Safety and immunogenicity of a modified vaccinia virus Ankara vector vaccine candidate for Middle East respiratory syndrome: an open-label, phase 1 trial

Abstract

Background: The Middle East respiratory syndrome coronavirus (MERS-CoV) causes a respiratory disease with a case fatality rate of up to 35%. Given its potential to cause a public health emergency and the absence of efficacious drugs or vaccines, MERS is one of the WHO priority diseases warranting urgent research and development of countermeasures. We aimed to assess safety and tolerability of an anti-MERS-CoV modified vaccinia virus Ankara (MVA)-based vaccine candidate that expresses the MERS-CoV spike glycoprotein, MVA-MERS-S, in healthy adults.

Methods: This open-label, phase 1 trial was done at the University Medical Center Hamburg-Eppendorf (Hamburg, Germany). Participants were healthy men and women aged 18-55 years with no clinically significant health problems as determined during medical history and physical examination, a body-mass index of 18·5-30·0 kg/m² and weight of more than 50 kg at screening, and a negative pregnancy test for women. A key exclusion criterion was a previous MVA vaccination. For the prime immunisation, participants received doses of 1 × 10⁷ plaque-forming unit (PFU; low-dose group) or 1 × 10⁸ PFU (high-dose group) MVA-MERS-S intramuscularly. A second identical dose was administered intramuscularly as a booster immunisation 28 days after first injection. As a control group for immunogenicity analyses, blood samples were drawn at identical study timepoints from six healthy adults, who did not receive any injections. The primary objectives of the study were safety and tolerability of the two dosage levels and reactogenicity after administration. Immunogenicity was assessed as a secondary endpoint by ELISA and neutralisation tests. T-cell immunity was evaluated by interferon-γ-linked enzyme-linked immune absorbent spot assay. All participants who were vaccinated at least once were included in the safety analysis. Immunogenicity was analysed in the participants who completed 6 months of follow-up. This trial is registered with ClinicalTrials.gov, NCT03615911, and EudraCT, 2014-003195-23 FINDINGS: From Dec 17, 2017, to June 5, 2018, 26 participants (14 in the low-dose group and 12 in the high-dose group) were enrolled and received the first dose of the vaccine according to their group allocation. Of these, 23 participants (12 in the low-dose group and 11 in the high-dose group) received a second dose of MVA-MERS-S according to their group allocation after a 28-day interval and completed follow-up. Homologous prime-boost immunisation with MVA-MERS-S revealed a benign safety profile with only transient mild-to-moderate reactogenicity. Participants had no severe or serious adverse events. 67 vaccine-related adverse events were reported in ten (71%) of 14 participants in the low-dose group, and 111 were reported in ten (83%) of 12 participants in the high-dose group. Solicited local reactions were the most common adverse events: pain was observed in 17 (65%; seven in the low-dose group vs ten in the high-dose group) participants, swelling in ten (38%; two vs eight) participants, and induration in ten (38%; one vs nine) participants. Headaches (observed in seven participants in the low-dose group vs nine in the high-dose group) and fatigue or malaise (ten vs seven participants) were the most common solicited systemic adverse events. All adverse events resolved swiftly (within 1-3 days) and without sequelae. Following booster immunisation, nine (75%) of 12 participants in the low-dose group and 11 (100%) participants in the high-dose group showed seroconversion using a MERS-CoV S1 ELISA at any timepoint during the study. Binding antibody titres correlated with MERS-CoV-specific neutralising antibodies (Spearman's correlation r=0·86 [95% CI 0·6960-0·9427], p=0·0001). MERS-CoV spike-specific T-cell responses were detected in ten (83%) of 12 immunised participants in the low-dose group and ten (91%) of 11 immunised participants in the high-dose group.

Interpretation: Vaccination with MVA-MERS-S had a favourable safety profile without serious or severe adverse events. Homologous prime-boost immunisation induced humoral and cell-mediated responses against MERS-CoV. A dose-effect relationship was demonstrated for reactogenicity, but not for vaccine-induced immune responses. The data presented here support further clinical testing of MVA-MERS-S in larger cohorts to advance MERS vaccine development.

Funding: German Center for Infection Research.

Figure 1

Trial profile Reasons for screening failures of the ineligible individuals are provided in the appendix (p 9). MERS=Middle East respiratory syndrome. MVA=modified vaccinia virus Ankara. PFU=plaque-forming unit. S=spike. *One participant had to move the day 180 visit to day 110; this data point was therefore removed from immunological analysis.

Figure 2

Treatment-related local and systemic adverse events (A) The proportion of participants in each dose group who experienced at least one adverse event in the indicated symptom group. In case a participant reported two adverse events with differing degrees in the same symptom group, the more severe event was recorded. (B) Absolute number of related adverse events over time up to 43 days after prime immunisation with MVA-MERS-S in each dose group. MERS=Middle East respiratory syndrome. MVA=modified vaccinia virus Ankara. S=spike.

Figure 3

Biological monitoring Haematological changes after prime–boost immunisation with MVA-MERS-S. Lines represent the median value of measured counts of white blood cells, neutrophils, lymphocytes, and thrombocytes in the low-dose and high-dose groups. MERS=Middle East respiratory syndrome. MVA=modified vaccinia virus Ankara. S=spike.

Figure 4

MERS-CoV-specific antibody responses Dots represent data from individual participants, and the median is depicted by horizontal line within the boxes. Error bars represent minimum to maximum values. (A) Binding antibodies were measured against the MERS-CoV S1 protein using an in-house ELISA. The horizontal dashed line depicts the positive threshold. The optical density value of 0·5 was considered to be the threshold for seropositivity. (B) MERS-CoV-specific neutralising antibody responses were measured by the virus neutralisation test assay after prime and boost immunisation. Data are represented as reciprocal neutralisation titre. The geometric mean of four replicates per participant per timepoint is shown. The signal from samples with no neutralising capacity was set to 1. The horizontal dashed line represents the positive threshold. (C) PRNT titre was calculated on the basis of 80% or greater reduction of infected cells. Data are shown as reciprocal titre. The horizontal dashed line represents the positive threshold. (D) Correlation analysis between binding antibodies (optical density value) and reciprocal PRNT₈₀ titres at day 35 after vaccination. MERS-CoV=Middle East respiratory syndrome coronavirus. PRNT₈₀=plaque reduction neutralisation test titre calculated on the basis of 80% or greater reduction of infected cells.

Figure 5

MERS-CoV spike-specific T-cell responses after prime–boost vaccination with MVA-MERS-S (A) Schematic represents the five MERS-CoV spike-specific overlapping peptide pools (M1–M5) that span the entire MERS-CoV spike glycoprotein. (B) Magnitude of T-cell responses targeting MERS-CoV spike glycoprotein. ELISpot responses to the MERS-CoV spike glycoprotein are shown for the five peptide pools by the median values. The sum of the medians of SFCs per million PBMCs is depicted per cohort, per pool, and per timepoint. (C) Proportion of assay responders. A positive response was defined as such if more than 50 SFCs per million PBMCs and the number of SFCs per million PBMCs was more than four times higher than the baseline (day 0) value. (D) Graph showing the breadth of the response to peptide pools. The darker the blue, the more peptide pool responses were observed. ELISpot=interferon-γ-linked enzyme-linked immune absorbent spot assay. MERS-CoV=Middle East respiratory syndrome coronavirus. MVA=modified vaccinia virus Ankara. RBD=receptor binding domain. S=spike. SFCs=spot-forming cells. PBMCs=peripheral blood mononuclear cells.