Viral infectivity in paediatric SARS-CoV-2 clinical samples does not vary by age
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At the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there was much uncertainty about the role of children in infection and transmission dynamics. Through the course of the pandemic, it became clear that children were susceptible to SARS-CoV-2 infection, although they were experiencing a notable lack of severe disease outcomes as compared to the adult population. This trend held true with the emergence of new SARS-CoV-2 variants, even in paediatric populations that were ineligible to be vaccinated. The difference in disease outcomes has prompted questions about the virological features of SARS-CoV-2 infection in this population. In order to determine if there was any difference in the infectivity of the virus produced by children with coronavirus disease 2019 (COVID-19), we compared viral RNA levels (clinical RT-qPCR C T ) and infectious virus titres from 144 SARS-CoV-2-positive clinical samples collected from children aged 0 to 18 years old. We found that age had no impact on the infectiousness of SARS-CoV-2 within our cohort, with children of all ages able to produce high levels of infectious virus.
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I am pleased to tell you that your article has now been accepted for publication in Access Microbiology. The work presented is clear and the arguments well formed. The manuscript is well written and contributes to the literature. Thank you for addressing all reviewers comments satisfactorily and in a timely manner.
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Thank you for submitting your revised manuscript for publication in Access Microbiology. After reviewing the manuscript, I'm happy that all reviewer's comments have been addressed. However, some minor changes are needed to include: 1. the PFU abbreviation in full when first mentioned (line 53) 2. use either the genome to PFU ratio or higher infectious virus to RNA ratio rather than using these interchangeably (lines 53-59) 3. correct some minor spelling and grammar mistakes e.g. asymptotic on line 150
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Thank you for submitting your manuscript for publication in Access Microbiology. It has been examined by expert reviewers who have concluded that the work is of potential interest to the readership of Access Microbiology. However, based on the comments received, it is clear that a major revision of this manuscript will be required before a decision can be made on its publication. I will be pleased to consider a revised manuscript along with a document including a point by point response to each of the reviewers comments. Your revised manuscript may be returned to one or more of the original reviewers, along with your itemised response to the reviewers’ comments.
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Comments to Author
Thank you for the opportunity to review your work. In summary, the researchers sought to evaluate if there was a virologic correlate of clinical severity of disease and infectivity in children (0-18 years) for SARS-CoV-2/COVID-19 by interrogating samples utilizing cell culture and comparing "viral load"/Ct values (from RT-PCR) to cell culture yield. Samples were obtained from Children's in Wisconsin from September 14, 2020 to May 17, 2021 (n = 144). Stratification by age groups and Ct values was performed and blinding by staff performing cell culture was also undertaken to reduce bias. Their finding was that though a relationship between viral titer and Ct was observed, there was no significant relationship between age and viral yield. Limitations are nicely outlined. The conclusion from their data …
Comments to Author
Thank you for the opportunity to review your work. In summary, the researchers sought to evaluate if there was a virologic correlate of clinical severity of disease and infectivity in children (0-18 years) for SARS-CoV-2/COVID-19 by interrogating samples utilizing cell culture and comparing "viral load"/Ct values (from RT-PCR) to cell culture yield. Samples were obtained from Children's in Wisconsin from September 14, 2020 to May 17, 2021 (n = 144). Stratification by age groups and Ct values was performed and blinding by staff performing cell culture was also undertaken to reduce bias. Their finding was that though a relationship between viral titer and Ct was observed, there was no significant relationship between age and viral yield. Limitations are nicely outlined. The conclusion from their data that children, regardless of age, produce high levels of viable virus is justified. I have a few suggestions to improve the work: -Overall the methods are appropriately described in terms of RT-PCR and cell culture. Based on the timeline of sample acquisition, I would assume that these isolates contained more ancestral SARS-CoV-2 and the Alpha VOC. Can the authors provide the epidemiological data to support those assumptions? Notably, the timeframe does not include Delta nor Omicron which are likely of more relevance in 2023. If available, including this data would add robustness and relevance. -It is possible to stratify by time from sampling to placement on cell culture? Was the yield significantly different between relatively fresh samples and older ones? Our work demonstrated reduced yield the longer it was from clinical sampling to cell culture. -Though references were provided to support that there was no difference between age groups, SARS-CoV-2 viral loads/Ct and viable virus, there are also references that found a difference. Bullard et al. (CMAJ April 2021) demonstrated an age dependent difference. The same group also showed that though Ct values between adults and children were different, viable virus yield was not different for the Delta VOC (Garnett et al. Microbiol Spectr August 2022). -The presentation of results is clear. I appreciate Figure 1 and it is formatted well. -The paper is organized and concisely and clearly conveys the key findings and background around the topic. The limitations are listed and are appropriate. I would add some of the limitations I mention above to the list if they cannot be rectified. -As mentioned above, the authors could include additional studies that did find a difference. Overall, I appreciate the work and think the results do add to the historical understanding of viral dynamics of SARS-CoV-2 in children. With the addition of Delta and Omicron variants, the work would become much more relevant. Thank you.
Please rate the manuscript for methodological rigour
Good
Please rate the quality of the presentation and structure of the manuscript
Very good
To what extent are the conclusions supported by the data?
Partially support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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Comments to Author
1. Methodological rigour, reproducibility and availability of underlying data Good. 2. Presentation of results The methods and results sections are clear and concise. 3. How the style and organization of the paper communicates and represents key findings 4. Literature analysis or discussion The rationale for investigating whether infectivity is associated with lower incidence of severe disease in pediatric population should be made clear in the introduction. To this end, the author should include (if possible) more references that support this hypothesis. Currently, only one of the papers referenced in the introduction supports an association between viral RNA load and age (ref.7). The results of ref 5 (line 79) should be discussed, or at least mentioned. The sentence beginning line 79 …
Comments to Author
1. Methodological rigour, reproducibility and availability of underlying data Good. 2. Presentation of results The methods and results sections are clear and concise. 3. How the style and organization of the paper communicates and represents key findings 4. Literature analysis or discussion The rationale for investigating whether infectivity is associated with lower incidence of severe disease in pediatric population should be made clear in the introduction. To this end, the author should include (if possible) more references that support this hypothesis. Currently, only one of the papers referenced in the introduction supports an association between viral RNA load and age (ref.7). The results of ref 5 (line 79) should be discussed, or at least mentioned. The sentence beginning line 79 should be associated with reference 7 only. A discussion of other factors that could contribute to differential disease severity between children and adults (e.g. innate immunity) would make for a more well-rounded introduction. In line 130, the statement "our findings suggest equal levels of viral infectivity in children and in adults with similar RNA viral loads" is inappropriate because there was no direct comparison with adult samples in this article. 5. Any other relevant comments The problem or question, as it is framed in the introduction, is essentially, "Why is there a lower prevalence of severe disease following SARS-COV-2 infection in children compared to adults?". The authors hypothesize that infectivity of the virus may be associated with this phenomenon. However they do not include a direct comparison to adult samples. By looking exclusively at samples from children (aged 0 to 18 years old), they can only conclude that infectivity does not change within childhood, which does not shed much light on the original problem / question. If the authors could provide some evidence or a reference supporting the idea that younger children have lower incidence of severe disease following sarscov2 infection compared to "older teens" that would strengthen the conclusion.
Please rate the manuscript for methodological rigour
Satisfactory
Please rate the quality of the presentation and structure of the manuscript
Good
To what extent are the conclusions supported by the data?
Partially support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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