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i comment the authors for having substantially improved the manuscript. The English was well revised and the paper is now clear overall, although there are still a few typos, but I hope they can be corrected by the editorial office.
The authors have also answered all my concerns to my satisfaction and have revised the manuscript accordingly.
Thank you very much.
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Bilge Sümbül et al revised their article “Is there a link between pre-existing antibodies acquired due to childhood vaccinations or past infections and COVID-19? A case control study" according to reviewers suggestion. The revised manuscript improved a lot from the previous version and it will be interesting read for the readers. The manuscript will enrich our knowledge about the possible link between childhood vaccination and it's non-specific effect on other diseases like COVID-19. I recommend this for publication in PeerJ.
Please find the reviewers' comments. It is important to edit the paper language.
In addition, a statistical reviewer asked that you address the following:
(1) Power calculations of ms are not very useful at all. In principle, power calculations are carried out only for one, primary outcome. However, in this ms primary outcome was not specified.
(2) Authors report quite large number of p-values. In my opinion, q-values or false discovery rates should also be reported. See reference sbelow.
Storey JD. (2002) A direct approach to false discovery rates. Journal of the Royal Statistical Society, Series B, 64: 479-498. http://onlinelibrary.wiley.com/doi/10.1111/1467-9868.00346/abstract Storey JD and Tibshirani R. (2003) Statistical significance for genome-wide experiments. Proceedings of the National Academy of Sciences, 100: 9440-9445. http://www.pnas.org/content/100/16/9440.full
Storey JD. (2003) The positive false discovery rate: A Bayesian interpretation and the q-value. Annals of Statistics, 31: 2013-2035. http://projecteuclid.org/DPubS/Repository/1.0/Disseminate?view=body&id=pdf_1&handle=euclid.aos/1074290335
Storey JD, Taylor JE, and Siegmund D. (2004) Strong control, conservative point estimation, and simultaneous conservative consistency of false discovery rates: A unified approach. Journal of the Royal Statistical Society, Series B, 66: 187-205. http://onlinelibrary.wiley.com/doi/10.1111/j.1467-9868.2004.00439.x/abstract
Storey JD. (2011) False discovery rates. In International Encyclopedia of Statistical Science. http://genomine.org/papers/Storey_FDR_2011.pdf http://www.springer.com/statistics/book/978-3-642-04897-5
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[# PeerJ Staff Note: The Academic Editor has identified that the English language must be improved. PeerJ can provide language editing services - please contact us at copyediting@peerj.com for pricing (be sure to provide your manuscript number and title) #]
1. The language used is precise, clear and without any ambiguities. Background information is succinct and covers the hypothesis generation well.
2. Tables contain all relevant information necessary to make conclusions.
3. Line 124, please correct 0,50 units to 0.50 units
1. Line 91 mentions that the demographic characteristics of the volunteers were questioned. Please elaborate on this.
2. Rest of the methods section is well described and all ethical standards have been followed to obtain and assess samples.
no comment
1. In the background, please give information about the vaccination status in the country where the sample patients and healthy volunteers were from.
2. in the discussion section, please talk about the involvement of the immune system with the vaccination status and how that could play a possible role in the COVID-19 case severity. Provide valid references. This is especially important since low lymphocyte count has been reported.
3. In discussion, a mention of increased fibrinogen has been made on line 226-227. How is this linked to coagulopathy, mentioned on line 228?
The article should be edited by a native English speaker. There are many awkward sentences, too many to be cited all. I just provide examples from the introduction and the methods section:
Lines 65-67: this sentence can be cut into two sentences
Lines 68-72: this sentence can also be cut into two sentences
Same for 80-82
Line 91: it is not clear what is meant by “… demographic characteristics were questioned.” Please rephrase.
Line 101: replace -80 degrees by -80°C.
Line 123: “Level” should be in plural (Levels).
Line 129: this sentence is strange
Line 73: these are not “theories” but “hypotheses” at best
Line 100: what is meant by “centrifugation for 10 minutes at 2000 cycles”?
Lines 114-122 can be deleted, this is textbook knowledge
Lines 123 and 124: the repetition of “antibody units” is not necessary. It is sufficient to mention this once at the end for the last one (≥ 15 antibody units)
Line 146 and throughout the manuscript: these are not clinical parameters, but biological or biochemical parameters.
Lines 249-250: Blok et al speak about Tdap, containing an acellular pertussis vaccine, and show that Tdap augments immunity only very slightly and very briefly (in a matter of days). In Turkey probably people were vaccinated with whole-cell pertussis vaccine, thus this is reference is irrelevant here.
Lines 254-261: this is essentially a repetition of the results section. The authors do not really explain and discuss the significance of this, except to say that a combination of antibodies may protect. It would be important to expand this and be more precise as to what combination the authors think may protect.
In this case-control study 53 COVID patients were compared to 40 controls with respect to antibody titers to vaccine antigens. For rubella, pneumococci and pertussis these titers were lower in the case group than in the control group. This led the authors to conclude that childhood vaccination with these vaccines or past infections may protect against COVID through cross-reactivity by vaccine-induced antibodies.
Methods: it would be nice for the reader to know what the actual antigens really are. Are they purified antigens or whole bacterial lysates/viruses? This is particularly important for B. pertussis and for pneumococci.
A study to link unrelated antibodies to COVID is potentially useful, but the interpretation of the results is not really obvious. In order to be convinced one would like to see that these, so called pre-existing antibodies do indeed cross-react with SARS-CoV-2 antigens. This was not done in this study.
Instead of linking unrelated antibodies to protection against COVID, I think there may be another explanation that would be much more plausible, and that is the induction of innate immune training by viral and/or bacterial infections.
The fact that only low anti-rubella antibodies appear to correlate with disease or infection, but not anti-mumps and anti-measles antibodies, suggests that it may be a rubella infection, even as a silent infection, rather than the MMR vaccine that is linked to protection. Similarly, the fact that only low anti-B. pertussis antibodies correlate with disease or infection and not anti-diphtheria or anti-tetanus antibodies, given that all three vaccines are administered simultaneously and that anti-tetanus and anti-diphtheria antibodies are much longer lived than anti-B. pertussis antibodies, it is more likely that the effect seen is due to silent B. pertussis infection.
Live bacterial and viral infections are known to induce innate immune memory which in the case here is more likely to have contributed to the protection.
Thus the final conclusion (final sentence of the paper) is not supported by the data.
Lines 169 and 170: The dip in pertussis IgG in mild disease should be discussed;
Lines 246-249: I am not sure I can follow the argument of the authors. If most of the COVID patients are co-infected with S. peumoniae, there should be more anti-S. pneumoniae antibodies in the patients than in the controls.
A study to link unrelated antibodies to COVID is potentially useful, but the paper has to be edited by a native English speaker and the interpretation of the results has to be reviewed in a more in-depth manner. Please refer to my comments above.
The manuscript is well structured and written professionally.
no comment
More meaningful discussion will improve the manuscript.
Bilge Sümbül et al in the article “Is there a link between pre-existing antibodies acquired due to childhood vaccinations or past infections and COVID-19? A case control study" tried to find the correlation between existing antibodies with severity of COVID-19.
Overall, the study is well designed, thoughtfully carried out with precision. This study may have significant impact in understanding the immune response against SARS-CoV-2. Their studies showed that pre-existing antibodies acquired due to childhood vaccinations or past infections may play some role in controlling the severity of COVID-19. But in the study, they didn’t discuss extensively the possible reason for this less severity of COVID-19. This protection is mainly non-specific, as pre-existing antibodies were generated possible due to childhood vaccination or any other infection acquired over lifetime. Apart from the acquired antibodies, different innate immune cells like monocyte/macrophage or NK cells may play a role in this context. There are already enough studies being carried out regarding non-specific memory response (trained immunity) showed by innate immune cells. BCG vaccination and resultant non-specific protection against other diseases are one such specific example.
This study would have been more appealing and interesting if some of the role played by immune cells were shown experimentally or discussed properly.
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