Anti-SARS-CoV-2 IgA and IgG in human milk after vaccination is dependent on vaccine type and previous SARS-CoV-2 exposure: a longitudinal study

  1. Marta Selma-Royo
  2. Christine Bäuerl
  3. Desirée Mena-Tudela
  4. Laia Aguilar-Camprubí
  5. Francisco J. Pérez-Cano
  6. Anna Parra-Llorca
  7. Carles Lerin
  8. Cecilia Martínez-Costa
  9. Maria Carmen Collado

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Abstract

Background

Breast milk is a vehicle to transfer protective antibodies from the lactating mother to the neonate. After SARS-CoV-2 infection, virus-specific IgA and IgG have been identified in breast milk, however, there are limited data on the impact of different COVID-19 vaccine types in lactating women. This study is aimed to evaluate the time course of induction of SARS-CoV-2-specific IgA and IgG in breast milk after vaccination.

Methods

In this prospective observational study in Spain, 86 lactating women from priority groups receiving the vaccination against SARS-CoV-2 were included. Breast milk samples were collected longitudinally at seven or eight-time points (depending on vaccine type). A group with confirmed SARS-CoV-2 infection ( n =19) and a group of women from pre-pandemic time ( n =20) were included for comparison.

Results

Eighty-six vaccinated lactating women [mean age, 34.6 ± 3.7 years] of whom 96% were Caucasian and 92% were healthcare workers. A total number of 582 milk samples were included, and vaccine distribution was BioNTech/Pfizer (BNT162b2, n =34), Moderna (mRNA-1273, n =20), and AstraZeneca (ChAdOx1 nCoV-19, n =32). For each vaccine, 7 and 8 longitudinal time points were collected from baseline up to 30 days after the second dose for mRNA vaccines and adenovirus-vectored vaccines, respectively. A strong reactivity was observed for IgG and IgA after vaccination mainly after the 2 nd dose. The presence and persistence of specific SARS-CoV-2 antibodies in breast milk were dependent on the vaccine type, with higher IgG and IgA levels in mRNA-based vaccines when compared to AstraZeneca, and on previous virus exposure. High intra- and inter-variability were observed, being relevant for IgA antibodies. In milk from vaccinated women, anti-SARS-CoV-2 IgG was significantly higher while IgA levels were lower than in milk from COVID-19-infected women. Women with previous COVID-19 increased their IgG antibodies levels after the first dose to a similar level observed in vaccinated women after the second dose.

Conclusions

COVID-19 vaccination induced anti-SARS-CoV-2 IgA and IgG in breast milk with higher levels after the 2 nd dose. Levels of anti-SARS-CoV-2 IgA and IgG are dependent on the vaccine type. Further studies are warranted to demonstrate the protective antibody effect against COVID-19 in infants from vaccinated and infected mothers.

Trial registration

NCT04751734 (date of registration is on February 12, 2021)

Article activity feed

  1. Version published to 10.1186/s13073-022-01043-9
  2. NCRC

    Our take

    This observational study of 75 lactating women in Spain, available as a preprint and thus not yet peer-reviewed, showed that vaccine type (Pfizer, Moderna or Astra-Zeneca) and previous SARS-CoV-2 infection both affect levels of SARS-CoV-2 specific IgG and IgA antibodies present in breastmilk. These results indicate the need for further study to see if these breastmilk antibodies could provide protection against COVID-19 to infants of vaccinated mothers via breastfeeding.

    Study design

    prospective-cohort

    Study population and setting

    This study was a prospective, observational study conducted in Spain from January through April of 2021. 75 lactating women who were in high-priority groups for vaccination participated. 19 of these women were confirmed to have had past SARS-CoV-2 infection. Participants had either received the Pfizer mRNA vaccine, the Moderna mRNA vaccine, or the Oxford/AstraZeneca adenoviral-vectored vaccine. Breastmilk samples were collected at seven time points: pre-vaccination (0 weeks), 1 week, 2 weeks, and 3 weeks following the first dose. For the two mRNA vaccines, samples were also collected 1 week, 2 weeks, and 3-4 weeks following the second dose. 13 pre-pandemic breastmilk samples were also included in the analysis. SARS-CoV-2 S protein RBD specific IgG and IgA antibodies were measured in the breastmilk samples.

    Summary of main findings

    The authors of this study found that SARS-CoV-2 specific antibodies in the breast milk were dependent on vaccine type and previous exposure to the virus. There was a significant increase in IgG and IgA antibodies after vaccination, especially after the second dose of the mRNA vaccines studied here. Levels were higher compared to the pre-pandemic breastmilk samples. While IgG levels increased even further after a second dose of vaccine, IgA levels did not increase further. No major differences were found between the two mRNA vaccines. IgG levels increased in the breastmilk of women who had previously been infected increased after the first dose of vaccine in a similar manner to the way they would increase after a second dose of vaccine in an uninfected person. IgG levels were higher in the milk of vaccinated women compared to naturally infected women, while the opposite trend was found for IgA. Finally, anti-SARS-CoV-2 IgG antibodies persisted in the breastmilk by the final time point of the study, while IgA antibody levels decreased by 3-4 weeks after the second dose, with only 50-60% of samples testing positive for it by the final time point.

    Study strengths

    Since lactating women were not included in vaccine trials, limited data is available about the vaccine in this group. Therefore, this study provides some important and novel information. The study is the first of its kind to investigate the effect of multiple different vaccines on antibody levels in breastmilk. Additionally, this study compared samples from vaccinated lactating women to pre-pandemic breastmilk samples, as well as samples from women naturally infected with SARS-CoV-2.

    Limitations

    The population included in this study was not very diverse, with over 95% of participants being white. The average age of participants was 34.9 +/- 3.9 years, and therefore few very young or old mothers were included, and age may affect the results. The study was of short duration, and longer-term samples will need to be collected in order to better study the persistence of the antibody response. Importantly, no data was collected after the second dose of the Oxford/AstraZeneca adenoviral-vectored vaccine. Therefore, comparisons cannot be made regarding the second dose of all three vaccines included in this study. Finally, no functional assays were performed in order to measure neutralizing activity of the antibodies found in the breastmilk samples.

    Value added

    Investigating the effect of COVID-19 vaccination type and previous SARS-CoV-2 infection status on the duration and levels of SARS-CoV-2 specific antibodies in breastmilk.

  3. ScreenIT

    SciScore for 10.1101/2021.05.20.21257512: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: Participants received information and written consent was obtained before enrollment.
    IRB: All procedures were in accordance with the ethical standards approved by the Ethical Committee of the Hospital Clínico Universitario (Ref. 2020/133), the Institut de Recerca Sant Joan de Déu (Ref. PIC-94-21), and CSIC (Ref. 061/2021).
    Sex as a biological variableStudy population and design: This is a prospective observational, longitudinal, and multicenter study in lactating women receiving vaccination against SARS-CoV-2 infection in Spain (ClinicalTrials.gov Identifier: NCT04751734).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line AuthenticationAuthentication: Women were excluded if cessation of breastfeeding and/or vaccine side-effects required specific treatment and/or hospitalization.

    Table 2: Resources

    Antibodies
    SentencesResources
    Detection of specific SARS-CoV-2-antibodies in breast milk: Antibodies against the receptor-binding domain (RBD) SARS-CoV-2 S protein were determined as previously described14. 1:4 diluted samples were incubated for 2 h in 1 % (w/v) milk powder and SARS-Cov-2 antibodies were detected using anti-human IgA (α-chain-specific) HRP antibody (Thermo-Fisher Scientific; A18781; 1:6.000) and anti-human IgG (Fc specific) HRP antibody (Sigma-Aldrich; A0170; 1:4.000).
    SARS-Cov-2
    suggested: None
    anti-human IgA
    suggested: (Thermo Fisher Scientific Cat# A18781, RRID:AB_2535558)
    α-chain-specific) HRP
    suggested: None
    anti-human IgG
    suggested: (Sigma-Aldrich Cat# A0170, RRID:AB_257868)
    Software and Algorithms
    SentencesResources
    Participants received either two doses of mRNA vaccines (BNT162b2 mRNA, BioNTech/Pfizer and mRNA-1273, Moderna) or just one dose of adenovirus-vectored vaccine (ChAdOx1 nCoV-19, Oxford/AstraZeneca).
    BioNTech/Pfizer
    suggested: None
    Detection of specific SARS-CoV-2-antibodies in breast milk: Antibodies against the receptor-binding domain (RBD) SARS-CoV-2 S protein were determined as previously described14. 1:4 diluted samples were incubated for 2 h in 1 % (w/v) milk powder and SARS-Cov-2 antibodies were detected using anti-human IgA (α-chain-specific) HRP antibody (Thermo-Fisher Scientific; A18781; 1:6.000) and anti-human IgG (Fc specific) HRP antibody (Sigma-Aldrich; A0170; 1:4.000).
    Thermo-Fisher Scientific
    suggested: None
    Statistical analysis: GraphPad Prism 8.4.3 was used for the statistical analysis.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04751734Enrolling by invitationImpact of Maternal COVID-19 Vaccines on Breast Milk
    NCT04768244RecruitingImpact of Maternal COVID-19 Disease on Breast Milk and Infan…
    NCT03552939CompletedThe Impact of Maternal Microbes on Infant Health Programming

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  4. Version published to 10.1101/2021.05.20.21257512v1 on medRxiv