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 | CPT PPP Coverage

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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.