Safety and Immunogenicity of Heterologous and Homologous 2-Dose Regimens of Adenovirus Serotype 26- and Modified Vaccinia Ankara-Vectored Ebola Vaccines: A Randomized, Controlled Phase 1 Study

Abstract

Background: This phase 1 placebo-controlled study assessed the safety and immunogenicity of 2-dose regimens of Ad26.ZEBOV (adenovirus serotype 26 [Ad26]) and MVA-BN-Filo (modified vaccinia Ankara [MVA]) vaccines with booster vaccination at day 360.

Methods: Healthy US adults (N = 164) randomized into 10 groups received saline placebo or standard or high doses of Ad26 or MVA in 2-dose regimens at 7-, 14-, 28-, or 56-day intervals; 8 groups received booster Ad26 or MVA vaccinations on day 360. Participants reported solicited and unsolicited reactogenicity; we measured immunoglobulin G binding, neutralizing antibodies and cellular immune responses to Ebola virus glycoprotein.

Results: All regimens were well tolerated with no serious vaccine-related adverse events. Heterologous (Ad26,MVA [dose 1, dose 2] or MVA,Ad26) and homologous (Ad26,Ad26) regimens induced humoral and cellular immune responses 21 days after dose 2; responses were higher after heterologous regimens. Booster vaccination elicited anamnestic responses in all participants.

Conclusions: Both heterologous and homologous Ad26,MVA Ebola vaccine regimens are well tolerated in healthy adults, regardless of interval or dose level. Heterologous 2-dose Ad26,MVA regimens containing an Ebola virus insert induce strong, durable humoral and cellular immune responses. Immunological memory was rapidly recalled by booster vaccination, suggesting that Ad26 booster doses could be considered for individuals at risk of Ebola infection, who previously received the 2-dose regimen.

Keywords: 2-dose; Ad26.ZEBOV; Ebola vaccine; MVA-BN-Filo; heterologous; homologous; immunogenicity; safety.

Figure 1.

Study flowcharts showing groups receiving vaccines at 7- and 14-day (top) or 28- and 56-day (bottom) intervals. Unless otherwise indicated, Ad26.ZEBOV (adenovirus serotype 26 [Ad26]) was administered at a dose of 5 × 10¹⁰ viral particles and MVA-BN-Filo (modified vaccinia Ankara [MVA]) at a dose of 1 × 10⁸ 50% tissue culture infective dose (TCID₅₀). The placebo used was 0.9% saline. Vaccination regimens are shown as “dose 1, dose 2 (booster).” Groups included active and placebo recipients. Groups 1 (MVA,Ad26 [Ad26]) and 10 (MVA,Ad26) are combined; all other groups are shown individually. Abbreviations: hdA626, high-dose Ad26 (1 × 10¹¹ viral particles); hdMVA, high-dose MVA (4.4 × 10⁸ TCID₅₀).

Figure 2.

Anti–Ebola virus glycoprotein immunoglobulin G binding antibody responses after heterologous or homologous 2-dose vaccination with Ad26.ZEBOV (adenovirus serotype 26 [Ad26]) and/or MVA-BN-Filo (modified vaccinia Ankara [MVA]) and booster vaccination at day 360 for groups 1–4 (A), 5 and 6 (B), 7 and 8 (C), and 9 and 10 (no booster vaccinations) (D). Vaccination regimens are shown as “dose 1, dose 2 (booster).” Responses represent geometric mean concentrations with 95% confidence intervals. Abbreviations: EU, enzyme-linked immunosorbent assay units; hdAd26, high-dose Ad26; hdMVA, high-dose MVA.

Figure 3.

Virus neutralizing antibody titer results, determined with luciferase-based virus neutralization assay, after heterologous or homologous 2-dose vaccination with Ad26.ZEBOV (adenovirus serotype 26 [Ad26]) and/or MVA-BN-Filo (modified vaccinia Ankara [MVA]) and booster vaccination at day 360 for groups 1–4 (A), 5 and 6 (B), 7 and 8 (C), and 9 and 10 (no booster vaccinations) (D). Vaccination regimens are shown as “dose 1, dose 2 (booster).” Abbreviations: hdAd26, high-dose Ad26; hdMVA, high-dose MVA; IC₅₀, 50% inhibitory concentration.