Safety, tolerability, and immunogenicity of the chimpanzee adenovirus type 3-vectored Marburg virus (cAd3-Marburg) vaccine in healthy adults in the USA: a first-in-human, phase 1, open-label, dose-escalation trial

Abstract

Background: WHO has identified Marburg virus as an emerging virus requiring urgent vaccine research and development, particularly due to its recent emergence in Ghana. We report results from a first-in-human clinical trial evaluating a replication-deficient recombinant chimpanzee adenovirus type 3 (cAd3)-vectored vaccine encoding a wild-type Marburg virus Angola glycoprotein (cAd3-Marburg) in healthy adults.

Methods: We did a first-in-human, phase 1, open-label, dose-escalation trial of the cAd3-Marburg vaccine at the Walter Reed Army Institute of Research Clinical Trials Center in the USA. Healthy adults aged 18-50 years were assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 10¹⁰ or 1 × 10¹¹ particle units (pu). Primary safety endpoints included reactogenicity assessed for the first 7 days and all adverse events assessed for 28 days after vaccination. Secondary immunogenicity endpoints were assessment of binding antibody responses and T-cell responses against the Marburg virus glycoprotein insert, and assessment of neutralising antibody responses against the cAd3 vector 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT03475056.

Findings: Between Oct 9, 2018, and Jan 31, 2019, 40 healthy adults were enrolled and assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 10¹⁰ pu (n=20) or 1 × 10¹¹ pu (n=20). The cAd3-Marburg vaccine was safe, well tolerated, and immunogenic. All enrolled participants received cAd3-Marburg vaccine, with 37 (93%) participants completing follow-up visits; two (5%) participants moved from the area and one (3%) was lost to follow-up. No serious adverse events related to vaccination occurred. Mild to moderate reactogenicity was observed after vaccination, with symptoms of injection site pain and tenderness (27 [68%] of 40 participants), malaise (18 [45%] of 40 participants), headache (17 [43%] of 40 participants), and myalgia (14 [35%] of 40 participants) most commonly reported. Glycoprotein-specific antibodies were induced in 38 (95%) of 40 participants 4 weeks after vaccination, with geometric mean titres of 421 [95% CI 209-846] in the 1 × 10¹⁰ pu group and 545 [276-1078] in the 1 × 10¹¹ pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 [95% CI 13-119] in the 1 ×10¹⁰ pu group and 27 [95-156] in the 1 ×10¹¹ pu group; both p<0·0001). T-cell responses to the glycoprotein insert and neutralising responses against the cAd3 vector were also increased at 4 weeks after vaccination.

Interpretation: This first-in-human trial of this cAd3-Marburg vaccine showed the agent is safe and immunogenic, with a safety profile similar to previously tested cAd3-vectored filovirus vaccines. 95% of participants produced a glycoprotein-specific antibody response at 4 weeks after a single vaccination, which remained in 70% of participants at 48 weeks. These findings represent a crucial step in the development of a vaccine for emergency deployment against a re-emerging pathogen that has recently expanded its reach to new regions.

Funding: National Institutes of Health.

Figure 1:. Study profile

pu=particle units.

Figure 2:. Maximum local and systemic solicited symptoms 7 days after vaccination with chimpanzee adenovirus type 3-vectored Marburg virus

For symptoms persisting for more than 1 day, a single count per person at the maximum severity of the symptom was used for the figure. No swelling or redness was observed at the vaccine injection site. pu=particle units.

Figure 3:. Chimpanzee adenovirus type 3-vectored Marburg virus vaccine antibody titres during the 48-week follow-up

Baseline-subtracted serum Marburg glycoprotein ELISA EC₉₀ titres are plotted by vaccine dose at the peak, week 4, of the response (A) and at weeks post vaccination during the 48 weeks after vaccination (B). Symbols indicate group geometric mean titres and whiskers denote 95% CIs. (C) Positive response rates at week 4 and week 48, as defined by a significant increase over baseline titres. EC₉₀=90% effective concentration. pu=particle units.

Figure 4:. Frequency of Marburg glycoprotein-specific non-naive CD4 and CD8 T cells at baseline and at 4 weeks after vaccination

Percentage of background-subtracted non-naive CD4 T cells or CD8 T cells producing any one of the three tested cytokines (interferon gamma, interleukin, and tumour necrosis factor) in response to Marburg glycoprotein peptide stimulation at baseline and 4 weeks post vaccination by dose group. Within each violin plot, the black line indicates the median and the coloured lines indicate the quartiles. n=20 per group at each timepoint. pu=particle units.