Both heterologous and homologous Ad26, MVA Ebola vaccine regimens are well tolerated in healthy adults regardless of interval or dose level, according to a study recently published in The Journal of Infectious Diseases.
There have been major Ebolavirus (EBOV) outbreaks in 2014-2016 and 2018-2020, prompting the accelerated development of several vaccine candidates that targeted the glycoprotein (GP) of Zaire Ebolavirus (ZEBOV). Study researchers sought to evaluate the immunogenicity and safety of two-dose regimens of Ad26.ZEBOV (Ad26) and MVA-BN-Filo (MVA) vaccines with booster vaccination at Day 360.
Phase 1 clinical studies in the United Kingdom and African countries that showed the heterologous two-dose vaccination strategy was highly immunogenic and well tolerated in healthy adults. This United States-based, Phase 1 placebo-controlled study assessed safety and immunogenicity of a variety of heterologous and homologous two-dose vaccination regimens based on different dosages, sequences, and intervals of Ad26 (Ad26.ZEBOV) and MVA (MCA-BN-Filo) vaccines with a Day 360 booster vaccination.
In total, 164 healthy adults aged 18 to 50 years in the United States were included. This study was performed in 3 parts with 10 groups.
- Part 1: subjects randomized into groups 1-6 to receive either vaccine or placebo followed by the second dose 14, 28, or 56 days later.
- Part 2:
- Group 7 received standard dose of Ad26 or placebo followed by high-dose MVA (hdMVA) or placebo 14 days later.
- Group 8 received high-dose Ad26 (hdAd26) or placebo followed by hdMVA 28 days later.
- Part 3: Groups 9 and 10 received standard doses of MVA or placebo followed by standard doses of Ad26 or placebo 7 and 14 days later, respectively.
To those who completed the primary vaccination with active vaccine, an open-label booster vaccination was administered at Day 360: Groups 1, 2, 3, 4, 5, and 7 received Ad26; Group 6 received hdAd26; and Group 8 received MVA. All vaccines were supplied as 0.5 mL doses for intramuscular injection in the deltoid and standard doses were used. Subjects were monitored for 1 hour post-vaccination for adverse events (AEs) and asked to record solicited local and systemic AEs on diary cards on the day of injection and for 7 subsequent days. The primary objective of this study was to assess the safety of different vaccine regimens in terms of AE, serious AE, and solicited and local systemic AEs. The secondary objectives of this study included the evaluation of EBOV GP-specific humoral and cellular immune responses.
Results suggested that heterologous (Ad26,MVA or MVA,Ad26) regimens elicited higher responses when compared to homologous Ad26, Ad26 regimens; however, both regimens were well tolerated in healthy adults regardless of interval or dose level. All regimens demonstrated an acceptable safety profile; there were no deaths, SAEs, or AEs that led to discontinuation reported during the study. No trends in reported laboratory abnormalities were observed and no Grade 3 abnormalities were considered to be related to the study vaccinations. After the first dose, standard and high-dose Ad26 vaccination induced higher binding antibody responses (Day 15, Groups 6 and 7: 84.6%-88.9% of subjects; Day 29, Groups 4 and 8: 100% of subjects) when compared to MVA (Day 15, Groups 1 and 5: 11.1%-13.3% of subjects; Day 29, Groups 2 and 3: 26.7%-46.7% of subjects). After the second dose, response levels were boosted for both vaccine sequences regardless of the interval. Homologous (Ad26, Ad26 or MVA, MVA), particularly the MVA, regimens were less immunogenic when compared to heterologous (Ad26, MVA or MVA, Ad26) regimens. The vaccination booster induced an anamnestic response in all heterologous vaccination groups with 12.4- to 38.6-fold increases in geometric mean concentrations; responses persisted until Day 720 in all subjects except for Group 2 (MVA,Ad26 28-day interval; 91%) and Group 3 (MVA,Ad26 56-day interval; 92%). This immunological memory recall by the booster suggests the Ad26 booster doses could be used for those at risk for Ebola infection who have already received the two-dose regimen.
The main limitations of this study were the small sample size and the study population not being representative of those at highest risk for Ebola infection. An ongoing clinical development program that includes larger Phase 2 and 3 studies will address both limitations.
Overall, the study authors state that “two-dose heterologous regimens with standard doses of Ad26 and MVA provide persistent humoral and cellular immune responses, as well as immune memory to EBOV GP.”
Disclosure: An author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of disclosures.
Golstein N, Bockstal V, Bart S, et al. Safety and immunogenicity of heterologous and homologous two dose regimens of Ad26- and MVA-vectored ebola vaccines: a randomized, controlled Phase 1 study. J Infect Dis. 2020.doi: 10.1093/infdis/jiaa586/5906668.