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Questions and Answers – Ebola ça suffit! - Phase III Vaccine Trial in Guinea

31 July 2015

What is the Ebola vaccine trial in Guinea trying to achieve?

The Ebola vaccine trial in Guinea is testing the efficacy of an experimental vaccine against Ebola. If the vaccine is found to be safe and effective, the evidence generated during the trial will support its use in the current Ebola outbreak and potential future outbreaks. If licensed, the vaccine would be the first preventive medical intervention in history against the Ebola virus.

Who is conducting the Guinea vaccine trial?

The Guinea Ebola vaccine trial is conducted under the responsibility of the Government of the Republic of Guinea.

The sponsor of the study is the World Health Organization (WHO); it is implemented by the Ministry of Health of Guinea, Médecins sans Frontières (MSF), EPICENTRE, the Norwegian Institute of Public Health and WHO. The trial is funded by WHO, with support from the Wellcome Trust (United Kingdom); MSF; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; and the Canadian government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development. The trial team includes experts from the University of Bern, the University of Florida, the London School of Hygiene and Tropical Medicine, Public Health England, and the European Mobile Laboratory among others.

What is a ‘ring vaccination’ strategy?

The trial uses a ‘ring vaccination’ strategy and is based on the approach that was used to eradicate smallpox. This involves the identification of a newly diagnosed Ebola case – an ‘index case’ – as well as of all her/his contacts and the contacts of those contacts, usually their family members, neighbours, co-workers and friends. In the current trial, where vaccination is confined only to adults, a ring is defined as the contacts and contacts of contacts of the index case, and is estimated to be around 50-100 people. The adults in the ring are vaccinated if they give their consent. There are two main objectives of the trial: first to assess if the vaccine protects those who were vaccinated and second to assess whether vaccination impacts the overall transmission of Ebola virus disease in the ring.

In practical terms, this means that the close contacts of a newly identified Ebola case will be vaccinated if they consent to it.

To evaluate the efficacy of the vaccine, half of the rings are vaccinated as soon as the index case is identified; this is called an immediate vaccination ring. The other half of rings are vaccinated 21 days later; this is called a delayed vaccination ring. This method is an alternative to using a placebo (an inactive preparation) as a control group; it provides a useful comparison between groups, and allows all consenting contacts – who are at risk of developing the disease - to be vaccinated within the context of the trial.

In addition, front line workers in the study area are all offered vaccination as part of a companion safety and immunogenicity study to the ring vaccination trial.

The trial design was developed by an international group of experts from Canada, Guinea, France, Norway, Switzerland, UK, USA, and WHO, which also included Prof. Donald A. Henderson, who led the WHO campaign to eradicate smallpox.

Which vaccine is being used and why?

The rVSV-ZEBOV (Merck, Sharp & Dohme, USA) vaccine was selected for this trial. This vaccine, one of the two most advanced Ebola vaccines under development, was developed by the Public Health Agency of Canada. The vaccine was licensed to NewLink Genetics, and on November 24, 2014, Merck & Co., Inc and NewLink Genetics Corp. entered into an exclusive worldwide licensing agreement wherein Merck assumes responsibility to research, develop, manufacture, and distribute the investigational rVSV-ZEBOV Ebola vaccine.

The choice of which vaccine to be tested among candidates was based on an evidence-based algorithm that was reviewed by independent experts specifically to help take this decision.

Where is the Guinea trial happening ?

The Ebola ça suffit! vaccine trial is being conducted in the areas of Guinea where most of the Ebola cases are being reported. Currently this is in an area including Conakry the capital of Guinea and surrounding prefectures known as Basse Guinée. At this moment, the trial teams are active in 7 prefectures of Guinea.

Are communities welcoming vaccination?

In preparation for the trial, social-anthropologists and community engagement teams provided advice on the best way to understand and approach communities in Guinea. Guinea is a multi-lingual multi-ethnic country with limited access to television and newspapers, where a one-size-fits-all approach or a reliance on mass media to communicate with the population would not work.

Since the trial started, communication with communities has been crucial to enrol fully informed consenting volunteer participants. Before the vaccinators arrive, community facilitators explain the purpose of the trial and the fact that it is not yet known whether the vaccine will provide protection against Ebola virus disease, or not. The community facilitators also provide a first level of information regarding real and perceived concerns about harm from the vaccine. Moreover, the trial staff always emphasizes the need for all participants to continue to protect themselves from Ebola virus infection through recommended practices.

Some of the contacts of Ebola patients – who are part of the “rings” that will be vaccinated - may already be infected and incubating the disease. Therefore, they may themselves develop the disease in the first few days after vaccination, even though they have been vaccinated, because the human immune system requires a few days to mount protection against disease after an individual is vaccinated. When communities see vaccinated people becoming sick with Ebola virus disease, they may fear that the vaccine itself is causing the disease, and death, which is of course not the case. The result could be a rejection of the vaccine trial and this could even put trial staff at risk. It is therefore of utmost importance that all these issues are well explained to the community, using local language and appropriate communication channels.

Are adolescents, children and pregnant women offered the vaccine?

The trial so far did not include persons younger than 18 years of age. As safety data is being collected and examined in vaccine trials on individuals under 18 in other countries, adolescents and children may also be included in the trial in the forthcoming weeks.

Because of unknown theoretical risks to the foetus, it is usual practice in vaccine development not to immunize pregnant or lactating women until the safety of the vaccine in other population groups has been definitively demonstrated.

Why are you vaccinating frontline workers in this trial?

Frontline workers, who are one of the highest-at-risk groups for Ebola virus disease, are being vaccinated in a “companion” study. The objectives of that study are to study the safety profile of the vaccine and to characterise the immune response which might protect them against infection from Ebola virus. Participating in the study will also give them the opportunity to get more familiar with the vaccination that they will help to implement in the communities and to access a potentially effective vaccine.

Is trial staff in danger of becoming infected with Ebola virus?

The vaccine is being administered to contacts of newly diagnosed Ebola cases who are healthy and without symptoms of Ebola. A person who does not show symptoms of Ebola cannot transmit the disease, even if he or she is actually infected and incubating the disease. The risk for staff administering Ebola vaccines to people without symptoms is therefore limited and comparable to routine contact tracing. Nevertheless, all necessary precautions to prevent Ebola virus infection are taken. All staff use protective clothing and gloves, masks and googles as appropriate.

What has the trial achieved so far?

Thus far, the trial has succeeded with the definition of over 100 rings (i.e., clusters of close adult contacts, or adult contacts of close contacts of a newly confirmed Ebola case), with the random (chance) allocation of those rings to immediate or delayed vaccination (21 days later) of over 4000 volunteers. The trial team has been able to follow over 90 percent of the people of those rings and this has allowed them to determine whether any of the people who are part of the ring develop Ebola virus disease over the next few days or weeks. Preliminary results from the trial were evaluated by an international group of experts - the Data and Safety Monitoring Board, DSMB - who concluded that the results are promising, with early indication of efficacy of the vaccine. The DSMB recommended that the trial continues, in order to generate more data on vaccine effectiveness. They also advised that in the future all rings should be vaccinated immediately (no more delayed vaccination). This takes into consideration the fact that in the last few months the level of Ebola virus disease transmission in Guinea is low. Updated results have been published on XXX in scientific article in The Lancet.. What is the efficacy of the vaccine in the trial so far? The results reported in The Lancet provide the first evidence that the rVSV-ZEBOV vaccine protects people exposed to Ebola virus disease. So far, not a single vaccinated person developed Ebola virus disease 10 days or more after receiving the vaccine. A few vaccinated people developed the disease 9 days or less after vaccination because they were most probably already incubating the disease by the time they received the vaccine. The results suggest that the efficacy of the rVSV vaccine is 100%. The results are called interim because the trial continues in Guinea

What is the efficacy of the vaccine in the trial so far?

The results reported in The Lancet provide the first evidence that the rVSV-ZEBOV vaccine protects people exposed to Ebola virus disease. So far, not a single vaccinated person developed Ebola virus disease 10 days or more after receiving the vaccine. A few vaccinated people developed the disease 9 days or less after vaccination because they were most probably already incubating the disease by the time they received the vaccine.

The results suggest that the efficacy of the rVSV vaccine is 100%. The results are called interim because the trial continues in Guinea.

What will happen now with the trial?

The DSMB recommended that more data should be generated in order to make definitive conclusions on vaccine effectiveness. A continuation of the trial is therefore needed.

Following the DSMB recommendation, the trial team has stopped randomisation and is now vaccinating volunteers in all the new rings immediately after these rings have been defined around new Ebola virus cases (no more randomization of delayed rings). This is being done within the context of a continued clinical trial setting and procedures.

This change has been approved by the National Regulatory Authority and the National Ethics Committee of the Republic of Guinea, and are been implemented since July 27, 2015.

As new evidence on safety in the age groups below 18 years of age emerges from other clinical trials, 13 to 17-year-olds and possibly 6 to 12-year-olds will soon be included in the Guinea ring vaccination trial.

When are final results expected to become available?

As soon as the trial is completed and final trial results become available, the information will be shared with the government of Guinea and with the relevant authorities involved in the national and international Ebola response, as well as with the communities which participated in the trial. The final results will also be submitted for publication in an international scientific journal in order to allow broader dissemination. It is difficult to anticipate the exact date of availability of the final results, but it is expected that definitive efficacy results might become available in the last quarter of 2015 if all goes according to current plans.

When will the vaccine be available to all the populations in the affected countries ?

The rVSV-ZEBOV candidate vaccine is not yet a licensed product, and it cannot therefore be recommended for mass/population level use (i.e. outside clinical trials settings). The current evidence from the trial suggests that “ring vaccination” (vaccinating contacts and contacts of contacts of an Ebola case) may be a promising approach to halt Ebola transmission, and that mass vaccination might therefore not be necessary. The trial will continue to collect more evidence on the effectiveness of this vaccine and of ring vaccination as a strategy to stop Ebola.

How can you ensure safety while fast-tracking the process?

Information on safety is already available from a number of Phase I, II and III clinical trials performed in Africa, Europe and North-America. Some of these data has already been published. The WHO Global Advisory Committee on Vaccine Safety, international experts as well as the ethics and regulatory authorities of the countries concerned have examined these data and concluded that the vaccine is safe and induces an immune response. Fast-tracking of the process has therefore not resulted from cutting corners in the process to evaluate the vaccines, but from doing phase II and III trials in parallel, reducing procedural time lags; for example, by facilitating multi-country joint reviews of trial data by the concerned authorities, by accelerating data sharing between reviewers and manufacturers, and by harmonizing the requirements of the different ethics and regulatory committees.

When will the vaccine be licensed so it can be used to contain any future outbreaks in West Africa or elsewhere?

The rVSV-ZEBOV vaccine is still an unlicensed experimental product and the results generated by the Guinea trial are interim results. Regulatory authorities will now consider whether the data available is sufficient to provide a licence to the manufacturer (Merck) and to allow use of the vaccine outside of a clinical trial. This may take a few weeks or months.

Not everybody in the population is at risk of Ebola. It may thus not be necessary to vaccinate everyone but only those at risk (the rings around each case of Ebola), as well as frontline workers involved in dealing with Ebola cases.

If the vaccine supply is limited, how will it be prioritised?

The principles used to prioritize allocation of potentially limited doses of the vaccine should be fully transparent and involve the governments of the affected countries and communities in a participatory, inclusive manner. WHO and partners (MSF, the International Federation of Red Cross and Red Crescent, UNICEF, Gavi the Vaccine Alliance and others) have been working on an International Coordinating mechanism to achieve this. In brief, using the experience from vaccines for epidemic-prone diseases like Yellow fever, meningococcal disease or Cholera, the proposed mechanism aims to put in place a sufficient amount of vaccines and other supplies. Affected countries would have rapid access to this stockpile based on a set of pre-established criteria. Scientific and technical advice on the most appropriate vaccination strategy will be provided by the WHO Strategic Advisory Group of Experts on Immunization (SAGE).

What are WHO and its partners doing to accelerate access to Ebola vaccines?

A Global Ebola Vaccine Implementation Team (GEVIT) has been created under WHO’s leadership in order to facilitate the collaborative planning for the potential introduction of Ebola vaccines. This team currently associates countries most affected by the current EVD outbreak and important partners (CDC, GAVI, UNICEF, USAID, BMGF), who will be involved in procuring and introducing an Ebola vaccine. The team has been following two main objectives: (1) to support development and dissemination of tools and guidelines, synthesis of evidence to inform strategies and policies, and community engagement strategies; (2) to provide capacity and work with Ministries of Health and partners to develop and implement their country plans, to enable and facilitate in-country planning, management, and coordination mechanisms including Emergency Operations Centres. The GEVIT is fully operational and reports from country visits and plans are available.

If the candidate vaccine works and the epidemic is still ongoing, how will WHO and its partners ensure that everyone who needs to be vaccinated will receive the vaccine?

In April 2015, the WHO Strategic Advisory Group of Experts (SAGE) on immunization reviewed a framework for making recommendations regarding use of Ebola vaccines. Considerations included: specific scenario relating to the epidemiology and the type of authorization for vaccine use; objectives for vaccination (primary – stopping transmission, secondary – individual protection); prioritization of target populations; and additional considerations. This framework will be utilized when SAGE will issue recommendations.

Access to a safe and effective vaccine today and in the future is among the trial partners’ primary objectives. In addition, WHO, UNICEF, US CDC, BMGF and the Gavi Alliance are collaborating with the affected countries within the GEVIT framework to develop plans and strategies for large-scale introduction, should this be needed.

Vaccine manufacturers have assured that enough vaccine will be available in the coming months, although the production capacity for VSV-EBOV is limited in the short time frame.

Who will fund the vaccines if large-scale vaccination is recommended?

Financial resources are in place to procure and make vaccines available to the Ebola-affected countries. Millions of doses will be funded by Gavi (the Global Vaccine Alliance), whose Executive Board approved a US$300 million funding envelope in December 2014. There are also U$90 million earmarked to support vaccine deployment.