A heterologous virus-vectored vaccine for prevention of Middle East respiratory syndrome induces long protective immune response against MERS-CoV

Kovyrshina, Anna V.; Dolzhikova, Inna V.; Grousova, Daria M.; Balyasin, Maxim; Ботиков, А. Г.; Panina, L.V.; Gordeychuk, Ilya; Gulyaev, Stanislav A.; Zubkova, Olga V.; Ozharovskaya, Tatiana A; Popova, Olga; Tukhvatulin, Amir I.; Tokarskaya, Elizaveta A.; Simakova, Ya.V.; Esmagambetov, Ilias B.; Shcheblyakov, Dmitry V.; Evgrafova, Irina; Deryabin, P. G.; Борисевич, С. В.; Naroditsky, Boris S.; Logunov, Denis Y.; Gintsburg, Alexander L.

doi:10.33029/0206-4952-2020-41-2-135-143

Cited by 10 publications

(11 citation statements)

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“…The sample size for both studies was calculated from previous clinical trials of a MERS vaccine 27 based on the same recombinant viral vectors as used in our vaccine but carrying the MERS-CoV glycoprotein S gene. Preliminary results of a study of a MERS vaccine in which more than 100 people participated showed a seroconversion rate of 100%.…”

Section: Discussionmentioning

confidence: 99%

“…Preliminary results of a study of a MERS vaccine in which more than 100 people participated showed a seroconversion rate of 100%. 27 When calculating the sample size for our study, we expected 99% efficiency, which required inclusion of 16 participants in each study. Considering the possibility of early dropout of volunteers, we decided that 20 volun teers should be recruited into the immunogenicity assessment group in phase 2 of each study.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, the best vaccination scheme is heterologous vaccination, when different viral vectors are used to overcome any negative effects of immune response to vector components. [25][26][27] Such an approach was successfully used with an Ebola virus disease vaccine developed in Russia and licensed in 2015. 25 We designed a novel, heterologous adenoviral vectorbased vaccine against SARS-CoV-2 suitable for primeboost vaccination.…”

Section: Implications Of All the Available Evidencementioning

confidence: 99%

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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

et al. 2020

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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...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Implications Of All the Available Evidencementioning

confidence: 99%

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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

et al. 2020

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“…Although adenoviral vectors might induce immune responses against vector components and attenuate antigen-induced responses, prime-boost heterologous vaccination with two different vectors allows minimisation of this effect. 9 , 10 , 11 Thus, the most effective approach for generating a powerful and long-lasting immune response that does not depend on the presence of a pre-existing immune response to the vector is the heterologous prime-boost vaccination approach. We used this approach when developing a vaccine for the prevention of COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia

et al. 2021

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Background A heterologous recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), showed a good safety profile and induced strong humoral and cellular immune responses in participants in phase 1/2 clinical trials. Here, we report preliminary results on the efficacy and safety of Gam-COVID-Vac from the interim analysis of this phase 3 trial. Methods We did a randomised, double-blind, placebo-controlled, phase 3 trial at 25 hospitals and polyclinics in Moscow, Russia. We included participants aged at least 18 years, with negative SARS-CoV-2 PCR and IgG and IgM tests, no infectious diseases in the 14 days before enrolment, and no other vaccinations in the 30 days before enrolment. Participants were randomly assigned (3:1) to receive vaccine or placebo, with stratification by age group. Investigators, participants, and all study staff were masked to group assignment. The vaccine was administered (0·5 mL/dose) intramuscularly in a prime-boost regimen: a 21-day interval between the first dose (rAd26) and the second dose (rAd5), both vectors carrying the gene for the full-length SARS-CoV-2 glycoprotein S. The primary outcome was the proportion of participants with PCR-confirmed COVID-19 from day 21 after receiving the first dose. All analyses excluded participants with protocol violations: the primary outcome was assessed in participants who had received two doses of vaccine or placebo, serious adverse events were assessed in all participants who had received at least one dose at the time of database lock, and rare adverse events were assessed in all participants who had received two doses and for whom all available data were verified in the case report form at the time of database lock. The trial is registered at ClinicalTrials.gov ( NCT04530396 ). Findings Between Sept 7 and Nov 24, 2020, 21 977 adults were randomly assigned to the vaccine group (n=16 501) or the placebo group (n=5476). 19 866 received two doses of vaccine or placebo and were included in the primary outcome analysis. From 21 days after the first dose of vaccine (the day of dose 2), 16 (0·1%) of 14 964 participants in the vaccine group and 62 (1·3%) of 4902 in the placebo group were confirmed to have COVID-19; vaccine efficacy was 91·6% (95% CI 85·6–95·2). Most reported adverse events were grade 1 (7485 [94·0%] of 7966 total events). 45 (0·3%) of 16 427 participants in the vaccine group and 23 (0·4%) of 5435 participants in the placebo group had serious adverse events; none were considered associated with vaccination, with confirmation from the independent data monitoring committee. Four deaths were reported during the study (three [<0·1%] of 16 427 participants in the vaccine group and one [<0·1%] of 5435 participants in the placebo group), none of which were considered related to the vaccine. Interpretation This interim analysis of the phase 3 trial of Gam-COVID-Vac showed 91·6% ...

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“…The encouraging results of S-Trimer booster doses in this study also warrant the further evaluation of heterologous prime-boost strategies across different platforms, utilizing our protein-based S-Trimers a booster dose following primary vaccination series with adenovirus-vectored, mRNA, or inactivated COVID-19 vaccines. Some concerns have emerged around the safety of multiple doses of mRNA vaccines including potential polyethylene glycol (PEG) sensitization ( 28 ), and anti-vector immunogenicity for adenovirus-vectored vaccines are known to reduce the effectiveness of subsequent homologous doses ( 29,30,31 ). Preliminary human clinical data indicates that heterologous prime-boost with adenovirus-vectored and mRNA COVID-19 vaccines (or vice versa) suggest that they induce higher rates of systemic reactogenicity than heir homologous prime-boost counterparts ( 32 ), further warranting the evaluation of protein-based candidates as booster doses.…”

Section: Discussionmentioning

confidence: 99%

Broad neutralization against SARS-CoV-2 variants induced by a modified B.1.351 protein-based COVID-19 vaccine candidate

et al. 2021

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Beginning in late 2020, the emergence and spread of multiple variant SARS-CoV-2 strains harboring mutations which may enable immune escape necessitates the rapid evaluation of second generation COVID-19 vaccines, with the goal of inducing optimized immune responses that are broadly protective. Here we demonstrate in a mouse immunogenicity study that two doses of a modified B.1.351 spike (S)-Trimer vaccine (B.1.351 S-Trimer) candidate can induce strong humoral immune responses that can broadly neutralize both the original SARS-CoV-2 strain (Wuhan-Hu-1) and Variants of Concern (VOCs), including the UK variant (B.1.1.7), South African variant (B.1.351) and Brazil variant (P.1). Furthermore, while immunization with two doses (prime-boost) of Prototype S-Trimer vaccine (based on the original SARS-CoV-2 strain) induced lower levels of cross-reactive neutralization against the B.1.351 variant, a third dose (booster) administered with either Prototype S-Trimer or B.1.351 S-Trimer was able to increase neutralizing antibody titers against B.1.351 to levels comparable to neutralizing antibody titers against the original strain elicited by two doses of Prototype S-Trimer.

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A heterologous virus-vectored vaccine for prevention of Middle East respiratory syndrome induces long protective immune response against MERS-CoV

Cited by 10 publications

References 2 publications

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

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

Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia

Broad neutralization against SARS-CoV-2 variants induced by a modified B.1.351 protein-based COVID-19 vaccine candidate

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