1. Our take

    Evidence is offered here that the Novavax NVX-CoV2373 is well tolerated and provides protection against symptomatic SARS-CoV-2 infection from the B.1.351 variant. Claims that prior infection with pre-B.1.351 viruses did not reduce the risk of COVID-19 due to re-infection with B.1.351 variants are unsupported.

    Study design

    randomized-controlled-trial

    Study population and setting

    This study, available as a preprint thus not yet been peer-reviewed, summarized the results of a phase IIa/b multicenter randomized placebo-controlled trial of Novavax’s NVX-CoV2737 conducted in South Africa. The NVX-CoV2737 vaccine contains full-length, pre-fusion SARS-CoV-2 spike protein (AA sequence from the original Wuhan isolate) and a saponin-based adjuvant. The primary study population included 2,684 predominantly (95%) Black-African participants aged 18-84 years (18-64 years for a subset of medically stable people living with HIV [PLWH]) who were randomized in an approximately 1:1 ratio to receive two injections spaced 21 days apart of either NVX-CoV2737 or saline placebo. The primary endpoint assessed was vaccine efficacy (defined as prevention of diagnostically confirmed symptomatic mild, moderate, or severe COVID-19 in initially seronegative participants) seven or more days after receiving the second vaccine dose. Various separate analyses were also conducted on seropositive participants who received either vaccine or placebo. Monitoring for safety was conducted throughout the study, and is planned to continue for a year.

    Summary of main findings

    Fifteen cases of COVID-19 were detected amongst the 1,357 two-dose vaccine recipients, and 29 cases of COVID-19 were detected amongst the 1,327 two-dose placebo recipients, producing an overall estimated vaccine efficacy of 49.4% (95% CI 6.1 to 72.8%). The majority (38/41) of available SARS-CoV-2 full-genome sequences obtained from positive, symptomatic participants (n = 44) in this trial belonged to the B.1.351 lineage, suggesting that viruses of this lineage were predominant in overall circulation. No vaccine-related serious adverse events were recorded at the time of writing, although adverse events overall were slightly more common amongst the vaccine recipients versus the placebo recipients.

    Study strengths

    Participants with an appropriate range of ages were included, and some had preexisting comorbidities (e.g. hypertension, diabetes mellitus, etc).

    Limitations

    As these are phase IIa/b trials, sample sizes are small, and any finding will need to be confirmed in larger phase III trials. Small sample sizes resulted in very large confidence intervals for the vaccine efficacy calculations (e.g., vaccine efficacy of 49.4% [95% CI 6.1 to 72.8%]). The authors’ claim that prior infection with pre-B.1.351 viruses did not reduce the risk of COVID-19 due to re-infection with B.1.351 variants is based solely on the initial serological status of the participants as determined by an in-house IgG ELISA. This is insufficient evidence for such claims. As history of prior or current symptomatic COVID-19 excluded participation in the study, these recorded seropositive cases likely represent either asymptomatic infection or false positives from their in-house ELISA. However, it is unclear as the time since infection, severity of infection, and variant causing infection are all unknown or unreported for these cases. Additionally, the authors report approximately 30% of the total study population was seropositive at the start of the study. This is questionably high given that South Africa has currently reported about 1.5 million total infections out of a population of 59 million, which equates to about 2.5% of the population known to have been infected overall. To more convincingly demonstrate that previous infection with pre-B.1.351 SARS-CoV-2 provides no protection from infection with B.1.351, prior natural infection would need to be demonstrated by more than serology (e.g., a history of diagnostic nucleic acid amplification testing [NAAT], symptoms, etc.). Finally, while inclusion of the PLWH participants was advantageous and various attempts are made to evaluate the efficacy amongst this subgroup, the study was underpowered for these purposes (as acknowledged by the authors) and thus inclusion of these participants adds very little meaningful data.

    Value added

    This study provides the first efficacy data for Novavax’s NVX-CoV2373 vaccine.

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  2. SciScore for 10.1101/2021.02.25.21252477: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: All participants provided written informed consent prior to enrollment.
    IRB: The trial protocol was approved by the South African Health Products Regulatory Authority (SAHPRA; Ref 20200420) and Institutional Ethics Review Boards and registered in Clinicaltrials.gov (NCT045333990 and the Pan African Clinical trials Registry (PACTR202009726132275)
    RandomizationTrial Objectives, Participants and Oversight: In this randomized, observer-blinded, placebo-controlled phase 2a/b trial, we assessed the safety and efficacy of two doses of NVX-CoV2373, administered 21 days apart.
    BlindingAll other study staff and trial participants remained blinded to treatment assignment.
    Power AnalysisThe official, event-driven efficacy analysis targeted a minimum number of 23 endpoints to provide approximately 90% power to detect vaccine efficacy of 80% based on an incidence rate of symptomatic Covid-19 of 2% to 6% in the placebo group.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.


    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:
    Our study was subject to certain limitations. The efficacy results are preliminary (median follow-up of 66 and 45 days following first and second doses, respectively), and are limited in scope to the primary endpoint and subgroups of the primary endpoint, as well as post-hoc analysis of B.1.351 variant sequencing data; therefore, caution is warranted in the interpretation of our results, particularly in the PLWH cohort, which represents a relatively small fraction of the study population. Importantly, at the time of analysis, the study had captured almost exclusively mild to moderate Covid-19 endpoints in a predominantly young, healthy population; consequently, we have not as yet been able to report on vaccine efficacy against severe Covid-19. Most large Covid-19 vaccine efficacy trials have observed increasing efficacy with longer follow-up periods than ours and have reported notably increased vaccine efficacy against severe vs mild to moderate disease.4-7 We may observe a similar pattern with additional follow-up and higher numbers of efficacy endpoints that are expected to accrue. Secondary efficacy analyses will shed light on efficacy against severe disease, and whether naturally acquired immunity to prototype-like virus modulates severity of infection due to variant viruses. In conclusion, we have demonstrated that a prototype-sequenced NVX-CoV2373 vaccine was efficacious and induced notable cross-protection in the setting of dominant circulation of B.1.351 variants that...

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

    IdentifierStatusTitle
    NCT04533399RecruitingA Study Looking at the Effectiveness and Safety of a COVID-1…
    NCT045333990Trial number did not resolve on clinicaltrials.gov. Is the number correct?NA


    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.

    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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