Approaches to demonstrating the effectiveness of filovirus vaccines: Lessons from Ebola and COVID-19.

Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV) and Marburg virus (MARV), are members of the Filoviridae family that can cause severe disease and death in humans and animals. The reemergence of Ebola, Sudan and Marburg virus disease highlight the need for continued availability of safe and effectives vaccines as well as development of new vaccines. While randomized controlled trials using disease endpoints provide the most robust assessment of vaccine effectiveness, challenges to this approach include the unpredictable size, location, occurrence and duration of filovirus disease outbreaks. Thus, other approaches to demonstrating vaccine effectiveness have been considered. These approaches are discussed using examples of preventive vaccines against other infectious diseases. In addition, this article proposes a clinical immunobridging strategy using licensed EBOV vaccines as comparators for demonstrating the effectiveness of filovirus vaccine candidates that are based on the same licensed vaccine platform technology.

How has Guinea learnt from the response to outbreaks? A learning health system analysis.

INTRODUCTION: Learning is a key attribute of a resilient health system and, therefore, is central to health system strengthening. The main objective of this study was to analyse how Guinea's health system has learnt from the response to outbreaks between 2014 and 2021. METHODS: We used a retrospective longitudinal single embedded case study design, applying the framework conceptualised by Sheikh and Abimbola for analysing learning health systems. Data were collected employing a mixed methods systematic review carried out in March 2022 and an online survey conducted in April 2022. RESULTS: The 70 reports included in the evidence synthesis were about the 2014-2016 Ebola virus disease (EVD), Measles, Lassa Fever, COVID-19, 2021 EVD and Marburg virus disease. The main lessons were from 2014 to 2016 EVD and included: early community engagement in the response, social mobilisation, prioritising investment in health personnel, early involvement of anthropologists, developing health infrastructure and equipment and ensuring crisis communication. They were learnt through information (research and experts' opinions), action/practice and double-loop and were progressively incorporated in the response to future outbreaks through deliberation, single-loop, double-loop and triple-loop learning. However, advanced learning aspects (learning through action, double-loop and triple-loop) were limited within the health system. Nevertheless, the health system successfully controlled COVID-19, the 2021 EVD and Marburg virus disease. Survey respondents' commonly reported that enablers were the creation of the national agency for health security and support from development partners. Barriers included cultural and political issues and lack of funding. Common recommendations included establishing a knowledge management unit within the Ministry of Health with representatives at regional and district levels, investing in human capacities and improving the governance and management system. CONCLUSION: Our study highlights the importance of learning. The health system performed well and achieved encouraging and better outbreak response outcomes over time with learning that occurred.

CoViD-19 rRT-PCR Testing Capacity in Ghana; Indications of Preparedness for Marburg virus Outbreak? (preprint)

Abstract Introduction: Ghana, as of July 2022, has had 168,350 Real-Time Reverse Transcription-Polymerase Chain Reaction (rRT-PCR)-confirmed cases of CoViD-19 infections and 1,458 deaths. Besides, 2 cases of Marburg virus diseases (MVD) were confirmed in the country within the same month. Both CoViD-19 and MVD require rRT-PCR for diagnosis, however, rRT-PCR facilities are scarce in Ghana, especially, hitherto, the CoViD-19 pandemic. The objectives of this study were to assess the current testing capacity of CoViD-19 rRT-PCR in Ghana, and to make some recommendations in case of an MVD outbreak, or recurrence of the CoViD-19 pandemic. Methods: The study was cross-sectional. Questionnaires were administered to 100 health professionals actively involved in the testing cycle of CoViD-19 across rRT-PCR testing institutions. Responses with regards to CoViD-19 rRT-PCR testing, biosafety, and relationship with Surveillance Outbreak Response Management and Analysis System (SORMAS), PanaBios and Zipline, were obtained for 2020-through-2022. The responses were analyzed with Microsoft Excel office-365 and SPSS v.23. Results: Thirty-five (35) of the 53 testing institutions were in the Greater Accra Region, but none in seven (7) regions of the country. Many (49%) were privately owned. Nine (9) different professionals were involved in rRT-PCR testing. The testing institutions increased from 2 (in March 2020) to 53 by June-ending 2022, and most (90%) had Biosafety Cabinet class II (BSCII). PPEs were inadequate between march and June, 2020 (25%), but enough (100%) by June 2022. Zipline, SORMAS, and PanaBios, respectively, saw transactions from 28%, 81%, and 77% of the institutions. Conclusion: Ghana is adequately resourced for recurrence of CoViD-19, or any MVD outbreak, in terms of diagnosis with rRT-PCR. However, the country needs redistribution of these testing resources, expand the services of Zipline and SORMAS, satisfy additional biosafety requirements for MVD testing and equip over 180 GeneXpert facilities to help in accessible and affordable testing. KEYWORDS: CoViD-19, rRT-PCR, Testing, BSC, SORMAS, Zipline, Marburg virus, Ghana

Marburg virus disease: A deadly rare virus is coming.

Two cases of the deadly Marburgvirus were reported in Ghana, which might be a new global virus alert following COVID-19 and novel monkeypox. Thus far, there is no vaccine or treatment for Marburg virus disease, which is a disease with a mortality rate as high as that of Ebola. Although now human infections with Marburgvirus occurred mainly in Africa, outbreaks were twice reported in Europe over the past 55 years. A concern is that globalization might promote its global viral transmission, just like what happened with COVID-19. The current study has briefly summarized the etiology, epidemiology, and clinical symptoms of the Marburgvirus as well as vaccine development and experimental treatments in order to prevent and control this virus.

A platform trial design for preventive vaccines against Marburg virus and other emerging infectious disease threats.

BACKGROUND: The threat of a possible Marburg virus disease outbreak in Central and Western Africa is growing. While no Marburg virus vaccines are currently available for use, several candidates are in the pipeline. Building on knowledge and experiences in the designs of vaccine efficacy trials against other pathogens, including SARS-CoV-2, we develop designs of randomized Phase 3 vaccine efficacy trials for Marburg virus vaccines. METHODS: A core protocol approach will be used, allowing multiple vaccine candidates to be tested against controls. The primary objective of the trial will be to evaluate the effect of each vaccine on the rate of virologically confirmed Marburg virus disease, although Marburg infection assessed via seroconversion could be the primary objective in some cases. The overall trial design will be a mixture of individually and cluster-randomized designs, with individual randomization done whenever possible. Clusters will consist of either contacts and contacts of contacts of index cases, that is, ring vaccination, or other transmission units. RESULTS: The primary efficacy endpoint will be analysed as a time-to-event outcome. A vaccine will be considered successful if its estimated efficacy is greater than 50% and has sufficient precision to rule out that true efficacy is less than 30%. This will require approximately 150 total endpoints, that is, cases of confirmed Marburg virus disease, per vaccine/comparator combination. Interim analyses will be conducted after 50 and after 100 events. Statistical analysis of the trial will be blended across the different types of designs. Under the assumption of a 6-month attack rate of 1% of the participants in the placebo arm for both the individually and cluster-randomized populations, the most likely sample size is about 20,000 participants per arm. CONCLUSION: This event-driven design takes into the account the potentially sporadic spread of Marburg virus. The proposed trial design may be applicable for other pathogens against which effective vaccines are not yet available.

Combination therapy protects macaques against advanced Marburg virus disease.

Monoclonal antibodies (mAbs) and remdesivir, a small-molecule antiviral, are promising monotherapies for many viruses, including members of the genera Marburgvirus and Ebolavirus (family Filoviridae), and more recently, SARS-CoV-2. One of the major challenges of acute viral infections is the treatment of advanced disease. Thus, extending the window of therapeutic intervention is critical. Here, we explore the benefit of combination therapy with a mAb and remdesivir in a non-human primate model of Marburg virus (MARV) disease. While rhesus monkeys are protected against lethal infection when treatment with either a human mAb (MR186-YTE; 100%), or remdesivir (80%), is initiated 5 days post-inoculation (dpi) with MARV, no animals survive when either treatment is initiated alone beginning 6 dpi. However, by combining MR186-YTE with remdesivir beginning 6 dpi, significant protection (80%) is achieved, thereby extending the therapeutic window. These results suggest value in exploring combination therapy in patients presenting with advanced filovirus disease.