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. MethodsThis 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 ant...

Prospects for a safe COVID-19 vaccine

“…In phase 1 clinical trials, a MERS-CoV DNA vaccine was well tolerated (NCT03721718) (103) as was an MVA vectorspike protein vaccine (NCT03615911) (104). A chimp adenovirus vector (ChAdOx1) vaccine expressing the MERS-CoV spike protein did not result in any severe adverse events over a 12-month follow-up period in 24 trial participants, and all mild or moderate adverse events resolved within 6 days (NCT03399578) (105). Moreover, no evidence of immune enhancement of disease was noted in a clinical trial of an inactivated whole virus SARS-CoV-1 vaccine (106) or a DNA vaccine expressing SARS-CoV-1 spike protein in 10 individuals (NCT00099463) (107).…”

Emerging treatment strategies for COVID-19 infection

“…All participants in the non-randomized prime boost group ( n = 19) at both dose levels had neutralizing activity following a booster dose and antibody responses correlated with ELISA assessed antibody levels. No serious adverse events were observed and the results for the randomized cohort are awaited [ 105 ].…”

A single intranasal dose of chimpanzee adenovirus-vectored vaccine confers sterilizing immunity against SARS-CoV-2 infection

“…Adenovirus (Ad)-based vaccines against betacoronaviruses have been evaluated previously. A single dose of a chimpanzee Ad-vectored vaccine encoding the full-length S protein of MERS-CoV protected human dipeptidyl peptidase 4 (hDPP4) transgenic mice from infection (Munster et al, 2017), reduced virus shedding and enhanced survival in camels (Alharbi et al, 2019), and was safe and immunogenic in humans in a phase 1 clinical trial (Folegatti et al, 2020).…”