rando2
commented
1 year ago Draft response to reviewer 1:
In this manuscript, the authors provided a thorough review of the two major vaccine technologies- whole virus vaccines and subunit vaccines and their use in the COVID pandemic. This review manuscript is overall comprehensive and is significant to the current situation. Some minor comments have been listed below for the authors to address:
Thank you for your kind words and we are very grateful for your suggestions about how to improve the manuscript.
1.1 Lines 56-57: Are these data from the John Hopkins covid-19 tracker (PMID: 32087114)? Please consider including the appropriate reference(s).
Thank you for bringing our attention to this omission. The citation has been added.
1.2 Lines 353-355/Line 358-360: repetitive sentences- both sentences talk about the beta variant being more resistant to nAbs. Please refine the paragraph.
Thank you for pointing this error out. The text on Lines 358-360 has been removed to keep all discussion of Covaxin together.
1.3 Lines 427-428: Despite that RBD is absolutely a good vaccine candidate for coronaviruses, authors may need to be very cautious about the statement in Lines 427- 428, i.e., most of the vaccine development efforts for SARS and MERS focused on RBD of the S protein. Many of the cited publications for RBD were published by Du et al., who studied mainly the RBD-based vaccines while there seem to be more groups of scientists who studied the S protein-based vaccine. In fact, the group from the protein science corporation (PMID: 16497416) also used S protein as the vaccine candidate. Thank you for pointing out this error. This section has been modified as followed: "Protein subunit vaccine development efforts for both SARS-CoV-1 and MERS-CoV explored a variety of immunogens as potential targets. The search for a potential SARS-CoV-1 vaccine included the development of vaccines based on the full-length or trimeric S protein [@doi:10.1128/JVI.00083-06; @doi:10.1089/vim.2012.0076; @doi:10.1016/j.vaccine.2006.01.059], those focused on the RBD protein only [@doi:10.1016/j.vaccine.2006.10.031; @doi:10.1016/j.bbrc.2009.05.003; @doi:10.1089/vim.2009.0090; @doi:10.1016/j.vaccine.2006.06.084] or non-RBD S protein fragments [@doi:10.1089/vim.2012.0076; @doi:10.1089/dna.2005.24.510], and those targeting the N and M proteins [@doi:10.1128/jcm.43.8.3718-3726.2005; @doi:10.1016/j.vaccine.2009.05.073; @doi:10.1016/j.vaccine.2006.01.058]."
1.4 Lines 436-439: the sentence talks about the data for MERS vaccine development. Please move it to the corresponding paragraph.
This change has been made.
1.5 Lines 454-455: The authors stated that the subunit vaccines have not played a major role in previous pandemics. When compared to nucleic acid-based vaccines? viral vector vaccines? or LAV and IWV vaccines? Please consider adding the following text "when compared to the LAV and IWV vaccines"
This change has been made.
1.6 Sections 6.2 and 6.3 (starting from Line 465): While in section 5.1, authors provided more thorough reviews and went over many different IWV-based COVID-19 vaccines, only two specific subunit vaccines, Nuvaxoid and Covifenz, were mentioned. Please consider including more subunit vaccines in Table 2 in the paragraphs and make them concise, as needed. This change may also impact Section 6.4, so please update Section 6.4 accordingly.
Reviewer 3:
We are very grateful to the reviewer for this detailed feedback, which has allowed us to make important corrections and updates to the text. For the sake of clarity, any references mentioned in the responses below are provided in CURIE format.
3.1
3.2
3.3
3.4 As the authors point out in the Introduction, the terms "efficacy" and "effectiveness" have a defined usage. Please make sure this "rule" is followed throughout. Thank you for pointing out these oversights. We have gone through the text to check the usage of these terms and change the terminology where appropriate.
3.5 The authors acknowledge the difference between clinical trial efficacy and RW effectiveness. I would recommend also mentioning the cohort differences between trials vs real-world. Beyond the variability introduced by time and geography, efficacy within a trial and effectiveness in the real-world setting can also differ due to cohort differences. Patients participating in a clinical trial are likely to receive more medical oversight, resulting in better follow-up, adherence, and patient engagement [@pubmed:17112328]. Additionally, the criteria for participant inclusion in a trial often bias trials towards selection of younger, healthier individuals [@doi:10.1093/rheumatology/key109]. The ability of an RCT to accurately assess safety can be biased by the fact that a clinical trial might not reveal rare adverse events that might become apparent on a larger scale [@doi:10.1093/rheumatology/key109]. Therefore, while clinical trials are the gold standard for evaluating vaccines for COVID-19, the results of these trials must be considered in a broader context when real-world data is available.
3.6
3.7
3.8 The authors could consider updating all time-sensitive data (currently usually "as of August 15") closer to submitting the next draft/publishing.
We absolutely agree, and in fact, because COVID-19 is such a fast-moving area, we built this manuscript using an innovative approach to publishing (software called Manubot) that allows us to integrate data from other places on the web into the manuscript. Therefore, these values are automatically updated each time the manuscript is regenerated.
3.9
3.10 Line 73: "approaches to [developing] vaccines"
Thank you for pointing out this awkward phrasing. To avoid using the word "develop" too many times in this sentence, we modified it to read:
"Over the past 150 years, several approaches to vaccination have been developed and refined."
3.11 Sentence, lines 103-107: the rapid control of an infectious disease is not an only reason for relatively slower vaccine development against it, sometimes the agents are not controlled per se but still the development/regulatory process has taken longer. The authors could mention the novelty, pandemic spread, scale and respective implications.
This text has been updated to read: "The duration and intensity of the COVID-19 pandemic has made it possible to test multiple vaccines in phase III trials, where the effect of the vaccines on a cohort’s likelihood of contracting SARS-CoV-2 can be evaluated, whereas this has not always been feasible for other infectious diseases. In some cases (e.g., SARS), the pathogen has been controlled before vaccine candidates were available, while in others (e.g., MERS), the scale of the epidemic has been smaller. Vaccine development is traditionally a slow process, but the urgency of the COVID-19 pandemic created an atypical vaccine development ecosystem where fast development and production was prioritized."
3.12 Lines 142-143: pathogen-naïve, but against rabies as a disease
This sentence has been amended to read: "The first deliberate (albeit pathogen-naïve) attempt to develop an attenuated viral vaccine dates back to Louis Pasteur's efforts in 1885 to inoculate a child against rabies."
3.13 Lines 153-154: could include mumps
This change has been made.
3.14 Line 167: SARS-CoV-2 spike antigen?
Thank you for catching this omission. The sentence has been corrected.
3.15 Lines 179-180: additional detail (perhaps a sentence or two) about a live chimeric vaccine would be interesting.
This section has been expanded in line with the reviewer’s feedback and to include a recent study on this vaccine candidate. The paragraph now reads: “Another company, Meissa Vaccines in Kansas, U.S., which also develops vaccines for respiratory syncytial virus (RSV), has developed an intranasal live-attenuated chimeric vaccine MV-014-212 [@doi:10.1038/s41541-022-00509-6]. Chimeric vaccines integrate genomic content from multiple viruses to create a more stable LAV [@doi:10.3389/fmicb.2019.02881]. To develop a SARS-CoV-2 vaccine candidate, Meissa Vaccines built on their prior work developing RSV vaccines [@doi:10.1038/s41541-022-00509-6]. A live attenuated recombinant strain of RSV previously investigated as a vaccine candidate was modified to replace two surface glycoproteins with a chimeric protein containing components of the SARS-CoV-2 Spike protein as well as the RSV fusion (F) protein [@doi:10.1038/s41541-022-00509-6]. Preclinical results describing the intranasal administration of MV-014-212 to African green monkeys and mice indicated that the vaccine candidate produced neutralizing antibodies (nAb) as well as a cellular immune response to SARS-CoV-2 challenge, including the Alpha, Beta, and Delta VOC [@doi:10.1038/s41541-022-00509-6]. Enrollment for phase I human trials began in March 2021 and recruitment is ongoing [@url:https://covid-19tracker.milkeninstitute.org; @clinicaltrials:NCT04798001].“
3.16 Lines 190-191: stronger Ab and cytokine response to what? Spike? N? whole virus?
This text has been clarified to read: "Despite these findings, BCG vaccination was associated with a stronger cytokine (IL-6) response following _ex vivo_ stimulation of peripheral blood mononuclear cells in patients with no known history of COVID-19 [@doi:10.1093/cid/ciac182]. Additionally, SARS-CoV-2-positive individuals who had received the BCG vaccine one year prior showed increased immunoglobulin (Ig) responses to the SARS-CoV-2 spike protein and receptor binding domain (RBD) relative to individuals who had received a placebo vaccine [@doi:10.1093/cid/ciac182]."
3.17 Line 220: I assume the authors refer to YF-S0* here, not YF-S0.
This error has been corrected.
3.18 Line 222: several VOC - which? Also, if same VOC as in the previous sentence, did the animals shed the virus despite not being infected?
This text has been updated to read: "No breakthrough infections were observed following vaccination with YF-S0* and exposure to the index strain and the Alpha, Beta, Gamma, and Delta variants [@doi:10.1101/2021.11.12.468374]. YF-S0* also reduced the infectious viral load in the lungs of several VOCs (Alpha, Beta, Gamma, and Delta) relative to a sham comparison [@doi:10.1101/2021.11.12.468374], and the likelihood of the Delta variant spreading to unvaccinated co-housed hamsters was significantly reduced by YF-S0* [@doi:10.1101/2021.11.12.468374]. The updated vaccine was also associated with the increased production of nAbs against the Omicron variant compared to YF-S0 [@doi:10.1101/2021.11.12.468374]."
3.19 Lines 243-244: please define "emerged". For example, China has granted the first EUA for Sinopharm vaccine in July 2020, which is earlier than either of mRNA vaccines were widely distributed. Full authorization almost coincided with Pfizer and Moderna vaccines. Do the authors mean WHO approval? Please, indicate.
This is an important distinction. Thank you for pointing this out. We have amended the text to read: "Inactivated vaccines can generally be generated relatively quickly once the pathogenic virus has been isolated and can be passaged in cell culture [@doi:10.3389/fimmu.2020.602256; @doi:10.1111/1751-7915.13818]. During COVID-19, though the World Health Organization (WHO) has been slower to approve IWV vaccine candidates than those developed with nucleic acid-based technologies, IWV vaccine development was also fast. In China, the first emergency use authorization (EUA) was granted to an IWV vaccine in July 2020, with full approval following that December [@url:https://www.reuters.com/business/healthcare-pharmaceuticals/china-gives-its-first-covid-19-vaccine-approval-sinopharm-2020-12-31; @url:https://www.nytimes.com/2020/07/16/business/china-vaccine-coronavirus.html]. The fact that these vaccines have not received as much public attention (at least in Western media) as nucleic acid vaccines for SARS-CoV-2 may be due at least in part to the novelty of nucleic acid vaccine technologies [@doi:10.1038/d41586-020-03626-1], which are more modular and immunogenic [@individual-vaccines-novel]."
3.20 Lines 305-308 are identical to lines 324-327, please leave where more appropriate. The text has been reorganized for clarity and the duplication removed.
3.21 Lines 318-321: What about humoral responses? Based on this suggestion, the text has been modified to read: "Phase I (July 2020) and phase I/II (September to October 2020) studies indicated that Covaxin adjuvanted with alum and a Toll-like receptor 7/8 (TLR7/8) agonist was safe and immunogenic [@doi:10/gkrthh; @doi:10/gh7597]. These two studies demonstrated that the vaccine induced significant humoral and cell-mediated responses, as assessed by measuring binding [@doi:10/gkrthh] and neutralising [@doi:10/gkrthh; @doi:10/gh7597] antibodies, cytokines [@doi:10/gkrthh; @doi:10/gh7597], CD3^+, CD4^+, and CD8^+ T-cells [@doi:10/gkrthh], with some formulations also eliciting Th1-skewed memory T-cell responses [@doi:10/gh7597]."
3.22 Section 5.2 could generally benefit from a slight reorganization. Please see comments 1-3. This text has been reorganized to keep the discussion of each vaccine in one section and then draw some comparisons in a concluding paragraph.
3.23 Lines 347-348: VADE has been an important topic for discussion and speculation during the pandemic. Please elaborate in 1-2 sentences about the reported cases. This paragraph has been expanded to include the following details about the case study: "Rare cases of VADE have been reported in association with CoronaVac [@doi:10.1155/2021/9673453]. In this case study, the two male patients both presented with COVID-19 pneumonia following vaccination with CoronaVac [@doi:10.1155/2021/9673453]. This study identified the timeline of disease presentation, vaccination, and known COVID-19 exposure in the two patients and suggest that the inflammatory response induced by the vaccine could have caused an asymptomatic case of COVID-19 to present with symptoms [@doi:10.1155/2021/9673453]. However, no causal relationship between CoronaVac and COVID-19 symptom onset was evaluated by the study."
3.24 Lines 349-351: That is perhaps the limitation of vaccines beyond IWV vaccines.
This sentence has been rephrased to read: "A major consideration in vaccine development is that vaccines lose efficacy as mutations accumulate in the epitopes of the circulating virus; IWV vaccines may be particularly affected by viral evolution [@doi:10.3389/fimmu.2019.00594]."
3.25 Lines 349-364: Please, clearly separate the discussion of Sinovac and Covaxin. Each vaccine is now separated into its own section.
3.26 Lines 353-355 are identical to lines 358-360, please leave where more appropriate. The change has been made -- please see the response to Reviewer 1, comment 2.
3.27 Lines 352-353: Please, specify the antigen.
This reference to the Spike protein has been clarified.
3.28 Line 360: Another preprint - which was the other one?
Investigating this sentence revealed that both referenced preprints have now been published, so the sentence has been updated to read as follows: "Another study reported that sera from individuals immunized with Covaxin produced effective nAbs against the Delta variant and the so-called Delta plus variant (AY.1) [@doi:10.1093/jtm/taab154]."
3.29 Line 397: Please, specify "several"
This text has been amended as follows: "Today, the WHO has developed recommendations for booster immunization for several whole-virus vaccines. In some cases (Valneva-VLA2001 [@url:https://www.who.int/news-room/feature-stories/detail/the-valneva-vla2001-covid-19-vaccine--what-you-need-to-know], Covaxin [@url:https://www.who.int/news-room/feature-stories/detail/the-bharat-biotech-bbv152-covaxin-vaccine-against-covid-19-what-you-need-to-know], Covilo [@url:https://www.covid19infovaccines.com/en-posts/is-the-sinopharm-bibp-covilo-covid-19-vaccine-safe-and-effective]), boosters are recommended only for high-risk and/or high-priority groups (e.g., the immunocompromised and medical professionals, respectively), while for Sinovac-CoronaVac [@url:https://www.who.int/news-room/feature-stories/detail/the-sinovac-covid-19-vaccine-what-you-need-to-know], they are recommended more broadly. Studies are also investigating the effects of booster doses in other vaccines (that have not yet received WHO approval) [@doi:10.3390/v14092016; @url:https://www.fda.moph.go.th/sites/drug/Shared%20Documents/Vaccine/U1DR1C1072640000711C-SPC-EN.pdf; @clinicaltrials:NCT05172193; @clinicaltrials:NCT04510207], though some are being investigated or deployed primarily as heterologous boosters in populations vaccinated with a different primary series [@doi:10.1080/21645515.2022.2122503; @doi:10.3390/vaccines10111800 @clinicaltrials:NCT05172193]. As new vaccines are approved by the WHO, more time elapses since many received the primary series, and new variants emerge, booster recommendations are likely to increase."
3.30
3.31 Lines 420-421: Adjuvants are always used to increase immunogenicity but are not always immunogens per definition.
This sentence has been corrected to read: "Adjuvants, which are compounds that elicit an immunogenic effect, include alum (aluminum hydroxide), squalene- or saponin-based adjuvants, and Freund’s incomplete/complete adjuvants, although the latter is avoided in human and veterinary medicine due to high toxicity [@doi:10.1016/j.vaccine.2019.04.055; @doi:10.3390/vaccines2030515; @doi:10.1093/ilar.46.3.280]."
3.32 Line 425: The authors could mention that Freund's adjuvants are not used in humans.
The change has been made -- please see 3.31.
3.33 Line 435: high RBD-specific humoral response? The text has been clarified to read: "There have been examples of successful preclinical research including candidate RBD219N-1, a 218-amino-acid residue of the SARS-CoV-1 RBD that, when adjuvanted to aluminum hydroxide, was capable of eliciting a high antibody response of both nAbs and RBD-specific mAbs in both pseudovirus and live virus infections of immunized mice [@doi:10.4161/hv.27464]."
3.34 Line 448: Hepatitis B, pertussis and HPV
The text has been modified to read: "However, protein subunit vaccines do play a role in public health and have contributed to vaccination against hepatitis B [@doi:10/d4g86c] and pertussis [@doi:10.1128/mBio.01339-14; @doi:10.1371/journal.ppat.1003418] since the 1980s and human papillomavirus since 2006 [@doi:10.1188/06.CJON.559-560]. They are likely to continue to contribute to public health for the foreseeable future due to ongoing research in vaccines against influenza, SARS-CoV-2, Epstein-Barr virus, dengue virus, and human papillomavirus among others [@doi:10.1016/j.micinf.2014.12.006; @url:https://covid19.trackvaccines.org/vaccines; @doi:10.1080/21655979.2016.1191707]."
3.35 Lines 471-473: Thermostability only? This sentence has been corrected to mention stability broadly and now reads: "The spike protein is recombinantly expressed in Sf9 insect cells [@doi:10.1038/s41467-020-20653-8], which have previously been used for several other FDA-approved protein therapeutics [@doi:10.1021/acs.iecr.8b00985], and contains mutations in the furin cleavage site (682-RRAR-685 to 682-QQAQ-685) along with two proline substitutions (K986P and V987P) that stabilize the protein [@doi:10.3389/fimmu.2021.660198], including improving thermostability [@doi:10.1038/s41467-020-20653-8]."
3.36 Line 489: Which U.K. trial? Mention above, with the trial This paragraph was confusing and has been restructured in line with the query raised by the reviewer. It now reads: "In a phase III randomized, observer-blinded, placebo-controlled clinical trial in the U.K., 14,039 participants received two 5-μg doses of NVX-CoV2373 or placebo administered 21 days apart in a 1:1 ratio from late September to late November 2020 [@doi:10.1056/nejmoa2107659]. In the phase III trial, the efficacy of Novavax's Nuvaxovid was reported to be 89.7%, with a total of 10 patients developing COVID-19 in the vaccine group versus 96 in the placebo group [@doi:10.1056/NEJMoa2107659]. No hospitalizations or deaths were reported in the vaccine group. An additional phase III randomized, observer-blinded, placebo-controlled trial was conducted in the U.S. and Mexico, enrolling 29,949 participants and administering at least 1 vaccine in a 2:1 ratio from late December 2020 to late February 2021 [@doi:10.1056/NEJMoa2116185]. This trial [@doi:10.1056/NEJMoa2116185] used the same primary endpoints as the initial phase III trial conducted in the U.K. [@doi:10.1056/nejmoa2107659]."
3.37 Lines 490-491: Hospitalizations? Deaths? These outcomes are included in the secondary endpoint associated with severe cases of COVID-19 and were not reported individually in this study. To address this, we have added the following sentence: "Hospitalization and death were not evaluated as individual secondary endpoints, but were instead included in the definition of severe COVID-19; all-cause mortality was comparable between the placebo and treatment conditions [@doi:10.1056/NEJMoa2116185]."
3.38 Lines 510: please, specify the adjuvant. This sentence has been updated to read: "This study reported that when the VLPs were administered with AS03, an oil-in-water emulsion containing α-tocopherol and squalene [@doi:10.1586/erv.11.192], as an adjuvant, the vaccine elicited an nAb response that was significantly (approximately 10 times) higher than that in convalescent sera [@doi:10.1038/s41591-021-01370-1]."
3.39 Line 537: Which "other variants"? Please, specify. In this study, strain determination was based on PCR, rather than sequencing, and strain composition is reported only in terms of B.1.1.7 vs non-B.1.1.7 (based on presence/absence of the 69-70del polymorphism). Therefore, this sentence has been amended to read: "Post hoc analysis in the phase III trial determined that the NovaVax vaccine had an efficacy of 86.3% against the Alpha variant (identified based on the presence/absence of the 69–70del polymorphism) and 96.4% against variants lacking the 69-70del polymorphism [@doi:10.1056/NEJMoa2107659]."
3.40 The authors could consider mentioning the discrepancy between the vaccine Spike and VOC Spike with Nuvaxovid (it is mentioned with Covifenz, albeit making a slightly different point). Section 6.4 has been reframed to discuss that both vaccines were developed based on the index strain and to outline similarities and differences in the data available for these vaccines in different VOC-dominanted environments.
3.41 Line 545: activity against VOC. This change has been made.
3.42 Lines 567-569: Are these values vaccine doses/million population/day? Would it be also (or even, instead) insightful to give doses/million/overall? Otherwise, it reflects the recent vaccination rate and could be affected by a huge number of additional variables. Please, also indicate values for North America, Europe and Australia. This information comes from the New York Times and would be difficult to reanalyze (although we could potentially do a separate analysis based on the OWID data, but it would be less comprehensive given that that source does not include all countries). Therefore, this section has been modified to read: "Latin America leads world vaccination rates with at least 82% of individuals in this region receiving one vaccine dose followed by the U.S. and Canada (81%), Asia-Pacific (81%), Europe (70%), the Middle East (58%), followed by Africa with only 33% by November 2022 [@url:https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html]. It is estimated that only ~25% of individuals in low- and middle-income countries have received one vaccine dose [@url:https://ourworldindata.org/covid-vaccinations; @doi:10.1038/s41562-021-01122-8]."
3.43 Paragraph 582-587: The last sentence is not implied from the previous one directly. Either elaborate on the argumentation or consider rephrasing. There was an omitted word here that made this paragraph unnecessarily confusing. We have corrected this mistake and elaborated on this point as follows: "There is a clear relationship between a country's gross domestic product (GDP) and its access to these cutting-edge types of vaccines (Figure 4). Whole-virus and subunit vaccine development programs are responsible for a much higher percentage of the vaccinated populous in lower-income countries. Therefore, vaccine development programs that utilized established vaccine technologies have played a critical role in providing protection against SARS-CoV at the global level."
3.44 I would recommend briefly addressing the issues of vaccine hesitancy, logistics (such as -80C freezer shortages, geographical barriers) in different countries, as they also affect vaccine equity, independent of collaborations such as COVAX. Also, in addition to focusing on COVAX, I would suggest the authors also explore the benefits that the use of traditional platforms in terms of mitigating the pandemic burden in middle- and low-income countries; could also provide examples. Text addressing these topics has been added to the end of section 7.
3.45 Line 639: This is the first time the authors are comparing mRNA vaccines' efficacy/ effectiveness to the platforms discussed in the text. Not major, but I recommend moving this in previous sections and briefly revisiting in the Conclusion. The authors could also consider mentioning the bias involved in comparing vaccines head-to-head. A paragraph addressing this point has now been added. It reads: "Overall, the vaccine landscape remains heterogeneous even as the pandemic nears its third year, with certain vaccines much more accessible in high-income countries than in low- and middle-income countries. The vaccines described in this manuscript, which were developed using well-established technologies, have played a crucial role in improving the feasibility and accessibility of vaccination programs worldwide. While the novel technologies have received the bulk of public attention in countries like the U.S., these more traditional vaccine platforms also provide safe and highly effective protection against SARS-CoV-2. Although companies developing cutting-edge technologies, namely Moderna and Pfizer/BioNTech, reported very high efficacies greater than 90% in their clinical trials [@individual-vaccines-novel], the efficacies identified in whole-virus and subunit trials have also been very high. While the clinical trial efficacy estimates for IWV and subunit have been lower, some of these trials have also reported efficacies over 80% (e.g., Novavax's Nuvaxovid, 89% [cite]; CoronaVac 83.5% [cite]). Variation among studies investigating the efficacy of these vaccines, especially CoronaVac, clearly indicate that clinical trials of the same vaccine might not identify the same efficacy, depending on conditions such as the specific variants circulating in a clinical trial population during the trial period. Additionally, there are many cohort- and population-level characteristics that can introduce bias to clinical trials [@doi:10.1016/j.vaccine.2021.05.099] and the extent to which these different factors are present may influence trial outcomes. While head-to-head comparisons of VE across different studies may therefore not be appropriate, the results make it clear that effective vaccines have been developed with a wide variety of technologies. The vaccines discussed here, which took advantage of well-established approaches, have proven to be especially valuable in pursuing vaccine equity."
3.46 Figure 4: Does the Y axis represent total vaccine doses administered per country? If so, the authors could consider plotting doses/million population. Otherwise, the administered doses could reflect population size and this population might in reality be more/less %covered by vaccination/vaccine doses... Also, which countries/regions are included? The y-axis represents the total vaccine doses within each category administered by country. This data is taken from OWID, and specifically the "total_vaccinations" column described here: https://github.com/owid/covid-19-data/tree/master/public/data/vaccinations
We agree that the y-axis must be considered in the context of population size. However, the x-axis (GDP) must also be considered in terms of population size, as a small country with a GDP of $X and a population of 1M is functionally much wealthier than a large country with a GDP of $X and a population of 100M. Therefore, we suggest that these two denominators (functionally) cancel each other out.
The countries and regions included are those that report their data to OWID. This data is available here: https://github.com/owid/covid-19-data/blob/master/public/data/vaccinations/locations.csv
Based on the above feedback, we have modified the legend to read: "The total number of doses distributed within each country as of {{owid_most_recent_date}}, by platform type, is shown as a function of GDP. These data are retrieved from Our World in Data [@url:https://ourworldindata.org/coronavirus; @doi:10.1038/s41562-021-01122-8] and plotted using the Python package plotnine [@url:https://github.com/has2k1/plotnine]. Lines show a general trend in the data and are drawn using geom_smooth [@url:https://ggplot2.tidyverse.org/reference/geom_smooth.html]. The list of countries included in the dataset is available from OWID [@url:https://github.com/owid/covid-19-data/blob/master/public/data/vaccinations/locations.csv]. See https://greenelab.github.io/covid19-review/ for the most recent version of this figure, which is updated daily. Axes are not scaled per capita because both variables should be considered relative to the nation's population size."
RLordan
agitter
Manuscript is accepted in principle, we just need to make these updates!
Reviewer 1:
Reviewer 3:
Reviewer 1 (Comments for the Author):
In this manuscript, the authors provided a thorough review of the two major vaccine technologies- whole virus vaccines and subunit vaccines and their use in the COVID pandemic. This review manuscript is overall comprehensive and is significant to the current situation. Some minor comments have been listed below for the authors to address:
1.1 Lines 56-57: Are these data from the John Hopkins covid-19 tracker (PMID: 32087114)? Please consider including the appropriate reference(s).
1.2 Lines 353-355/Line 358-360: repetitive sentences- both sentences talk about the beta variant being more resistant to nAbs. Please refine the paragraph.
1.3 Lines 427-428: Despite that RBD is absolutely a good vaccine candidate for coronaviruses, authors may need to be very cautious about the statement in Lines 427- 428, i.e., most of the vaccine development efforts for SARS and MERS focused on RBD of the S protein. Many of the cited publications for RBD were published by Du et al., who studied mainly the RBD-based vaccines while there seem to be more groups of scientists who studied the S protein-based vaccine. In fact, the group from the protein science corporation (PMID: 16497416) also used S protein as the vaccine candidate.
1.4 Lines 436-439: the sentence talks about the data for MERS vaccine development. Please move it to the corresponding paragraph.
1.5 Lines 454-455: The authors stated that the subunit vaccines have not played a major role in previous pandemics. When compared to nucleic acid-based vaccines? viral vector vaccines? or LAV and IWV vaccines? Please consider adding the following text "when compared to the LAV and IWV vaccines"
1.6 Sections 6.2 and 6.3 (starting from Line 465): While in section 5.1, authors provided more thorough reviews and went over many different IWV-based COVID-19 vaccines, only two specific subunit vaccines, Nuvaxoid and Covifenz, were mentioned. Please consider including more subunit vaccines in Table 2 in the paragraphs and make them concise, as needed. This change may also impact Section 6.4, so please update Section 6.4 accordingly.
Reviewer 3 (Comments for the Author):
This well-written and comprehensive review manuscript addresses the important topic of inactivated/subunit/VLP COVID-19 vaccines by generally discussing each platform first, then focusing on the most used COVID-19 vaccines employing these platforms - reviewing their efficacy/safety in clinical trials, their real-world effectiveness/safety and application to emerging VoC - and finally, by overviewing global vaccine distribution. The manuscript is very informative and generally well-structured and written. There are several comments/suggestions to be considered. First, I provided general comments that would be recommended to consider throughout. Below are several more detailed comments/recommendations by line, section.
The manuscript is subdivided into sections and sub-sections with headings and subheadings, respectively. Please ensure that the text under each subsection is reflecting the heading/subheading and that the information the reader intuitively seeks for under a specific heading is included in that heading. If such information/data are not or not yet available, I would recommend mentioning the lack of such. For example(s), certain sections such as 6.4 the authors revisit clinical trials of Novavax and do not discuss safety. Please make the distinctions between trials and real-world data clear throughout the manuscript.
As I understood, the authors generally aim to discuss the platform, dose/regimen, clinical trial efficacy and safety data in sections named Application to COVID-19 or ones with vaccine name (Covifenz, Nuvaxovid) and then RW effectiveness, safety and response/implications for VoC under sections named Real-World Safety and Efficacy. I would first suggest using a uniform naming system for different platforms. Some Real-World Safety and Efficacy sections go back to clinical trials and overview VoC, some are entirely dedicated to VoC. You could add VoC to the subheadings or, as with live attenuated vaccines section, have a separate subsection devoted to VoC, as large part of VoC-related text represents immune outcome data, not RWE per se. With, for example, CoronaVac, the real-world data from Chile is addressed in the more general section and not mentioned in the RW Safety and Efficacy section. As above, I would recommend clearly separating the source of data (trial vs real-world). Also, I suggest logically structuring the RW Safety and Efficacy section as follows: first - effectiveness data (or lack of such) shortly following vaccination, over time, as related to boosters, as pertaining to the VoC.
The authors discuss efficacy/effectiveness, side effect profile, sometimes regulatory details for most of the vaccines. Please make sure each of these outcomes are addressed for each vaccine. For example, RW safety and effectiveness information is lacking for IWV vaccines section, while all of them discuss VoC. Similarly, safety and side effect details are not provided for Nuvaxovid, for example. As above, I recommend ensuring the data points given for each platform/vaccine are uniform; separating immune outcome data from the real-world effectiveness; mentioning the lack of data wherever relevant.
As the authors point out in the Introduction, the terms "efficacy" and "effectiveness" have a defined usage. Please make sure this "rule" is followed throughout.
The authors acknowledge the difference between clinical trial efficacy and RW effectiveness. I would recommend also mentioning the cohort differences between trials vs real-world.
When providing percent-efficacy or effectiveness, I recommend to consistently indicate the time period/interval over which the outcome is reported (already included in many cases).
I would suggest using the same naming for vaccines after they (and their alternative names) are first mentioned. For example, Covilo and Sinopharm, CoronaVac and Sinovac are used interchangeably, and it can be confusing for some readers.
The authors could consider updating all time-sensitive data (currently usually "as of August 15") closer to submitting the next draft/publishing.
Please make sure all relevant sentences are followed by a reference, where appropriate, e.g. (not limited to) lines 143, 191, 469.
Line 73: "approaches to [developing] vaccines"
Sentence, lines 103-107: the rapid control of an infectious disease is not an only reason for relatively slower vaccine development against it, sometimes the agents are not controlled per se but still the development/regulatory process has taken longer. The authors could mention the novelty, pandemic spread, scale and respective implications.
Lines 142-143: pathogen-naïve, but against rabies as a disease
Lines 153-154: could include mumps
Line 167: SARS-CoV-2 spike antigen?
Lines 179-180: additional detail (perhaps a sentence or two) about a live chimeric vaccine would be interesting.
Lines 190-191: stronger Ab and cytokine response to what? Spike? N? whole virus?
Line 220: I assume the authors refer to YF-S0* here, not YF-S0.
Line 222: several VOC - which? Also, if same VOC as in the previous sentence, did the animals shed the virus despite not being infected?
Lines 243-244: please define "emerged". For example, China has granted the first EUA for Sinopharm vaccine in July 2020, which is earlier than either of mRNA vaccines were widely distributed. Full authorization almost coincided with Pfizer and Moderna vaccines. Do the authors mean WHO approval? Please, indicate.
Lines 305-308 are identical to lines 324-327, please leave where more appropriate.
Lines 318-321: What about humoral responses?
Section 5.2 could generally benefit from a slight reorganization. Please see comments 1-3.
Lines 347-348: VADE has been an important topic for discussion and speculation during the pandemic. Please elaborate in 1-2 sentences about the reported cases.
Lines 349-351: That is perhaps the limitation of vaccines beyond IWV vaccines.
Lines 349-364: Please, clearly separate the discussion of Sinovac and Covaxin.
Lines 353-355 are identical to lines 358-360, please leave where more appropriate.
Lines 352-353: Please, specify the antigen.
Line 360: Another preprint - which was the other one?
Line 397: Please, specify "several"
Lines 409-411 are identical to lines 415-417, please leave where more appropriate.
Lines 420-421: Adjuvants are always used to increase immunogenicity but are not always immunogens per definition.
Line 425: The authors could mention that Freund's adjuvants are not used in humans.
Line 435: high RBD-specific humoral response?
Line 448: Hepatitis B, pertussis and HPV
Lines 471-473: Thermostability only?
Line 489: Which U.K. trial? Mention above, with the trial
Lines 490-491: Hospitalizations? Deaths?
Lines 510: please, specify the adjuvant.
Line 537: Which "other variants"? Please, specify.
The authors could consider mentioning the discrepancy between the vaccine Spike and VOC Spike with Nuvaxovid (it is mentioned with Covifenz, albeit making a slightly different point).
Line 545: activity against VOC.
Lines 567-569: Are these values vaccine doses/million population/day? Would it be also (or even, instead) insightful to give doses/million/overall? Otherwise, it reflects the recent vaccination rate and could be affected by a huge number of additional variables. Please, also indicate values for North America, Europe and Australia.
Paragraph 582-587: The last sentence is not implied from the previous one directly. Either elaborate on the argumentation or consider rephrasing.
I would recommend briefly addressing the issues of vaccine hesitancy, logistics (such as -80C freezer shortages, geographical barriers) in different countries, as they also affect vaccine equity, independent of collaborations such as COVAX. Also, in addition to focusing on COVAX, I would suggest the authors also explore the benefits that the use of traditional platforms in terms of mitigating the pandemic burden in middle- and low-income countries; could also provide examples.
Line 639: This is the first time the authors are comparing mRNA vaccines' efficacy/ effectiveness to the platforms discussed in the text. Not major, but I recommend moving this in previous sections and briefly revisiting in the Conclusion. The authors could also consider mentioning the bias involved in comparing vaccines head-to-head.
Figure 4: Does the Y axis represent total vaccine doses administered per country? If so, the authors could consider plotting doses/million population. Otherwise, the administered doses could reflect population size and this population might in reality be more/less %covered by vaccination/vaccine doses... Also, which countries/regions are included?