SARS-CoV-2 Intermittent Virulence as a Result of Natural Selection

Round 1

Reviewer 1 Report

In this interesting manuscript dedicated to the analysis of the temporal and epidemiological behavior of SARS-CoV-2 the authors came to an important conclusion that this virus is characterized by the “intermittent virulence”, where after the outbreak, virulence does not steadily decrease as expected by classical evolutionary theory, but goes in waves, reflecting an evolutionary equilibrium between transmissibility and virulence. Based on their comparative analysis of the main genetic mutations in the Delta and Omicron (BA.1, BA.2. BA.4, and BA.5) variants of SARS-CoV-2, the authors conclude that there is a chance that Omicron does not signal end of epidemic, and new more virulent variants will emerge, indicating that the pandemic will continue. This increased virulence of new variants could guarantee the survival of this pathogen, confirming the validity of the term “intermittent virulence”.  This work adds significantly to the field and will have a noticeable impact. 

Author Response

We are thankful to this reviewer for high evaluation of our work and for agreement with our "intermittent virulence" hypothesis.

Reviewer 2 Report

The authors are commended for submitting a well-written review summarizing the temporal genomic and epidemiologic characteristics of SARS-CoV-2 and its related major mutants during this pandemic, proposing a concept of “intermittent virulence” trying to elucidate the mechanism of COVID-19 evolutionary and in the past and future. A very important topic and worth to discuss at the right time. Generally, this is a well written paper with comprehensive summary and thoughtful discussion.

One possible comment on the discussion:

The author mentioned in paragraphs [274-298] that new emerging Omicron variants including BA2/4/5 carries not only higher transmissibility as we observed before but also shown higher virulence based on animal/neutralization studies. However, in epidemiologic data, those observed higher virulence were not consistent with observed continuously declining mortality in real world. I believe this worth a further discussion that might support the concern that pandemic phase of COVID-19 is about to end and may transition to epidemic level.  

1)    Spike mutation that dodges Abs might reduce the virus’s ability to recognize and bind host cell (ACE2) as evolving to evade immune response could carry evolutionary costs

2)    Repeated exposures to varies mutants (spike protein) whether through global natural infection or repeated vaccines would build up an immunity that is hard to overcome across the populational level

3)    T-cell mediated immunity could play a major role in herd immunity even if vitro naturalization effect wade.

4)    All previous constrains might slow the COVID-19 immunity evasion and could explain the continuously lower mortality level among population even with higher virulence mutations and support the conclusion that pandemic is near end and will transit into endemic phase.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 3 Report

General comments

Please check the style used. avoid informal words. The style should be direct, concise and scientific.

Language should be checked and improved.

A graphical abstract simmarizing the main findings (mechanisms suggested) should be added.

In spite of being of great interest for scientists, the suggested concept of intermittent virulence  should be more corroborated. Although authors gave in their discussion different arguments (epidemiology, deaths, some proteins), a biological (receptors, signalling pathways, .....) should be added and discussed.

Specific comments

Lines 33-34. "The evolution of viral adaptability is the result of selective pressure acting across different mechanisms"

This should be more detailed since it is important to the reader in relation with Sars-Cov-2 evolution discussed in the paper.

A figure summarizing the different mechanisms involved in evolution of viral adaptability would be useful to the reader. 

Lines 50-52. "The evolution of a pathogen should ........ pathogen's spread"

this statement should be rewritten in a more scientific sounding style.

Line 63-65. A reference should be added.

Line 70. isn't   should be corrected to is not (check and correct all the text).

Figure  2. 

although, authors wrote that the figure is under CC BY license, its free use should be confirmed.

Figure 3. is a caption from a website. 

The figure should  be replmaced by another with high resolution and from an official source (do not forget the permission to use it in the paper).

Author Response

Please see the attachment

Author Response File: Author Response.docx

Round 2

Reviewer 3 Report

Comments answered correctly.