Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia

Denis Y Logunov, Inna V Dolzhikova, Olga V Zubkova, Amir I Tukhvatullin, Dmitry V Shcheblyakov, Alina S Dzharullaeva, Daria M Grousova, Alina S Erokhova, Anna V Kovyrshina, Andrei G Botikov, Fatima M Izhaeva, Olga Popova, Tatiana A Ozharovskaya, Ilias B Esmagambetov, Irina A Favorskaya, Denis I Zrelkin, Daria V Voronina, Dmitry N Shcherbinin, Alexander S Semikhin, Yana V Simakova, Elizaveta A Tokarskaya, Nadezhda L Lubenets, Daria A Egorova, Maksim M Shmarov, Natalia A Nikitenko, Lola F Morozova, Elena A Smolyarchuk, Evgeny V Kryukov, Vladimir F Babira, Sergei V Borisevich, Boris S Naroditsky, Alexander L Gintsburg, Denis Y Logunov, Inna V Dolzhikova, Olga V Zubkova, Amir I Tukhvatullin, Dmitry V Shcheblyakov, Alina S Dzharullaeva, Daria M Grousova, Alina S Erokhova, Anna V Kovyrshina, Andrei G Botikov, Fatima M Izhaeva, Olga Popova, Tatiana A Ozharovskaya, Ilias B Esmagambetov, Irina A Favorskaya, Denis I Zrelkin, Daria V Voronina, Dmitry N Shcherbinin, Alexander S Semikhin, Yana V Simakova, Elizaveta A Tokarskaya, Nadezhda L Lubenets, Daria A Egorova, Maksim M Shmarov, Natalia A Nikitenko, Lola F Morozova, Elena A Smolyarchuk, Evgeny V Kryukov, Vladimir F Babira, Sergei V Borisevich, Boris S Naroditsky, Alexander L Gintsburg

Abstract

Background: We developed a heterologous COVID-19 vaccine consisting of two components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S). We aimed to assess the safety and immunogenicity of two formulations (frozen and lyophilised) of this vaccine.

Methods: We did two open, non-randomised phase 1/2 studies at two hospitals in Russia. We enrolled healthy adult volunteers (men and women) aged 18-60 years to both studies. In phase 1 of each study, we administered intramuscularly on day 0 either one dose of rAd26-S or one dose of rAd5-S and assessed the safety of the two components for 28 days. In phase 2 of the study, which began no earlier than 5 days after phase 1 vaccination, we administered intramuscularly a prime-boost vaccination, with rAd26-S given on day 0 and rAd5-S on day 21. Primary outcome measures were antigen-specific humoral immunity (SARS-CoV-2-specific antibodies measured by ELISA on days 0, 14, 21, 28, and 42) and safety (number of participants with adverse events monitored throughout the study). Secondary outcome measures were antigen-specific cellular immunity (T-cell responses and interferon-γ concentration) and change in neutralising antibodies (detected with a SARS-CoV-2 neutralisation assay). These trials are registered with ClinicalTrials.gov, NCT04436471 and NCT04437875.

Findings: Between June 18 and Aug 3, 2020, we enrolled 76 participants to the two studies (38 in each study). In each study, nine volunteers received rAd26-S in phase 1, nine received rAd5-S in phase 1, and 20 received rAd26-S and rAd5-S in phase 2. Both vaccine formulations were safe and well tolerated. The most common adverse events were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and joint pain (18 [24%]). Most adverse events were mild and no serious adverse events were detected. All participants produced antibodies to SARS-CoV-2 glycoprotein. At day 42, receptor binding domain-specific IgG titres were 14 703 with the frozen formulation and 11 143 with the lyophilised formulation, and neutralising antibodies were 49·25 with the frozen formulation and 45·95 with the lyophilised formulation, with a seroconversion rate of 100%. Cell-mediated responses were detected in all participants at day 28, with median cell proliferation of 2·5% CD4+ and 1·3% CD8+ with the frozen formulation, and a median cell proliferation of 1·3% CD4+ and 1·1% CD8+ with the lyophilised formulation.

Interpretation: The heterologous rAd26 and rAd5 vector-based COVID-19 vaccine has a good safety profile and induced strong humoral and cellular immune responses in participants. Further investigation is needed of the effectiveness of this vaccine for prevention of COVID-19.

Funding: Ministry of Health of the Russian Federation.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile Gam-COVID-Vac=frozen vaccine formulation. Gam-COVID-Vac-Lyo=lyophilised vaccine formulation. rAd26-S=recombinant adenovirus type 26 carrying the gene for SARS-CoV-2 full-length glycoprotein S. rAd5-S=recombinant adenovirus type 5 carrying the gene for SARS-CoV-2 full-length glycoprotein S. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
Figure 2
Figure 2
Humoral immune response Data are geometric mean titres and 95% CIs. (A) RBD-specific antibodies on days 0, 14, 21, and 28, as measured by ELISA, in participants vaccinated with rAd26-S or rAd5-S only. (B) RBD-specific antibodies on days 0, 14, 21, 28, and 42, as measured by ELISA, in participants vaccinated with rAd26-S on day 0 and rAd5-S on day 21. (C) Neutralising antibodies on days 0, 14, and 28, as measured by neutralisation assay with 100 TCID50, in participants vaccinated with rAd26-S or rAd5-S only. (D) Neutralising antibodies on days 0, 14, 28, and 42, as measured by microneutralisation assay with 100 TCID50, in participants vaccinated with rAd26-S on day 0 and rAd5-S on day 21. RBD-specific IgGs and neutralising antibodies of in convalescent plasma are also shown in (B) and (D). Gam-COVID-Vac=frozen vaccine formulation. Gam-COVID-Vac-Lyo=lyophilised vaccine formulation. rAd26-S=recombinant adenovirus type 26 carrying the gene for SARS-CoV-2 full-length glycoprotein S. rAd5-S=recombinant adenovirus type 5 carrying the gene for SARS-CoV-2 full-length glycoprotein S. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. RBD=receptor-binding domain. TCID50=50% tissue culture infective dose.
Figure 3
Figure 3
Cell-mediated immune response to SARS-CoV-2 glycoprotein Data are median and 95% CI. Antigen-specific proliferation of CD4+ and CD8+ T cells and increase in interferon-γ secretion in peripheral blood mononuclear cells in participants vaccinated with rAd26-S or rAd5-S only (A, C, E) and in participants vaccinated with rAd26-S on day 0 and rAd5-S on day 21 (B, D, F). Gam-COVID-Vac=frozen vaccine formulation. Gam-COVID-Vac-Lyo=lyophilised vaccine formulation. rAd26-S=recombinant adenovirus type 26 carrying the gene for SARS-CoV-2 full-length glycoprotein S. rAd5-S=recombinant adenovirus type 5 carrying the gene for SARS-CoV-2 full-length glycoprotein S. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
Figure 4
Figure 4
Neutralising antibody response to rAd26 and rAd5 vectors after immunisation The ordinate axis designates reciprocal neutralising antibody titres to recombinant adenoviral vectors. rAd=recombinant adenovirus. Gam-COVID-Vac=frozen vaccine formulation. Gam-COVID-Vac-Lyo=lyophilised vaccine formulation. rAd26-S=recombinant adenovirus type 26 carrying the gene for SARS-CoV-2 full-length glycoprotein S. rAd5-S=recombinant adenovirus type 5 carrying the gene for SARS-CoV-2 full-length glycoprotein S. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.

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