Posted on behalf of Declan Butler.
The World Health Organization (WHO) announced plans on 24 October to produce millions of doses of two experimental Ebola vaccines by the end of 2015.
Hundreds of thousands of doses should be available to help affected countries before the end of June, the WHO said at the conclusion of a meeting in Geneva, Switzerland. Vaccine makers, high-level government representatives and regulatory and other bodies gathered to discuss the design and timing of planned clinical trials, as well as issues of supply and funding for mass vaccination programmes.
Phase I trials of two vaccine candidates have started, and as many as five other vaccines could begin testing by 2015, says Marie-Paul Kieny, WHO assistant director-general for health systems and innovation.
As of 19 October, Ebola had infected almost 10,000 people in Sierra Leone, Liberia and Guinea and killed around 5,000 of them, the WHO estimates. The true figures are probably higher, as many cases go unreported. With no end to the epidemic yet in sight, a working vaccine could be a game changer.
First clinical trials under way
The two vaccines whose production will be increased are already in early-stage testing in healthy volunteers. One is a chimpanzee adenovirus vaccine containing a surface Ebola protein (ChAd3), developed by the US National Institute of Allergy and Infectious Diseases and drug giant GlaxoSmithKline (GSK). It is being tested in the United States, the United Kingdom and Mali.
The other is a recombinant vesicular stomatitis virus (rVSV) vaccine, developed by the Public Health Agency of Canada and licensed to NewLink Genetics in Ames, Iowa. It is being tested in the United States, with plans to start trials soon in Europe and Africa.
These phase I trials will assess the vaccines’ safety and whether they elicit levels of immune response that have been shown to confer protection in non-human primates. The trials will also assess the dose needed to generate sufficient immune response, which in turn helps to determine how quickly manufacturers can produce doses.
A third candidate is a two-vaccine regimen: one developed by US pharmaceutical company Johnson and Johnson and the US National Institute of Allergy and Infectious Diseases, and another by Bavarian Nordic, a biotechnology company based in Denmark. It will begin phase I testing in the United States and Europe in January. Johnson and Johnson announced on 22 October that it would spend up to US$200 million to fast track the vaccine’s development; it plans to produce more than 1 million doses in 2015, with 250,000 available by May.
The first phase II and III trials, to test efficacy as well as safety, are set to start in Liberia in December and in Sierra Leone in January. The current plan is to test both the GSK and NewLink vaccines simultaneously, but that could change depending on the results of the ongoing phase I trials. Data from the phase II and III tests are expected by April, Kieny says.
The ‘three-arm’ Liberia trial would test and compare the safety and effectiveness of the two vaccines against each other and a placebo. Each vaccine would be tested on 10,000 subjects, with an equal number of subjects given placebo. This allows researchers to obtain quick, reliable data on how well the vaccines work.
A ‘stepped-wedge’ randomized trial in Sierra Leone would give subjects vaccine sequentially, with no group given a placebo. This is useful for testing products that are expected to benefit patients, and products that are in short supply.
No trial design has yet been fixed for Guinea, where a lack of infrastructure has precluded early testing. If the Liberia and Sierra Leone trials show that the vaccines works and is safe, subsequent trials in Guinea would be used to answer follow-up questions.
Ethical and practical considerations
The Sierra Leone trial will enrol at least 8,000 health-care workers, and other frontline responders, such as ambulance drivers and burial workers. The Liberia trial might include health-care workers, but these would not be the primary study population, Kieny says.
Any decision to give a placebo to health-care and other frontline workers will be controversial; many consider it to be unethical, given these individuals’ work caring for Ebola patients, and the risks that they face in doing so.
Mass vaccinations are usually only carried out after years of trials to accumulate full safety and efficacy data. The proposed timeline for Ebola vaccine development is therefore unprecedented.
If existing public-health interventions to control Ebola outbreaks begin to slow the epidemic, the need for mass vaccination will lessen, Kieny says. But if the epidemic continues to expand, the WHO could consider expanding vaccination programmes.
In the meantime, the WHO and its partners are considering how best to engage with communities to prepare for vaccination programmes. Another issue is simply determining how to keep vaccine at –80 degrees Celsius, the temperature needed to maintain its efficacy. This will require specialized refrigerators and the establishment of cold supply chains to affected areas.
Also to be determined is who will pay for mass vaccination. Kieny says simply that “money will not be an issue”. Aid groups and governments have begun to pledge support for such efforts. Médecins Sans Frontières (MSF, also known as Doctors Without Borders) has said that it will create a fund for Ebola vaccination, and the European Union has committed €200 million (US$255 million). The Gavi vaccine alliance, the main sponsor of routine vaccinations in low-income countries, is also looking at how it could bring its vast resources and experience to the table. It will put a plan to its board in December as to what role it could have in any Ebola mass vaccination.