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

Abstract

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.

Assessing the feasibility of Phase 3 vaccine trials against Marburg Virus Disease: a modelling study

“…Our results suggest that the vast majority of future outbreaks may have no cases in both the vaccine and placebo arms, and would in fact be controlled before VE estimations could begin (ten days after implementing the vaccination campaign, which is when cases are included in any VE calculations). It was previously calculated that 150 cases, both in the vaccine and control arms, would be required to estimate VE (8). Figure 2 shows a histogram of the number of simulated MVD outbreaks required to reach 150 combined cases in the vaccine and placebo arms.…”

Modelling Vaccination Strategies for the Control of Marburg Virus Disease Outbreaks

“…Although efforts are ongoing to develop MVD vaccines (4), the results of our study suggest that it may be difficult to carry out Phase 3 trials, since we predict that few cases will be observed in a typical outbreak, and these may well be rapidly controlled by other interventions. To counter this problem, the World Health Organisation has developed a Core Protocol approach that is designed to allow trial results to be combined across multiple outbreaks to accrue sufficient data and statistical power to assess vaccine effectiveness (26, 29). There has also been a recent paper from WHO on a core protocol for estimating Marburg virus vaccine efficacy (29).…”

“…To counter this problem, the World Health Organisation has developed a Core Protocol approach that is designed to allow trial results to be combined across multiple outbreaks to accrue sufficient data and statistical power to assess vaccine effectiveness (26, 29). There has also been a recent paper from WHO on a core protocol for estimating Marburg virus vaccine efficacy (29). The results of our model could be helpful in estimating how many cases and outbreaks may be necessary to include in such a longitudinal multi-outbreak study.…”

Marburg Virus Disease – A Mini-Review

“…Such a subunit (recombinant) vaccine platform can thereby help in developing multivalent vaccine candidates for protecting against filoviruses while retaining their safety and efficacy (Lehrer et al 2021). Few other vaccines being tried include multi-epitope vaccine, proteomebased vaccine exploiting computational methods, virus-like particles (VLP), adenoviral vector-based multi-filovirus vaccine, rprotein based filovirus multivalent vaccine, and rVSV-based vesiculovax vector vaccine (rVSV-N4CT1-MARV-GP), and efforts are being made for effective platform designing of preventive MVD vaccines (Reynolds and Marzi 2017;Hasan et al 2019;Suschak and Schmaljohn 2019;Dulin et al 2021;Lehrer et al 2021;Sami et al 2021;Longini et al 2022;Sebastian et al 2020;Soltan et al 2022;Woolsey et al 2022;Zhao et al 2022). Another candidate vaccine (recombinant VSV/ rVSV-based) known as PHV01 has been tested in the guinea pig model for confirming the efficacy (protective effects) against MVD (Zhu et al 2022).…”