PONE-D-24-47904Longitudinal assessment of COVID-19 vaccine immunogenicity in people with HIV stratified by CD4+ T-cell count in the Netherlands: a two-year follow-up studyPLOS ONE

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This trial was funded by the Dutch Organization for Health Research and Development (ZonMw) [grant number 10430072010008].  

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RDdV is supported by the Health~Holland grant EMCLHS20017, co-funded by the PPP Allowance made available by the Health~Holland, Top Sector Life Sciences & Health, to stimulate public–private partnerships, and is listed as an inventor of the fusion inhibitory lipopeptide [SARSHRC-PEG4]2-chol in a provisional patent application. KSH has received support for attending meetings and travel from Gilead. BJAR declares the receipt of research grants from Gilead and MSD and honoraria for advisory boards from AstraZeneca, Roche, Gilead, and F2G. KB has received research and educational grants from ViiV and Gilead, as well as consulting fees for advisory boards from ViiV, Gilead, MSD, and AstraZeneca. CR has received research grants from ViiV, Gilead, ZonMW, AIDSfonds, Erasmus MC, and Health~Holland, and honoraria for advisory boards from Gilead and ViiV. AR has received grants from the Bill and Melinda Gates Foundation and the Leids Universitair Fonds, participated on the board of an investor-initiated clinical trial on convalescent plasma for COVID-19, and is the chief editor of the Dutch Journal of Infectious Diseases and a member of the European Medicines Agency expert group on vaccines. All other authors declare no competing interests. 

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This study presents a prospective cohort study in adult people with HIV. The primary outcome was the SARS-CoV-2 spike-specific antibody level at 1, 6, 12, 18, and 24 months after completing a primary COVID-19 vaccination series. The authors compared the antibody kinetics over two years between PWH with a baseline CD4+ T-cell count <200 (n=16) vs. ≥200 (n=432) with a mixed-effects model. The authors conclude that long-term humoral responses were lower in PWH with a CD4+ T-cell count <200 compared to those with a CD4+ T-cell count ≥200.

This is a well-written manuscript presenting important data and emphasizing the importance of individual assessment of the need of COVID-19 vaccination among people living with HIV. See my comments below.

Abstract

Q1. Background: I would consider rephrasing the description of guideline recommendations given that both EACS, BHIVA and CDC are quite united in that priority should be giving those with advanced HIV-infection (low CD4 and detectable viral load). See EACS Guidelines 12.0 page 100, BHIVA (https://www.bhiva.org/SARS-CoV-2-vaccine-advice-for-adults-living-with-HIV-update) and CDC (https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html)

Q2. In the method section, lines 30-31, consider including a definition of primary series.

Introduction

Q3. Page 5, lines 51-52: Consider rephrasing. Some studies have shown higher mortality, some have not. Suggest adding references that represents both findings. Example: doi: 10.1097/QAD. 0000000000003129; doi: 10.1111/hiv.13174; doi: 10.1111/hiv.13515.

Q4. Page 5, line 63, first sentence, suggest adding references regarding earlier studies with follow-up.

Q5. Suggest adding a sentence in the Introduction that states current guidelines on vaccination in people with HIV (see examples above). In particular guidelines from the country the study was conducted in.

Method

Q6. Primary outcome is stated as The primary outcome was the level of S1-specific antibodies in PWH at 1, 6, 12, 18, and 24 months after primary vaccination.

Perhaps it should be clarified somehow “primary vaccination including/adjusted for the following boosters”? Because you do in fact account for the boosters?

Q7. In the subheading Clinical procedures, it says that data on comorbidities and co-medications were collected. I suggest presenting this in Table 1 and consider taken this into consideration in the statistical analysis or state why this was not deemed necessary.

Q8.Suggest stating more clearly the definition of Primary series vaccination in the Clinical procedures section where you state the different types of possible primary vaccinations. “Participants received two doses of BNT162b2, mRNA-1273, or ChAdOx1-S, or one dose of Ad26.COV2.S between January and August 2021 according to manufacturer’s regulations as part of the Dutch COVID-19 vaccination campaign”

Q9. In the Statistical analysis you state among variables added to the model “time since the last COVID-19 vaccination dose or last SARS-CoV-2 infection” .I guess this refers to the boosters? Perhaps it would be good to clarify that boosters were considered in the model.

Table 1:

Q10. History of a third SARSCoV-2 infection is marked with a b but it should perhaps be c?

Q11. In the first column, including all PWH, n=448. The sum in the column of “Covid-19 vaccines received” is just 403. Do you have missing data? Suggest updating table 1 so the numbers add up.

Q12. The same goes for History of at least one SARS-CoV-2 infection. The numbers do not add up. Missing data?

Q13. Same for: Dominant variant in the Netherlands at the time of first reported SARS-CoV-2 infection. Missing data?

Results

Q14. Page 15, lines 215-216: “Of these, one participant– a 61-year-old male – was admitted to the intensive care unit. His most recent CD4+ Tcell count was 316 cells per µL, and his nadir CD4+ T-cell count was 50 cells per µL.” This maybe reveals too much information about one patient and could potentially violate his integrity? This needs to be considered through the whole paragraph.

Discussion

Q15. The Discussion is quite short and could benefit from a more elaborate discussion of its findings and how it compares to other studies. For example, you state that this is the only study “this is the first longitudinal study in PWH extending beyond one year of follow-up after COVID-19 vaccination”. What is the follow-up time of the most recent studies?

Q16. Page 16, 222-225; here you conclude lower antibody levels after COVID-19 vaccination, as mentioned in Q9 it could be clearer what you mean by “COVID-19 vaccination”. Primary or primary including/adjusted for boosters?

Q17. You state in line 224 that the booster rates was comparable, but they are quite different in Table 1 between groups (primary + 2 boosters: 26, 7% vs 35,1%)?

Q18.Page 17, lines 249-251, please include references to these section

Limitations:

Q19. Suggest adding to the conclusion that the majority of your sample are men and how that effects generalizability.

Reviewer #2: Dear Dr. Roukens,

I appreciate the opportunity to review this interesting and important article longitudinal assessment of COVID-19 vaccine immunogenicity in people with HIV stratified by CD4+ T-cell count in the Netherlands: a two-year follow-up study. I enjoyed reading the manuscript. I commend the work on several strengths including:

1. Addressing the immunogenicity in PWH with CD4 < 200 and showing that this group needs to be prioritized. This is especially important during an epidemic and in low resource setting where prioritization is important.

2. Large sample size drawn from multiple centers, along with comprehensive follow-up

3. Longitudinal and prospective data collection, for an impressive duration of more than a year.

Considering the strengths of the manuscript, I noted a few areas where additional clarity would enhance its overall impact. Specifically, the paper could be further strengthened by incorporating more detailed information on the following points:

1. If the author could clarify the power calculations to clarify the need to include more participants, and the rationale for the inclusion of participants with a CD4 cell count of <500, along with precautions taken to minimize any potential bias with retrospective inclusion of participants. Furthermore, the inclusion of retrospective participants was not reflected in the figure. We would appreciate more clarification on the inclusion of the participants in the attached figure as well.

2. In the baseline results, there is a mention of a questionnaire, it is the first mention of a it being used in the study and was not mentioned in the methods. Please include it in the methods section as well with details as to how it was administered.

3. In the limitations, if you could also include the retrospective inclusion of participants could influence the results and precautions that were taken.

4. Additionally, if the authors could comment in manuscript, in the group with pre vaccination CD4 of >200, the participants who had a nadir of CD4 < 200 vs. the participants who had a nadir of CD4>200, would benefit from a booster. If it is not possible to calculate, can it be added to the limitations or the discussion (as per author’s discretion).

5. If the authors could clarify what was the cutoff age used to classify “higher age”, as referred to in the manuscript.

Best,

Soahum

Reviewer #3: Overall, I find this article interesting and valuable. The proposed study addresses an important and novel research question. The writing is easy to understand, and the flow of the text is good; the topic is clinically relevant and has ethics committee approval; there are some spelling and grammar errors that need revision.

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Reviewer #1: Yes:  Christina Carlander

Reviewer #2: Yes:  Soahum Bagchi

Reviewer #3: No

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Attachments

Attachment

Submitted filename: PONE-D-24-47904-Nov-16.pdf

Longitudinal assessment of COVID-19 vaccine immunogenicity in people with HIV stratified by CD4+ T-cell count in the Netherlands: a two-year follow-up study

PONE-D-24-47904R1

Dear Dr. Roukens,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Jianhong Zhou

Staff Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: Thank you for adressing the comments and edits.

The paper looks good, I appreciate the opportunity of being a part of this important publication.

Best regards,

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: Yes:  Christina Carlander

Reviewer #2: Yes:  Soahum Bagchi

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