Perspectives on Advancing Countermeasures for Filovirus Disease: Report From a Multisector Meeting

Abstract

Although there are now approved treatments and vaccines for Ebola virus disease, the case fatality rate remains unacceptably high even when patients are treated with the newly approved therapeutics. Furthermore, these countermeasures are not expected to be effective against disease caused by other filoviruses. A meeting of subject-matter experts was held during the 10^th International Filovirus Symposium to discuss strategies to address these gaps. Several investigational therapeutics, vaccine candidates, and combination strategies were presented. The greatest challenge was identified to be the implementation of well-designed clinical trials of safety and efficacy during filovirus disease outbreaks. Preparing for this will require agreed-upon common protocols for trials intended to bridge multiple outbreaks across all at-risk countries. A multinational research consortium including at-risk countries would be an ideal mechanism to negotiate agreement on protocol design and coordinate preparation. Discussion participants recommended a follow-up meeting be held in Africa to establish such a consortium.

filoviruses, disease outbreaks, clinical trials, therapeutics, vaccines

With the United States (US) Food and Drug Administration’s (FDA) approval of monoclonal antibody therapies and vaccines to treat and prevent Ebola virus disease (EVD), countermeasures are now available against Ebola virus (EBOV). However, although EBOV causes most cases of filovirus disease (FVD), it is responsible for only about half of FVD outbreaks [1, 2]. No countermeasures have yet been shown to be effective in humans against any other causative agents of FVD, including Sudan virus (SUDV), Bundibugyo virus (BDBV), Marburg virus (MARV), Ravn virus, or Taï Forest virus. Despite having antibody therapies effective at improving EVD survival, there is dire need for improvements in patient outcomes as mortality rates due to EBOV infection remain unacceptably high, even with treatment [3]. Furthermore, the therapeutic interventions that might reduce clinical sequelae of EVD and persistent EBOV infection leading to renewed human-to-human transmission and reignition of outbreaks is yet to be established [4, 5].

Several products are in different stages of development for preventing and treating the full range of disease caused by filoviruses, yet advancement of the development process toward regulatory approval is demanding and has many obstacles. Optimization and validation of manufacturing processes, evaluation of safety and toxicity in preclinical studies, and identification of optimal dose regimens in animal models that can be extrapolated to humans are critical aspects of the development process that require considerable time and resources to complete. Developers are supporting activities to establish acceptable animal models of infection to enable use of the FDA's Animal Rule for approval in parallel to maintaining readiness to be included in potential outbreak clinical trials, such as those that supported licensure of the approved EBOV vaccines and therapeutics. For some countermeasures, such trials will be a necessary step toward licensure, and execution of trials has been challenging.

Although the countermeasure development progress has advanced steadily during interoutbreak periods, attempts to implement clinical trials during recent outbreaks have not been successful. The challenges to execute high-quality registrational studies that demonstrate clinical efficacy and safety of a vaccine or a therapeutic sufficient for licensure are significant [6]. To date, only the 2 largest EVD epidemics, in West Africa (2014–2016) and the Democratic Republic of the Congo (DRC) (2018–2020), represented public health emergencies of sufficient magnitude and duration to bring about licensure of EVD countermeasures. Given the fact that EBOV has been shown to infect the respiratory tract, a future FVD outbreak may have the potential to cause a larger epidemic.

The 10^th International Filovirus Symposium provided an opportunity to convene a meeting of subject-matter experts to discuss countermeasure opportunities, gaps, and potential development paths. On 22 September 2022, representatives of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health; the Biomedical Advanced Research and Development Authority (BARDA), part of the Administration for Strategic Preparedness and Response; the Centers for Disease Control and Prevention; the Public Health Agency of Canada; the University of Texas Medical Branch–Galveston National Laboratory (UTMB-GNL); Médecins Sans Frontières; Mapp Biopharmaceutical; Gilead Sciences; and the DRC's National Institute for Biomedical Research met to discuss how current investigational countermeasures could be advanced to licensure and made available to improve outcomes in future FVD outbreaks. The meeting's participants were asked to consider vaccines and antibody therapies for FVDs not caused by EBOV, the combination of remdesivir and antibody therapy as treatment for FVD, and an investigational oral antiviral analog of remdesivir.

Mapp Biopharmaceutical presented MBP134, a cocktail of 2 monoclonal antibodies effective in nonhuman primates (NHPs) against multiple ebolavirus species, for which safety has been demonstrated in a phase 1 trial (personal communication, Mapp Biopharmaceutical). NHP studies suggest the drug's efficacy in protection against EBOV, SUDV, and BDBV challenges [7]. MBP-091 is a single monoclonal antibody, also developed by Mapp Biopharmaceutical, that demonstrates efficacy in protection against MARV challenge in the rhesus macaque model [8] and safety established in a phase 1 trial (personal communication, Mapp Biopharmaceutical). These 2 products could allow for the treatment of all diseases caused by filoviruses, but, as of September 2022, neither was available in sufficient quantities to allow for phase 3 trials. Since then, Mapp Biopharmaceutical has worked diligently to prepare for patient access and potential clinical efficacy studies while continuing to pursue approval under the FDA's Animal Rule; funding for development of both antibody products is from the US government through BARDA.

BARDA presented several vaccine candidates for protection against FVD for which they support preclinical and clinical development. Vaccines analogous to the currently approved recombinant vesicular stomatitis virus (rVSV)–EBOV (ERVEBO) vaccine produced by Merck are being developed by the International AIDS Vaccine Initiative and Public Health Vaccines for protection against MARV and SUDV [9–11]. While limited cross-protection is observed with heterologous filovirus immunogens, preclinical studies indicate that rVSV-MARV and rVSV-SUDV may offer similar protection against homologous challenges observed with ERVEBO [9, 12, 13]. Also in development from the Sabin Vaccine Institute are vaccines against MARV and SUDV using a chimpanzee adenovirus platform and a trivalent rVSV vaccine against EBOV, SUDV, and MARV [14, 15]. Vaccines based on the rVSV platform improve survival in NHPs when given shortly after exposure [16]. Whether they have this effect in humans is currently uncertain and will be difficult to determine. In any case, protective immunity is rapidly induced (eg, following ring vaccination), with the clinical efficacy study of ERVEBO showing no EVD cases after 6 days postvaccination [17]. Vaccine researchers estimate that at least 10 000 doses of vaccine are needed to support a clinical trial like the one that demonstrated the efficacy of Merck's ERVEBO vaccine. None of these candidate vaccines were available in such quantities as of September 2022, but efforts were made to expedite manufacturing during the outbreaks to get to at least 10 000 doses of vaccine that could be used in clinical trials [18].

A collaborative effort between UTMB-GNL, Mapp Biopharmaceutical, and Gilead demonstrated that the combination of MBP431 (an extended half-life version of MBP134) and remdesivir provided protection that was superior to either treatment alone against SUDV challenge in the rhesus macaque model when delivered at a very advanced stage of disease [19]. In an analogous study, the combination of MR186 (an anti–Marburg virus glycoprotein antibody) and remdesivir was similarly superior to either treatment alone against advanced MARV disease [20]. As care of FVD patients is frequently complicated by late arrival of the patient for definitive care, these studies suggest that the combination therapy of a monoclonal antibody or antibodies and a direct-acting antiviral might further improve patient survival, even in late stages of illness, as compared to either monotherapy alone. Neither of these studies was designed to assess human safety; however, the NHP data did not suggest immediate safety concerns for similar clinical use. Nonetheless, clinical safety should be assessed in the future. The meeting participants agreed an important next step would be to conduct a similar study of the therapeutic window afforded by the combination of remdesivir and 1 of the currently approved antibody treatments against an EBOV challenge in NHPs.

Obeldesivir (GS-5245) is an investigational nucleoside prodrug that is metabolized in cells and tissues to the same active GS-441524 triphosphate metabolite as remdesivir and thus exerts the identical antiviral mechanism of action [21]. Unlike remdesivir, obeldesivir is administered orally. It demonstrated efficacy in an NHP model of severe acute respiratory syndrome coronavirus 2 infection, successfully completed a phase 1 pharmacokinetics and safety trial in healthy humans, and is currently in 2 phase 3 trials for outpatient treatment of coronavirus disease 2019 in high-risk and standard-risk participants [19, 22–24]. Gilead Sciences is currently testing obeldesivir in several NHP models of filovirus infection. In vivo efficacy demonstrated in these models would open a significant opportunity to test obeldesivir in future FVD outbreaks and/or to continue the development under the FDA Animal Rule. Availability of an oral agent for FVD, such as obeldesivir, will allow for an easy oral postexposure prophylaxis of healthcare workers and other direct contacts of FVD patients, which holds great potential for improving the active control of future FVD outbreaks, particularly in cases when another efficacious prophylaxis is not available or practical.

On the day of the meeting in La Jolla, California, Uganda declared an outbreak of Sudan virus disease (SVD). In the following months, there were attempts to make use of some of the countermeasures discussed in the La Jolla meeting, both in the Uganda SVD outbreak and the subsequent Marburg virus disease outbreaks that occurred in Equatorial Guinea and Tanzania in early 2023. In partnership with the Ugandan Ministry of Health, several patients with SVD were treated with MBP134 or remdesivir under compassionate use, and the MBP134/remdesivir combination therapy was introduced into the design of a clinical trial proposed by the World Health Organization (WHO) for Uganda, but no trial design was agreed upon prior to outbreak end [25, 26]. Several MARV vaccines and MBP091 were considered by WHO for use in Equatorial Guinea and Tanzania but were not deployed during these outbreaks [27, 28].

Well-designed clinical trials are complex undertakings and require time to prepare if they are expected to generate robust and interpretable data. As FVD outbreaks occur without warning and usually run their course within a few months, implementing trials in time to enroll patients during the outbreak is difficult. The 2 outbreaks in which clinical trials have been successfully conducted were 2 of the longest in history, each extending over approximately 2 years.

The environment in which FVD outbreaks occur also can be an impediment. Epizootic spillover typically occurs in remote underserved parts of equatorial Africa with limited resources and infrastructure to support research, posing logistical problems and occasionally adding the difficulty of working in a region experiencing armed conflict. Cultural differences and local beliefs are often at odds with disease control measures, creating an environment of mistrust into which research is not easily introduced [29]. These obstacles are not insurmountable, but overcoming them requires labor, resources, and time, none of which are in abundance during FVD outbreaks, and so being well prepared improves the chances of success.

Although the discussion in La Jolla was structured around the countermeasures described here, preparing to meet the challenge of implementing clinical trials during an outbreak was a common theme. For clinical trials to even be considered feasible, there needs to be sufficient GMP material, and formulated investigational drug product must be available beforehand to support these trials. Moreover, well-controlled nonclinical studies demonstrating efficacy and phase 1 trials establishing safety, pharmacokinetics, and, where relevant, immunogenicity also should be complete. If these steps can be accomplished, considerable time and effort will be required to reach agreement on which vaccines or treatments to study, achieve consensus on the study design and other details of the protocol (especially as it relates to acceptance by regulatory agencies toward the goal of licensure), obtain ethical approval and importation permits for investigational products, ship these products to the outbreak location, identify local principal investigators, and set up the trial infrastructure. If a trial is launched, the window to enroll patients is rather short given previous outbreak kinetics, so all preparative work that can be completed ahead of time should be. All of this pretrial preparation would be a major undertaking if it were needed in only 1 country. However, as the location of the next outbreak is not known, these preparations must be made in each country where an outbreak is likely to begin. As of early 2023, 18 African countries experienced FVD outbreaks, and these have many neighboring countries that could be considered at risk [1, 2]. Given the number of at-risk countries, preparedness for just the highest-risk countries will be no small matter.

Further complicating matters, the number of patients needed for enrollment in randomized clinical trials of FVD therapeutics to realistically support regulatory approval of tested products is often significantly larger than the size of most outbreaks. The PALM trial conducted in Eastern DRC in 2018–2020, which demonstrated the safety and efficacy of 2 subsequently approved antibody treatments, enrolled 681 patients in 4 study arms [3]. Of the 52 naturally occurring FVD outbreaks since 1967, only 13 resulted in >100 recorded cases of the disease, and only the 2 largest had enough patients for a trial like PALM to complete enrollment during the outbreak [1, 2]. Very large outbreaks, like the EVD epidemics in West Africa in 2014–2016 or in DRC in 2018–2020, can provide an opportunity to gather sufficient data within the outbreak to complete a clinical trial, but these are exceptional events, and outbreaks of comparable size caused by filoviruses other than EBOV have not occurred. Each FVD outbreak is a rare and unpredictable event and by itself is usually a limited opportunity to advance our understanding of the effectiveness of treatments and vaccines. To make the most of these opportunities, clinical trials should be ready to be launched as soon as the outbreak is detected and designed in a way that allows conducting the trial over the course of multiple outbreaks until fully enrolled.

The location of the next FVD outbreak cannot be predicted, placing many African countries at risk. Given this, and as multiple outbreaks may be required to complete 1 clinical trial, a single international protocol is needed. To have this, all at-risk countries need to agree on trial protocol details. In fact, a set of shared protocols is necessary to study treatment of the infected, postexposure prophylaxis for the exposed, vaccination of the unexposed, and mitigation of the risk of late transmission from survivors, with some details of each protocol varying according to the particular filovirus involved. Negotiation of multicountry platform trials and oversight of trial preparations in each interested country is a significant undertaking and will require robust intergovernmental collaborations and partnerships across multiple sectors in the form of a consortium able to work across the diverse geographies, languages, and cultures in Africa. In addition, contingency plans and study protocol extensions should be available in case an FVD outbreak further extends globally.

The participants in La Jolla recognized that the absence of representatives from African nations at the meeting, with the exception of the DRC, was a significant limitation. It is absolutely critical for the success of the proposed strategies and countermeasures that there is leadership in their development and expertise from relevant at-risk countries. Therefore, meeting participants concluded that the next urgent step in advancing filovirus countermeasures is to organize a follow-up meeting in Africa with public health representatives from countries at risk of FVD outbreaks who are interested in implementing these measures in their countries as a part of preparation for future outbreak response. The objective of such a meeting would be to establish a consortium capable of developing strategies designed to stop or prevent future outbreaks and spread, negotiating a common set of shared protocols, and organizing trial preparations in at-risk countries ahead of FVD outbreaks. Beyond the development and prepositioning of clinical trial protocols, advancing research on filovirus countermeasures will also require efforts to improve healthcare infrastructure, surveillance systems, education, and community engagement. Once these pretrial preparations have been made, clinical trials can be rapidly implemented during future outbreaks and the evidence base generated to complete the development of the most promising vaccines and treatments and make these globally available for use against all forms of FVD.

Notes

Acknowledgments. The authors thank the other participants at this meeting, all of whom contributed to the constructive discussion and conclusions: Carol Diaz-Diaz, Malen Link, and Eric Stavale (Biomedical Advanced Research and Development Authority [BARDA]); Larry Zeitlin, Chia-Wei Tsai, Ron Aimes, Kelly Allen, Jamie Harper, Rebecca Routh, and Ellen Monson (Mapp Biopharmaceutical); Victor Chu and Danielle Porter (Gilead Sciences); and Rebekah Varela (Médecins Sans Frontières [MSF]). The authors also express their appreciation to Erica Ollmann Saphire and the organizers of the 10^th International Filovirus Symposium for providing logistical support for this meeting.

Disclaimer. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the US Department of Health and Human Services (HHS) or its components nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Financial support. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024 (I. C.). MSF provided support for travel related expenses for some participants (S. A.-M. and J.-J. M.).

Supplement sponsorship. This article appears as part of the supplement “10^th International Symposium on Filoviruses.”

Author notes

Potential conflicts of interest. T. C. is a full-time employee of Gilead Sciences and holds stock or stock options in the company. T. N. holds stock or stock options in Mapp Biopharmaceutical. H. F. and T. W. G. claim intellectual property for VSV-based viral hemorrhagic fever vaccines. G. K. has received grants or contracts from the Defense Advanced Research Projects Agency for a phase 1 clinical trial of an Ebola vaccine boost (ended in March 2023). All other authors report no potential conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.