PONE-D-20-40313

The Abbott PanBio WHO emergency use listed, rapid, antigen-detecting point-of-care diagnostic test for SARS-CoV-2

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Evaluation of the accuracy and ease-of-use

PLOS ONE

Dear Dr. Denkinger,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Both Reviewers were very enthusiastic about the manuscript  and have provided lists of minor corrections/edits to be made. Please note that Reviewer 2's has several more substantive comments that should be addressed.

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PLOS ONE

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: This is an excellent manuscript and I agree is an important contribution to the field about an important topic that should be accepted for publication after a minor revision.

I would change "CT" to "Ct" for cycle threshold as this is the convention

Line 39: would change "days of symptoms" to "day after symptom onset"

Line 44: change "days from symptom onset" to "days after symptom onset"

Line 51-52: sentence is awkward. Perhaps change to: "In March 2020, the World Health Organisation (WHO) emphasized the importance of access to testing..."

Line 53: would delete "all" from "remains the gold standard among all diagnostic tests"

Line 55: Would add a point about the limitations of PCR testing given the prolonged PCR positivity (not always a meaningful test in terms of telling whether someone has active replicating virus or transmission potential, see: https://wwwnc.cdc.gov/eid/article/26/8/20-1097_article

Line 64-65: sentence is awkward. Consider changing to "This manufacturer-independent study follows a WHO-approved..."

Line 69: would change "an excellent" to "a" to make more neutral

Line 72: I believe this is your first use of "POC" would add "point of care (POC)" since the first time it is being used

Line 87-88: This is not clear. Perhaps "Colloidal gold conjugated antibodies on the membrane strip react with viral antigens generating a colour change in the device window..."

Line 89: Awkward sentence. Perhaps change to "The results must be interpreting following 15 to 20 minutes of incubation..."

Line 98: change "in English or German" to "of English or German"

Line 98: change "a protocol" to "The study protocol"

Line 192: Would be helpful to know day of exposure relative to testing for all asymptomatic cases. If not known would write "14 participants without symptoms with recent high-risk contacts."

Line 203: would note that this sensitivity and specificity is for people with symptoms or a recent close confirmed contact with SARS-CoV-2 infection

Would add a new paragraph between your current first and second paragraphs in the discussion quickly reviewing viral load dynamics. Ie viral loads rise before symptom onset and peak around symptom onset and decline quickly after symptom onset. Should also note that the period of transmission for immunocompetent adults with symptomatic infection is from a couple days before symptom onset to around a week after symptom onset. Here are a couple reviews of the topic: https://wwwnc.cdc.gov/eid/article/26/8/20-1097_article, https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(20)30172-5/fulltext

Line 206: change "overall viral load" to "mean viral load"

Line 208: would change to "low viral loads in Berlin, later in the course of infection."

Line 210: would delete "false-negative" and change to "discordant results"

Line 212: would change perhaps to "is likely to detect the vast majority of people with SARS-CoV-2 infections with transmission potential,..."

Line 213: Add a sentence reminding readers that since sensitivity is so good during first week of symptoms (which is the period of transmission) these tests have great utility as public health tools.

Line 214: change "asymptomatic participants" to "participants without symptoms at the time of testing"

Line 216: would add a sentence noting that you did not assess whether these individuals eventually develop symptoms and could have therefore been presymptomatic at the time of testing. Given their high viral loads they are presumed to have transmission potential so very important for them to get a positive result so they can isolate.

Line 224: change to "the use in symptomatic patients within the first week of illness"

Line 241: Would add that a limitation is that for asymptomatic cases the time of exposure to high risk cases was not recorded. Note that if tests are done to early they cannot exclude infection since viral load may not yet have had time to rise. The importance of this is that a negative test performed too early should not be used to support removing an individual from quarantine if a high risk exposure was very recent. Would cite: https://www.acpjournals.org/doi/10.7326/M20-1495

Reviewer #2: The authors evaluated the performance of the Panbio COVID-19 Ag Rapid Test Device for SARS-CoV-2 in nasopharyngeal swab specimens. For the ease of communication, Panbio stands for this kit in this review.

It was a prospective multicenter study, conducted in two sites in Germany, one was in Heidelberg while another was in Berlin. A total of 1108 individuals were recruited. Paired swabs were obtained for each individual, the ‘routine swab’ was used for RT-PCR while the ‘second study-exclusive swab’ was used for Panbio test.

Among these 1108 individuals, 106 were positive by RT-PCR. Among these 106 RT-PCR positive, 92 were Panbio positive, the sensitivity of the Panbio test was 86.8% (92/106).

There are two comments about this manuscript:

Comment 1

Lines 102-107

The description of the swabs used for RT-PCR and Panbio was confusing. There are four different terms of swabs: (1) routine swab, (2) nasopharyngeal swab, (3) combined nasopharyngeal and oropharyngeal swab, (4) study-exclusive swab.

Comment 2

There are at least five peer review articles evaluating the Panbio kit:

1. Linares et al. Panbio antigen rapid test is reliable to diagnose SARS-CoV-2 infection in the first 7 days after the onset of symptoms. J Clin Virol. 2020 Oct 16;133:104659. doi: 10.1016/j.jcv.2020.104659.

2. Fenollar et al. Evaluation of the Panbio Covid-19 rapid antigen detection test device for the screening of patients with Covid-19. J Clin Microbiol. 2020 Nov 2:JCM.02589-20. doi: 10.1128/JCM.02589-20.

3. Lanser et al. Evaluating the clinical utility and sensitivity of SARS-CoV-2 antigen testing in relation to RT-PCR Ct values. Infection. 2020 Nov 13. doi: 10.1007/s15010-020-01542-0.

4. Albert et al. Field evaluation of a rapid antigen test (Panbio™ COVID-19 Ag Rapid Test Device) for COVID-19 diagnosis in primary healthcare centers. Clin Microbiol Infect. 2020 Nov 12:S1198-743X(20)30697-2. doi: 10.1016/j.cmi.2020.11.004.

Based on these four articles, the sensitivity of the Panbio ranged from 60.8% to 79.6%.

5. Gremmels, H., et al., Real-life validation of the Panbio COVID-19 Antigen Rapid Test (Abbott) in community-dwelling subjects with symptoms of potential SARS-CoV-2 infection. EClinicalMedicine Available online 5 December 2020 https://doi.org/10.1016/j.eclinm.2020.100677

Table 2.

The authors reported high sensitivity of Panbio test 86.8% (92/106). It might be due to the high viral load study groups enrolled:

Figrue 2.

70 individuals (66.7%) with viral load >= 10^(7-8)

35 individuals (33.3%) with viral load <= 10^(6-7)

Lines 204-210

The authors also discussed the sensitivity difference observed between Berlin and Heidelberg.

The authors have to state the reasons for the high sensitivity of Panbio test clearly when comparing with those five studies (listed above), sensitivity ranged from 60.8%-81.1%.

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Reviewer #1: No

Reviewer #2: No

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The Abbott PanBio WHO emergency use listed, rapid, antigen-detecting point-of-care diagnostic test for SARS-CoV-2

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Evaluation of the accuracy and ease-of-use

PONE-D-20-40313R1

Dear Dr. Denkinger,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Nicholas J Mantis

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: