The Importance of Sleep and Circadian Rhythms for Vaccination Success and Susceptibility to Viral Infections

Round 1

Reviewer 1 Report

This review addresses a very imortant health issue, the relationship and the influence of sleep and circiadian rhythms on vaccination success. The state-of-the-art in this field and the related background are clearly presented. The manuscript is excellently written. 

I have only one critical comment regarding $ 4.2 - Recommendations

These recommendations are interesting. However, supporting citations are lacking and should be added. 

Author Response

This review addresses a very imortant health issue, the relationship and the influence of sleep and circiadian rhythms on vaccination success. The state-of-the-art in this field and the related background are clearly presented. The manuscript is excellently written. 

I have only one critical comment regarding $ 4.2 - Recommendations

These recommendations are interesting. However, supporting citations are lacking and should be added. 

We thank the reviewer for the positive appraisal of our manuscript. In line with the comment on the Recommendations that was also noted by Reviewer 3, we have now taken the opportunity to structure the section better and have provided more information and three references

Reviewer 2 Report

The current paper aimed to review the link between sleep/circadian rythm and viral infections. The topic of the paper is of interest.

I have several concerns that, according to me, make the paper unclear to me.

• It seems that there is two parts in the paper, one related to sleep/circadian rythm and immunity and one related to vaccines. It may be an option to remove one of the other to have a clearer message.
• Although results described have implications for COVID19 vaccin effects, it seems too strong to make a direct link with Sarcov infection or COVID vaccin. I suggest to keep COVID19 as a perspective question instead of focusing on it.
• I miss very often references to support the text. 
• It could be useful to define more some concepts (example: immune homeostasis) and to include additional figures to support the text.
• Regarding sleep effects, I miss effects related to both acute and chronic sleep deprivation.
• Some results are unclear and should be more described (example, beginning of page 4, uninterrupted sleep ; page 6, line 266, peaople with sleepp problems and risk of COVID19).
• I am not sure keeping the part related to vaccination success (3.4) and the one related to COVID vaccin (3.5) is needed in the current version of the paper as it seems out of purpose.
• Because of the remarks above, it is not clear to me what is precisely the aim of the paper and how it will bring additional studies. 

Author Response

The current paper aimed to review the link between sleep/circadian rythm and viral infections. The topic of the paper is of interest.

I have several concerns that, according to me, make the paper unclear to me.

We thank the reviewer for the interest in the topic; we have now made changes throughout the manuscript that hopefully add to the scope and purpose of the manuscript.

It seems that there is two parts in the paper, one related to sleep/circadian rythm and immunity and one related to vaccines. It may be an option to remove one of the other to have a clearer message.

Thank you for the comment; we would naturally be happy to modify the manuscript to strengthen the message. But at this stage we feel these two aspects both deserve equal attention, as both have been documented and deserve recommendation. If the reviewer or editor deem it of importance we are happy to reconsider paragraphs in the manuscript. For the moment, we have kept both themes (susceptibility and vaccination success) and hope that with the modifications in response to the other comments the manuscript has become stronger.

Although results described have implications for COVID19 vaccin effects, it seems too strong to make a direct link with Sarcov infection or COVID vaccin. I suggest to keep COVID19 as a perspective question instead of focusing on it.

We agree that the SARS-Cov infection and vaccination in relation to sleep are at the current moment more of a perspective. We have for this reason removed all mention of Covid from the abstract to focus the manuscript on infection and vaccination in general, and have also modified the Discussion similarly in the first and last sentence. We have added in paragraph 4.1 the notion that the review serves to ‘offer a perspective’ for the Covid pandemic

I miss very often references to support the text. 

We have added references to the manuscript, in particular to the possible effects of melatonin that were admittedly scantily addressed

It could be useful to define more some concepts (example: immune homeostasis) and to include additional figures to support the text.

We agree that the concept of immune homeostasis is ill-defined and have replaced all mention of it to ‘immune function’

Regarding sleep effects, I miss effects related to both acute and chronic sleep deprivation.

We agree that this aspect is missing in the available literature. We have included references to studies on people with shift-work in paragraph 3.4 and to the relationship between insomnia and Covid infection in paragraph 2.4 and 3.5; in addition, we have now added a mention on this gap of knowledge in the Recommendations for future studies.

Some results are unclear and should be more described (example, beginning of page 4, uninterrupted sleep ; page 6, line 266, peaople with sleepp problems and risk of COVID19).

We regret the wording of those sentences and have modified and shortened both to be more precise.

I am not sure keeping the part related to vaccination success (3.4) and the one related to COVID vaccin (3.5) is needed in the current version of the paper as it seems out of purpose.

We feel the paragraphs 3.4 and 3.5 are integral to the manuscript as we include relevant references to studies on shift workers and importantly, indicate that controlled studies on sleep and vaccination success are now underway. We would be happy to hear if the reviewer and editor deem these aspects of importance.

Reviewer 3 Report

Manuscript ID: clockssleep-1548427

 

Title: "The importance of sleep and circadian rhythms for vaccination success and susceptibility to viral infections"

 

 

The aim of this review was to summarize the available knowledge about the relationship between sleep-wake cycle and immune system efficiency in humans.

 

The topic of the manuscript is interesting and current considering the pandemic situation. Manuscript is clearly written and well documented.

 

I have few marginal suggestions.

 

The first section about the relationship between circadian rhythms and immune homeostasis is a little bit too short (2.1). For example, writing that body temperature varies during the 24 hours is not informative enough. If instead we write that the body temperature varies over the 24 hours, reaching maximum values in the late afternoon and minimum values in the early hours of the morning, I leave the reader with a much more precise idea. Writing that immune system is regulated in a time-of-day dependent manner is not enough for a reader.

 

In the same way, Figure 1 is not clear. For example, the arrow near the clock seems to indicate short or long sleep. However, I do not think that this is the case.

 

In the recommendations section, I expected to find more precise indications, in particular with respect to the ideal time to have the vaccination. I believe that a Table summarizing the recommendations could be very useful.

 

In the same section, suddenly, melatonin is quoted. It has never been mentioned before. Moreover, there is not even one bibliographic reference on this hormone. It would seem more prudent to remove any reference to melatonin which possible effects on the immune system are still controversial.

Author Response

The aim of this review was to summarize the available knowledge about the relationship between sleep-wake cycle and immune system efficiency in humans.

The topic of the manuscript is interesting and current considering the pandemic situation. Manuscript is clearly written and well documented.

I have few marginal suggestions.

The first section about the relationship between circadian rhythms and immune homeostasis is a little bit too short (2.1). For example, writing that body temperature varies during the 24 hours is not informative enough. If instead we write that the body temperature varies over the 24 hours, reaching maximum values in the late afternoon and minimum values in the early hours of the morning, I leave the reader with a much more precise idea. Writing that immune system is regulated in a time-of-day dependent manner is not enough for a reader.

Thank you for this comment; we agree that the paragraph needed more specifics; we have taken this opportunity to provide more detailed information on the precise circadian and sleep-related effects on immune function, that we expand on in paragraph 2.2.

In the same way, Figure 1 is not clear. For example, the arrow near the clock seems to indicate short or long sleep. However, I do not think that this is the case.

Thank you for pointing this out; we have now added a more elaborate figure legend with an explanation of the arrows and the interpretation of the figure.

In the recommendations section, I expected to find more precise indications, in particular with respect to the ideal time to have the vaccination. I believe that a Table summarizing the recommendations could be very useful.

We have added specific recommendations about the timing of the vaccination, on the basis of the findings in this review. We have also structured the recommendation in a more stringent way, to provide a better overview of possible approaches

In the same section, suddenly, melatonin is quoted. It has never been mentioned before. Moreover, there is not even one bibliographic reference on this hormone. It would seem more prudent to remove any reference to melatonin which possible effects on the immune system are still controversial.

We agree the mention of melatonin was ill-phrased and have shortened this section now. In addition, we have strengthened the recommendation by providing recent and relevant references showing the effects of melatonin in clinical trials on patients with Covid-19.

Round 2

Reviewer 2 Report

I thank the authors for having done such modification to their paper. I have the feeling that the current version of the manuscript is clearer and more focused with only perspective related to COVID19.