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Human Milk Antibodies Against Covid: Potent and Persistent

    mother, baby, infant, human, milk, breastfeeding, antibodies, breast milk

    Written by: Lauren Milligan Newmark, Ph.D. | Issue # 117 | 2023

    • Mammal mothers pass on antibodies in milk that are specific to pathogens they encounter during their lifetime.  
    • COVID-19 infection and mRNA vaccination for SARS-CoV-2 in pregnant or lactating human mothers both result in the production of milk antibodies specific to and able to neutralize the SARS-CoV-2 virus.
    • The response to vaccine is dominated by IgG antibodies and is short-lived, whereas the response to infection is dominated by sIgA and can last up to a year, if not longer.

    As the COVID-19 pandemic enters its fourth year and Americans line up to receive the third formulation of the SARS-CoV-2 mRNA vaccine [1], there is one group that should be right at the front. “The lactating population should be first in line to get the vaccine,” explains milk immunologist Dr. Rebecca Powell, Assistant Professor in the Icahn School of Medicine at Mount Sinai. “Even if the mothers don’t think they need it, they should get vaccinated for the protective effect it has on their baby.”

    The protective effect Powell refers to is passive immunity—the maternal transfer of pathogen-specific antibodies to the fetus via the placenta and to infants in human milk. Human infants are born with immature and naïve immune systems and first encounters with pathogens can be challenging for even fully-developed immune systems—something many people experienced with the novel SARS-CoV-2 virus. These encounters would be even more difficult for an infant with a reduced capacity to make antibodies and other important immune cells. The transfer of maternal antibodies specific to pathogens the infant is most likely to encounter is an evolved mechanism that protects infants from infection while their own immune systems are still developing. 

    Powell has been studying the maternal transfer of antibodies directed at SARS-CoV-2 in human milk since the start of the pandemic and was one of the first to report the presence of SARS-CoV-2-reactive milk antibodies from mothers who had previously tested positive for COVID-19 [2, 3]. Powell’s advice for lactating people to get vaccinated is based on a growing body of research [4-10], including data from her own lab, that indicates SARS-CoV-2 mRNA vaccination while pregnant or nursing results in a robust milk antibody response. Passive immunity may have evolved to protect infants from pathogens that had previously infected their mother, but because vaccines were designed to mimic infection, they can also increase pathogen-specific milk antibodies (an immunological two for one!). 

    SARS-CoV-2 Milk Antibodies are Potent

    Maternal COVID mRNA vaccination produces a strong response from immunoglobulin G (IgG) and, to a lesser extent, IgA in the milk [4-11]. Both types of milk antibodies have demonstrated neutralization capabilities against SARS-CoV-2, suggesting protective effects for infants who would otherwise have no level of defense [4-11]. IgG and IgA are common antibodies in the bloodstream and their increase in milk after vaccination can be explained by the intramuscular delivery of the COVID mRNA vaccines. Muscle tissue is highly vascular, which means that the antigen contained in the vaccine—in this case, an mRNA sequence that codes for part of the spike protein that surrounds the virus—is quickly moved into circulation and detected by the immune system. Levels of milk IgG and IgA specific to the spike protein mirror serum levels (or systemic immunity), peaking in the weeks following vaccination and then waning over time [4-11]. This is why lactating individuals that have previously received a vaccine are urged to get their booster—keeping milk antibody levels high provides better protection for infants. 

    Unlike vaccines, SARS-CoV-2 does not take an intramuscular route and instead infects mucosal surfaces such as the nose, throat, and lungs. As a result, the milk antibody response to infection looks very different than the vaccine-specific antibody response. “COVID-19 affects the immune system like other respiratory viruses that promote a classic milk response to mucosal infections,” explains Powell.

    This “classic” response includes the production of secretory IgA (sIgA) as the predominant antibody in milk, with little IgG. Milk IgA that originates from serum is monomeric (i.e., made up of just one IgA molecule). In contrast, milk sIgA is manufactured in the mammary gland; two IgA molecules are attached by a joining chain and then combined with a secretory component. Rather than pulling IgA molecules from the circulation, the IgA that eventually become milk sIgA are derived from special antibody-producing cells in the mother’s gut called GALT (gut associated lymphoid tissue). Human milk sIgA is the main responding factor in the nursing infant’s mucosal immune system; the secretory component protects the antibody from enzymatic degradation, allowing sIgA to thrive in areas where other antibodies might not survive, including the gastrointestinal tract [3, 11-13].  

    Over the last three years, Powell and colleagues [2, 3, 13] have demonstrated that COVID-19 infection among lactating individuals almost universally results in the production of potent antibodies that target the very areas that SARS-CoV-2 is known to infect. COVID-19-positive mothers were found to produce milk with high levels of sIgA specific to the SARS-CoV-2 spike protein and the levels of these antibodies in their milk were correlated with effective neutralization [2, 3, 13]. Even more impressive, the mammary gland continued to produce these virus-neutralizing, spike-specific sIgA well after mothers had recovered from their COVID-19 infection.

    SARS-CoV-2 Milk Antibodies are Persistent

    Powell’s lab started collecting milk samples from mothers that recovered from COVID-19 at the start of the pandemic (spring 2020) and continued collection as mothers continued to produce milk. They found that despite decreases in serum levels of sIgA and other antibodies after infection, milk sIgA levels were durable across lactation [2, 3, 13]. 

    “My suspicion, based on the literature, is that there are long-lived B cells in the gut and these cells continue to produce antibodies even after they start waning in the serum,” says Powell. “I don’t think COVID-19 is unique in eliciting this long-lived antibody response, this is just part of our evolved response to mucosal infections.”

    Just how long lived might these antibodies be? In a new paper [13], Powell’s lab reports that milk sIgA specific to SARS-CoV-2 spike protein were present at significant levels in 94% of samples for 9–12 months after infection. Because they had been following the same group of mothers, they knew none of the mothers included in the study were reinfected with COVID-19 and none of the mothers had been vaccinated for COVID-19. Moreover, the novelty of SARS-CoV-2 to humans meant that no one in the study group had previous exposure. And, just to be sure these weren’t antibodies that were commonly found in human milk, Powell’s team used milk samples that were collected for other studies prior to the pandemic as a control [2, 3, 13]. “We are able to show that these [sIgA] antibodies are definitely from the initial COVID infection and not just there by chance,” says Powell. “I didn’t expect it to be so long lasting. This is the most important thing we’ve shown in our work.”

    Despite finding that natural immunity from COVID-19 infection has the potential to produce a more robust and durable milk immune response than COVID-19 vaccination, Powell still recommends that pregnant or lactating mothers get vaccinated. The risks of COVID-19 infection, particularly in pregnant women who have reduced lung capacity and are immuno-compromised, are just too great and vaccination does provide a robust antibody response, just not the same type of antibodies for the same duration. The mRNA vaccines were not designed with the milk immune response in mind; indeed, lactating people were excluded from any clinical trials. Powell hopes that this will change. 

    “The goal of my lab’s work is to design vaccines targeted to the lactating population that will also produce an ideal response to protect infants,” explains Powell. “The ideal response would be long-lived, neutralizing sIgA because we have evolved to produce this antibody class to protect nursing infants.”

    To get such a response, however, might require a different mode of delivery from the usual intramuscular route or alterations to the current formulation. But a new study [7] looked at how the current vaccine could be optimized for lactating people by changing the timing of inoculation. Sixty-two Israeli women were given their second dose of the Pfizer mRNA vaccine (BNT162b2) during either their second or third trimester of pregnancy. Vaccination during the third trimester resulted in the expected milk vaccine-specific antibody response, high IgG and lower IgA [7]. However, vaccination during the second trimester had the opposite result, higher IgA and lower IgG. There was also greater persistence of IgA antibodies with second trimester vaccination than is usually observed after mRNA vaccination [7]. 

    Although these results seem to suggest that it might be possible to mimic the milk immune response to COVID-19 infection by targeting vaccination to a certain time frame during pregnancy, there are two important caveats. First, the study measured total IgA and the assays did not distinguish between IgA and sIgA. Second, the investigators did not control for asymptomatic COVID-19 infection across their cohort meaning they cannot say with certainty that the effect they measured is solely due to the timing of the vaccine. Hopefully, future studies will overcome these limitations and provide guidance to help pregnant mothers optimize protection for their infants through vaccination. “Vaccine design should absolutely consider the lactating population,” says Powell. 

    References

    1. U.S. Food and Drug Administration. (2023, September 11). FDA takes action on updated mRNA covid-19 vaccines to better protect against currently circulating variants [Press release]. https://www.fda.gov/news-events/press-announcements/fda-takes-action-updated-mrna-covid-19-vaccines-better-protect-against-currently-circulating variants
    2. Fox A, Marino J, Amanat F, Krammer F, Hahn-Holbrook J, Zolla-Pazner S, Powell RL. Evidence of a significant secretory-IgA-dominant SARS-CoV-2 immune response in human milk following recovery from COVID-19. MedRxiv. 2020 May 8: 2020-05.
    3. Fox A, Marino J, Amanat F, Krammer F, Hahn-Holbrook J, Zolla-Pazner S, Powell RL. Robust and specific secretory IgA against SARS-CoV-2 detected in human milk. Iscience. 2020 Nov 20; 23(11).
    4. Gray KJ, Bordt EA, Atyeo C, Deriso E, Akinwunmi B, Young N, Baez AM, Shook LL, Cvrk D, James K, De Guzman R. 2021. COVID-19 vaccine response in pregnant and lactating women: a cohort study.
    5. Golan Y, Prahl M, Cassidy A, Wu AH, Jigmeddagva U, Lin CY, Gonzalez VJ, Basilio E, Warrier L, Buarpung S, Asiodu IV. Immune response during lactation after anti-SARS-CoV2 mRNA vaccine. medRxiv. 2021 Mar 12: 2021-03.
    6. Young BE, Seppo AE, Diaz N, Rosen-Carole C, Nowak-Wegrzyn A, Vasquez JM, Ferri-Huerta R, Nguyen-Contant P, Fitzgerald T, Sangster MY, Topham DJ. Association of human milk antibody induction, persistence, and neutralizing capacity with SARS-CoV-2 infection vs mRNA vaccination. JAMA Pediatrics. 2022 Feb 1;176(2): 159-68.
    7. Kigel A, Vanetik S, Mangel L, Friedman G, Nozik C, Terracina C, Taussig D, Dror Y, Samra H, Mandel D, Lubetzky R. Maternal immunization during the second trimester with BNT162b2 mRNA vaccine induces a tobust IgA tesponse in human milk: a prospective cohort study. The American Journal of Clinical Nutrition. 2023 Sep 1;118(3): 572-8.
    8. Dimitroglou M, Sokou R, Iacovidou N, Pouliakis A, Kafalidis G, Boutsikou T, Iliodromiti Z. Anti-SARS-CoV-2 immunoglobulins in human milk after coronavirus disease or vaccination—time frame and duration of detection in human milk and factors that affect their titers: a systematic review. Nutrients. 2023 Apr 14;15(8): 1905.
    9. Baird JK, Jensen SM, Urba WJ, Fox BA, Baird JR. SARS-CoV-2 antibodies detected in human breast milk post-vaccination. MedRxiv. 2021 Mar 2: 2021-02.
    10. Esteve-Palau E, Gonzalez-Cuevas A, Guerrero ME, Garcia-Terol C, Alvarez MC, Casadevall D, Diaz-Brito V. Quantification of specific antibodies against SARS-CoV-2 in breast milk of lactating women vaccinated with an mRNA vaccine. JAMA Network Open. 2021 Aug 2;4(8): e2120575.
    11. Pieri M, Maniori MA, Shahabian L, Kanaan E, Paphiti-Demetriou I, Pipis S, Felekkis K, Nicolaidou V, Papaneophytou C. Survival of vaccine-induced human milk SARS-CoV-2 IgG, IgA and SIgA immunoglobulins across simulated human infant gastrointestinal digestion. Nutrients. 2022 Aug 17;14(16): 3368.
    12. Donald K, Petersen C, Turvey SE, Finlay BB, Azad MB. Secretory IgA: Linking microbes, maternal health, and infant health through human milk. Cell Host & Microbe. 2022 May 11;30(5): 650-9.
    13. Yang X, Fox A, DeCarlo C, Pineda N, Powell RL. The secretory IgA response in human milk against the SARS-CoV-2 spike is highly durable and neutralizing for at least 1 year of lactation postinfection. Breastfeeding Medicine. 2023 Aug 1;18(8): 602-11.