RNA Viruses, Pregnancy and Vaccination: Emerging Lessons from COVID-19 and Ebola Virus Disease

Round 1

Reviewer 1 Report

In the manuscript by Dhanya et al.,  authors compare the impact of SARS-CoV-2 and Ebola infections and vaccination on pregnancy. 

I find the topic and the contents of the review very interesting and impactful. The manuscript is certainly comprehensive and complete but in some sections it is, in my opinion, excessively long and could be summarized in shorter paragraphs. I refer in particular to paragraph 3. The point of the work is to compare the effects of infection on pregnancy, so I think this section needs to be more concise. 

Author Response

We thank the reviewer for the kind and encouraging words of appreciation. Thank you pointing out that section 4.3. is excessively long and contains general information that can be avoided and not mandatorily required considering the context of the review. Hence we have deleted  second paragraph of section 4.3.

Reviewer 2 Report

The authors provide a basic review of COVID-19 and Ebola viral disease focused on mechanisms of immune response and devoting special attention to the

risks of pregnancy in infected women. The review is rather basic, but will be a good starting point for readers with a limited knowledge of

viral host defense mechanisms. The organization of the manuscript is good at paragraph level and above. However, the writing at sentence level is mediocre

and could be substantially improved. The numbering of lines starts at 1 in three places. Unless noted otherwise, comments refer to the first set of line numbers.

Major comments:

1. Lines 16-17, whether the management of the COVID-19 pandemic has been efficient is quite debatable and the authors should not make this claim

2. Early on, the authors should distinguish between RNA viruses that are transmitted human-to-human and RNA viruses, such as Dengue and Zika, that are transmitted via an intermediate host, usually an insect.

3. At Line 110 and in Table 1, The  Ebola receptor is definitely TIM-1, encoded by the gene HAVCR1. The authors should not repeat earlier, erroneous suggestions that other proteins are Ebola receptors.

B. Brunton et al. TIM-1 serves as a receptor for Ebola virus in vivo, enhancing viremia and pathogenesis. PLoS Neglected Tropical Diseases 2019; 13:e0006983 PMID31242184

A. Kondratowicz et al. T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus, PNAS 2011; 108:8426-8431

4. Line 391-393 the consensus is that antibody-dependent enhancement is at at most uncommon for COVID-19 and the authors should not make this claim without citing conflicting papers.

5. Table 4 could be safely deleted since there are other sources for COVID-19 vaccines as the authors noted.

6. The claim about the humoral response after COVID-19 vaccination at the third lines 41-42 is misleading since multiple studies show that antibody levels decline much faster in vaccinated individuals

than in infected individuals and that is why booster does are needed.

Sentence-level rewrites that should be done:

Line 22, change "which illustrate" to "that illustrate"

Line 23, change "So we have summarized" to "We summarize" and more generally change present perfect to present tense in many places

Line 30, delete "identified by us,"

Line 36 change "Global Catastrophic Biological Events" to "global catastrophic biological events"

Line 57 change "at the earliest" to "as early as possible"

Line 59 change "on the mechanism of immune response" to "on the mechanisms of the immune response"

Line 114 change "Table-1" to "Table 1"

Line 137 change "in human comprises instant" to "in humans is comprised of a rapid"

Lines 138-139 change "adapative response" to "adaptive responses"

Line 167 change "trap" to "traps"

Line 203 change "humarl immune" to "The humoral immune"

Line 210 change "fatal patients" to "patients who died of infection"

Line 233 change "which suggest" to "that suggest"

Line 241 the acronym RBD standing for receptor binding domain is introduced without any explanation. The RBD should be introduced where the spike protein is introduced around line 99

Lines 242-243 change "6.2 months" to "6.2 months after infection"

Line 247 change first Ebola outbreak occurred" to "first recognized Ebola outbreak"

Line 255 change "could prevail" to "could exist"

Line 262 change {102, p.} to [102]

Line 265 change "investigated for," to "investigated"

Line 272 change "less fatality rates" to "lower fatality rates"

Line 278 change "of adaptive" to "to the adaptive"

Line 280 change "of immune response" to "of the immune response"

Line 282 change "alterations of which" to "alterations of these two cell subsets"

Line 347 the phrase "within a period of 3 months and 5.1 years" does not make sense; I am unsure what the authors mean here

Line 354 change "The Reuters" to "Reuters"

Line 387 change "Disease-modifying" to "disease-modifying"

Lines 398, 400 change "plasmodium" to "Plasmodium" in italics

Line 400 I do not understand what "Similar observation" means

Line 403 change "and immune system" to "and the immune system"

Line 404 change "which indicate" to "that indicate"

Line 413-414 change "which report" to "that report"

Line 415 change "is thought" to "are thought"

Line 416 change "the pregnant women" to "pregnant women"

Line numbering restarted on page 23

Line 2 change "Significance of placenta" to "The importance of the placenta"

Line 3, change "of placenta" to "of the placenta"

Line 27, change "Placenta has" to "The placenta has"

Line 28 change "protects the neonate" to "protect the neonate"

Line 29 change "Viral antigens" to "viral antigens"

Line 31 change "enter trophoblast" to "enter trophoblasts"

Line 39 change "has reported" to "reported

Line 59 change "suggest possibility" to "suggest the possibility"

Line 77 change "which attracts" to "that attracts"

Line 83 change "triggers formation" to "trigger formation"

Line 84 change "to comprise of immune cells like" to "to be comprised of immune cells such as"

Line 98 change "which indicate" to "that indicate"

Line 101 change "which plasy" to "that plays"

Line 110 change "Table-2" to "Table 2"

Line 110 change "indicate possibility" to "indicate a possibility"

Line 113 change "in placenta" to "in the placenta"

Line 123 change "in Supplementary table" to "in the Supplementary Table"

Line 125 change "which generate immune" to "that generate an immune"

Line 128 change "which are developed" "and they have been developed"

Line 130 change "Table-3 lists out" to "Table 3 lists"

Line numbering restarted on page 32

Line 4 change "Table-4" to "Table 4"

Line 20 change "bivalent" to "the bivalent"

Line 36 change "which needs to be discussed" to "that needs to be discussed"

Line 69 change "which demonstrated" to "that demonstrated"

Line 100 change "which could be" to "that could be"

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 3 Report

Dhanya et al present a comprehensive review of the literature to date pertaining to SARS-CoV-2 and Ebola.  While this review is highly critical and important to the field, at times can be disjointed. Please see below for summary of comments that would need to be addressed. Overall a mammoth effort by the authors but it might be worth addressing all the points below to really improve this very important review.

Strengths of the paper

-       Comprehensive tables however titles in column 1 can be shortened to simply, Structural proteins; Non structural proteins;

-       Great figures.

Weaknesses of the paper

Major comments

Section 4.2 surprisingly appears to be the start of its own section with its own line numbering etc, immediately after table 4. I would attempt to make the sections more cohesive.

The same thing happens following table 3

Other comments

Line 36/37 (Grammatical errors)

Please Rephrase: …threat to Public Health, with the potential to cause Global Catastrophic Biological Events necessitating the identification of….

Line 39 (Grammatical errors)

Remove ‘the’ in front of vulnerable

Line 54/55 (Grammatical errors)

Rephrase to: Pregnancy alone, being associated with …..exposes the maternal immune system to many challenges.

Line 58 (Grammatical errors)

Remove ‘the’ in front of pregnant women.

Remove ‘of the’ at the end of line 58 just before clinical trials

Line 59 (Grammatical errors)

Remove ‘the’ in front of ‘available studies.

Line 67

Can be rephrased to: Since elucidation of the molecular profile of the virus, evolution of several variants of concern have occurred.

Line 69

Can be rephrased:

In contrast, there is comparatively more literature available for Ebola virus disease (EVD)n also known as viral hemorrhagic fever. EVD caused by EBOV belongs to the Filoviridae family…..

Line 74

Replace ‘supposed’ with believed.

Line 77 (Grammatical errors)

Suggested Rephrase:

…the natural reservoirs, likely spreading to humans upon contact. And subsequent entry following breach in mucosal surfaces

Line 86 (Grammatical error)

Change to ‘have been proposed’

Line 93-102

Please rephrase this.

You start of with RNA viruses having small genomes then immediately talk about SARS-CoV-2 having the largest genome. Perhaps talk first about Ebola which comparatively has a smaller genome (~ half of SARS-CoV-2) to put into context of the first sentence you write, then introduce SARS-CoV-2. This way your sentence will flow better.

Line 103 (Grammatical error)

Remove ‘the’ in front of viral entry

Line 106 (Grammatical error)

Remove ‘the’ in front of viral entry

Line 107

Change COVID-19 to SARS-CoV-2 since you are now discussing the virus interaction with its host receptor and not the disease.

Line 108

Change ‘such as’ to including

Line 125

Remove ‘the’ in front of envelope viruses

Line 126

Remove ‘the’ in front of apoptotic mimicry

Line 126

Remove ‘the’ in front of Phosphatidylserine

Line 190/191

There is no need for CD4 and CD8 to have the numbers superscripted.

Line 193

Remove ‘the’ before B cells

Line 196 -201

Needs to be completely rephrased. This is very convoluted sentence. Simply state that, Sette et al propose that the innate immune response is the first line of defense, as has been previously suggested/reported, and the adaptive response takes over soon after waning of the innate response. And rather than saying ‘however’ then proceed with, ‘the contributions of…..

Stating the way you have, makes it look like you are contrasting two different diseases yet its just COVID19.

Line 206

Remove ‘the’ in front of patients.

Figure 2

Propose to choose 1 colour for each virus. Perhaps Maroon/Red for Ebola and Teal/Green for SARS-CoV-2 and then perhaps darker shades for IgG and lighter shades of the colours for IgM.

Line 228

Insert ‘the’ in front of Fc domain.

Line 232 and 233

Phagocytosis is also an Fc mediated activity. Perhaps swap these around and connect the sentences with ‘such as’ phagocytosis.

Line 253

Insert ‘the’ in front of ability

Line 254

Remove ‘the’ long term

Line 259

Remove ‘has’ in front of carried out

Line 264 (Grammatical error)

Remove “needs to be investigated for, in COVID19, too,”  and replace with

‘warrants investigation also in the context COVID19’

Line 271

Replace

“this has been attributed to 271 be responsible for the less fatality rates observed among females “

With

“likely responsible for the lower fatality rates observed for females”

Figure 4

Improve resolution of the person coughing.

Line 354

Not sure if including Reuters makes the argument strong. Requires a scientific publication.

Line 403

Remove ‘the’ in front of pregnant women.

Line 416

Remove ‘the’ in front of pregnant women.

Line 37  in the section

Effects of COVID-19 and EVD on Placenta and Vertical Transmission

Replace ‘ talked about’ to discussed.

Line 39

Remove ‘has’ in front of reported

Line 99

Change superscripted 8 in CD8+ T cells

This is a very comprehensive review however authors need to address the above points

Author Response

Please see the attachment

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors have addressed my comments adequately.

Author Response

Thank you for reviewing the manuscript

Reviewer 3 Report

Thank you kindly to the authors for considering and addressing reviewer comments. Very kindly appreciated.

It has been greatly improved. 

Author Response

We thank the reviewer for helping us improving the manuscript