The Ebola virus has caused more than 8500 deaths in West Africa. This is an international public health crisis that may require an effective vaccine to contain. No major infectious disease outbreak has ever seen a new vaccine tested first on humans and then developed within a matter of months to control its spread. In this case, however, the chimpanzee adenovirus and the modified vaccinia virus Ankara had been manufactured to a clinical grade by the National Institute of Allergy and Infectious Diseases before the Ebola virus took hold in August 2014. This provided an opportunity to implement an accelerated program to deploy the potential Ebola vaccine in 2015.
The difficulty of manufacturing large amounts of the chimpanzee adenovirus Ebola vaccine (ChAd-Ebola, chAD3-ZEBOV, cAd3-EBO) was one of the problems faced in the acceleration of large trials and deployment of the vaccine. The use of a monovalent rather than a bivalent formulation cut in half the challenges inherent in manufacturing the Ebola vaccine, not to mention that in past assessments where more than one mixture of a viral strain was used there was sometimes reduced immunity in participants. Furthermore, there was the possibility that a lower dose of the chimpanzee advenovirus might engender sufficient immunity to allow for more vaccine doses from each formulation.
Ebola Vaccine Trials
In concert with the World Health Organization a plan was implemented to go quickly to clinical trials with the monovalent formula of the chimpanzee adenovirus vaccine against the Ebola virus in August 2014. Three clinical sites were chosen for the trials – Oxford, United Kingdom; Lausanne, Switzerland; and Bamako, Mali. The aim was to immunize and then evaluate 240 participants by the end of November 2014.
The study participants were healthy adults aged between 18 and 50 years. Each provided written informed consent. Safety oversight was undertaken by an independent data and safety monitoring board. The chimpanzee adenovirus vaccine was provided by the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases and by GlaxoSmithKline.
This was an open-label study to assess the safety and effectiveness of the experimental monovalent chimpanzee advenovirus vaccine against the Ebola virus. The vaccine was given in a single intramuscular injection in one of three doses. The lowest dose was used on the first group, who were followed for a minimum of 48 hours before immunizing participants in the next dose group at a higher dose. Different dosing levels were obtained by adjusting the volume of the Ebola vaccine injected.
The participants were observed for an hour after the vaccination. Follow-up was obtained at days 1, 7, 14, 28, 90 and 180 after the vaccination. There was an added follow-up at day 10 for those in the highest dose group. All of the participants were given an electronic diary to record requested symptoms for 7 days after Ebola vaccine administration and unsolicited symptoms for 28 days.
Review of symptoms was taken at each of the follow-up visits, as well as measurement of urea and electrolytes, liver enzymes, full blood count, activated partial thromboplastin time, prothrombin time and fibrinogen. Grading of adverse events and assignment of a cause and effect relationship for unsolicited adverse events were also conducted.
Ebola Vaccine Trials Results
A total of 60 participants were vaccinated from September 17, 2014, to November 18, 2014. All but one completed at least 28 days of follow-up, and that one dropped out voluntarily with no reported adverse symptoms.
The majority of the adverse symptoms reported in all dosing groups were mild. There were no serious adverse events. Two participants had episodes of moderate fever, both of which occurred within the first 24 hours and both of which resolved within 24 hours. Prolonged activated partial thromboplastin time was seen in four participants during the first 14 days after vaccination, none of which were associated with symptoms, and all of which had resolved by 10 weeks after Ebola vaccination.
Mild and transient lymphocytopenia was seen in some participants, as well as mild-to-moderate bilirubin elevations. Severe but transient spikes in bilirubin was recorded in two participants who had a diagnosis of Gilbert’s syndrome before the trial.
The antibody response was highest in all groups at 28 days after vaccination. Before vaccination there was little to no detection of antibodies in the participants, indicating that the Ebola vaccine provoked a response to the virus and conferred immunity, regardless of dose strength.
The safety and effective immune response to the vaccine encourages further study of this Ebola vaccine, both alone and in concert with other regimens in future trials and in phase 3 trials in countries experiencing Ebola epidemics in 2015.