Safety and immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial

Abstract

Background: Cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Arabian Peninsula 7 years after it was first described in Saudi Arabia. MERS-CoV poses a significant risk to public health security because of an absence of currently available effective countermeasures. We aimed to assess the safety and immunogenicity of the candidate simian adenovirus-vectored vaccine expressing the full-length spike surface glycoprotein, ChAdOx1 MERS, in humans.

Methods: This dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included healthy people aged 18-50 years with negative pre-vaccination tests for HIV antibodies, hepatitis B surface antigen, and hepatitis C antibodies (and a negative urinary pregnancy test for women). Participants received a single intramuscular injection of ChAdOx1 MERS at three different doses: the low-dose group received 5 × 109 viral particles, the intermediate-dose group received 2·5 × 1010 viral particles, and the high-dose group received 5 × 1010 viral particles. The primary objective was to assess safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited, unsolicited, and serious adverse events after vaccination. The secondary objective was to assess the cellular and humoral immunogenicity of ChAdOx1 MERS, measured by interferon-γ-linked enzyme-linked immunospot, ELISA, and virus neutralising assays after vaccination. Participants were followed up for up to 12 months. This study is registered with ClinicalTrials.gov, NCT03399578.

Findings: Between March 14 and Aug 15, 2018, 24 participants were enrolled: six were assigned to the low-dose group, nine to the intermediate-dose group, and nine to the high-dose group. All participants were available for follow-up at 6 months, but five (one in the low-dose group, one in the intermediate-dose group, and three in the high-dose group) were lost to follow-up at 12 months. A single dose of ChAdOx1 MERS was safe at doses up to 5 × 1010 viral particles with no vaccine-related serious adverse events reported by 12 months. One serious adverse event reported was deemed to be not related to ChAdOx1 MERS. 92 (74% [95% CI 66-81]) of 124 solicited adverse events were mild, 31 (25% [18-33]) were moderate, and all were self-limiting. Unsolicited adverse events in the 28 days following vaccination considered to be possibly, probably, or definitely related to ChAdOx1 MERS were predominantly mild in nature and resolved within the follow-up period of 12 months. The proportion of moderate and severe adverse events was significantly higher in the high-dose group than in the intermediate-dose group (relative risk 5·83 [95% CI 2·11-17·42], p<0·0001) Laboratory adverse events considered to be at least possibly related to the study intervention were self-limiting and predominantly mild in severity. A significant increase from baseline in T-cell (p<0·003) and IgG (p<0·0001) responses to the MERS-CoV spike antigen was observed at all doses. Neutralising antibodies against live MERS-CoV were observed in four (44% [95% CI 19-73]) of nine participants in the high-dose group 28 days after vaccination, and 19 (79% [58-93]) of 24 participants had antibodies capable of neutralisation in a pseudotyped virus neutralisation assay.

Interpretation: ChAdOx1 MERS was safe and well tolerated at all tested doses. A single dose was able to elicit both humoral and cellular responses against MERS-CoV. The results of this first-in-human clinical trial support clinical development progression into field phase 1b and 2 trials.

Funding: UK Department of Health and Social Care, using UK Aid funding, managed by the UK National Institute for Health Research.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial profile MERS=Middle East respiratory syndrome.

Figure 2

Humoral responses to ChAdOx1 MERS vaccine (A) Individual IgG titres at each dose group. Data points represent geometric means, and error bars represent 95% CIs. The dashed line represents the cutoff value for seropositivity. (B) Data points represent median and error bars represent IQRs for IgG titres in each group. The dashed line represents the cutoff value for seropositivity (225 ELISA units). (C) Virus-neutralising titres at day 0 and day 28 for each group. Data points represent geometric means, and error bars represent 95% CIs. The dashed line represents the lower limit of detection under our experimental condition. p values calculated by Kruskal-Wallis with Dunn's multiple comparison post test. MERS=Middle East respiratory syndrome.

Figure 3

MERS-CoV spike-pseudotyped neutralisation p values were calculated using Kruskall-Wallis with Dunn's multiple comparison post test. The dashed lines represent lower limit of detection under our experimental condition. Data points represent geometric means, and error bars represent 95% CIs. MERS-CoV=Middle East respiratory syndrome coronavirus.

Figure 4

T-cell responses to ChAdOx1 MERS Ex-vivo interferon-γ-linked enzyme-linked immunospot responses to MERS spike protein. Panels A, B, and D show the total response to MERS spike peptides (sum of 13 pools), and panel C shows the response to each pool. In the low-dose group, data were missing for three participants for day 364. In the intermediate group, data were missing for one participant for day 56 and three participants for day 364. In the high-dose group, data were missing for four participants for day 364. (A) Data points represent median and error bars represent IQR for SFCs per million PBMCs during 12-month follow-up. (B) Responses for individual participants. Data points represent geometric means, and error bars represent 95% CIs. The dashed line represents the lower limit of detection under our experimental condition. Kruskal-Wallis with Dunn's multiple comparison post test. (C) Heat map of responses to each peptide pool for each participant, arranged by ascending dose group. (D) Correlation between baseline (day 0) and 6-month (day 182) responses. MERS=Middle East respiratory syndrome. PBMCs=peripheral blood mononuclear cells. SFCs=spot-forming cells.