RESUMO
BACKGROUND: Shorter prophylactic vaccine schedules may offer more rapid protection against Ebola in resource-limited settings. METHODS: This randomized, observer-blind, placebo-controlled, phase 2 trial conducted in five sub-Saharan African countries included people without HIV (PWOH, n = 249) and people living with HIV (PLWH, n = 250). Adult participants received one of two accelerated Ebola vaccine regimens (MVA-BN-Filo, Ad26.ZEBOV administered 14 days apart [n = 79] or Ad26.ZEBOV, MVA-BN-Filo administered 28 days apart [n = 322]) or saline/placebo (n = 98). The primary endpoints were safety (adverse events [AEs]) and immunogenicity (Ebola virus [EBOV] glycoprotein-specific binding antibody responses). Binding antibody responders were defined as participants with a > 2.5-fold increase from baseline or the lower limit of quantification if negative at baseline. RESULTS: The mean age was 33.4 years, 52% of participants were female, and among PLWH, the median (interquartile range) CD4+ cell count was 560.0 (418.0-752.0) cells/µL. AEs were generally mild/moderate with no vaccine-related serious AEs or remarkable safety profile differences by HIV status. At 21 days post-dose 2, EBOV glycoprotein-specific binding antibody response rates in vaccine recipients were 99% for the 14-day regimen (geometric mean concentrations [GMCs]: 5168 enzyme-linked immunosorbent assay units (EU)/mL in PWOH; 2509 EU/mL in PLWH), and 98% for the 28-day regimen (GMCs: 6037 EU/mL in PWOH; 2939 EU/mL in PLWH). At 12 months post-dose 2, GMCs in PWOH and PLWH were 635 and 514 EU/mL, respectively, for the 14-day regimen and 331 and 360 EU/mL, respectively, for the 28-day regimen. CONCLUSIONS: Accelerated 14- and 28-day Ebola vaccine regimens were safe and immunogenic in PWOH and PLWH in Africa. TRIAL REGISTRATION: NCT02598388.
RESUMO
Since the discovery of the Marburg virus (MARV) in 1967 and Ebola virus (EBOV) in 1976, there have been over 40 reported outbreaks of filovirus disease with case fatality rates greater than 50%. This underscores the need for efficacious vaccines against these highly pathogenic filoviruses. Due to the sporadic and unpredictable nature of filovirus outbreaks, such a vaccine would likely need to be vetted through the U.S. Food and Drug Administration (FDA), following the Animal Rule or similar European Medicines Agency (EMA) regulatory pathway. Under the FDA Animal Rule, vaccine-induced immune responses correlating with survival of non-human primates (NHPs), or another well-characterized animal model, following lethal challenge, will need to be bridged for human immune response distributions in clinical trials. A correlate of protection has not yet been identified for the filovirus disease, but antibodies, specifically anti-glycoprotein (GP) antibodies, are believed to be critical in providing protection against the filovirus disease following vaccination and are thus a strong candidate for a correlate of protection. Thus, species-neutral methods capable of the detection and bridging of these antibody immune responses, such as methods to quantify anti-GP immunoglobulin G (IgG)-binding antibodies and neutralizing antibodies, are needed. Reported here is the development and qualification of two Filovirus Animal Nonclinical Group (FANG) anti-GP IgG Enzyme-Linked Immunosorbent Assays (ELISAs) to quantify anti-MARV and anti-Sudan virus (SUDV) IgG antibodies in human and NHP serum samples, as well as the development of pseudovirion neutralization assays (PsVNAs) to quantify MARV- and SUDV-neutralizing antibodies in human and NHP serum samples.