Immunogenicity and safety of a recombinant adenovirus type-5 COVID-19 vaccine in adults: Data from a randomised, double-blind, placebo-controlled, single-dose, phase 3 trial in Russia

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1. Version published to 10.1371/journal.pone.0278878

   Mar 8, 2023
2. 

   ScreenIT

   Mar 14, 2022

   SciScore for 10.1101/2022.03.01.22271507: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   Ethics	IRB: The trial protocol was reviewed and approved by the Independent Ethics Committees of the involved sites and the Ethics Council of the Ministry of Health of the Russian Federation. Consent: To be included, participants needed to be able to understand the content of the informed consent documents and be willing to sign the informed consent form.
   Sex as a biological variable	Men and women aged 18–85 years with a body mass index (BMI) between 18.5 and 30.0 kg/m2 were selected to participate if they had no indication of a current or previous SARS-CoV-2 infection (e.g., respiratory infection in last 14 days, axillary temperature ≥37.0 °C) or close contact with a suspected or confirmed case of …

   SciScore for 10.1101/2022.03.01.22271507: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   Ethics	IRB: The trial protocol was reviewed and approved by the Independent Ethics Committees of the involved sites and the Ethics Council of the Ministry of Health of the Russian Federation. Consent: To be included, participants needed to be able to understand the content of the informed consent documents and be willing to sign the informed consent form.
   Sex as a biological variable	Men and women aged 18–85 years with a body mass index (BMI) between 18.5 and 30.0 kg/m2 were selected to participate if they had no indication of a current or previous SARS-CoV-2 infection (e.g., respiratory infection in last 14 days, axillary temperature ≥37.0 °C) or close contact with a suspected or confirmed case of SARS-CoV-2 infection.
   Randomization	Study Design and Participants: Prometheus is a multicentre, randomised, double-blind, placebo-controlled, clinical trial being conducted in six centres in the Russian Federation.
   Blinding	not detected.
   Power Analysis	Initially, as part of the interim analysis and to ensure 90% power for the between-group comparison of the primary variable, 180 subjects were to be included.
   Cell Line Authentication	Authentication: Eligible participants were randomly allocated to the Ad5-nCoV group or the Placebo group, in a 3:1 ratio, by an independent statistician using a validated system including a pseudorandom number generator with a seed value; allocation used block randomisation and stratification by study site.

   Table 2: Resources

   Antibodies
   Sentences	Resources
   Screening included the detection of SARS-CoV-2 RNA using real-time polymerase chain reaction (PCR) via a swab, and SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody testing to ensure negative results, as well as testing for human immunodeficiency virus (HIV), syphilis, hepatitis B and hepatitis C viruses via blood serum.	SARS-CoV-2 immunoglobulin M (IgM suggested: None immunoglobulin G (IgG suggested: None
   Determination of serum antibodies against the S protein and RBD of SARS-CoV-2 and the presence of neutralising antibodies against SARS-CoV-2 were conducted on Day 0, Day 14, Day 28 and after Month 6; neutralising antibodies against Ad5 were assessed on Day 0, Day 28 and after Month 6.	SARS-CoV-2 suggested: None Ad5 suggested: None
   Horseradish-peroxidase conjugated mouse monoclonal anti-human IgG antibody was used to detect antibodies, visualised with tetramethylbenzidine substrate solution.	anti-human IgG suggested: None
   Anti-coronavirus neutralising antibodies were determined with a microneutralisation assay in which Vero cell (#ССL-81, American Type Culture Collection) monolayers were incubated in 96-well plates with 2-fold serial dilutions (1:10 to 1:1280) of participant serum.	Anti-coronavirus neutralising antibodies suggested: None Anti-coronavirus neutralising suggested: None
   Anti-adenovirus neutralising antibodies were also determined using microneutralisation assay; A549 cell monolayers were incubated in 96-well plates with serial dilutions (1:10 to 1:1280) of participant serum and working dilutions of Ad5 (Adenovir; Smorodintsev Research Institute of Influenza).	Anti-adenovirus neutralising suggested: None
   Plates were washed twice with PBS, washed twice with PBS + 0.05% Tween-20, and then incubated at room temperature with biotinylated anti-human IFN-γ detection antibody for 2 h.	anti-human IFN-γ suggested: None
   The primary and secondary endpoints used the quantitative definition: the proportion of participants with at least a 4-fold increase in antibody titres against SARS-CoV-2 S protein and/or its RBD, specifically.	SARS-CoV-2 S protein suggested: None
   Experimental Models: Cell Lines
   Sentences	Resources
   Anti-coronavirus neutralising antibodies were determined with a microneutralisation assay in which Vero cell (#ССL-81, American Type Culture Collection) monolayers were incubated in 96-well plates with 2-fold serial dilutions (1:10 to 1:1280) of participant serum.	Vero suggested: None
   Anti-adenovirus neutralising antibodies were also determined using microneutralisation assay; A549 cell monolayers were incubated in 96-well plates with serial dilutions (1:10 to 1:1280) of participant serum and working dilutions of Ad5 (Adenovir; Smorodintsev Research Institute of Influenza).	A549 suggested: None
   Recombinant DNA
   Sentences	Resources
   Sequence encoding ΔFurin variant of SARS-CoV-2 S protein (amino acids 1–1213) containing a C-terminal Gly-Gly-6xHis tag was subcloned into the pMCAG-2T vector using the GeneArt Type IIs Assembly Kit, BbsI (Thermo Fisher Scientific), according to the manufacturer’s instructions.	pMCAG-2T suggested: None
   Software and Algorithms
   Sentences	Resources
   Statistical Methods: Statistical analysis was performed using SPSS Statistics, Version 26.0 (IBM Corp.).	SPSS suggested: (SPSS, RRID:SCR_002865)

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   Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

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   Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

   This study has several limitations. First, the participants included in this study were all white, although conversely, this also provided the first data in a non-Chinese, European population. Second, this trial did not include children or pregnant women, and there were only a small number of older adults (35 were ≥60 years in the Ad5-nCoV group). An ideal candidate vaccine for COVID-19 should cover vulnerable populations of all ages. Anti-S protein-specific antibodies have been reported to decline rapidly in individuals who have recovered from COVID-19, especially those who were asymptomatic or had mild symptoms [23]. Third, the sample size was relatively small and some of the calculated 95% CIs were wide. Finally, virus mutation, an emerging problem, may reduce the effectiveness of current vaccines [24]. It is not known whether participants of this study were exposed to any COVID-19 variants. Further study is underway to determine neutralising antibodies to the widely circulating variants following vaccination with Ad5-nCoV, which include but are not limited to the Alpha (B.1.1.7), Beta (B.1.351) and Gamma (P.1 ) variants. Conclusions: Analysis of data from this phase 3 trial demonstrated the immunogenicity and safety of this Ad5-vector based COVID-19 vaccine. More data are required to determine whether this vaccine reduces infections and transmission. Overall, this stable, single-dose vaccine could contribute to the global fight against the evolving SARS-CoV-2 virus.

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   Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
   

   Identifier	Status	Title
   NCT04540419	Active, not recruiting	Clinical Trial of Recombinant Novel Coronavirus Vaccine (Ade…

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   Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

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   Results from JetFighter: We did not find any issues relating to colormaps.

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   Results from rtransparent:

   • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
   • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
   • Thank you for including a protocol registration statement.

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   Results from scite Reference Check: We found no unreliable references.

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3. 

   Version published to 10.1101/2022.03.01.22271507 on medRxiv

   Mar 11, 2022