Review 1: "The Spike-specific IgA in milk commonly-elicited after SARS-Cov-2 infection is concurrent with a robust secretory antibody response, exhibits neutralization potency strongly correlated with IgA binding, and is highly durable over time"

Talat Kilic

doi:doi:10.1162/2e3983f5.75432552

This study finds SARS-CoV-2 infection elicits a SARS-CoV-2 IgA Ab response detectable in breastmilk and these antibodies demonstrate neutralizing activity against SARS-CoV-2. Reviewers deem these findings reliable but request more detailed descriptions of the study design.

by Talat Kilic

Published onMay 21, 2021

The Spike-specific IgA in milk commonly-elicited after SARS-Cov-2 infection is concurrent with a robust secretory antibody response, exhibits neutralization potency strongly correlated with IgA binding, and is highly durable over time

by Alisa Fox, Jessica Marino, Fatima Amanat, Kasopefoluwa Oguntuyo, Jennifer Hahn-Holbrook, Benhur Lee, Florian Krammer, Susan Zolla-Pazner, and Rebecca L. Powell

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Published on Mar 20, 2021
www.medrxiv.org

Description

Abstract Approximately 10% of infants will experience COVID-19 illness requiring advanced care (1). A potential mechanism to protect this population could be provided by passive immunity through the milk of a previously infected mother. We and others have reported on the presence of SARS-CoV-2-specific antibodies in human milk (2-5). We now report the prevalence of SARS-CoV-2 IgA in the milk of 75 COVID-19-recovered participants, and find that 88% of samples are positive for Spike-specific IgA. In a subset of these samples, 95% exhibited robust IgA activity as determined by endpoint binding titer, with 50% considered high-titer. These IgA positive specimens were also positive for Spike-specific antibodies bearing the secretory component. Levels of IgA antibodies and antibodies bearing secretory component were shown to be strongly positively correlated. The secretory IgA response was dominant among the milk samples tested compared to the IgG response, which was present in 75% of samples and found to be of high-titer in only 13% of cases. Our IgA durability analysis using 28 paired samples, obtained 4-6 weeks and 4-10 months after infection, found that all samples exhibited persistently significant Spike-specific IgA, with 43% of donors exhibiting increasing IgA titers over time. Finally, COVID-19 and pre-pandemic control milk samples were tested for the presence of neutralizing antibodies; 6 of 8 COVID-19 samples exhibited neutralization of Spike-pseudotyped VSV (IC50 range, 2.39 – 89.4ug/mL) compared to 1 of 8 controls. IgA binding and neutralization capacities were found to be strongly positively correlated. These data are highly relevant to public health, not only in terms of the protective capacity of these antibodies for breastfed infants, but also for the potential use of such antibodies as a COVID-19 therapeutic, given that secretory IgA is highly stable not only in milk and the infant mouth and gut, but in all mucosa including the gastrointestinal tract, upper airway, and lungs (6).

RR:C19 Evidence Scale rating by reviewer:

Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

This manuscript reports data regarding “The Spike-specific IgA in milk commonly-elicited after SARS-Cov-2 infection is concurrent with a robust secretory antibody response, exhibits neutralization potency strongly correlated with IgA binding, and is highly durable over time.” It is interesting and timely work and, indeed, covers a topic that can be useful in clinical practice. This is apparently a well-conducted study. The design seems adequate and the collection of data sufficient to demonstrate the author´s point. However, there is a number of problems that should be addressed by the authors. After these minor revisions, the article will be more clear and readable.

These problems:

1- There has been some evidence that SARS-CoV-2 RNA was detected in human milk. I recommend that the authors cite the following article in their manuscript on this subject.

-Kilic T, Kilic S, Berber NK, Gunduz A, Ersoy Y. Investigation of SARS-CoV-2 RNA in milk produced by women with COVID-19 and follow-up of their infants: A preliminary study. Int J Clin Pract. 2021;00:e14175. https:// doi.org/10.1111/ijcp.14175

2- How many of the mothers whose milk samples were examined breastfed their babies for 4-6 weeks and 4-10 months after infection? During this time, have any of the breastfed babies caught COVID-19? The answers to these questions are extremely important. The authors should specify if they have this information for the mother and baby.

3- How was milk obtained from women? For instance, were manual or electric breast pumps used? Please specify.

4- Are the test methods the authors use for antibody detection validated for human milk? Please specify.

5- The authors should be detailed in the last paragraph of the conclusion section to elaborate on their important conclusion(s) and detail the potential avenues for further research.

Review 1: "The Spike-specific IgA in milk commonly-elicited after SARS-Cov-2 infection is concurrent with a robust secretory antibody response, exhibits neutralization potency strongly correlated with IgA binding, and is highly durable over time"

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