Safety and immunogenicity of an inactivated whole virion SARS-CoV-2 vaccine, TURKOVAC, in healthy adults: Interim results from randomised, double-blind, placebo-controlled phase 1 and 2 trials

Abstract

Background: Development of safe and effective vaccine options is crucial to the success of fight against COVID-19 pandemic. Herein, we report interim safety and immunogenicity findings of the phase 1&2 trials of ERUCoV-VAC, an inactivated whole virion SARS-CoV-2 vaccine.

Methods: Double-blind, randomised, single centre, phase 1 and 2 trials included SARS-CoV-2 seronegative healthy adults aged 18-55 years (18-64 in phase 2). All participants, except the first 4 in phase 1 who received ERUCoV-VAC 3 μg or 6 μg unblinded and monitored for 7 days for safety purposes, were assigned to receive two intramuscular doses of ERUCoV-VAC 3 μg or 6 μg (an inactivated vaccine containing alhydrogel as adjuvant) or placebo 21 days apart (28 days in phase 2) according to computer-generated randomisation schemes. Both trials are registered at ClinicalTrials.gov (phase 1, NCT04691947 and phase 2, NCT04824391).

Results: Forty-four participants (3 μg [n:17], 6 μg [n:17], placebo [n:10]) in phase 1 and 250 (3 μg [n:100], 6 μg [n:100], placebo [n:50]) in phase 2 received ≥1 dose. In phase 1 trial, 25 adverse events AEs (80 % mild) occured in 15 participants (34.1 %) until day 43. There was no dose-response relationship noted in safety events in ERUCoV-VAC recipients (p = 0.4905). Pain at injection site was the most common AE (9/44;20.5 %). Both doses of ERUCoV-VAC 3 μg and 6 μg groups were comparable in inducing SARS-CoV-2 wild-type neutralising antibody (MNT50): GMTs (95 %CI) were 8.3 (6.4-10.3) vs. 8.6 (7.0-10.2) at day 43 (p = 0.7357) and 9.7 (6.0-13.4) vs. 10.8 (8.8-12.8) at day 60 (p = 0.8644), respectively. FRNT50 confirmed MNT50 results: SARS-CoV-2 wild-type neutralising antibody GMTs (95 %CI) were 8.4 (6.3-10.5) vs. 9.0 (7.2-10.8) at day 43 (p = 0.5393) and 11.0 (7.0-14.9) vs. 12.3 (10.3-14.5) at day 60 (p = 0.8578). Neutralising antibody seroconversion rates (95 %CI) were 86.7 % (59.5-98.3) vs 94.1 % (71.3-99.8) at day 43 (p = 0.8727) and 92.8 % (66.1-99.8) vs. 100 % (79.4-100.0) at day 60 (p = 0.8873), in ERUCoV-VAC 3 μg and 6 μg groups, respectively. In phase 2 trial, 268 AEs, (67.2 % moderate in severity) occured in 153 (61.2 %) participants. The most common local and systemic AEs were pain at injection site (23 events in 21 [8.4 %] subjects) and headache (56 events in 47 [18.8 %] subjects), respectively. Pain at injection site was the only AE with a significantly higher frequency in the ERUCoV-VAC groups than in the placebo arm in the phase 2 study (p = 0.0322). ERUCoV-VAC groups were comparable in frequency of AEs (p = 0.4587). ERUCoV-VAC 3 μg and 6 μg groups were comparable neutralising antibody (MNT50): GMTs (95 %CI) were 30.0 (37.9-22.0) vs. 34.9 (47.6-22.1) at day 43 (p = 0.0666) and 34.2 (23.8-44.5) and 39.6 (22.7-58.0) at day 60, (p = 0.2166), respectively. FRNT50 confirmed MNT50 results: SARS-CoV-2 wildtype neutralising antibody GMTs were 28.9 (20.0-37.7) and 30.1 (18.5-41.6) at day 43 (p = 0.3366) and 34.2 (23.8-44.5) and 39.6 (22.7-58.0) at day 60 (p = 0.8777). Neutralising antibody seroconversion rates (95 %CI) were 95.7 % (91.4-99.8) vs. 98.9 % (96.9-100.0) at day 43 (p = 0.8710) and 96.6 % (92.8-100.0) vs 98.9 % (96.7-100.0) at day 60 (p = 0.9129) in ERUCoV-VAC 3 μg and 6 μg groups, respectively.

Conclusions: Two-dose regimens of ERUCoV-VAC 3 μg and 6 μg 28 days both had an acceptable safety and tolerability profile and elicited comparable neutralising antibody responses and seroconversion rates exceeding 95 % at day 43 and 60 after the first vaccination. Data availability Data will be made available on request.

Keywords: COVID-19; ERUCoV-VAC; Inactivated whole virion vaccine; SARS-CoV-2; TURKOVAC.

Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aykut Ozdarendeli, Shaikh Terkis Islam Pavel, Hazel Yetiskin, Muhammet Ali Uygut and Gunsu Aydin are the named inventors on patent applications covering inactivated COVID-19 vaccine development.

Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1

Study profiles for (A) phase 1 and (B) phase 2 trials. n = number of participants.*not included as the targeted number of randomised patients was achieved. **The first four patients enrolled in the study (two in each vaccine arm) unblindly received ERUCoV-VAC and were monitored for a week for safety purposes (see randomisation and masking). #Placebo recipients were released from the trials to allow them to receive one of the vaccines that became available for emergency use.

Fig. 1

Study profiles for (A) phase 1 and (B) phase 2 trials. n = number of participants.*not included as the targeted number of randomised patients was achieved. **The first four patients enrolled in the study (two in each vaccine arm) unblindly received ERUCoV-VAC and were monitored for a week for safety purposes (see randomisation and masking). #Placebo recipients were released from the trials to allow them to receive one of the vaccines that became available for emergency use.

Fig. 2

Titres of SARS-CoV-2 wild-type neutralising antibodies (A-D) and anti-S1-RBD IgG (E-F) and anti- SARS-CoV-2 total IgG (G-H) antibodies at baseline, day 43 and day 60 in the ERUCoV-VAC (3 µg and 6 µg) and placebo groups in the phase 1 and phase 2 trials. Dose schedule: two doses 21 days apart in the phase 1 trial; two doses 28 days apart in the phase 2 trial. *placebo recipients were released from the trial after day 43, therefore not included in day 60 analyses. **ns = not significant. The numbers above the spots are the GMT estimates, the error bars represent the 95 %CI of the GMT and the spots indicate the individual antibody titres. ELISA = enzyme-linked immunosorbent assay; FRNT = focus-reduction neutralisation test; GMT = geometric mean titre; IgG = immunoglobulin G. MNT = microneutralisation test. SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; S1-RBD = spike 1-receptor binding domain.

Fig. 2

Titres of SARS-CoV-2 wild-type neutralising antibodies (A-D) and anti-S1-RBD IgG (E-F) and anti- SARS-CoV-2 total IgG (G-H) antibodies at baseline, day 43 and day 60 in the ERUCoV-VAC (3 µg and 6 µg) and placebo groups in the phase 1 and phase 2 trials. Dose schedule: two doses 21 days apart in the phase 1 trial; two doses 28 days apart in the phase 2 trial. *placebo recipients were released from the trial after day 43, therefore not included in day 60 analyses. **ns = not significant. The numbers above the spots are the GMT estimates, the error bars represent the 95 %CI of the GMT and the spots indicate the individual antibody titres. ELISA = enzyme-linked immunosorbent assay; FRNT = focus-reduction neutralisation test; GMT = geometric mean titre; IgG = immunoglobulin G. MNT = microneutralisation test. SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; S1-RBD = spike 1-receptor binding domain.

Supplementary figure 1

Correlation between MNT50 and FRNT50 results, responses to SARS-Cov-2 in the A) phase 1 on day 43. FRNT=focus-reduction neutralisation test; MNT=microneutralisation test.

Supplementary figure 2

Correlation between MNT50 and FRNT50 results, responses to SARS-Cov-2 in the B) phase 2 trials on day 43. FRNT=focus-reduction neutralisati

Supplementary figure 3

ELISPOT results from phase 2 trial. PBMC=peripheral blood mononuclear cells.