Clinical research as a critical component of epidemic response: the case of PREVAIL in Liberia

The failure to develop effective vaccines and therapeutics for pathogens of high consequence pre-emptively was recognised during the 2014–15 outbreak of Zaire Ebola virus disease in west Africa. The world was unarmed to confront the outbreak despite discovery of the virus in 1976 and a history of repeated subsequent outbreaks. The consequences were dire, with high morbidity and mortality, economic disruption, and global threats.1WHOWHO Statement on the 1st meeting of the IHR Emergency Committee on the 2014 Ebola outbreak in West Africa. World Health Organization, Geneva2014Google Scholar, 2Dixon MG Schafer IJ Ebola viral disease outbreak—West Africa, 2014.MMWR Morb Mortal Wkly Rep. 2014; 63: 548-551PubMed Google Scholar Although three of the five species of Ebola virus (Zaire, Bundibugyo, and Sudan) are associated with large outbreaks in Africa, advanced global research and development has primarily focused on the Zaire strain.3Laupland KB Valiquette L Ebola virus disease.Can J Infect Dis Med Microbiol. 2014; 25: 128-129Crossref PubMed Scopus (31) Google Scholar The costly price of this strategy was reflected in the recent Sudan Ebola virus outbreak in Uganda, where countermeasures were inadequate.4Lucey DR New Uganda Sudan ebolavirus outbreak means FDA-licensed vaccine for Zaire ebolavirus cannot be used.https://www.idsociety.org/science-speaks-blog/2022/new-uganda-sudan-ebolavirus-outbreak-means-fda-licensed-vaccine-for-zaire-ebolavirus-cannot-be-used/#/+/0/publishedDate_na_dt/desc/Date: Sept 21, 2022Date accessed: December 18, 2022Google Scholar Here, we describe key lessons learned during the establishment of a rapid clinical research infrastructure in Liberia to assess the benefits of therapeutic and vaccine candidates during the 2014–15 outbreak of Ebola virus disease in west Africa to inform strategies for research during outbreaks.5Kamradt-Scott A Harman S Wenham C Smith 3rd, F Civil–military cooperation in Ebola and beyond.Lancet. 2016; 387: 104-105Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar In Liberia and the USA, strong political leadership at the highest level initiated the entire process for the establishment of the clinical research infrastructure in the country to assess the vaccine and therapeutic candidates for Ebola virus disease during the 2014–15 outbreak. The champions were the then Minister of Health and Social Welfare of Liberia, the late Walter Gwenigale; the former US Ambassador to Liberia, Deborah Malac; and the former US Secretary of Health and Human Services, Sylvia M Burwell. The US National Institute of Allergy and Infectious Diseases (NIAID) partnered with the Liberian Ministry of Health and Social Welfare to develop a research programme to study two experimental vaccines, rVSV and ChAd3, and the monoclonal antibody ZMapp.6Kennedy SB Bolay F Kieh M et al.Phase 2 placebo-controlled trial of two vaccines to prevent Ebola in Liberia.N Engl J Med. 2017; 377: 1438-1447Crossref PubMed Scopus (164) Google Scholar Alignment of research priorities was essential. With a potentially limited time window and an urgency to assess the benefits of investigational vaccines, a decision was taken to use the existing phase 1 trial data to move to a combined phase 2/3 trial. Once it (fortunately) became clear that the outbreak was coming under control through standard public health measures, the study was converted to a pure phase 2 trial with concurrence from the international Data and Safety Monitoring Board. These decisions showed mutual respect and trust between the USA (NIAID) and Liberia, with an alignment on joint research priorities. Similar considerations could be appropriate in other outbreaks. Building a partnership between US and local experts enabled the research to operate smoothly within an organisational and governance structure that was created with the USA. The Ambassador to Liberia, Malac, and Liberian Minister of Health and Social Welfare, Gwenigale, were the key decision makers. A buddy system was created, with US scientists from the National Institutes of Health and their Liberian counterparts assigned to supervise different functions of the research. These functions were data information and technology, pharmacy, site development and management, protocol development, laboratory, training, regulatory and ethics, and social mobilisation and communication teams (figure). The research partnership was initially named the Partnership for Research on Ebola Vaccines in Liberia (PREVAIL) and involved multiple face-to-face and virtual meetings to plan and execute the research. Leveraging existing capabilities from the Ebola response structures was an essential element for the rapid establishment of the clinical research activities. The Liberia Institute for Biomedical Research that was destroyed by the 14-year Liberian civil war had been upgraded with support from the US Government to be used as a research laboratory for Ebola diagnostics. It was also converted to being able to store and test blood samples from the research participants. Liberian scientists and experts who were supporting the Ebola response joined the research enterprise. Focusing efforts on social mobilisation and communication, and community engagement was crucial in minimising the fear and distrust towards experimental vaccines. The PREVAIL team leveraged the existing social mobilisation and community engagement pillar that was used during the Ebola response to overcome the initial resistance to any new effort to contain the outbreak. These initial fears, distrust, and resistance to all Ebola response activities were precipitated by pre-existing distrust in government, traditional practices, media disinformation, and certain cultural beliefs and norms. However, these were eventually overcome by the implementation of well structured social mobilisation, community engagement, and communication strategies, which contributed substantially to the successful recruitment of participants for the vaccine trial. Similar challenges with any new research effort in any environment, regardless of the country, have been seen during the COVID-19 pandemic. Negotiating the ethical and regulatory hurdles governing the clinical trial required navigating politics and dealing with polarising fears and misinformation fuelled by the media and civil society. At one point, the Ministry of Justice put an injunction on the clinical trial, and it took the then Liberian Vice President, Joseph Boakai, to politically resolve the impasse. As a result, the capacity of the Liberia Medicines and Health Regulatory Authority and the National Research Ethics Board were strengthened to meet international standards. In Liberia, we lost the element of speed and, therefore, were not able to reap the full benefits of clinical trials during outbreaks. The first visit of NIAID to Liberia was in early October, 2014. However, the dose for the vaccine study was not finalised until the end of January, 2015, with the first patient enrolled on Feb 2, 2015. As a result, a phase 3 efficacy trial was not able to be conducted (appendix); however, the preliminary safety and immunogenicity data from the Liberian trial were able to help inform the ring trial in Guinea,7Gsell PS Camacho A Kucharski AJ et al.Ring vaccination with rVSV-ZEBOV under expanded access in response to an outbreak of Ebola virus disease in Guinea, 2016: an operational and vaccine safety report.Lancet Infect Dis. 2017; 17: 1276-1284Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar which eventually led to licensure of the first Ebola Zaire vaccine. Following the 2014–15 Ebola virus outbreak, clinical research has become a critical response strategy during pandemics and epidemics, as evidenced in the licensure and use of vaccines and therapeutics such as ERVEBO, REGN-EB3, mAb114,6Kennedy SB Bolay F Kieh M et al.Phase 2 placebo-controlled trial of two vaccines to prevent Ebola in Liberia.N Engl J Med. 2017; 377: 1438-1447Crossref PubMed Scopus (164) Google Scholar, 9Roby C 5 experimental treatments introduced in latest DRC Ebola outbreak.https://www.devex.com/news/5-experimental-treatments-introduced-in-latest-drc-ebola-outbreak-93303Date: Aug 17, 2018Date accessed: December 18, 2022Google Scholar, 10National Academies of Sciences, Engineering, and MedicineIntegrating clinical research into epidemic response: the Ebola experience. The National Academies Press, Washington, DC2017Google Scholar, 11Lévy Y Lane C Piot P et al.Prevention of Ebola virus disease through vaccination: where we are in 2018.Lancet. 2018; 392: 787-790Summary Full Text Full Text PDF PubMed Scopus (47) Google Scholar remdesivir, dexamethasone, and nirmatrelvir-ritonavir. A review of the west African research response by the US National Academies concluded that science and ethics do not change during an outbreak and that adequately powered, randomised controlled trials are the quickest way to get the most effective countermeasures to the largest number of people in the shortest period of time. These lessons can be transferred to subsequent outbreaks to help determine the safety and efficacy of experimental countermeasures. We declare no competing interests. Download .pdf (.19 MB) Help with pdf files Supplementary appendix