Safety, tolerability, and immunogenicity of the Ebola Sudan chimpanzee adenovirus vector vaccine (cAd3-EBO S) in healthy Ugandan adults: a phase 1, open-label, dose-escalation clinical trial

Abstract

Background: Sudan Ebola virus can cause severe viral disease, with an average case fatality rate of 54%. A recent outbreak of Sudan Ebola virus in Uganda caused 55 deaths among 164 confirmed cases in the second half of 2022. Although vaccines and therapeutics specific for Zaire Ebola virus have been approved for use during outbreak situations, Sudan Ebola virus is an antigenically distinct virus with no approved vaccines available.

Methods: In this phase 1, open-label, dose-escalation trial we evaluated the safety, tolerability, and immunogenicity of a monovalent chimpanzee adenovirus 3 vaccine against Sudan Ebola virus (cAd3-EBO S) at Makerere University Walter Reed Project in Kampala, Uganda. Study participants were recruited from the Kampala metropolitan area using International Review Board-approved written and electronic media explaining the trial intervention. Healthy adults without previous receipt of Ebola, Marburg, or cAd3 vectored-vaccines were enrolled to receive cAd3-EBO S at either 1 × 10¹⁰ or 1 × 10¹¹ particle units (PU) in a single intramuscular vaccination and were followed up for 48 weeks. Primary safety and tolerability endpoints were assessed in all vaccine recipients by reactogenicity for the first 7 days, adverse events for the first 28 days, and serious adverse events throughout the study. Secondary immunogenicity endpoints included evaluation of binding antibody and T-cell responses against the Sudan Ebola virus glycoprotein, and neutralising antibody responses against the cAd3 vector at 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT04041570, and is completed.

Findings: 40 healthy adults were enrolled between July 22 and Oct 1, 2019, with 20 receiving 1 × 10¹⁰ PU and 20 receiving 1 × 10¹¹ PU of cAd3-EBO S. 38 (95%) participants completed all follow-up visits. The cAd3-EBO S vaccine was well tolerated with no severe adverse events. The most common reactogenicity symptoms were pain or tenderness at the injection site (34 [85%] of 40), fatigue (29 [73%] of 40), and headache (26 [65%] of 40), and were mild to moderate in severity. Positive responses for glycoprotein-specific binding antibodies were induced by 2 weeks in 31 (78%) participants, increased to 34 (85%) participants by 4 weeks, and persisted to 48 weeks in 31 (82%) participants. Most participants developed glycoprotein-specific T-cell responses (20 [59%, 95% CI 41-75] of 34; six participants were removed from the T cell analysis after failing quality control parameters) by 4 weeks after vaccination, and neutralising titres against the cAd3 vector were also increased from baseline (90% inhibitory concentration of 47, 95% CI 30-73) to 4 weeks after vaccination (196, 125-308).

Interpretation: The cAd3-EBO S vaccine was safe at both doses, rapidly inducing immune responses in most participants after a single injection. The rapid onset and durability of the vaccine-induced antibodies make this vaccine a strong candidate for emergency deployment in Sudan Ebola virus outbreaks.

Funding: National Institutes of Health via interagency agreement with Walter Reed Army Institute of Research.

Figure 1:. Study Consort Diagram.

Forty participants were enrolled into one of two dose groups; safety and immune responses were followed for 48 weeks following vaccination. Two participants in the 10¹¹ PU dose group moved from the area (one after week four and one after week 16). “Follow-up completed” indicates the participant was followed through the duration of the protocol-specified visits.

Figure 2:. Maximum local and systemic solicited symptoms.

Percent of participants (x axis) reporting local or systemic symptoms (y axis) in the seven days following cAd3-EBO S vaccination. For symptoms persisting more than one day, a single count per person at the maximum severity of the symptom was used for the figure. Number of participants reporting each symptom noted in overlaid text.

Figure 3.. cAd3-EBO S vaccine elicits increases in antibody titers that are sustained through 48 weeks post-vaccination.

Baseline-subtracted serum Sudan GP ELISA EC₉₀ titers (y axis) are plotted by (A) vaccine dose (x axis) at the peak (week four) of the response and (B) weeks post-vaccination (x axis) through 48 weeks following vaccination. In (A), each square indicates a participant’s individual titer, and black lines indicate the group GMTs, which are also provided numerically above the population. In (B) squares indicate group GMTs and whiskers are 95% CIs. In (A) and (B), p values result from a Wilcoxon rank-sum test comparing dose groups. (C) Positive response rates at weeks 4 and 48 as defined by a significant increase over baseline titers.

Figure 3.. cAd3-EBO S vaccine elicits increases in antibody titers that are sustained through 48 weeks post-vaccination.

Baseline-subtracted serum Sudan GP ELISA EC₉₀ titers (y axis) are plotted by (A) vaccine dose (x axis) at the peak (week four) of the response and (B) weeks post-vaccination (x axis) through 48 weeks following vaccination. In (A), each square indicates a participant’s individual titer, and black lines indicate the group GMTs, which are also provided numerically above the population. In (B) squares indicate group GMTs and whiskers are 95% CIs. In (A) and (B), p values result from a Wilcoxon rank-sum test comparing dose groups. (C) Positive response rates at weeks 4 and 48 as defined by a significant increase over baseline titers.

Figure 4.. The frequency of Sudan GP-specific non-naive CD4 and CD8 T cells increases by four weeks after vaccination.

Percent of background-subtracted non-naïve (A) CD4 T cells or (B) CD8 T cells (y axis) producing any one of the three tested cytokines (IFN-γ, IL-2 or TNF-α) in response to Sudan GP peptide stimulation at baseline and four weeks post-vaccination by dose group (x axis). Within each violin plot, the black line indicates the median and the colored lines indicate the quartiles. Above each violin plot, the group mean (and standard deviation) is indicated. n=20 for 10¹⁰ and 14 for 10¹¹ at each time point. p values result from paired t-tests comparing background-subtracted non-naïve T cell frequencies from baseline to week 4.