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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - EbolaVac (Development of a Chimpanzee Adenovirus Type 3 Ebolavirus Zaire Vaccine)

Teaser

Summary

The Ebolavirus Zaire (EBOV) outbreak of 2014 was declared March 22nd in Guinea and six month later, the epidemic had already spread to Liberia, Sierra Leone, Nigeria and Senegal.

To date, this outbreak is reported to be the largest and most complex outbreak ever described since the Ebola virus was first identified in 1976 and has led to more than 11,000 deaths in West Africa. A significant proportion of these fatalities occurred among front line health care workers attempting to contain the epidemic.

In early August 2014, the Ebola outbreak was declared an international public health emergency by the WHO and several organizations from around the world mobilized their efforts in order to control and stop the epidemic. This is when, following a request from the WHO, GSK offered its support to attempt to control the Ebola epidemic in West Africa.

Following this, the EBOLAVAC consortium was created in the context of a global two-step program including:

1. Obtaining Phase 1 safety and immunogenicity data for the Chimpanzee Adenovirus Type 3 Ebolavirus Zaire (ChAd3-EBO-Z) vaccine candidate (developed according to a joint effort between VRC/NIH and GSK) from populations located in the US, the UK, Switzerland, and West Africa. In this regard, Phase I clinical trials began in the US on September 2nd, 2014 (sponsored by the National Institutes of Health (NIH)) and in the UK on September 17th, 2014 (sponsored by The Chancellor Masters and Scholars Of the University of Oxford (Oxford)).

2. This was followed in 2015, by Phase 2 clinical trials (sponsored by GSK) in non-outbreak countries in Africa.

EBOLAVAC seeks to build upon the preclinical development activities of the ChAd3 EBO Z vaccine candidate which were conducted and funded by the VRC in partnership with the US Military (United States Army Medical Institute of Infectious Diseases; USAMRIID) and which demonstrated the efficacy of ChAd3-EBO-Z in a lethal intramuscular challenge model in cynomologous macaques as well as previous human clinical experiences with HCV, HIV and malaria vaccine candidates using similar ChAd vectors.

In addition to the aforementioned preclinical work, EBOLAVAC also relies on the results generated by a number of other Phase 1 clinical trials to guide the design and the conduct of the Phase 2 studies. These Phase I studies are however not in scope of EBOLAVAC.

The specific EBOLAVAC project objectives are to:

1. Support a Phase 1 clinical trial of the ChAd3-EBOV vaccine sponsored by the Centre Hospitalier Universitaire Vaudois / University Hospital of Lausanne (CHUV) (WP2).

2. Evaluate the ChAd3-EBO-Z vaccine in the course of Phase 2, randomized, observer-blind, controlled studies sponsored by GSK and performed in clinical study centers in Central and West Africa outside geographical zones where the epidemic was the most active (Guinea, Sierra Leone, and Liberia) (WP3).

3. Evaluate in West Africans the safety and immunogenicity of boosting a single dose of the ChAd3-EBO-Z vaccine with a heterologous boost 1 week or 2 and 4 weeks later with the same ebolavirus insert expressed by a Modified vaccinia Virus Ankara (MVA) vector. Preclinical studies with the ebolavirus insert and clinical studies with other microbial antigens indicate that this could enhance the humoral and cellular immunogenicity of the vaccination and may lead to higher and more durable efficacy (WP4).

4. Accelerate the development of a suitable cGMP process for the biomanufacture of MVAGSK EBOZ on a cell line (WP7).
In addition to the clinical trials summarized above, other activities of EBOLAVAC include data management and data analysis (WP5), communication and dissemination of results (WP6) and project management and coordination (WP1).

Work performed

Within the first 18 months of the start of the project, the EBOLAVAC consortium has made good progress in the development of the ChAd3-EBO-Z vaccine candidate.

In terms of clinical trials, four clinical trials were initiated.

The first, a Phase 1/2 randomised-controlled study, sponsored by CHUV (WP2) started in October 2014 and was completed by June 2015. In this trial, 120 subjects were randomized to receive either high-dose (5x1010 vp) or low-dose (2.5x1010 vp) ChAd3-EBO-Z vaccine candidate, or placebo. All 120 immunized subjects were followed up for 6 months for safety signals and up to 180 days for immunogenicity data. Safety, cellular and humoral immunity data (ELISPOT, ELISA, ICS and neutralization assays) were generated and analysed, leading to a publication (De Santis et al., 2016. Lancet Infect Dis.).

The clinical data generated in WP2, together with clinical data from other Phase 1 trials with the ChAd3-EBO-Z candidate but which are nott in scope of EBOLAVAC, enabled the 1x1011 vp dose of ChAd3-EBO-Z to be selected as the dose for subsequent Phase 2 (and Phase 3) trials.
The second and third clinical trials are the Phase 2 studies in adult and children population of Central and West Africa (WP3) sponsored by GSK which started in 2015 (July and November, respectively). During the first reporting period, the Phase 2 adult study was able to fully recruit a total of 3032 subjects by December 2015 and initiate an interim analysis to assess safety, reactogenicity and immunogenicty data up to 30 days after vaccination. In regards to the Phase 2 paediatric study, age de-escalation to the last cohort (1-5 years) was authorized by the IDMC and the study was fully recruited in May 2016.

Finally, the fourth EBOLAVAC supported clinical trial, a booster study in Senegal (sponsored by the University of Oxford) (WP4) was initiated and completed early 2016 with a total of 40 subjects vaccinated with ChAd3-EBO-Z and MVA-EBO Z vaccines. Moreover, an interim clinical study report was developed with safety and humoral immunogenicity data.

By the end of the projectâ€™s first reporting period, the EBOLVAC consortium had also performed the following activities:

First, activities included in WP7 were completed and a process to accelerate the development of a suitable cGMP for the biomanufacture of MVA-EBO Z on a cell line was established. This process allows the manufacture to 200 liter scale with the subsequent prospect of scaling up to 2000 liter scale. Final reports on biomanufacturing process development activities and analytical development and stability plans for MVA-EBO Z were developed.

Second, with regards to WP5, the EBOLAVAC consortium selected the Contract Research Organization that would perform the data collection, storage, management and analysis of the GSK-sponsored Phase 2 clinical trials, and agreed upon a data management and statistical analysis plan, along with case report form procedures.

Third, in terms of communication and dissemination activities, the EBOLAVAC project website was developed (www.ebolavac.eu) and a dissemination plan was defined. Several communication and dissemination materials, including press-releases, articles in press and TV/radio programs were produced and distributed. Project visibility has also been gained through the publication of 1 scientific manuscript and by the presentation of EBOLAVAC at several meetings, workshops and national and international conferences by representatives of the EBOLAVAC consortium.

Finally, as part of WP1 activities, GSK has been coordinating the overall EBOLAVAC project management, thereby ensuring that the project tasks from all work packages are performed on time, within the EBOLAVAC grant budget and at the appropriate quality standard as expected by the European Commission and described in the EBOLAVAC Consortium Agreement. During the first reporting period, WP1 activities focused on establishing internal knowledge management and implementing several

Final results

The EBOLAVAC consortium was created in response to the WHOâ€™s urgent request to test, license and make available safe and effective public health measures against Ebola and assist in the control of the outbreak in Western Africa. Specifically, the EBOLAVAC project seeks to accelerate the clinical development of the ChAd3-EBOV vaccine candidate to be able to make a safe and effective vaccine available to people exposed to an Ebola epidemic risk, including frontline health care workers (HCWs). This will be achieved through the rapid deployment of the resources needed to prepare for and conduct multiple clinical trials all while meeting internal governance, ethical and regulatory requirements.

In addition to using innovative vaccine technology, much of the innovation of this program resides in its successful performance of vaccine clinical development activities under significant time pressure and complex logistical challenges while maintaining appropriate quality standards.

With the completion of the Lausanne Phase 1/2 trial, EBOLAVAC complements the clinical development plan for a ChAd3-vectored Ebola vaccine in several ways. First, because the trial was performed with the use of a placebo group, it is the only approach that enables precise assessment of the vaccine reactogenicity. Also, due to the relatively large sample size and balanced inclusion of men and women in the study, the trial results substantially increase the data already available from previous ChAd3-EBO-Z studies and allow for a better assessment of safety data; furthermore, the trial results enable a more advanced and a valid comparison between doses, increasing the likelihood of identification of an optimum dose that balances both immunogenicity and reactogenicity and detection of a possible doseâ€“response effect. Finally, among all ChAd3-vectored Ebola vaccine trials, this was the first to generate safety and immunogenicity results up to 6 months after injection, thereby providing some insight into the value of the vaccine over the course of an epidemic.

The two GSK-sponsored Phase 2 studies in adults and children will further expand the safety, reactogenicity and immunogenicity dataset of ChAd3-EBO-Z.

Also, the monovalent MVA-EBO Z vaccine (produced by Emergent BioSolutions) was administered for the first time in African volunteers to boost a single dose of the ChAd3-EBO-Z during the Phase 2 trial sponsored by Oxford, which is also referred to as EBL06 study (WP4). Data from this trial will complement and extend current Phase I and II data available on the safety, reactogenicity and immunogenicity of the ChAd3-EBO-Z candidate vaccine. Moreover, the fact that the MVA-EBO Z was manufactured on a cell line, as opposed to chicken embryo fibroblasts (CEFs) could potentially allow much larger scale biomanufacture of MVA than is possible using CEFs. Considering that Ebola affects some of the worldâ€™s poorer countries and can spread rapidly, getting the scale of manufacturing up while keeping the cost down is key to delivering an effective response.