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  1. Our take

    Vaccines are highly efficacious at preventing severe disease and reducing likelihood of infection, but breakthrough infections do occur. This study from the Netherlands was available as a preprint and thus has not yet been peer reviewed. When comparing primary infections occurring between April and December 2020 to breakthrough infections (infections after vaccination) that occurred between April and July 2021, it was found that Ct values were similar but that the probability of detection of infectious virus was lower among breakthrough infections. Comparing these two groups should be done cautiously as there are a number of reasons that could explain these differences in virological characteristics (changes in attitudes and behaviors at the hospital over time, different dominant variants, etc.). This study does not provide sufficient evidence of the comparability of these two groups. Further, given the dominance of the Delta variant which is known to be more virulent, in the latter time period when the breakthrough infections occurred, the effectiveness of the vaccine at reducing viral replication and infectiousness may have been greater had the Alpha variant remained the dominant variant in circulation.  

    Study design


    Study population and setting

    Virological data (RT-PCR and Ct values) were compared between unvaccinated healthcare workers (HCWs) with primary infection (April-December 2020) and vaccinated HCWs with breakthrough infections (April-July 2021, n=161) at two tertiary care centers in the Netherlands. Virological characteristics were compared using the first RT-PCR positive sample. Positive samples underwent sequencing to determine the variant (Alpha, Beta, Gamma, or Delta) and were cultured to assess viability of the virus. Testing algorithms remained constant across the two periods, with symptomatic HCWs seeking testing and contact tracing performed in the event of a positive case.

    Summary of main findings

    Among the 161 breakthrough infections detected between April and July 2021, the majority (70.8%, n=114) were identified as the Delta variant (B.1.617.2). None of the infections required hospitalization and were described as mild. The mean age of HCWs experiencing a breakthrough infection was 25.5 years old. Ct values were significantly lower in symptomatic vs. asymptomatic breakthrough infections (23.2 vs. 26.7), indicating a higher viral load among symptomatic breakthrough infections vs. asymptomatic breakthrough infections. When comparing those with breakthrough infections and those with primary infections, Ct values were similar but the probability of infectious virus detection based on culture was lower among those with breakthrough infections.   

    Study strengths

    The sequencing data for all cases is a strength, as was the availability of viral culture data.


    The authors indicate that the two groups did not differ with respect to demographic characteristics, but a Table indicating symptom status, age, variant, and Ct-value are only provided for the breakthrough infections (April-July 2021), making it difficult for the reader to evaluate similarities and differences between the two groups. Comparison between the two groups is challenged because these two groups were infected in two different time periods (could have been changes in attitudes, behaviors, mandated NPIs) and predominantly by different variants, which could mean different virological characteristics regardless of whether a breakthrough or primary infection. Primary infection sequencing data appear to have been collected, but were not reported in the paper.

    Value added

    This study helps us better understand differences in transmission likelihood between those who are vaccinated with breakthrough infections and those who are unvaccinated with primary SARS-CoV-2 infections.

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  2. SciScore for 10.1101/2021.08.20.21262158: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Ethical approval: This study was approved by Radboud university medical center Committee on Research Involving Human Subjects and the Erasmus Medical Center Medical Ethics Committee.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    Virus culture: Virus culture was performed on all samples collected in the Erasmus Medical Center, by inoculating Vero cells (clone 118) as previously described19.
    suggested: None
    Software and Algorithms
    Statistical analysis: All statistical analyses was performed using R Statistical Software version 4.1.1 (Foundation for Statistical Computing, Austria) and STATA statistical software program version 13.1 (Statacorp, USA).
    R Statistical Software
    suggested: None
    suggested: (Stata, RRID:SCR_012763)
    suggested: None

    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).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Considering these limitations of RT-PCR, demonstrating viral viability through replication in cell culture is currently considered the best proxy to demonstrate infectious virus in a clinical specimen20,21. We and others previously showed that the viability of SARS-CoV-2 depends on several factors among which the severity of disease, timing of sampling, the type of specimen and presence of antibodies19,22. To our knowledge this is the first study to report on virus cultures in COVID-19 vaccine breakthrough infections. Although reduced immune responses may likely account for breakthrough infections, further studies are needed to investigate whether these are still able to reduce infectious virus shedding. Obviously, the use of virus culture has its limitations as well: it is a laborious method only performed in specialized BSL-3 laboratories and therefore not widely applicable. In addition, lack of standardization of methods (e.g. the cell line used) still hampers interchangeability of results between laboratories. Nevertheless, an experimental animal study on SARS-CoV-2 transmission recently confirmed a strong correlation between transmission and virus culture 23. To study the effect of vaccination on infectivity, it would be preferable to compare infections occurring in vaccinated and unvaccinated individuals during the same time period, to minimize the impact of different SARS-CoV-2 variants. Due to the high vaccine coverage in HCW, we diagnosed very few infections in unvac...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

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

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

    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.
    • No protocol registration statement was detected.

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

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

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