TY - JOUR
T1 - A platform trial design for preventive vaccines against Marburg virus and other emerging infectious disease threats
AU - Longini, Ira M.
AU - Yang, Yang
AU - Fleming, Thomas R.
AU - Muñoz-Fontela, César
AU - Wang, Rui
AU - Ellenberg, Susan S.
AU - Qian, George
AU - Halloran, M. Elizabeth
AU - Nason, Martha
AU - Gruttola, Victor De
AU - Mulangu, Sabue
AU - Huang, Yunda
AU - Donnelly, Christl A.
AU - Henao Restrepo, Ana Maria
N1 - Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The source of financial support for research described in this article, in part, is supported by the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grant entitled “Statistical Issues in AIDS Research” (R37 AI 29168) TRF, “Design and Analysis of Vaccine Trials for Emerging Infectious Disease Threats” (R01 AI 139761) IML, MEH, YY, and (R01 AI136947) RW. The UK Medical Research Council (MRC) Centre for Global Infectious Disease Analysis, the National Institute for Health Research (NIHR) Health Protection Research Unit in Emerging and Zoonotic Infections and the NIHR-funded Vaccine Efficacy Evaluation for Priority Emerging Diseases (PR-OD-1017-20007) CAD.
Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The source of financial support for research described in this article, in part, is supported by the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grant entitled “Statistical Issues in AIDS Research” (R37 AI 29168) TRF, “Design and Analysis of Vaccine Trials for Emerging Infectious Disease Threats” (R01 AI 139761) IML, MEH, YY, and (R01 AI136947) RW. The UK Medical Research Council (MRC) Centre for Global Infectious Disease Analysis, the National Institute for Health Research (NIHR) Health Protection Research Unit in Emerging and Zoonotic Infections and the NIHR-funded Vaccine Efficacy Evaluation for Priority Emerging Diseases (PR-OD-1017-20007) CAD.
Publisher Copyright:
© The Author(s) 2022.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Marburg virus
KW - Randomized placebo-controlled vaccine trial
KW - cluster-randomized vaccine trial
KW - emerging infectious disease threat
KW - vaccine efficacy
UR - http://www.scopus.com/inward/record.url?scp=85135151409&partnerID=8YFLogxK
U2 - 10.1177/17407745221110880
DO - 10.1177/17407745221110880
M3 - Article
C2 - 35866633
AN - SCOPUS:85135151409
SN - 1740-7745
VL - 19
SP - 647
EP - 654
JO - Clinical Trials
JF - Clinical Trials
IS - 6
ER -