Safety and Immunogenicity of Accelerated Heterologous 2-Dose Ebola Vaccine Regimens in Adults With and Without HIV in Africa

Abstract

Ebola disease (ED) outbreaks have continued to ravage sub-Saharan Africa, with the most recent outbreak occurring in 2022–2023 [1]. The largest ED outbreak occurred in 2014–2016 and resulted in >11 000 deaths, highlighting their epidemic potential [2]. The Ad26.ZEBOV (Zabdeno), MVA-BN-Filo (Mvabea) 56-day interval vaccine regimen was authorized under exceptional circumstances by the European Medicines Agency to protect against ED caused by Zaire ebolavirus [3, 4]; this regimen was also granted World Health Organization prequalification [5, 6]. In clinical trials, the Ad26.ZEBOV, MVA-BN-Filo 56-day interval regimen was safe, immunogenic, and induced both antibody and T-cell responses [7–12].

ED outbreaks often occur in regions with high human immunodeficiency virus (HIV) prevalence [13, 14]. As antibody responses to other vaccines (eg, hepatitis B, yellow fever, influenza) are lower or suboptimal in people with HIV (PWH), evaluation of ED vaccines in PWH is important in the context of their intended use in sub-Saharan Africa [15–19].

Limited information is available for regimens administering MVA-BN-Filo and Ad26.ZEBOV in the reverse order or that use a compressed administration schedule [7, 8, 20–25]. Shortened vaccination schedules could be advantageous for immunization in outbreak settings, especially for frontline workers. In a phase 1 study in people without HIV (PWOH), MVA-BN-Filo, Ad26.ZEBOV administered 14 days apart induced cellular immune responses at a higher rate and magnitude, but humoral responses at a similar rate and lower magnitude, as compared to a 56-day interval regimen [22].

Therefore, this trial aimed to assess the safety, tolerability, and immunogenicity of 1 accelerated reverse-administration order regimen and 1 accelerated regimen in adult PWOH and PWH in sub-Saharan Africa.

METHODS

Study Design

EBL2003/RV456 (ClinicalTrials.gov Identifier: NCT02598388) was a 2-part, observer-blind, randomized, placebo-controlled, phase 2 trial conducted in the United States (part 1) and Africa (part 2). Part 1 evaluated only the 14-day MVA-BN-Filo, Ad26.ZEBOV regimen, and its results are described separately [26]. Part 2 evaluated 2 vaccine regimens: MVA-BN-Filo followed by Ad26.ZEBOV 14 days later and Ad26.ZEBOV followed by MVA-BN-Filo 28 days later. Part 2 results are presented herein. The study received ethical approvals from independent ethics committees in each participating country and was conducted in accordance with the Helsinki Declaration. The study protocol and statistical analysis plan are available in the Supplementary Materials.

Participants

PWOH and PWH aged 18–70 years were enrolled at 6 sites in 5 African countries: Kenya, Mozambique, Nigeria, Tanzania, and Uganda. A CD4⁺ count >200 cells/μL at screening was an eligibility requirement for PWH, and those with a screening CD4⁺ count >200 to <350 cells/μL must have been on stable antiretroviral therapy (ART; no regimen change in the 4 weeks preceding screening). Full inclusion/exclusion criteria are listed in the Supplementary Methods. All participants provided written informed consent.

Randomization and Masking

Participants were centrally randomized using computer-generated block randomization. Participants were randomized 1:4 to either the 14-day or 28-day interval regimen, and within each group, randomized 4:1 to receive vaccine or placebo. Specific group assignment was obtained by the investigational product (IP) dispenser through an interactive web response system (IWRS). Randomization codes were maintained in the IWRS and were not available to the study personnel, except the IP dispenser. The study was blinded for study personnel (except the IP dispenser) and participants until all participants completed the 12-month post–dose 2 visit or discontinued earlier, and the database was locked. Dispensing syringes were covered with masking tape and administered by a blinded IP administrator.

Vaccines and Vaccinations

Ad26.ZEBOV (Janssen Vaccines & Prevention B.V.) is a recombinant, replication-incompetent, adenovirus type 26 (Ad26)–vectored vaccine encoding the Ebola virus (EBOV) Mayinga glycoprotein (GP). MVA-BN-Filo (Bavarian Nordic) is a recombinant, nonreplicating, modified vaccinia Ankara–vectored vaccine encoding the EBOV Mayinga GP, Sudan virus Gulu GP, Marburg virus Musoke GP, and Taï Forest virus nucleoprotein [3, 4]. All doses were administered via a 0.5-mL intramuscular injection in the deltoid muscle. Active vaccine participants received 5 × 10¹⁰ viral particles of Ad26.ZEBOV and 1 × 10⁸ infectious units of MVA-BN-Filo. Placebo recipients received 2 injections of 0.9% saline.

Safety Evaluations

Postvaccination adverse event (AE) assessments occurred within 30 (±10) minutes after each vaccination. Participants then recorded local and systemic solicited AEs in a diary card for the next 7 days. Unsolicited AEs were recorded from signing of informed consent until 42 days post–dose 2. Serious AEs (SAEs) were recorded from informed consent through end of study. Viral load and CD4⁺ T-cell count measurements were performed for PWH. Additional details on safety evaluations are provided in the Supplementary Methods.

Immunogenicity Assessments

Immunogenicity was primarily assessed through evaluation of EBOV GP–specific binding antibodies. Blood samples for immunogenicity assessments were collected prevaccination on each dosing day, at 21 and 42 days post–dose 2, and 6 and 12 months post–dose 2. Serum and peripheral blood mononuclear cells were collected, processed, and stored. Total immunoglobulin G (IgG) EBOV GP (Kikwit)–specific binding antibody concentrations were measured using the Filovirus Animal Non-clinical Group (FANG) enzyme-linked immunosorbent assay (ELISA) at Q² Solutions Laboratories (San Juan Capistrano, California) [27].

Exploratory analyses evaluated vaccine-induced neutralizing and other functional antibodies, T cells, antivector immunity, and changes in viral load in PWH. EBOV GP–specific neutralizing antibody titers were measured by pseudovirion neutralization assays using the Makona and Kikwit strains for PWOH and PWH, respectively (Supplementary Methods). Samples from PWH and PWOH were tested in different assays because ART present in sera can cause interference with the standard assay, which utilizes pseudovirions derived from HIV type 1; therefore, neutralizing antibody titers cannot be directly compared between PWH and PWOH. Neutralizing antibody titers against Ad26 were measured using an Ad26 neutralization assay (Supplementary Methods). Fc-mediated effector functions (EBOV GP–specific antibody-dependent complement deposition [ADCD], antibody-dependent natural killer cell activation [ADNKA], and antibody-dependent cellular phagocytosis [ADCP]) were also measured (Supplementary Methods) [28]. Intracellular cytokine staining (ICS) methodology and associated cellular polyfunctionality assessment used to evaluate T-cell immunogenicity are described in the Supplementary Methods.

Statistical Analysis and Sample Size

The planned sample size for part 2 was 500 participants, with an even distribution of PWOH and PWH: 80 for the 14-day interval regimen, 320 for the 28-day interval regimen, and 100 for placebo. No formal statistical hypothesis testing of safety or immunogenicity data was planned or performed. Unsolicited AEs were analyzed in the full analysis set (ie, those who received ≥1 dose of study vaccine). Solicited AE analyses were based on participants in the full analysis set who had recorded reactogenicities documented in their case report form. The primary immunogenicity analysis was performed on the per-protocol analysis set, which included participants who received both doses within the protocol-defined window, had ≥1 postvaccination evaluable immunogenicity sample, and had no major protocol deviations influencing immune response. ICS and combinatorial polyfunctionality analysis of single cells were conducted in the per-protocol set using only samples obtained within the protocol-defined windows. Spearman correlation coefficients for EBOV GP (Kikwit)–binding antibody concentrations and neutralizing antibody titers were calculated at 21 days post–dose 2. Spearman correlation coefficients for EBOV GP–binding antibody concentrations and HIV viral load or CD4⁺ T-cell count were calculated for 21 days post–dose 2 and baseline, respectively. Prism version 9.4.1 software was used for statistical analyses shown in Figures 3, 5, and 7 and Supplementary Figures 3–5; R version 4.2.3 was used for Supplementary Figure 6. All other statistical analyses employed SAS version 9.2 software.

RESULTS

The study was performed from 9 March 2017 to 12 December 2018. A total of 503 participants were randomized and 499 received ≥1 vaccination (Figure 1). Of these 499 participants, 52% were female and the mean age was 33.4 years (Table 1). Demographics and baseline characteristics were generally balanced among groups. Half (50%) of the participants were diagnosed with HIV. The median CD4⁺ count in PWH was 560.0 (interquartile range, 418.0–752.0) cells/μL. ART regimens were predominantly based on nonnucleoside reverse transcriptase inhibitors; the most common regimen was tenofovir disoproxil fumarate/lamivudine/efavirenz. Overall, 480 of 499 (96%) participants completed the study.

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT) diagram. ^aParticipants who discontinued study vaccination could still complete study participation. ^bTwo participants moved and both later indicated that they would like to discontinue study participation. ^cOne participant moved out of the country, 1 participant was traveling and could not attend the day 209 and day 394 visits, and 1 participant did not attend the day 394 visit. ^dParticipant's husband did not agree with her participation. ^eParticipant withdrew for personal reasons. ^fParticipant received blood products. Abbreviations: Ad26, Ad26.ZEBOV; AE, adverse event; MVA, MVA-BN-Filo; PWH, people with human immunodeficiency virus; PWOH, people without human immunodeficiency virus.

Open in new tabDownload slide

The majority of solicited AEs were of mild to moderate severity in the 14- and 28-day interval groups (Figure 2; Supplementary Tables 1 and 2). Additionally, most solicited AEs were ≤3 days in duration (61% and 91% of solicited local AEs in the vaccine and placebo groups, respectively, and 53% and 50% of solicited systemic AEs, respectively). The most frequent (occurring in >20% of participants) solicited local AEs were injection-site pain and injection-site pruritus, while the most frequent (occurring in >40% of participants) solicited systemic AEs were fatigue, headache, and myalgia. There were no remarkable safety profile differences between PWOH and PWH. Solicited local and systemic AEs were more common with active vaccine versus placebo. Grade 3 fever was reported in 7 participants (4 active vaccine, 3 placebo) in the 28-day interval group; the maximum durations were 2 and 4 days for those in the active vaccine and placebo groups, respectively.

Open in new tabDownload slide

Open in new tabDownload slide

Figure 2.

Solicited adverse events (AEs) (full analysis set). Percentages reflect n/N, where n is the number of participants with ≥1 AE and N is the number of participants with available reactogenicity data after the given dose. “Placebo” refers to the group of participants who received placebo for both injections. ^aPost–dose 2, reactogenicity data were not available for 2 participants in the people with human immunodeficiency virus (PWH) group who received MVA, Ad26, and 1 participant in the PWH group who received placebo, placebo. ^bPost–dose 2, reactogenicity data were not available for 2 participants in the people without human immunodeficiency virus (PWOH) group who received Ad26, MVA; 2 participants in the PWOH group who received placebo, placebo; 1 participant in the PWH group who received Ad26, MVA; and 1 participant in the PWH group who received placebo, placebo. Abbreviations: Ad26, Ad26.ZEBOV; MVA, MVA-BN-Filo; PWOH, people without human immunodeficiency virus; PWH, people with human immunodeficiency virus.

No remarkable trends by HIV status were noted in unsolicited AEs (Supplementary Table 3). Infections and infestations were the most frequently reported unsolicited AEs and, among active vaccinees, occurred in 23% of PWOH and 20% of PWH in the 14-day interval group (placebo recipients: 40% and 30%, respectively) and in 29% of PWOH and 30% of PWH in the 28-day interval group (placebo recipients: 21% and 21%, respectively). Overall, 6 participants reported SAEs, including 5 active vaccine recipients (Supplementary Table 4). All SAEs were considered unrelated to the study vaccine. No deaths were reported.

In PWH, rates of viral load suppression (<200 copies/mL) postvaccination were similar to rates observed at baseline, and most participants were virally suppressed for the study duration (Supplementary Table 5).

Responder rates for active vaccine recipients were 16% in the 14-day interval group and 82% in the 28-day interval group on the day of dose 2 administration, based on EBOV GP–binding antibody concentrations (Figure 3, Supplementary Figure 1, and Supplementary Table 6). Responder rates increased at 21 days post–dose 2 to 99% and 98% in the 14- and 28-day interval groups, respectively; there were no notable differences in responder rate by HIV status. Binding antibody geometric mean concentrations (GMCs) for both populations across both regimens decreased by 6 and 12 months post–dose 2, but responder rates remained high at 12 months post–dose 2 (86%–89% across both populations). In almost all placebo recipients, EBOV GP–specific binding antibodies were low or not quantifiable across time points. The impact of HIV parameters on EBOV GP–binding antibody concentrations was negligible (Figure 4).

Figure 3.

Ebola virus glycoprotein (EBOV GP)–specific binding antibody responses measured by Filovirus Animal Non-clinical Group anti–EBOV GP immunoglobulin G enzyme-linked immunosorbent assay (ELISA). The points (symbols) denote individual geometric mean concentrations, and error bars denote 95% confidence intervals. EBOV GP–specific binding antibody concentrations were measured at days 1, 15, 36, 57, 195, and 380 (14-day interval regimen) or days 1, 29, 50, 71, 209, and 394 (28-day interval regimen). The lower limit of quantification (dotted line) was 36.11 EU/mL. The numbers of participants with available data at each time point are reported below the x-axes. Abbreviations: Ad26, Ad26.ZEBOV; EU, enzyme-linked immunosorbent assay unit; LLOQ, lower limit of quantification; MVA, MVA-BN-Filo; PWOH, people without human immunodeficiency virus; PWH, people with human immunodeficiency virus.

Open in new tabDownload slide

Figure 4.

Correlation between Ebola virus glycoprotein–binding antibody in active vaccine recipients at 21 days post–dose 2 and HIV viral load at baseline (A and B) and CD4⁺ T-cell count at baseline (C and D). The lower limit of quantification (dotted line) for the Filovirus Animal Non-clinical Group enzyme-linked immunosorbent assay was 36.11 EU/mL. Abbreviations: EU, enzyme-linked immunosorbent assay unit; HIV, human immunodeficiency virus; LLOQ, lower limit of quantification.

Open in new tabDownload slide

Neutralizing antibodies against the EBOV GP Makona and Kikwit strains were frequently detected in PWOH and PWH, respectively (Figure 5). Neutralization remained stable for PWOH in the 14-day interval group and declined after 21 days post–dose 2 among PWH in the 14-day interval group and PWOH and PWH in the 28-day interval group; neutralizing antibodies remained detectable 12 months post–dose 2 in PWOH but not PWH. Positive correlations (Spearman correlations: 0.356–0.797) between EBOV neutralizing and binding antibody levels are shown in Figure 6. Baseline anti-Ad26 neutralizing antibodies, observed in 154 of 176 (88%) participants evaluated, had a negligible impact on peak binding antibody GMCs (Supplementary Figure 2).

Figure 5.

Ebola virus glycoprotein (EBOV GP)–specific neutralizing antibody responses to EBOV GP Zaire Makona (Monogram Biosciences [MG] pseudovirion neutralization assay [psVNA]; A and C) and EBOV GP Zaire 95 Kikwit (US Army Medical Research Institute of Infectious Diseases [USAMRIID] psVNA; panels B and D). Specimens from people without or with human immunodeficiency virus who were vaccinated with MVA, Ad26, or placebo were evaluated by psVNA to measure the neutralizing antibody response against EBOV Zaire Makona or EBOV Zaire 95 Kikwit strains. Blood was collected on days 1, 15, 36, and 380 (14-day interval regimen) or days 1, 29, 50, and 394 (28-day interval regimen) for use in the assays. Data are plotted as geometric mean 50% inhibitory concentration (IC₅₀) titers ± 95% confidence interval, and the lower limit of quantification (dotted line) was 120 IC₅₀ titer for the MG-psVNA and 79 IC₅₀ titer for the USAMRIID-psVNA (with an assay limit of 20 IC₅₀ titer for the USAMRIID-psVNA; see Supplementary Methods for additional psVNA details). The n/N values reported below the x-axes represent the numbers of responders/numbers of participants with available data at each time point. Abbreviations: Ad26, Ad26.ZEBOV; CI, confidence interval; IC₅₀, 50% inhibitory concentration; LLOQ, lower limit of quantification; MVA, MVA-BN-Filo; PWH, people with human immunodeficiency virus; PWOH, people without human immunodeficiency virus.

Open in new tabDownload slide

Figure 6.

Correlation between Ebola virus glycoprotein (EBOV GP)–binding antibody (Kikwit) and neutralizing antibody responses at 21 days post–dose 2 in people without human immunodeficiency virus (PWOH) and people with human immunodeficiency virus (PWH), active vaccine recipients. Correlation between binding antibody responses as measured by Filovirus Animal Non-clinical Group (FANG) anti-EBOV GP immunoglobulin G enzyme-linked immunosorbent assay (ELISA) (y-axis) and pseudovirion neutralization assay (psVNA) 50% inhibitory concentration (IC₅₀) titers for EBOV Zaire Makona (A and C) or 95 Kikwit (B and D) virus strains. PWOH neutralization titers are from Monogram Biosciences (MG) psVNA and PWH neutralization titers are from US Army Medical Research Institute of Infectious Diseases (USAMRIID) psVNA. Lower limits of quantification are 36.11 EU/mL for the FANG ELISA, 120 IC₅₀ titer for the MG-psVNA, and 79 IC₅₀ titer for the USAMRIID-psVNA (with an assay limit of 20 IC₅₀ titer; see Supplementary Methods for additional psVNA details) and are shown as dotted lines. Abbreviations: EU, enzyme-linked immunosorbent assay unit; IC₅₀, 50% inhibitory concentration; LLOQ, lower limit of quantification; PWOH, people without human immunodeficiency virus; PWH, people with human immunodeficiency virus.

Open in new tabDownload slide

EBOV GP–specific ADCP responses were highest in vaccine recipients at 21 days post–dose 2, when 85% and 71% of PWOH and PWH, respectively, were considered responders in the 14-day interval group and 90% and 85%, respectively, in the 28-day interval group (Supplementary Figure 3). ADNKA responder rates among vaccine recipients at 21 days post–dose 2 were 62% and 53% for PWOH and PWH, respectively, in the 14-day interval group and 68% and 46%, respectively, in the 28-day interval group (Supplementary Figure 4). At 21 days post–dose 2, ADCD responder rates were 69% and 47% for PWOH and PWH, respectively, in the 14-day interval group and in 75% and 57%, respectively, in the 28-day interval group (Supplementary Figure 5). ADCP, ADNKA, and ADCD responses declined by 12 months post–dose 2 among PWOH and PWH with both vaccine regimens.

Among all active vaccine recipients (PWOH and PWH) in the 14-day interval group, EBOV GP–specific CD4⁺ T cells expressing interferon gamma (IFN-γ) and/or interleukin 2 (IL-2) were detected in 26%–32% of participants at 21 days post–dose 2 and in 0%–25% of participants at 12 months post–dose 2 (Figure 7A and 7B); in the 28-day interval group, these T cells were detected in 41%–52% and 23%–49% of participants, respectively (Figure 7C and 7D). Among all active vaccine recipients in the 14-day interval group, EBOV GP–specific CD8⁺ T cells expressing IFN-γ and/or IL-2 were detected in 5%–21% of participants at 21 days post–dose 2 and 5%–13% of participants at 12 months post–dose 2 (Figure 7E and 7F); in the 28-day interval group, CD8⁺ T cells were detected in 8%–12% and 6%–7% of participants, respectively (Figure 7G and 7H).

Figure 7.

Analysis of Ebola virus (EBOV)–specific vaccine (A–D) CD4⁺ and (E–H) CD8⁺ T-cell responses. EBOV glycoprotein–specific T-cell responses were measured by intracellular cytokine staining. Total cytokine response, identified by qualified cytokines interferon-γ and/or interleukin 2, were measured at days 1, 15, 36, and 380 (14-day interval regimen) or days 1, 29, 50, and 394 (28-day interval regimen). Participants (N), responders (%), and median responses are listed for each corresponding graph. Data are plotted as individual points with bars showing median and interquartile range. Abbreviations: Ad26, Ad26.ZEBOV; MVA, MVA-BN-Filo; NA, not applicable; PWH, people with human immunodeficiency virus; PWOH, people without human immunodeficiency virus.

Open in new tabDownload slide

In PWOH and PWH, posterior probability heatmaps at 21 days post–dose 2 showed the cytokine profile that contributed the most to EBOV GP–specific CD4⁺ T cells, with both vaccine regimens consisting of a T-helper 1 (Th1) cell–mediated response expressing CD154, IFN-γ, tumor necrosis factor alpha (TNF-α), and IL-2 (Supplementary Figure 6). Of note, in the 14-day interval group, 4% and 17% of PWOH and PWH, respectively, had a T-helper 2 (Th2) cytokine profile with the additional expression of interleukin 4, and in the 28-day interval group, 27% and 33%, respectively, had additional expression of interleukin 21. CD8⁺ T-cell responses at 21 days post–dose 2 included expression of CD154 alone in 13% of PWOH and 26% of PWH in the 14-day interval group, and 8% and 13%, respectively, in the 28-day interval group; coexpression of IFN-γ and TNF-α was seen in 17% of PWOH and 17% of PWH in the 14-day interval group, and 25% and 40%, respectively, in the 28-day interval group (Supplementary Figure 6).

DISCUSSION

This study demonstrates that 2 accelerated heterologous Ebola vaccination schedules are well tolerated and induce humoral and cellular responses against the EBOV Mayinga GP in both PWOH and PWH. Most solicited AEs were mild to moderate and of short duration in both populations and with both regimens. Vaccination had no clinically significant effect on HIV viral suppression.

Compared to the Ad26.ZEBOV, MVA-BN-Filo 56-day interval regimen, the 2 accelerated regimens in this study generally resulted in lower binding antibody concentrations 21 days post–dose 2 [7–9, 11, 21, 23], with the magnitude of response in the reverse-order 14-day regimen numerically lower versus the 28-day regimen. However, responder rates were >95% with both regimens, and antibody concentrations at 6 and 12 months post–dose 2 were generally similar, as well as compared to the 56-day regimen [8–12, 23]. Importantly, binding antibody responder rates were generally similar among PWOH and PWH within each regimen at all time points assessed; however, at 21 days post–dose 2, GMCs were higher among PWOH than PWH in the 28-day interval group (ie, the 95% confidence intervals for the GMCs were nonoverlapping).

An analysis of neutralizing antibodies demonstrated robust and, for PWOH, durable, titers against the Ebola Zaire Makona and Kikwit strains that correlated with anti-EBOV GP (Kikwit) binding antibody concentrations. Previous results from animal models suggest that antibody effector functions [29–32] and cellular responses [33] may contribute to protection against EBOV infection. In the current study, 46% (ADNKA, PWH, 28-day interval) to 90% (ADCP, PWOH, 28-day interval) of active vaccine recipients were considered responders based on ADCP, ADNKA, and ADCD at 21 days post–dose 2, with a lower percentage of responders in PWH versus PWOH. ADCP, ADNKA, and ADCD response magnitude and responder rates generally declined by 12 months post–dose 2 with both regimens in PWOH and PWH. Of note, ADNKA levels appeared higher at 21 days post–dose 2 among PWOH in the placebo group versus those who received active vaccine; however, this may be due to higher baseline ADNKA activity in the placebo group and should be interpreted with caution due to the small sample size. Both CD4⁺ and CD8⁺ T-cell responders were more frequent in the 28- versus 14-day interval regimen (except that CD8⁺ T-cell responders in PWOH were greater in the 14-day interval regimen), and responders persisted through 12 months post–dose 2. Notably, only small numbers of participants who received placebo, particularly in the 14-day interval group, were included in the ICS analysis.

The data from this trial are consistent with previous observations in different geographic areas that vaccines stimulate polyfunctional immune responses in both PWH with well-controlled infections and PWOH [34, 35]. Results from the combinatorial polyfunctionality analysis of antigen-specific T-cell subsets suggest that administering either Ad26.ZEBOV or MVA-BN-Filo as the first dose in an accelerated regimen can produce balanced Th1 and Th2 cell–mediated EBOV-specific T-cell responses. Both regimens also induced polyfunctional antibody response in PWOH and PWH. Although the likelihood of protection against ED has not been established for compressed schedules, these data suggest that accelerated, heterologous, 2-dose vaccination regimens may establish immune memory that can be rapidly induced by subsequent booster doses or exposure to ED.

This study has some limitations. Due to the relatively small sample size of the MVA-BN-Filo, Ad26.ZEBOV 14-day interval group, the practical impacts from this study are limited and would benefit from a larger dataset. The exclusion of people with advanced HIV (CD4⁺ count <200 cells/μL), people aged <18 years, and pregnant women limits the generalizability of the results. Furthermore, the addition of an approved Ad26.ZEBOV, MVA-BN-Filo 56-day interval regimen for comparison would have benefited this study's interpretation given the subtle outcomes.

In conclusion, during a time of accelerated filovirus outbreaks in Africa, this study contributes to the general safety and immunogenicity data available for the Ad26.ZEBOV, MVA-BN-Filo regimen and strengthens consideration for administration of the vaccine doses in shorter intervals than the approved 56-day interval during active ED outbreaks. This was also the first study to test the accelerated MVA-BN-Filo, Ad26.ZEBOV 14-day interval regimen in Africa, and the results presented here are consistent with those from part 1 of this study, conducted in the United States [26]. This study indicates that the MVA-BN-Filo, Ad26.ZEBOV 14-day and the Ad26.ZEBOV, MVA-BN-Filo 28-day interval regimens induce humoral and cellular immune responses. Both regimens also result in a high percentage of antibody responders, which persisted to ≥12 months post–dose 2. Most importantly, both accelerated regimens were safe and well tolerated in PWOH and PWH, supporting their further evaluation to mitigate ED outbreaks in the African setting. These findings also support the safe administration of any available ED vaccine to provide some protection in an emergency setting where supplies may be limited.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. The authors thank the participants, communities, investigators, and study staff from all of the countries that participated in the study. Medical writing assistance was provided by Kim Fuller, PhD, and Vinay Pasupuleti, PhD, of Lumanity Communications Inc. Additional publication coordination was provided by Sónia Silva (Janssen Vaccines & Prevention B.V., Leiden, The Netherlands). Members of the VAC52150/EBL2003/RV456 Study Team in Africa are listed in the Supplementary Materials. Appreciation is given to the US Military HIV Research Program, Walter Reed Army Institute of Research team, for trial oversight support rendered to the African trial sites.

Data sharing. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.

Disclaimer. The views and opinions expressed in this article are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense (DOD), National Institutes of Health, the US Department of Health and Human Services, the US government, or the authors’ affiliated institutions. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70-25.

Financial support. This work was funded by Janssen Vaccines & Prevention B.V. and the US Department of Defense's Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense, Joint Project Manager for Chemical, Biological, Radiological and Nuclear Medical (JPM-CBRN Medical), with support from a cooperative agreement (W81XWH-11-2-0174) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US DOD. The US Army Medical Research Acquisition Activity is the awarding and administering acquisition office for the cooperative agreement. Funding for medical writing and editorial assistance was provided by Janssen Vaccines & Prevention B.V. Janssen Pharmaceuticals participated in design and conduct of the study; safety monitoring; data analysis and interpretation; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. JPM-CBRN Medical participated in design of the study; safety monitoring; data analysis and interpretation; and review and approval of the manuscript.

References

Author notes