Immune Responses to Novel Adenovirus Type 26 and Modified Vaccinia Virus Ankara–Vectored Ebola Vaccines at 1 Year

The Ebola virus vaccine strategies evaluated by the World Health Organization in response to the 2014-2016 outbreak in West Africa included a heterologous primary and booster vaccination schedule of the adenovirus type 26 vector vaccine encoding Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia virus Ankara vector vaccine, encoding glycoproteins from Ebola, Sudan, Marburg, and Tai Forest viruses nucleoprotein (MVA-BN-Filo). This schedule has been shown to induce immune responses that persist for 8 months after primary immunization, with 100% of vaccine recipients retaining Ebola virus glycoprotein-specific antibodies.¹

A vaccine that provides durable immune responses is important in maintaining sustained protection against disease, both during outbreaks and outside of an outbreak for at-risk populations, such as health care and aid workers in risk areas, individuals in areas experiencing low-grade endemic disease,² and contacts of Ebola survivors, given evidence of prolonged shedding of the virus from body fluids with the potential for transmission.^3,4

We report the 1-year data for the study of the Ad26.ZEBOV and MVA-BN-Filo vaccines,¹ the longest duration follow-up for any heterologous primary and booster Ebola vaccine schedule to our knowledge.

The single-center, randomized, placebo-controlled, observer-blind, phase 1 trial received approval from the National Research Ethics Service. Participants provided written informed consent. The trial was performed in Oxford, United Kingdom, enrolling 87 healthy participants aged 18 to 50 years from December 2014. Twelve-month follow-up was completed March 2016. Seventy-two participants were randomized to 4 groups, each with 18 participants (3 placebo and 15 active vaccine). Individuals in the vaccine groups received either Ad26.ZEBOV (5 × 10¹⁰ viral particles) or MVA-BN-Filo (1 × 10⁸ median tissue culture infective dose) first, followed by boosting with the alternate vaccine 28 days or 56 days later. An open-label fifth group consisted of an additional 15 participants vaccinated with Ad26.ZEBOV followed by MVA-BN-Filo 14 days later.

The primary outcome was adverse events. Secondary outcomes were the magnitude of humoral and cellular immune responses assessed by enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot (ELISpot) and the percentage of vaccine responders (see Table for definitions). The number of CD4+ and CD8+ T cells and their cytokine expression patterns were assessed by intracellular cytokine staining, as exploratory outcomes. Data analysis was descriptive (SAS [SAS Institute], version 9.2) without formal statistical testing. Collection of day 360 data was a preplanned secondary analysis for vaccine recipients only; further details are available in the protocol (see the Supplement of the original publication).¹

Of 75 active vaccine recipients, 64 attended follow-up at day 360 (median age, 39 years; women, 66%). Eleven participants withdrew (1-3 per group) and missing data were not imputed. No serious adverse events were recorded from day 240 through day 360.

All of the active vaccine recipients maintained Ebola virus–specific immunoglobulin G responses at day 360 (Figure; Table). Vaccine-induced T-cell responses persisted in 60% to 83% of participants receiving Ad26.ZEBOV first followed by MVA-BN-Filo as a booster compared with 69% to 100% of those receiving the reverse regimen (Table). Persistence of the CD8+ and CD4+ responses is shown in the Table.

Immunity after heterologous primary and booster vaccination with Ad26.ZEBOV and MVA-BN-Filo persisted at 1 year. Although no correlate of protection has yet been established, Ebola virus glycoprotein-specific antibodies appear to play an important role in immunity.⁵ A strategy of preemptive use of an AD26.ZEBOV followed by MVA-BN-Filo immunization schedule in at-risk populations (where durability of immune response is likely to be of primary importance) may offer advantages over reactive use of single-dose vaccine regimens.^2,6 A limitation is that this study was conducted in a European population. Immune responses may differ in a sub-Saharan African population; these vaccine candidates are being assessed in this region. Additional research is also warranted to explore the persistence of immunity beyond 1 year following immunization and response to booster doses of vaccine.

Corresponding Author: Matthew D. Snape, MD, Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Headington, OX3 7LE, United Kingdom (matthew.snape@paediatrics.ox.ac.uk).

Author Contributions: Dr Snape and Ms Voysey had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Milligan, Luhn, Shukarev, Douoguih, Snape.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Winslow, Voysey, Snape.

Critical revision of the manuscript for important intellectual content: Winslow, Milligan, Luhn, Shukarev, Douoguih, Snape.

Statistical analysis: Voysey.

Obtained funding: Douoguih.

Administrative, technical, or material support: Winslow, Douoguih.

Supervision: Milligan, Douoguih, Snape.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Snape reports receiving grant funding from GlaxoSmithKline, Pfizer, Novartis Vaccines, and MedImmune; being a Jenner investigator; being funded by the National Institute for Health Research Oxford Biomedical Research Centre; having participated in advisory boards for vaccine manufacturers such as Sanofi-Pasteur MDS and MedImmune; presenting at industry-sponsored symposia; and having assistance from vaccine manufacturers to attend conferences. Payments for these activities are made to the University of Oxford. Dr Douoguih reports pending patents related to the work in the study. No other disclosures were reported.

Funding/Support: This trial was funded by grant 115854 from the European Union’s Innovative Medicines Initiative, as part of the EBOVAC1 consortium. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations. The study sponsor was Janssen Vaccines and Prevention BV. Dr Snape receives salary support from the National Institute for Health Research Oxford Biomedical Research Centre.

Role of the Funder/Sponsor: The study was designed as a collaboration between the sponsor (Janssen Vaccines) and the investigators. Data were collected by investigators at the Oxford Vaccine Group. Data analysis was performed by employees of the sponsor and independently verified by a statistician at the University of Oxford. The funders of the study had no role in the preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Andrew Pollard, FRCPCH, PhD, FMedSci (University of Oxford), for reviewing the article. No compensation was received.