PONE-D-21-10606

Antibody responses induced by trivalent inactivated influenza vaccine among pregnant and non-pregnant women in Thailand: a matched cohort study

PLOS ONE

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5. Review Comments to the Author

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Reviewer #1: This is a carefully done study and the findings are of considerable interest. Findings of this paper suggest that pregnancy did not alter immune responses to trivalent inactivated influenza vaccine (IIV3).

A few minor revisions are listed below.

In this paper, it is written that the highest sero-protection was found against A(H3N2) at 92.6% among vaccinated non-pregnant participants. However, recently lower effectiveness or no effectiveness of inactivated vaccine against A/H3N2 strain is frequently reported. Accordingly, although immune responses of pregnant women are sufficient, actual effectiveness may be low. In the Discussion, authors should explain about this problem, egg-adapted H3N2 vaccine strain problem, although in this study, vaccine effectiveness was not tested.

Skowronski DM, et al. Low 2012-13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PLoS One. 2014;9(3):e92153.

In this paper, authors concluded that seasonal IIV3 was immunogenic against all three vaccine strains and pregnancy did not seem to alter the immune response to the IIV3. And authors wrote that larger cohort studies with supplementary markers of humoral and cellular immunity may be needed.It is right, but in Thailand, I think that vaccine effectiveness study in adults, including pregnant women, is probably more needed, by cohort study or by test-negative study.

Reviewer #2: The authors present results from a matched cohort study in Thailand focused on antibody responses induced by the trivalent influenza vaccine (IIV3) among pregnant and non-pregnant women. They find that vaccinated women (both pregnant and non-pregnant) exhibited stronger antibody responses at 1 month than non-vaccinated women and conclude that pregnancy does not alter the response to the vaccine. The manuscript will be strengthened if the authors consider the following points:

1. More detail should be provided for the multilevel models used for analysis. Presumably a different model (though still within the broader class of multilevel models) was used for seroconversion or seroprotection than for the continuous antibody response variables. Authors should clarify the specific model(s) used, which variables or factors were included, including any interactions of interest, and information about any random effects utilized in the models.

2. Throughout the manuscript (lines 40, 48, 202, 219, 230, 249, 253, 258) authors use "similar" or "comparable" when presenting results with a p-value>0.05. Authors should be careful in their terminology, as a conclusion of not rejecting the null hypothesis (p>0.05) does not mean groups are similar or comparable - this just means there is insufficient evidence in the data to support a hypothesis that they are different. This is especially important given the small sample sizes in the groups. A test to evaluate whether groups are "similar" or "equivalent" is different than one used to evaluate whether groups are different. One possible change would be to replace "similar" or "comparable" with "not significantly different" (or modified appropriately in the context of the sentence).

3. STATA should be changed to Stata (lines 163, 182) - https://www.statalist.org/forums/help#spelling

Reviewer #3: This is an interesting and well-written article describing antibody responses in pregnant and non-pregnant women in rural Thailand. Though studies are sometimes deemed less influential when no differences are found, I believe this study will have an important impact by demonstrating the high antibody titers induced in both pregnant and non-pregnant women.

The authors elaborated on the concerns regarding immunogenicity and clinical correlation on page 16 in the Discussion, but the Introduction includes a sentence that "immunogenicity of influenza vaccine is an important measure of vaccine effectiveness." This statement made me question the results and should be tempered by the later discussion points.

Additionally, I think it is important to recognize that immunogenicity data helps us understand vaccine responses in different populations and may be used for more than physician recommendations.

The Methods section is clear and concise. I appreciated that pregnant participants were matched by age group, gestational age, and week of vaccination to prevent undue influence from these factors. I also valued the contribution of study nurses who were able to travel to participants' homes to obtain blood samples when participants were unable to travel.

The Results section is also clear and easy to follow. I find it very interesting that so few women received influenza vaccine in the previous year, and I think this may at least partially explain the excellent responses to vaccination. The authors do an excellent job of comparing and contrasting these responses to Schlaudecker et al.'s study in the Discussion section. The previous vaccination may be an interesting idea for future research, especially if some of these women end of receiving more influenza vaccines in the future. I also valued the thorough discussion of HI titers and clinical correlation, as this is a growing area of concern. The authors appropriately mention future areas of study, such as neutralization titers and plasmablasts.

All in all, this article makes an important contribution to the understanding of influenza vaccination in pregnant women, which will likely increase in importance as more vaccines are recommended during pregnancy.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Antibody responses induced by trivalent inactivated influenza vaccine among pregnant and non-pregnant women in Thailand: a matched cohort study

PONE-D-21-10606R1

Dear Dr. Shrestha,

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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Kind regards,

Ray Borrow, Ph.D., FRCPath

Academic Editor

PLOS ONE

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