SARS–CoV-2 Immuno-Pathogenesis and Potential for Diverse Vaccines and Therapies: Opportunities and Challenges
Round 1
Reviewer 1 Report
This review discusses the current state of the knowledge on the immunopathology of SARS-CoV-2 as well as some current approaches to vaccine development and potential therapeutic strategies.
The authors face the challenge of compiling a scientific review while the current state of research is constantly and rapidly evolving. Reviews such as this one are therefore in constant danger of being outdated by numerous new findings before publication. Nevertheless, this manuscript has succeeded in providing a rather up-to-date and comprehensive overview of the discussed topic. In particular, the immunopathogenesis as well as the genetic basis of the virus-will interaction of a SARS-CoV-2 infection are discussed in detail.
I consider the submitted manuscript to be well worth reading and of great interest to readers of Infect. Dis. Rep.
However, I suggest that the following aspects should be added before publication: the new virus variant B1.1.7, which has just recently been detected in Great Britain, contains a mutation in the ORF8 region in addition to numerous other changes. For these mutations, at least in SARS-CoV-1, a relevant effect on the immunomodulatory effect of the virus has been shown (https://doi.org/10.1038/s41598-018-33487-8). This particular aspect, which is probably also relevant for SARS-CoV-2, has not been mentioned by the authors so far and should be added if possible.
Furthermore, I recommend to add relativizing references to the numerous other development projects in the section on vaccine development. Especially in the explanations to Tab. 1 it should be pointed out that only a selection of candidate vaccines is presented here.
Author Response
This review discusses the current state of the knowledge on the immunopathology of SARS-CoV-2 as well as some current approaches to vaccine development and potential therapeutic strategies. The authors face the challenge of compiling a scientific review while the current state of research is constantly and rapidly evolving. Reviews such as this one are therefore in constant danger of being outdated by numerous new findings before publication. Nevertheless, this manuscript has succeeded in providing a rather up-to-date and comprehensive overview of the discussed topic. In particular, the immunopathogenesis as well as the genetic basis of the virus-will interaction of a SARS-CoV-2 infection are discussed in detail.I consider the submitted manuscript to be well worth reading and of great interest to readers of Infect. Dis. Rep. However, I suggest that the following aspects should be added before publication:
1: The new virus variant B1.1.7, which has just recently been detected in Great Britain, contains a mutation in the ORF8 region in addition to numerous other changes. For these mutations, at least in SARS-CoV-1, a relevant effect on the immunomodulatory effect of the virus has been shown (https://doi.org/10.1038/s41598-018-33487-8). This particular aspect, which is probably also relevant for SARS-CoV-2, has not been mentioned by the authors so far and should be added if possible.
Response: We thank the reviewer for their comments. The manuscript has been updated to reflect in much greater detail about the emerging variants of SARS-CoV-2 and their implications.
2: Furthermore, I recommend to add relativizing references to the numerous other development projects in the section on vaccine development. Especially in the explanations to Tab. 1 it should be pointed out that only a selection of candidate vaccines is presented here.
Response: The references have been updated as requested throughout the manuscript and the vaccines section has been accordingly updated and described as requested in the comment.
Reviewer 2 Report
This review claims to discuss SARS-CoV-2 immuno-pathogenesis and the potential role of therapeutics and vaccines. The mechanistic interfaces between SARS-CoV-2 infection and subsequent immune responses are nicely described on the molecular level and summarized in detail. However, the readership of this journal might be more interested in the detailed pathologic consequences of these mechanisms and the respective therapeutic approaches. Currently, there are increasing numbers of reviews being published, covering SARS-CoV-2-mediated inflammation and cytokine release syndrome. For example, Soy et al. (Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol. 2020 Jul;39(7):2085-2094. doi: 10.1007/s10067-020-05190-5. Epub 2020 May 30. PMID: 32474885; PMCID: PMC7260446.) properly addressed the most important SARS-CoV-2 sequelae related to misguided immunity also on the tissue level. What exactly happens within infected tissues such as the lung? What is the role of neutrophils (elastase, MPO, oxygen radicals, netosis etc.). Neutrophils are the first line of innate immune responses upon viral infection and prolonged neutrophil activity may lead to tissue damage. This is only one example. There is only one citation related to neutrophils which rather underestimates neutrophil-mediated pathogenicity. The aspects addressing SARS-Cov-2 infected macrophages, IL-6 stimulation etc. and the pathogenic consequences are not sufficiently covered. The contradictory published reports about the treatment of COVID-19 patients with anti-IL-6 antibodies has not sufficiently discussed. There is no information showing the clinical and immunological benefits of Remdesivir and vaccines also specifically in the light of humoral and cell-mediated immunity? Table 1 should be complete. There are around 250 vaccine development projects worldwide according to the WHO. It would be nice to learn more about the different approaches in the context of antiviral and immunomodulatory effects as well as the putative advantages or disadvantages of either vaccine (expected balanced humoral/cellular immunity etc.) also in the context of logistics. For example, vaccines ought to be stable during shipping and storage. Loss of function and degradation of ingredients may entail safety issues, higher costs and delay in availability for broad immunization.
The interesting discussion about the antibody dependent enhancement has not been sufficiently addressed (only mentioned in Figure 1). Overall, what can we expect from the currently available vaccines in the light of transient or long-term humoral and cellular immunity (e.g. memory cells).
My major concern with this manuscript is the lack of information about the timing of disease progression , starting after infection and the respective treatment opportunities during the first days. How many patients are at high risk? How many patients are at low risk with only mild symptoms or are even asymptomatic. Is it possible to identify those with a high risk to undergo severe progression with cytokine release syndrome (stratification for co-morbidities, age, IL-6 levels etc. in the beginning?)? Anyone skilled in the art is aware about the importance of early treatment after diagnosis of infection. If not treated early, SARS-CoV-2 travels from the upper respiratory tract to the pulmonary tissue where it elicits inflammatory reactions with known results. The cytokine storm is difficult to treat due to its complexity and rapid progression. A recently published review about the potential of early treatment approaches showing accumulating evidence for effective disease progression management ought to be cited by the authors:
McCullough PA, et al. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19). Rev Cardiovasc Med. 2020 Dec 30;21(4):517-530. doi: 10.31083/j.rcm.2020.04.264. PMID: 33387997.
Author Response
This review claims to discuss SARS-CoV-2 immuno-pathogenesis and th potential role of therapeutics and vaccines. The mechanistic interfaces between SARS-CoV-2 infection and subsequent immune responses are nicely described on the molecular level and summarized in detail.
1)However, the readership of this journal might be more interested in the detailed pathologic consequences of these mechanisms and the respective therapeutic approaches. Currently, there are increasing numbers of reviews being published, covering SARS-CoV-2-mediated inflammation and cytokine release syndrome. For example, Soy et al. (Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol. 2020 Jul;39(7):2085-2094. doi: 10.1007/s10067-020-05190-5. Epub 2020 May 30. PMID: 32474885; PMCID: PMC7260446.) properly addressed the most important SARS-CoV-2 sequelae related to misguided immunity also on the tissue level.
Response: We thank the reviewer for their comments. Greater explanation of the pathological consequences have been included in the manuscript now, focusing on the activity of neutrophils, prominent risk factors, and the debated cytokine storm.
2)What exactly happens within infected tissues such as the lung? What is the role of neutrophils (elastase, MPO, oxygen radicals, netosis etc.). Neutrophils are the first line of innate immune responses upon viral infection and prolonged neutrophil activity may lead to tissue damage. This is only one example. There is only one citation related to neutrophils which rather underestimates neutrophil-mediated pathogenicity.
Reponses: We have explained these phenomena in greater detail, have including a greater description of neutrophil activity as it pertains to SARS-CoV-2 and included more references pertaining their role in disease
3)The aspects addressing SARS-Cov-2 infected macrophages, IL-6 stimulation etc. and the pathogenic consequences are not sufficiently covered. The contradictory published reports about the treatment of COVID-19 patients with anti-IL-6 antibodies has not sufficiently discussed.
Reponses: We have discussed the cytokine storm phenomenon in greater detail and illustrated where the disagreements are on the role of this proposed syndrome impacting COVID-19
4)There is no information showing the clinical and immunological benefits of Remdesivir and vaccines also specifically in the light of humoral and cell-mediated immunity?
Response: We addressed this by increasing the information regarding Remdesivir response, window of therapeutic efficacy analyzed via meta-analysis, and updated information regarding vaccine elicited immunity.
5)Table 1 should be complete. There are around 250 vaccine development projects worldwide according to the WHO. It would be nice to learn more about the different approaches in the context of antiviral and immunomodulatory effects as well as the putative advantages or disadvantages of either vaccine (expected balanced humoral/cellular immunity etc.) also in the context of logistics. For example, vaccines ought to be stable during shipping and storage. Loss of function and degradation of ingredients may entail safety issues, higher costs and delay in availability for broad immunization.
Response: We have redescribed elements in our vaccine section to focus on a selection of prominent candidate vaccines as well as vaccines that have been authorized. We have stated in the manuscript that the vaccines being discussed are a sample of all the total vaccines being investigated, which number in the hundreds.
6)The interesting discussion about the antibody dependent enhancement has not been sufficiently addressed (only mentioned in Figure 1). Overall, what can we expect from the currently available vaccines in the light of transient or long-term humoral and cellular immunity (e.g. memory cells).
Response: We have now discussed this point in greater detail in the manuscript
7)My major concern with this manuscript is the lack of information about the timing of disease progression , starting after infection and the respective treatment opportunities during the first days. How many patients are at high risk? How many patients are at low risk with only mild symptoms or are even asymptomatic. Is it possible to identify those with a high risk to undergo severe progression with cytokine release syndrome (stratification for co-morbidities, age, IL-6 levels etc. in the beginning?)? Anyone skilled in the art is aware about the importance of early treatment after diagnosis of infection. If not treated early, SARS-CoV-2 travels from the upper respiratory tract to the pulmonary tissue where it elicits inflammatory reactions with known results. The cytokine storm is difficult to treat due to its complexity and rapid progression. A recently published review about the potential of early treatment approaches showing accumulating evidence for effective disease progression management ought to be cited by the authors:
McCullough PA, et al. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19). Rev Cardiovasc Med. 2020 Dec 30;21(4):517-530. doi: 10.31083/j.rcm.2020.04.264. PMID: 33387997.
Response: We have updated the manuscript with meta-analysis based reports that describe the particularly vulnerable populations, as well as greater explanation on the disease progression. We thank the reviewer for this reference, and it has been included in the manuscript accordingly.
Round 2
Reviewer 2 Report
The authors addressed all points of criticism/commets adequately.
