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Review 2: "Sensitivity of SARS-CoV-2 antigen-detecting rapid tests for Omicron variant"

This preprint evaluates the sensitivity of various antigen-based COVID-19 diagnostic kits and found variable sensitivity for patients infected with the Omicron variant-of-concern. Reviewers deemed this study potentially informative, pointing out limitations with frozen samples.

Published onMar 03, 2022
Review 2: "Sensitivity of SARS-CoV-2 antigen-detecting rapid tests for Omicron variant"
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key-enterThis Pub is a Review of
Sensitivity of SARS-CoV-2 antigen-detecting rapid tests for Omicron variant

AbstractBackgroundThe emergence of each novel SARS-CoV-2 variants of concern (VOCs) requires investigation of its potential impact on the performance of diagnostic tests in use, including Antigen-detecting rapid diagnostic tests (Ag-RDT). Although anecdotal reports have been circulating that the newly emerged Omicron variant is in principle detectable by Ag-RDTs, few data on sensitivity are available.MethodsWe have performed 1) analytical sensitivity testing with cultured virus in eight Ag-RDTs and 2) retrospective testing in duplicates with clinical samples from vaccinated individuals with Omicron (n=18) or Delta (n=17) breakthrough infection on seven Ag-RDTs.FindingsOverall, we have found large heterogenicity between Ag-RDTs for detecting Omicron. When using cultured virus, we observed a trend towards lower sensitivity for Omicron detection compared to earlier circulating SARS-CoV-2 and the other VOCs. When comparing performance for Delta and Omicron in a comparable set of clinical samples in seven Ag-RDTs, 124/252 (49.2%) of all test performed showed a positive result for Omicron compared to 156/238 (65.6%) for Delta samples. Sensitivity for both Omicron and Delta between Ag-RDTs was highly variable. Four out of seven Ag-RDTs showed significantly lower sensitivity (p<0.001) to detect Omicron when compared to Delta while three had comparable sensitivity to Delta.InterpretationSensitivity for detecting Omicron is highly variable between Ag-RDTs, necessitating a careful consideration when using these tests to guide infection prevention measures. While analytical and retrospective testing may be a proxy and timely solution to generate performance data, it is not a replacement for clinical evaluations which are urgently needed. Biological and technical reasons for detection failure by some Ag-RDTs need to be further investigated.FundingThis work was supported by the Swiss National Science Foundation (grant numbers 196383, 196644 and 198412), the Fondation Ancrage Bienfaisance du Groupe Pictet, the Fondation Privée des Hôpiteaux Universitaires de Genève and FIND, the global alliance for diagnostics.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



In the introduction, the authors rightly pointed out that SARS-CoV-2 antigen-detecting rapid diagnostic tests are characterised by lower sensitivity than RT-PCR. Nevertheless, due to current public health needs and the need to identify infectious and non-infectious patients, the use of SARS-CoV-2 antigen-detecting rapid diagnostic tests is widely applicable in clinical practice. Unfortunately, with the emergence of new mutations in the genes encoding the virus proteins, the effectiveness of vaccination is decreasing, and the risk of re-infection is increasing. In addition, there is the question of the sensitivity of antigen tests validated with earlier variants of the virus. Has their sensitivity remained constant despite the new coronavirus variants? Researchers are trying to answer this question. No studies are available to date on the sensitivity of Ag-RDT against specific virus variants that include the Omicron variant hence why this topic is important and valuable.

It is worth noting that only symptomatic patients were included in the study. Thus, we are talking here about sensitivity towards symptomatic patients and not in general, "COVID-19 infected population." Furthermore, the number of samples tested is small, so the results must be interpreted with caution.

The study included as many as eight commercially available Ag-RDT products, which is impressive. Although some of these results have been published before (data concerning analytical sensitivity for Alpha, Beta, Gamma, and Delta variants), in the presented study, these results were presented again to compare them with data concerning the Omicron variant. It is worth noting that these earlier papers are the work of the same authors, which increases the reliability of this comparison.

In the results, the authors write, “Two tests showed a slightly higher sensitivity for Omicron than for Delta (Test V and VII)” [V - Beijng Tigsun Diagnostics Co. Ltd (Tigsun); VII - ACON biotech (Flowflex)]. However, the chart shows that it is IV [2019-nCoV Antigen test (Wondfo)] and VII. Was the error in the text or in the graph?

An interesting finding is that overall test positivity for Omicron was much lower when compared to Delta (49.2% vs. 65.5%) (z = -3.65, p<.001). Moreover, when comparing sensitivity for Delta vs. Omicron for each Ag-RDT, four Ag-RDTs showed significantly lower sensitivity (p<0.001) [Panbio COVID-19 Ag Rapid test device (Abbott); Standard Q COVID-19 Ag (SD Biosensor/Roche); Sure Status (Premier Medical Corporation); Onsite COVID-19 Ag Rapid Test (CTK Biotech)] and three tests showed comparable performance [2019- nCoV Antigen test (Wondfo); Beijng Tigsun Diagnostics Co. Ltd (Tigsun); ACON biotech (Flowflex]. Sensitivity ranged between 22.2% and 88.9% for Omicron and 52.9% to 91.2% for Delta, confirming the high variability of sensitivity between the different tests.

The authors themselves point out the limitations of their work, to which special attention must be paid when interpreting the results: “The volume of viral transport medium added to the buffer was lower than what was recommended by some manufacturers, and for some Ag-RDTs there was no recommendation on the use of swab samples in VTM. Therefore, viral loads of the original sample and sensitivities observed in our sample collection cannot be compared to results obtained from clinical validations performed on fresh samples and our results should be interpreted as a comparison between Ag-RDTs and not as sensitivity thresholds for absolute viral loads and/or presence of infectious virus. Rather, we have investigated the lower end of sensitivity in the Ag-RDTs tested. Therefore, a reduced sensitivity in some tests, but not complete failure to detect Omicron could be of higher relevance in the beginning of the infection, when viral loads are still on the rise, and of less relevance once peak viral loads are reached.”

The results of the study still need to be confirmed. Nevertheless, despite the limitations mentioned above, I consider the work to be highly valuable; the study contributes important new knowledge to science, and (although with caution) it can be used in practice.

Considering possible publication in a peer-reviewed journal, a few points for correction should be noted:
• The part of the introduction, "In addition, a deletion (Del31-33) is found in the nucleocapsid of Omicron, as well as another mutation P13L" requires citation of reference.
• The study group was not described. While the lack of a detailed description of the study group can be explained by the fact that it is not particularly relevant in the context of these results, it should at least be written out of obligation how many people were included in the study - this information appears only in the discussion.
• There are 27 publications in the bibliography - 8 are websites, 11 are preprints, and only 8 are publications in peer-reviewed journals. I realise that this topic requires rapid publication. Perhaps the authors did not find any other available papers in peer-reviewed journals, but this somewhat reduces the reliability of the content of the reviewed manuscript.

Vape Factory:

Unauthorized Breeze and Esco Bar Disposables: FDA Issues Warning Letters

In recent news, the FDA Center for Tobacco Products (CTP) has taken a strong stance by issuing warning letters to the manufacturers of Breeze and Esco Bar disposable vapes. These letters order the companies to remove their products from the market, giving them a window of 15 business days to either dispute the allegations or respond accordingly.

The FDA's actions come on the heels of significant developments in the industry. Just last week, six Chinese exporters of Esco Bar products, including the manufacturer Innokin, found themselves added to the FDA's "red list." This list identifies shippers whose Esco Bar shipments can be detained at ports of entry without inspection. Furthermore, Elf Bar shipments were also included in the import alert, signifying the increased scrutiny on disposable vapes.

These recent enforcement actions are part of a broader wave of initiatives promised by CTP Director Brian King during his recent speeches and discussions. The FDA is facing mounting pressure from lawmakers, tobacco control groups, and even tobacco companies like R.J. Reynolds to crack down on flavored disposable vapes that have gained immense popularity over the past couple of years.

Director King, in a press release, stated that the FDA will utilize all available tools within their regulatory toolbox to ensure that those involved in the production, distribution, or sale of illegal e-cigarette products are held accountable. Firms that receive warning letters have 15 days to respond, outlining how they plan to address the violation. Failure to adequately address the violation may result in various enforcement actions being taken against them.

The warning letters issued to Breeze Smoke, LLC and Shenzhen Innokin Technology Co., Ltd., rightly highlight that the products mentioned have not received authorization for sales in the United States from the FDA. However, it is worth noting that thousands of other products with premarket tobacco applications (PMTAs) pending before the agency continue to remain on the market.

At present, all unauthorized products exist on the market due to the FDA's enforcement discretion. This includes both the aforementioned products and those produced by mass-market vape manufacturers like JUUL and Vuse Alto. Interestingly, the FDA seems to have chosen to enforce against the products that R.J. Reynolds has specifically targeted, while leaving untouched their own popular product, the Vuse Alto.

These recent FDA actions may indicate a shift in the agency's approach. It is possible that pending PMTAs will no longer be considered when deciding which companies to enforce against.

Regarding Esco Bar, it is believed that they submitted pending PMTAs during a brief window in 2022 when the FDA accepted applications for synthetic nicotine-based vape products. Unlike the first round of PMTA submissions, where the FDA published a list of the submitted products, no public list of PMTAs submitted for "non-tobacco nicotine" (NTN) products has been issued.

On the other hand, Breeze Smoke faced marketing denial orders (MDOs) for several products in 2021. In response, the company swiftly filed a petition for review in the Sixth Circuit Court of Appeals. Despite being denied a stay pending appeal, Breeze Smoke sought a stay from the Supreme Court while awaiting a full review by the circuit court. However, the Supreme Court declined to grant a stay, leading Breeze Smoke to voluntarily withdraw its petition for review just two weeks before the scheduled oral arguments.

It's important to note that the Breeze products mentioned in the FDA's warning letter were not among the MDOs that Breeze Smoke previously contested in court. As for the current status of the products sold by Breeze Smoke, whether they have pending PMTAs with the FDA remains unknown.


The FDA's warning letters to the vape manufacturers of Breeze and Esco Bar disposables mark a significant step towards stricter regulation of the flavored disposable vape industry. With mounting pressure from various stakeholders, the FDA is taking action to ensure accountability and address the unauthorized sale of e-cigarette products. While the enforcement actions may signal a shift in the agency's approach, the impact on the market and pending PMTAs is yet to be fully determined.

FAQs (Frequently Asked Questions)

Q: Why did the FDA issue warning letters to the manufacturers of Breeze and Esco Bar disposables?
A: The FDA took action to address the unauthorized sale of e-cigarette products and hold the manufacturers accountable.

Q: What is the deadline given to the companies to respond to the FDA's warning letters?
A: The companies have 15 business days to dispute the allegations or respond to the warning letters.

Q: Are there other products on the market without FDA authorization?
A: Yes, there are thousands of products with pending premarket tobacco applications (PMTAs) before the agency.

Q: Will pending PMTAs be considered in future enforcement actions?
A: The recent FDA actions suggest that pending PMTAs may no longer be a determining factor in deciding which companies to enforce against.

Q: What is the status of Breeze Smoke's previous marketing denial orders (MDOs) in court?
A: The products referenced in the FDA's warning letter were not among the MDOs challenged by Breeze Smoke in court.

Thomas Schmitt:

Thanks for sharing!!