The ongoing outbreak of Ebola virus disease has been unprecedented in scale and severity, leading to over 5000 deaths to date. With no licensed drugs or vaccines for Ebola, unprecedented measures are being taken to accelerate new drugs and vaccines through clinical development to deployment in early 2015. The Jenner Institute at Oxford University has been undertaking the first clinical trial of the leading candidate vaccine for Ebola. These trials have been initiated with remarkable speed and the subsequent African trials, which are now ongoing, were started as soon as initial safety data were available from the UK. In parallel, extraordinary efforts are being made to manufacture, initially, tens of thousands, and later millions, of doses of a chimpanzee adenovirus vaccine against Ebola.
Two virus-vectored vaccines are now in their first clinical trials for Ebola vaccination. Neither of these had been tested in humans in August 2014, when the scale of the outbreak in West Africa became apparent to all. With coordination from the World Health Organization, the first of the two vaccines to enter clinical trials reached that goal in September. This required a consortium effort, with the trial being undertaken at Oxford University with a vaccine co-owned by the GlaxoSmithKline (GSK) vaccine company and the US National Institutes of Health (NIH), with funding support from UK funders. This vaccine candidate is a simian adenovirus vector based on chimpanzee adenovirus type 3 (ChAd3), which had previously been tested in humans as a hepatitis C vaccine candidate in Oxford, UK, and is now in a phase II prophylactic efficacy trial in the USA. In total, about 250 humans have been immunized in this hepatitis C vaccine development programme. However, two other types of chimpanzee adenovirus have also been in human vaccine trials. ChAd63, the first simian adenovirus to be tested in humans in 2007, has been extensively studied in over 1000 subjects for malaria vaccination and also in one trial as a candidate human immunodeficiency virus vaccine. Interestingly, this chimpanzee vector has been assessed in seven trials in Africa, in adults, children and infants, as part of the malaria vaccine programme. In all these trials, this new vaccine type has shown a well-tolerated safety profile.
This adenovirus technology was chosen for Ebola immunization because it can induce potent cellular immunity in addition to antibody responses. ChAd3 had been assessed as a vaccine in cynomolgus macaques, by the NIH group led by Nancy Sullivan, and impressive single-dose efficacy was demonstrated. However, to induce durable efficacy throughout the first year after immunization, a booster dose of a second type of virus-vectored vaccine was required. This modified vaccinia virus Ankara, or ‘MVA’, vector has been widely used as a vaccine type in clinical trials over the last 15 years and effectively amplifies both antibody and cellular immunity. Originally used as a smallpox vaccine, MVA used as a recombinant vector has been administered to over 4000 subjects in Europe, Africa and the USA with satisfactory safety data.
It was decided to initially test the ChAd3 vector alone and to consider a boosting strategy with MVA if this appeared to be useful for increasing the immune response further. Following a funding application in mid-August, and a rapid award from the Wellcome Trust, Medical Research Council and Department of International Development in London, regulatory and ethical approvals for the Oxford trials were awarded exceptionally quickly. In parallel, the vaccine which had been manufactured in Italy by the Okairos group (now owned by GSK) had to be specially vialled for this trial. A US trial was already planned using a mixture of vaccine vectors targeting both the Zaire and Guinea strains of Ebola virus. However, the West African outbreak was caused by the Guinea strain of Ebola, which is very similar to the Zaire strain and quite different from the Sudan strain. Therefore, the Zaire strain vaccine was chosen for the trial in Oxford and for use in West Africa.
The Oxford trial started on 17 September 2014, aiming to recruit and immunize 60 healthy adult volunteers, assessing three different dose levels of a single shot of the vaccine. The objectives were to evaluate vaccine safety and immunogenicity at these dose levels and to determine if the immune responses generated appeared sufficient to provide high-level efficacy – a difficult judgement. The final vaccination occurred in mid-November and immune responses are being actively measured and followed over time.
Meanwhile, the safety profile observed in the first 15 Oxford vaccinees allowed the vaccine to proceed to further testing in Bamako, Mali, at the Center for Vaccine Development. Already, 80 vaccinees have been immunized at this site and a new trial started recently in Lausanne, Switzerland. Vaccine manufacture of the chimpanzee adenovirus has been accelerated and tens of thousands of doses will be ready for critical phase II and III trials starting in West Africa in January 2015. The major goal of the phase III trial will be to assess the efficacy of the vaccine used against the current outbreak with plans to deploy the vaccine very widely and quickly if efficacy is confirmed.
The second vaccine type being developed rapidly for possible use in outbreak control is another viral vector, a recombinant vesicular stomatitis virus, which, again, encodes a major surface glycoprotein of the Ebola virus. This is a very new vaccine type which has not been previously used in human vaccine trials but has shown good efficacy in macaque monkeys. Trials of this vaccine have also now been initiated in the USA and in Switzerland.
Overall, the speed and coordination of the vaccine development response to this outbreak is unprecedented. It now seems likely that at least one vaccine will proceed from immunization of the first human to a phase III efficacy trial in a few months, in contrast to the many years or more than a decade required for other vaccines. This exceptional response may provide lessons on how to develop other much-needed vaccines more quickly.
This major outbreak and its costs, in terms of both mortality and financial losses, which already amount to billions of dollars, has highlighted the need for better preventative approaches for microbial pathogens that cause outbreaks with pandemic potential. There are at least 15 such outbreak pathogens that constitute a threat that merits consideration and preventative action. These include the causative agents of Marburg and Lassa virus diseases, Rift Valley fever and Middle East respiratory syndrome. Candidate vaccines for most of these viral pathogens have been developed for experimental studies in small animals but few have progressed to clinical trials and none to licensure. There are clearly barriers to further development of such vaccines that must be addressed. A new approach to development of suitable vaccines for outbreak diseases is needed urgently to prevent the occurrence of a major outbreak for which a vaccine could have been available much earlier.