (ALIMA). Pharmaceutical companies Janssen Vaccines & Prevention B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, Bavarian Nordic and Merck Sharp & Dohme, Corp. (known as MSD outside the United States and Canada) are donating the experimental vaccines being tested in the PREVAC vaccine study.
The PREVAC vaccine study, being conducted in West Africa, is a large, randomized, placebo-controlled Phase 2 clinical trial to assess the safety and ability of three different Ebola vaccine strategies to stimulate an immune response to the virus that may protect against Ebola virus disease.
Inserm and the U.S. National Institutes of Health are funding the study in Guinea, with the support of the Guinean Ministry of Health. The Liberian Ministry of Health and the U.S. National Institutes of Health are funding the study in Liberia. Pending confirmation of funding, LSHTM will sponsor the planned site in Sierra Leone, which will be conducted by the University of Sierra Leone’s College of Medicine and Allied Health Sciences.
The study began enrolling participants on 27th March 2017 in Guinea and 3rd April 2017 in Liberia.
The study will test three different vaccine strategies compared to placebo. In the first stage, which began in March 2017, one prime-boost strategy will be evaluated. The experimental vaccine Ad26.ZEBOV (Janssen) will be given as the primer dose, followed 8 weeks later by a booster dose of MVA-BN-Filo (Bavarian Nordic). This vaccine strategy will be compared to a regimen that is identical in dosage and timing but contains two inactive placebos.
In the second stage of the PREVAC study, which is expected to begin in the latter half of 2017, two additional experimental Ebola vaccine strategies will be tested:
- rVSV∆G-ZEBOV-GP (Merck Sharp & Dohme, Corp) given as the primer dose followed 8 weeks later by a booster dose
- rVSV∆G-ZEBOV-GP given as a first dose, followed 8 weeks later by an inactive placebo
Each of these vaccine strategies will also be compared with a regimen of inactive placebo that is identical in dosage volume and timing.
The vaccines being tested contain a single gene coding for a single protein from the Ebola virus. This protein cannot cause infection. The vaccines stimulate the body to make an immune response to Ebola in the form of infection-fighting antibodies. The principle is the same as for many other existing vaccines.
The study aims to enroll 5,500 people overall. In the first stage, the trial intends to enrol up to 600 participants 12 years or older. In the second stage, the trial intends to enrol 4,900 participants: 3,500 healthy adults aged 18 years or older, and 1,400 children aged 1-17 years. Children younger than 12 years old will be enrolled in the study only after the safety of the vaccine strategies is demonstrated in older participants. Some people are not eligible to join the study, for example, people who have a fever, Ebola survivors, and women who are pregnant or are breastfeeding.
Participation in the study is strictly voluntary. A detailed explanation of the study (oral explanation supported by materials either in writing or based on cartoons) will be given to potential participants, who also will have the opportunity to ask questions of the study team. Once an individual has decided to join the study, he or she will be asked to sign an informed consent form. Even after signing a consent form, a participant can withdraw from the study at any time with no penalty.
It is not possible to get Ebola from the vaccines being tested in the study. The safety of the vaccines and matching placebo will be further evaluated in the PREVAC study. Like many vaccines, they can cause side effects in some people.
In other clinical studies of the Ad26.ZEBOV/MVA-BN-Filo vaccine regimen, nearly 2,500 adults have been vaccinated to date in countries including Sierra Leone, Burkina Faso, Côte d'Ivoire, Uganda, Kenya, the United States, the United Kingdom, and France. The Ad26.ZEBOV/MVA-BN-Filo vaccine regimen appears to be well tolerated by adult volunteers. Vaccination of adolescents (individuals aged 12-17 years) in clinical studies in Africa has now begun.
In other clinical studies of the rVSV∆G-ZEBOV-GP vaccine regimen, more than 16,000 people, mostly adults, have been vaccinated to date in countries including Guinea, Sierra Leone, Liberia, United States, Canada, Switzerland, Germany, Kenya, and Gabon. Vaccination of adolescents (individuals aged 12-17 years) and children (individuals aged 6-11 years) in clinical studies in Africa has been initiated.
Other studies have shown that these experimental Ebola vaccines, like many other vaccines, can cause side effects in some people. In clinical studies conducted to date with the Ad26.ZEBOV/MVA-BN-Filo vaccine regimen among healthy volunteers, side effects have included injection site pain and swelling; headache, fatigue, muscle aches and fever. In studies conducted on the rVSV∆G-ZEBOV-GP vaccine, side effects have included pain, redness, or swelling in the arm of the injection; fever, headaches, mouth sores, tiredness, muscle aches, arthritis, joint pain, joint swelling and loss of appetite.
No. It is not possible to get Ebola from the vaccines being tested in the study because they do not contain the whole Ebola virus. Only the whole Ebola virus can cause infection. The experimental vaccines contain only a small component of the Ebola virus to help the body fight against the whole Ebola virus.
The study will take part in two stages. In the first stage, participants will be assigned by chance to receive either the Ad26.ZEBOV/MVA-BN-Filo vaccine regimen or to receive two saltwater placebos.
In the second stage, participants will be assigned by chance to receive either one of the three vaccine strategies or to receive two saltwater placebos.
To avoid potential bias, neither the study participant nor the study staff will know which group the participant is in until the end of the study. Participants will be asked to come back to the clinic 8 or 9 times during the first year. The main goals of the study are to further evaluate the safety of the different vaccine strategies as well as their potential to stimulate an immune response that may protect against Ebola virus disease, and to study how long that immune response lasts.
Before the study began enrolling, social mobilization, community engagement, and communication (SMC) activities began in Guinea and Liberia to prepare communities for the study. These activities involve stakeholders to ensure there is dialogue and community engagement to enable community input, ensure accurate knowledge, answer questions, and address concerns people may have about the study and study processes. SMC activities continue throughout the conduct of the trial.
No, study participants will not be paid. However, they will receive compensation at each clinic visit to contribute to their transportation costs and time lost from work.
The study team hopes to follow the participants for five years.
If a person gets sick while enrolled in the study, he or she should contact the study staff right away by calling the telephone number on a card given out at the time of joining the study. The study staff will evaluate the individual and arrange health care for any participants who experience study-related side effects.
Pr. Yazdan Yazdanpannah (Inserm) is coordinating principal investigator for the study overall. Dr. Abdoul Habib Beavogui is principal investigator for PREVAC in Guinea; Dr. Mark Kieh is principal investigator for PREVAC in Liberia, where the study is also known as PREVAIL V.
There is a need for effective Ebola vaccines for adults and children in the event that another Ebola outbreak occurs. The vaccines being studied in the PREVAC trial have been tested in a number of clinical trials, but more data needs to be gathered to attain a sufficient level of proof regarding the safety and immune response of the vaccine strategies. In particular, PREVAC will provide important data on both the immediacy and durability of the immune response generated by each of the vaccine strategies, as well as additional safety data in both children and adults.
The recent outbreak in West Africa has been declared over, but there have been many outbreaks of Ebola across Africa in the last few decades and Ebola is likely to return. It is therefore crucial that effective, licensed vaccines that offer long-term protection are available to prevent Ebola wherever it may strike next.