The Fourth Dose of mRNA COVID-19 Vaccine Following 12 Different Three-Dose Regimens: Safety and Immunogenicity to Omicron BA.4/BA.5
, Jira Chansaenroj 1, Nungruthai Suntronwong 1, Suvichada Assawakosri 1,2, Ritthideach Yorsaeng 1, Pornjarim Nilyanimit 1, Ratchadawan Aeemjinda 1, Nongkanok Khanarat 1, Preeyaporn Vichaiwattana 1, Sirapa Klinfueng 1, Thanunrat Thongmee 1, Donchida Srimuan 1, Thaksaporn Thatsanathorn 1, Natthinee Sudhinaraset 1, Nasamon Wanlapakorn 1, Sittisak Honsawek 2,* and Yong Poovorawan 1,3,*Round 1
Reviewer 1 Report
The manuscript “The fourth dose of mRNA COVID-19 vaccine following 12 different three-dose regimens: Safety and immunogenicity to Omicron BA.4/BA.5” assessed actogenicity and immunogenicity of the COVID-19 vaccine. The study is important as the first study to assess safety profile of fourth doses of COVID-19 vaccines in Thailand population.
The work is interesting and precedent, although it is preliminary.
I think it is acceptable after some revision, taking into account the following points.
Minor points:
1. Content in Reference 29 should be an individual section, not part of References section.
Author Response
Response to reviewer 1 comment
Comments and Suggestions for Authors
The manuscript “The fourth dose of mRNA COVID-19 vaccine following 12 different three-dose regimens: Safety and immunogenicity to Omicron BA.4/BA.5” assessed actogenicity and immunogenicity of the COVID-19 vaccine. The study is important as the first study to assess safety profile of fourth doses of COVID-19 vaccines in Thailand population.
The work is interesting and precedent, although it is preliminary.
I think it is acceptable after some revision, taking into account the following points.
Minor points:
- Content in Reference 29 should be an individual section, not part of References section.
Response: We thank the reviewer for the proof. This content was already moved to the next individual section.
Reviewer 2 Report
Kanokudom et al. presented interesting data in comparing immune response between BNT162b2 and mRNA-1273 as a forth dose after mixed immunization of inactivated, vector and mRNA vaccinations in the previous three doses. It is encouraging that the type of previous immunization seemingly does not affcet the immune response elicited by mRNA vaccine as a booster dose.The reviewer finds no major comments but the authors can improve the manuscript according to the minor comments embeded in the pdf.
Comments for author File: 
Comments.pdf
Author Response
Response to reviewer 2 comment
Comments and Suggestions for Authors
Kanokudom et al. presented interesting data in comparing immune response between BNT162b2 and mRNA-1273 as a forth dose after mixed immunization of inactivated, vector and mRNA vaccinations in the previous three doses. It is encouraging that the type of previous immunization seemingly does not affcet the immune response elicited by mRNA vaccine as a booster dose.The reviewer finds no major comments but the authors can improve the manuscript according to the minor comments embeded in the pdf.
- Please clarify when the initial vaccination started in Thailand. (line 44)
Response: In Thailand, the COVID-19 vaccine was initiated since March 2020. This has been clarified.
- Please put pharmaceutical company names and city where the HQ is placed for each of vaccine, such as CoronaVac, BBIBP-CorV or AZD1222 (line 45)
Response: This has been revised accordingly.
- Please put pharmaceutical company names and city where the HQ is placed for each of vaccine,
Also please state this is monovalent or bivalent.
Response: This has been revised accordingly. The word “monovalent” has been addressed in the manuscript (both the abstract and main text).
- Can the authors change the color scheme depending on the manufactures? For example, SV/SV =blue, SV/AZ=green, AZ=yellow, PF=pink, MN=orange, so that the readers can understand the combinations visually (Figure 1)
Response: We would like to appreciate on your suggestion, but we think the use of a colorful scheme might confuse the readers. According to the original Figure 1, we use blue and green colors that already focus to the booster arm which also represent to the BNT162b2 (blue) and mRNA-1273 (green) groups in Fig 2 and 3, respectively. The primary vaccine history seems no affect the immune response elicited by mRNA vaccine as a booster dose. Thus, the figure doesn’t make any change.
- Why the authors used anti-N IgG as a marker for previous infections? Since it is known that anti-N IgG level declines over time after infections, so the false negative increases as time passes. Is there any reliable records or self-reposts for the previous infections? If authors cannot find those records, it should be mentioned in the methods or results.
Also, authors can discuss about it as a limitation. (line126)
Response:
We agreed that anti-N IgG level is not a perfect marker to confirm their history of infection due to the level of anti-N is declined over time pass. The previous study by Movsisyan demonstrated that the anti-N was slightly declined at 7th months, nevertheless, the mean level remains rather high up to 15th month after infection. It is possible to confirm that the detected anti-N IgG in this study represents to the previous infection during the pandemic in Thailand. Additionally, Louche demonstrated that seroconversion (Pos to Neg) of anti-N Ig from convalescent sera was 1.4%/month during 4‒12 months after infection. The seroconversion would be 19% at 2 years
In this study, all participants confirmed that there has never been infected and had the SARS-CoV-2 record following our enrollment criteria. However, we think that some participants might underestimate the SARS-CoV-2 testing caused by asymptomatic infection. Therefore, we used the anti-N IgG as a sero-marker for screening the infection both before (24 pre-existing) and during (8 sero-conversion) the period of this study. The exclusion of screening by anti-N IgG had already been mentioned in 99-102 (Method). After using anti-N as a marker we can exclude approximately 10% of infections and it might help to accurate the immunological data.
Besides, we added a sentence to show that all participants reported no history of infection in the result section (demographic line 165) as the reviewer’ suggestion.
The last, we also added some limitation about anti-N IgG accordingly. (line 323-327)
Key reference:
Mosisyan et al, 2022. Kinetics of anti-nucleocapsid IgG response in COVID-19 immunocompetent convalescent patients (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9297274/)
Louche et al., 2022. Longitudinal SARS-CoV-2 Nucleocapsid Antibody Kinetics, Seroreversion, and Implications for Seroepidemiologic Studies (https://pubmed.ncbi.nlm.nih.gov/35859108/)
- Please briefly explain the neutralizing assay used here.(line 132)
Response: The sVNT was performed according to the manufacturer’s instructions. Briefly explain has been added accordingly in line 137-143.
- I wonder how authors selected the vaccines given to participants? Randomized-blinded manner or open-label? Please clarify. (line 153)
Response: We mention the word “Regrading convenient sampling,….” in 2.1. Study designs and participant enrolment
- Can the authors show NT data against BA4/5 divided by subgroups just like Figure S2?
Is there any difference among subgroups for NT titer against BA4/5? If so, please state about it.
Response: The supplementary Figure S3 (NT of each subgroup) had been added and mentioned in main-text in line 237-240. A small number of participants in some subgroups was not suitable for statistical comparison.
- Is it possible to state as a limitation that the number of each subgroup was small due to complexity of combination in previous vaccinations?
Response: The limitation has been added accordingly.
