Maternal vaccination as an additional approach to improve the protection of the nursling: Anti-infective properties of breast milk

Zheng, Yingying; Correa-Silva, Simone; Palmeira, Patricia; Carneiro-Sampaio, Magda

doi:10.1016/j.clinsp.2022.100093

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Review articles • Clinics 77 • 2022 • https://doi.org/10.1016/j.clinsp.2022.100093 copy

Maternal vaccination as an additional approach to improve the protection of the nursling: Anti-infective properties of breast milk

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Human milk constitutes a secretion with unique functions of both nourishing the nursling and providing protection against enteric and respiratory infections, mainly due to its content of secretory IgA antibodies but also due to the presence of a plethora of bioactive factors. Specific IgA antibodies are produced locally by plasma cells derived from B lymphocytes that migrate from other mucosae to the mammary gland during lactation, particularly from the gastrointestinal and respiratory tracts. Therefore, here, the authors will provide a comprehensive review of the content and functions of different nutritional and bioactive anti-infectious components from breast milk, such as oligosaccharides, lactoferrin, haptocorrin, α-lactalbumin, k-casein, lysozyme, lactoperoxidase, mucin, fatty acids, defensins, cytokines and chemokines, hormones and growth factors, complement proteins, leukocytes and nucleic acids, including microRNAs, among many others, and the induction of antibody responses in breast milk after maternal vaccination with several licensed vaccines, including the anti-SARS-CoV-2 vaccine preparations used worldwide. Currently, in the midst of the pandemic, maternal vaccination has re-emerged as a crucial source of passive immunity to the neonate through the placenta and breastfeeding, considering that maternal vaccination can induce specific antibodies if performed during pregnancy and after delivery. There have been some reports in the literature about milk IgA antibodies induced by bacterial antigens or inactivated virus vaccines, such as anti-diphtheria-tetanus-pertussis, anti-influenza viruses, anti-pneumococcal and meningococcal polysaccharide preparations. Regarding anti-SARS-CoV-2 vaccines, most studies demonstrate elevated levels of specific IgA and IgG antibodies in milk with virus-neutralizing ability after maternal vaccination, which represents an additional approach to improve the protection of the nursling during the entire breastfeeding period.

Keywords:
Maternal immunization; Breast milk; Bioactive factors; Secretory IgA antibodies; Anti-SARS-CoV-2 vaccines

Highlights

Human milk is an essential source of immunonutrients for the nursing infant.
Maternal vaccination provides specific IgA and IgG antibodies in breast milk.
Milk from vaccinated mothers contains anti-SARS-CoV-2 antibodies that may protect the infant.

	Component/Nutrient (Unit)	Colostrum	Transitional milk	Mature Milk	Immune action
Antibodies	Secretory IgA antibody (g/L)²¹21 Lonnerdal B, Erdmann P, Thakkar SK, Sauser J, Destaillats F. Longitudinal evolution of true protein, amino acids and bioactive proteins in breast milk: a developmental perspective. J Nutr Biochem 2017;41:1–11.	5.45	1.5	1.0	Perform “immune exclusion” (bind to bacteria, prevent microbial adhesion and penetration through the epithelium, without triggering inflammatory reactions)⁹9 Palmeira P, Carneiro-Sampaio M. Immunology of breast milk. Rev Assoc Med Bras 2016;62(6):584–93.
	IgM antibody (g/L)³⁴34 Mickleson KN, Moriarty KM. Immunoglobulin levels in human colostrum and milk. J Pediatr Gastroenterol Nutr 1982;1(3):381–4.	1.13	0.15	0.05	Perform “immune exclusion”, has a compensatory activity in IgA-deficient patients⁹9 Palmeira P, Carneiro-Sampaio M. Immunology of breast milk. Rev Assoc Med Bras 2016;62(6):584–93.
	IgG antibody (g/L)³⁴34 Mickleson KN, Moriarty KM. Immunoglobulin levels in human colostrum and milk. J Pediatr Gastroenterol Nutr 1982;1(3):381–4.	0.53	0.04	0.03	Neutralizing and opsonizing activities, complement system activation and antibody-dependent cytotoxicity⁹9 Palmeira P, Carneiro-Sampaio M. Immunology of breast milk. Rev Assoc Med Bras 2016;62(6):584–93.
Carbohydrate	Oligosaccharides (g/L)³⁵35 Gidrewicz DA, Fenton TR. A systematic review and meta-analysis of the nutrient content of preterm and term breast milk. BMC Pediatr 2014;14:216.	16	16	14	Promotes the growth of lactobacilli and bifidobacteria; due to the homology of epithelial cell surface receptors, they inhibit pathogen adhesion to the infant gut³3 Hong DK, Lewis DB. Developmental immunology and role of host defenses in fetal and neonatal susceptibility to infection. In: Wilson CB, Nizet V, Maldonado YA, Remington JS, Klein JO, eds. Remington and Klein’s infectious diseases of the fetus and newborn infant, Philadelphia: Elsevier Saunders; 2016:81–188.
Proteins	Lactoferrin (g/L)¹⁸18 Trend S, Strunk T, Lloyd ML, Kok CH, Metcalfe J, Geddes DT, et al. Levels of innate immune factors in preterm and term mothers' breast milk during the 1st month postpartum. Br J Nutr 2016;115(7):1178–93.	5.71	4.32	3.64	Forms lactoferricin, limiting bacterial growth by removing essential iron; stimulates cytokine production; enhances mucosal immunity, Natural Killer (NK) cell activity and macrophage cytotoxicity; exerts activity against viruses and fungi³⁶36 Lonnerdal B. Nutritional and physiologic significance of human milk proteins. Am J Clin Nutr 2003;77(6):1537S–43S.
	Haptocorrin (g/L)³⁷37 Aoki Y, Kobayashi K, Kajii T. Enzyme-linked immunoassay of haptocorrin: analysis of milk and granulocytes. Biochem Med Metab Biol 1992;47(2):189–94.	4.83±1.23		3.17+1.77	Antibacterial activity and facilitates the uptake of vitamin B12 by the infant’s intestinal cells³⁶36 Lonnerdal B. Nutritional and physiologic significance of human milk proteins. Am J Clin Nutr 2003;77(6):1537S–43S.
	α-Lactalbumin (g/L)³³33 Donovan SM. Human milk proteins: composition and physiological significance. Nestle Nutr Inst Workshop Ser 2019;90:93–101.	4.56±0.41	3.52+0.27	2.85+0.24	Antimicrobial activity and binds to oleic acid to form a compound called HAMLET (a molecular complex that kills tumor cells by a process resembling programmed cell death)⁹9 Palmeira P, Carneiro-Sampaio M. Immunology of breast milk. Rev Assoc Med Bras 2016;62(6):584–93.
	k-Casein (mg/L)³³33 Donovan SM. Human milk proteins: composition and physiological significance. Nestle Nutr Inst Workshop Ser 2019;90:93–101.	860±90	800+100	550+50	Soluble receptor analog with inhibitory activity for adhesion of Helicobacter pylori to the human gastric mucosa³⁶36 Lonnerdal B. Nutritional and physiologic significance of human milk proteins. Am J Clin Nutr 2003;77(6):1537S–43S.
	α1-Antichymotrypsin (mg/L)³⁸38 Lindberg T, Ohlsson K, Weström B. Protease inhibitors and their relation to protease activity in human milk. Pediatr Res 1982;16(6):479–83.	670	95	12	Possible actions in the nursling’s gut: inhibition of DNA polymerase; IL-2 stimulation of T cells; neutrophil superoxide production; chemotaxis³⁹39 Uruena C, Tellería JJ, Blanco-Quirós A, Arranz E, Gomez-Carrasco JA. Alpha-1 anti-chymotrypsin levels are actively increased in normal colostrum. J Pediatr Gastroenterol Nutr 1998;26(4):376–9.
	Osteopontin (mg/L)³³33 Donovan SM. Human milk proteins: composition and physiological significance. Nestle Nutr Inst Workshop Ser 2019;90:93–101.	180±10		138+9	Induces a Th1 response⁴⁰40 Lönnerdal B. Bioactive Proteins in Human Milk-Potential Benefits for Preterm Infants. Clin Perinatol 2017;44(1):179–91.
	Lactoperoxidase (mg/L)⁴¹41 Shin K, Hayasawa H, Lonnerdal B. Purification and quantification of lactoperoxidase in human milk with use of immunoadsorbents with antibodies against recombinant human lactoperoxidase. Am J Clin Nutr 2001;73(5):984–9.			0.77+0.38	Catalyzes the oxidation of thiocyanate from saliva, forming hypothiocyanate, which can kill both grampositive and gram-negative pathogenic bacteria³⁶36 Lonnerdal B. Nutritional and physiologic significance of human milk proteins. Am J Clin Nutr 2003;77(6):1537S–43S.
	Mucin (μg/mL)³⁴34 Mickleson KN, Moriarty KM. Immunoglobulin levels in human colostrum and milk. J Pediatr Gastroenterol Nutr 1982;1(3):381–4.			554+52	Inhibition of enteric bacteria binding to intestinal cells⁹9 Palmeira P, Carneiro-Sampaio M. Immunology of breast milk. Rev Assoc Med Bras 2016;62(6):584–93.
	Bile Salt-Stimulated Lipase (BSSL) (μg/mL)⁴²42 Sha L, Zhou S, Xi Y, Li R, Li X. The level of bile salt-stimulated lipase in the milk of Chinese women and its association with maternal BMI. J Biomed Res 2019;34(2):122–8.	71.49±40.61		236.90+52.75	Binds to DC-SIGN receptor in dendritic cells and prevents its interaction with HIV-1, leading to the blocking of HIV-1 transfection of CD4⁺ T cells⁴³43 Naarding MA, Dirac AM, Ludwig IS, Speijer D, Lindquist S, Vestman EL, et al. Bile salt-stimulated lipase from human milk binds DC-SIGN and inhibits human immunodeficiency virus type 1 transfer to CD4+ T cells. Antimicrob Agents Chemother 2006;50(10):3367–74.
	Lactadherin (µg/mL)⁴⁴44 Peterson JA, Hamosh M, Scallan CD, Ceriani RL, Henderson TR, Mehta NR, et al. Milk fat globule glycoproteins in human milk and in gastric aspirates of mother's milk-fed preterm infants. Pediatr Res 1998;44(4):499–506.		139	66+5	Present in the milk fat globule membrane; binds to human rotavirus, preventing viral attachment to host epithelial cells⁴⁵45 Kvistgaard AS, Pallesen LT, Arias CF, Lopez S, Petersen TE, Heegaard CW, et al. Inhibitory effects of human and bovine milk constituents on rotavirus infections. J Dairy Sci 2004;87(12):4088–96.
	Lysozyme (µg/mL)¹⁸18 Trend S, Strunk T, Lloyd ML, Kok CH, Metcalfe J, Geddes DT, et al. Levels of innate immune factors in preterm and term mothers' breast milk during the 1st month postpartum. Br J Nutr 2016;115(7):1178–93.	81.7	81.9	84.4	Hydrolyzes bacterial walls from gram-positive bacteria and inner proteoglycan matrix in the membranes of gram-negative bacteria³⁶36 Lonnerdal B. Nutritional and physiologic significance of human milk proteins. Am J Clin Nutr 2003;77(6):1537S–43S.
	Soluble CD14 (sCD14) (µg/mL)¹⁸18 Trend S, Strunk T, Lloyd ML, Kok CH, Metcalfe J, Geddes DT, et al. Levels of innate immune factors in preterm and term mothers' breast milk during the 1st month postpartum. Br J Nutr 2016;115(7):1178–93.	40.67	30.80	21.20	Immunomodulatory activity on the immune and inflammatory responses in the infant gut⁹9 Palmeira P, Carneiro-Sampaio M. Immunology of breast milk. Rev Assoc Med Bras 2016;62(6):584–93.
	Trefoil factor 3 (pmoL/L)⁴⁶46 Vestergaard EM, Nexo E, Wendt A, Guthmann F. Trefoil factors inhuman milk. Early Hum Dev 2008;84(10):631–5.	1540	310	80	Downregulates anti-inflammatory cytokines and promotes human β-defensin expression in intestinal epithelial cells⁴⁷47 Barrera GJ, Sanchez G, Gonzalez JE. Trefoil factor 3 isolated from human breast milk downregulates cytokines (IL8 and IL6) and promotes human beta defensin (hBD2 and hBD4) expression in intestinal epithelial cells HT-29. Bosn J Basic Med Sci 2012;12(4):256–64.
	Osteoprotegerin (nM/L)⁴⁸48 Vidal K, van den Broek P, Lorget F, Donnet-Hughes A. Osteoprotegerin in human milk: a potential role in the regulation of bone metabolism and immune development. Pediatr Res 2004;55(6):1001–8.	2.8–40.6	0.7–39.9	2.9–32.1	Binds to TNF-Related Apoptosis-Inducing Ligand (TRAIL) and induces caspase-dependent apoptosis, especially in Th1 cells, regulating the Th1/Th2 balance of the infant immune system⁹9 Palmeira P, Carneiro-Sampaio M. Immunology of breast milk. Rev Assoc Med Bras 2016;62(6):584–93.
Fatty acids	Oleic acid (Omega-9)	35% of total fat⁴⁹49 Zhao P, Zhang S, Liu L, Pang X, Yang Y, Lu J, et al. Differences in the triacylglycerol and fatty acid compositions of human colostrum and mature milk. J Agric Food Chem 2018;66(17):4571–9.		(15.07 mg/g)²⁵25 Dai X, Yuan T, Zhang X, Zhou Q, Bi H, Yu R, et al. Short-chain fatty acid (SCFA) and medium-chain fatty acid (MCFA) concentrations in human milk consumed by infants born at different gestational ages and the variations in concentration during lactation stages. Food Funct 2020;11(2):1869–80.	Stimulates the synthesis of ROS⁵⁰50 Ganapathy S. Long chain polyunsaturated fatty acids and immunity in infants. Indian Pediatr 2009;46(9):785–90.
	LC-PUFA – AA (Omega-6)	26% of total fat⁴⁹49 Zhao P, Zhang S, Liu L, Pang X, Yang Y, Lu J, et al. Differences in the triacylglycerol and fatty acid compositions of human colostrum and mature milk. J Agric Food Chem 2018;66(17):4571–9.		(5.62 mg/g)²⁵25 Dai X, Yuan T, Zhang X, Zhou Q, Bi H, Yu R, et al. Short-chain fatty acid (SCFA) and medium-chain fatty acid (MCFA) concentrations in human milk consumed by infants born at different gestational ages and the variations in concentration during lactation stages. Food Funct 2020;11(2):1869–80.	Precursor of eicosanoids, promotes inflammatory processes by producing prostaglandins and leukotrienes, stimulates synthesis of ROS⁵⁰50 Ganapathy S. Long chain polyunsaturated fatty acids and immunity in infants. Indian Pediatr 2009;46(9):785–90.
	LC-PUFA – EPA/DHA (Omega-3)	0.6% of total fat⁴⁹49 Zhao P, Zhang S, Liu L, Pang X, Yang Y, Lu J, et al. Differences in the triacylglycerol and fatty acid compositions of human colostrum and mature milk. J Agric Food Chem 2018;66(17):4571–9.		(0.89 mg/g)²⁵25 Dai X, Yuan T, Zhang X, Zhou Q, Bi H, Yu R, et al. Short-chain fatty acid (SCFA) and medium-chain fatty acid (MCFA) concentrations in human milk consumed by infants born at different gestational ages and the variations in concentration during lactation stages. Food Funct 2020;11(2):1869–80.	Inhibits the immune response, decreasing monocyte and neutrophil chemotaxis and the production of proinflammatory cytokines⁵⁰50 Ganapathy S. Long chain polyunsaturated fatty acids and immunity in infants. Indian Pediatr 2009;46(9):785–90.
Antimicrobial peptides	β-Defensin 1 (ng/mL)¹⁸18 Trend S, Strunk T, Lloyd ML, Kok CH, Metcalfe J, Geddes DT, et al. Levels of innate immune factors in preterm and term mothers' breast milk during the 1st month postpartum. Br J Nutr 2016;115(7):1178–93.	110.9	185.4	66.9	Promotes monocyte-derived dendritic cell maturation and inhibits their apoptosis; promotes neonatal CD4 T-cell proliferation and activation⁵¹51 Wu J, Gong RL, Hu QF, Chen XT, Zhao W, Chen TX. Immunoregulatory effect of human β-defensin 1 on neonatal cord blood monocyte-derived dendritic cells and T cells. Mol Immunol 2019;109:99–107.
	β-Defensin 2 (ng/mL)¹⁸18 Trend S, Strunk T, Lloyd ML, Kok CH, Metcalfe J, Geddes DT, et al. Levels of innate immune factors in preterm and term mothers' breast milk during the 1st month postpartum. Br J Nutr 2016;115(7):1178–93.	745.6	397.5	197.8	Antimicrobial activity against a range of bacteria, including common pathogens that cause infant diarrhea and gram-negative nosocomial bacteria⁵²52 Baricelli J, Rocafull MA, Vazquez D, Bastidas B, Báez-Ramirez E, Thomas LE. β-defensin-2 in breast milk displays a broad antimicrobial activity against pathogenic bacteria. J Pediatr (Rio J) 2015;91(1):36–43.
	α-Defensin-5 (pg/mL)¹⁸18 Trend S, Strunk T, Lloyd ML, Kok CH, Metcalfe J, Geddes DT, et al. Levels of innate immune factors in preterm and term mothers' breast milk during the 1st month postpartum. Br J Nutr 2016;115(7):1178–93.	78.13	78.13	78.13	Protects against gastrointestinal and systemic infections and participates in the development of the mucosal immune system; possible inhibitory effect against SARS-CoV-2⁵³53 Li D, Chen P, Shi T, Mehmood A, Qiu J. HD5 and LL-37 Inhibit SARS-CoV and SARS-CoV-2 Binding to Human ACE2 by Molecular Simulation. Interdiscip Sci 2021;13 (4):766–77.,⁵⁴54 Armogida SA, Yannaras NM, Melton AL, Srivastava MD. Identification and quantification of innate immune system mediators in human breast milk. Allergy Asthma Proc 2004;25(5):297–304.
	Cathelicidin-derived antimicrobial peptide (LL37) (pg/mL)¹⁸18 Trend S, Strunk T, Lloyd ML, Kok CH, Metcalfe J, Geddes DT, et al. Levels of innate immune factors in preterm and term mothers' breast milk during the 1st month postpartum. Br J Nutr 2016;115(7):1178–93.	390.63	390.63	390.63	Antibacterial activity against both gram-positive and gram-negative bacteria; possible inhibitory effect against SARS-CoV-2⁵³53 Li D, Chen P, Shi T, Mehmood A, Qiu J. HD5 and LL-37 Inhibit SARS-CoV and SARS-CoV-2 Binding to Human ACE2 by Molecular Simulation. Interdiscip Sci 2021;13 (4):766–77.,⁵⁵55 Niyonsaba F, Iwabuchi K, Someya A, Hirata M, Matsuda H, Ogawa H, et al. A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology 2002;106(1):20–6.
Nonproteins	Nucleotide (µmoL/L)⁵⁶56 Hodgkinson A, Wall C, Wang W, Szeto IM, Ye W, Day L. Nucleotides: an updated review of their concentration in breast milk. Nutr Res 2021;99:13–24.	16.7–292.0	16.6–208.1	10.2–240.0	Modulation of lymphocyte and NK-cell maturation, activation and proliferation, and immunoglobulin production; reduces enterobacteria and increases bifidobacterial counts in the fecal microbiota⁹9 Palmeira P, Carneiro-Sampaio M. Immunology of breast milk. Rev Assoc Med Bras 2016;62(6):584–93.
	miRNA (miRNA-Let-7a, miRNA-30B and miRNA-378, respectively) (Log10 2^−ΔΔCt)⁵⁷57 Xi Y, Jiang X, Li R, Chen M, Song W, Li X. The levels of human milk microRNAs and their association with maternal weight characteristics. Eur J Clin Nutr 2016;70(4):445–9.	2.58±0.67, 4.05±0.61 and 4.64±0.69		2.39±0.62, 4.92±0.57 and 3.62±0.77	Regulation of development of monocyte and Treg cells; differentiation and maturation of B and T cells; proliferation of granulocytes⁵⁸58 Carrillo-Lozano E, Sebastian-Valles F, Knott-Torcal C. Circulating microRNAs in breast milk and their potential impact on the infant. Nutrients 2020;12(10):3066.

Author, year and country	Vaccine type	Pathogen analyzed/ Disease	Specific IgA^a a Comparison of specific IgA/SIgA or IgG levels in breast milk between vaccinated and non-vaccinated mothers. (↑) Higher level was found in breast milk from vaccinated women compared to non-vaccinated ones. (=) No differences were found between vaccinated and non-vaccinated women. NE, Not Evaluated.	Specific IgG^a a Comparison of specific IgA/SIgA or IgG levels in breast milk between vaccinated and non-vaccinated mothers. (↑) Higher level was found in breast milk from vaccinated women compared to non-vaccinated ones. (=) No differences were found between vaccinated and non-vaccinated women. NE, Not Evaluated.
Shahid et al. (2002) Bangladesh¹¹²112 Shahid NS, Steinhoff MC, Roy E, Begum T, Thompson CM, Siber GR. Placental and breast transfer of antibodies after maternal immunization with polysaccharide meningococcal vaccine: a randomized, controlled evaluation. Vaccine 2002;20(17-18):2404–9.	Meningococcal vaccine – polysaccharide from groups A, C, Y and W-135 (Menomune®, Sanofi Pasteur Inc., Swiftwater, PA)	Neisseria meningitidis/Sepsis and meningitis	↑	NE
Shahid et al. (1995) Bangladesh¹¹³113 Shahid NS, Steinhoff MC, Hoque SS, Begum T, Thompson C, Siber GR. Serum, breast milk, and infant antibody after maternal immunisation with pneumococcal vaccine. Lancet 1995;346(8985):1252–7.	23-valent pneumococcal polysaccharide vaccine (Pnu-Immune 23®, Lederle-Praxis Biologicals, Pearl River, NY)	Pneumococcus serotypes 6B and 19F/Pneumonia, meningitis, otitis media, sinusitis, and sepsis	↑	NE
Munoz et al. (2001) USA¹¹⁴114 Munoz FM, Englund JA, Cheesman CC, Maccato ML, Pinell PM, Nahm MH, et al. Maternal immunization with pneumococcal polysaccharide vaccine in the third trimester of gestation. Vaccine 2001;20(5-6):826–37.	23-valent pneumococcal vaccine (Pneumovax23®; Merck and Co. Inc., West Point, PA)	Pneumococcus serotypes 6B, 14, 19F and 23F	↑	↑
Lehmann et al. (2003) Papua New Guinean¹¹⁵115 Lehmann D, Pomat WS, Riley ID, Alpers MP. Studies of maternal immunisation with pneumococcal polysaccharide vaccine in Papua New Guinea. Vaccine 2003;21(24):3446–50.	23-valent pneumococcal polysaccharide vaccine (Pneumovax II; Pasteur Mérieux, Lyon, France)	Pneumococcus serotypes 5, 7F, 14 and 23F	↑	NE
Obaro et al. (2004) Gambian¹¹⁶116 Obaro SK, Deubzer HE, Newman VO, Adegbola RA, Greenwood BM, Henderson DC. Serotype-specific pneumococcal antibodies in breast milk of Gambian women immunized with a pneumococcal polysaccharide vaccine during pregnancy. Pediatr Infect Dis J 2004;23(11):1023–9.	23-valent pneumococcal polysaccharide vaccine (Pneumovax II; Pasteur Mérieux, Lyon, France)	Pneumococcus serotypes 4, 6B, 14, 19F and 23F	↑ SIgA	NE
Deubzer et al. (2004) Gambian¹¹⁷117 Deubzer HE, Obaro SK, Newman VO, Adegbola RA, Greenwood BM, Henderson DC. Colostrum obtained from women vaccinated with pneumococcal vaccine during pregnancy inhibits epithelial adhesion of Streptococcus pneumoniae. J Infect Dis 2004;190(10):1758–61.	Polyvalent pneumococcal polysaccharide vaccine (Pneumovax II; Pasteur Mérieux, Lyon, France)	Pneumococcus serotypes 6B and 14	↑ SIgA ↑ avidity and inhibition of pneumococcus adhesion to epithelial cells	NE
Schlaudecker et al. (2013) Bangladesh¹¹⁸118 Schlaudecker EP, Steinhoff MC, Omer SB, McNeal MM, Roy E, Arifeen SE, et al. IgA and neutralizing antibodies to influenza a virus in human milk: a randomized trial of antenatal influenza immunization. PLoS One 2013;8(8):e70867.	Inactivated influenza virus vaccine (Fluarix; GSK Biologicals, Rixensart, Belgium)	Influenza A/New Caledonia (H1N1), A/Fujian (H3N2), and B/Hong Kong/ Flu	↑ IgA and virus neutralization	NE
Abu Raya et al. (2014) Israel¹¹⁹119 Abu Raya B, Srugo I, Kessel A, Peterman M, Bader D, Peri R, et al. The induction of breast milk pertussis specific antibodies following gestational tetanus-diphtheria-acellular pertussis vaccination. Vaccine 2014;32(43):5632–7.	Tdap (Boostrix; GSK Biologicals, Rixensart, Belgium)	Pertussis toxin, filamentous hemagglutinin, and pertactin/ Whooping cough	↑	↑
Lima et al. (2019) Brazil¹²⁰120 Lima L, Molina MDGF, Pereira BS, Nadaf MLA, Nadaf MIV, TakanoOA, etal. Acquisition of specific antibodies and their influence on cell-mediated immune response in neonatal cord blood after maternal pertussis vaccination during pregnancy. Vaccine 2019;37(19):2569–79.	Tdap vaccine (Boostrix; GSK Biologicals, Rixensart, Belgium)	Pertussis toxin and whole cell B. pertussis	=	NE
Orije et al. (2021) Belgium¹²¹121 Orije MRP, Larivière Y, Herzog SA, Mahieu LM, Van Damme P, Leuridan E, et al. Breast milk antibody levels in Tdap-vaccinated women after preterm delivery. Clin Infect Dis 2021;73(6):e1305–e13.	Pertussis-containing vaccine (Tdap, Boostrix, GSK Biologicals)	Pertussis toxin	=	t

Authors/Year (Country)	Vaccine type	Sample	Specific IgA	Specific IgG
Calil et al. (2021) (Brazil)¹⁵⁴154 Calil VMLT, Palmeira P, Zheng Y, Krebs VLJ, Carvalho WB, Carneiro-Sampaio M. CoronaVac can induce the production of anti-SARS-CoV-2 IgA antibodies in human milk. Clinics (Sao Paulo) 2021;76:e3185.	CoronaVac (Sinovac Biotech Ltd., China and Butanta Institute, Brazil)	n (n = 20) Milk samples collected before and at eight additional timepoints after	↑ (anti-S1 SARS-CoV-2 IgA)	NE
Valcarce et al. (2021) (USA)¹⁵⁵155 Valcarce V, Stafford LS, Neu J, Cacho N, Parker L, Mueller M, et al. Detection of SARS-CoV-2-specific IgA in the human milk of COVID-19 vaccinated lactating health care workers. Breastfeed Med 2021;16(12):1004–9.	BNT162b2 (BioNTech/Pfizer) mRNA-1273 (Moderna/NIH)	(n = 21) Plasma and milk samples collected before and at two timepoints after	↑ (anti-SARS-CoV-2 IgA)	↑ (anti-SARS-CoV-2 IgG)
Lechosa-Muñiz et al. (2021) (Spain)¹⁵⁶156 Lechosa-Muniz C, Paz-Zulueta M, Mendez-Legaza JM, Irure-Ventura J, Cuesta Gonzalez R, Calvo Montes J, et al. Induction of SARS-CoV-2-specific IgG and IgA in serum and milk with different SARS-CoV-2 vaccines in breastfeeding women: a cross-sectional study in Northern Spain. Int J Environ Res Public Health 2021;18(16):8831.	1. mRNA vaccine (Moderna) 2. ChAdOx1-S (Astrazeneca) 3. BNT162b2 (Pfizer-BioNTech)	(n = 110) Blood and milk samples collected after the second vaccine dose	1- ↑ 2 - Slightly increased 3 - ↑ (Anti-S1 IgA)	1- ↑ 2 - Slightly increased 3 - ↑ (Anti-S1 IgG)
Juncker et al. (2021) (Netherlands)¹⁵⁷157 Juncker HG, Mulleners SJ, van Gils MJ, de Groot CJM, Pajkrt D, Korosi A, et al. The levels of SARS-CoV-2 specific antibodies in human milk following vaccination. J Hum Lact 2021;37(3):477–84.	BNT162b2 (BioNTech/Pfizer)	(n = 26) Milk samples collected before and at seven time-points after	↑ (Anti-S1 IgA)	↑ (Anti-S1 IgG)
Baird et al. (2021) (USA)¹⁵⁸158 Baird JK, Jensen SM, Urba WJ, Fox BA, Baird JR. SARS-CoV-2 antibodies detected in mother's milk post-vaccination. J Hum Lact 2021;37(3):492–8.	BNT162b2 (BioNTech/Pfizer) mRNA-1273 (Moderna/NIH)	(n = 7) Milk samples collected before and at eleven additional timepoints after	↑ (Anti-S1 IgA and Anti-RBD IgA)	↑ (Anti-S1 IgG and Anti-RBD IgG)
Selma-Royo et al. (2021) (Spain)¹⁵⁹159 Selma-Royo M, Bäuerl C, Mena-Tudela D, Aguilar-Camprubí L, Pérez-Cano FJ, Parra-Llorca A, et al. 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. MedR-xiv 2021 https://doi:10.1101/2021.05.20.21257512. https://doi:10.1101/2021.05.20.21257512...	1. BNT162b2 (BioNTech/Pfizer) and mRNA-1273 (Moderna/NIH)	(n = 75) Milk samples collected before and at six timepoints after	↑ (Anti-RBD IgA)	↑ (Anti-RBD IgG)
Perl et al. (2020) (Israel)¹⁶⁰160 Perl SH, Uzan-Yulzari A, Klainer H, Asiskovich L, Youngster M, Rinott E, et al. SARS-CoV-2-specific antibodies in breast milk after COVID-19 vaccination of breastfeeding women. JAMA2021;325(19):2013–4.	2. ChAdOx1 nCoV-19 (Oxford/AstraZeneca) BNT162b2 (Pfizer-BioNTech)	(n = 84) Milk samples collected before and at six timepoints after	↑ (Anti-S1 IgA)	↑ (Anti-S1 IgG)
Gray et al. (2021) (USA)¹⁴⁶146 Gray KJ, Bordt EA, Atyeo C, Deriso E, Akinwunmi B, Young N, et al. Coronavirus disease 2019 vaccine response in pregnant and lactating women: a cohort study. Am J Obstet Gynecol 2021;225(3). 303.e1-.e17.	1. BNT162b2 (Pfizer/BioNTech) 2. mRNA-1273 (Moderna/NIH)	(n = 31) Blood and milk samples collected before and at two timepoints after	↑ (Anti-S1 IgA and Anti-RBD IgA)	↑ (Anti-S1 IgG and Anti-RBD IgG)
Sadiq et al. (2021) (Pakistan)¹⁶¹161 Sadiq S, Arslan F. Detection of SARS-CoV-2 IgG antibodies in breast milk and serum of immunized lactating mothers. Adv Lab Med/Avances en Medicina de Laboratorio.; 2021 https://doi:10.1515/almed-2021-0077. https://doi:10.1515/almed-2021-0077...	Sinovac or Sino Pharm (Sinovac Biotech Ltd., China)	(n = 180) Blood and milk samples collected before the 1^st and after the 2^nd dose	↑ (Anti-S1 IgA)	NE
Low et al. (2021) (Singapore)¹⁶²162 Low JM, Gu Y, Ng MSF, Amin Z, Lee LY, Ng YPM, et al. Codominant IgG and IgA expression with minimal vaccine mRNA in milk of BNT162b2 vaccinees. NPJ Vaccines 2021;6(1):105.	BNT162b2 (Pfizer/BioNtech)	(n = 14) Milk samples collected before and at four timepoints after	↑ (Anti-S1 IgA and Anti-RBD IgA)	↑ (Anti-S1 IgG and Anti-RBD IgG)
Narayanaswamy et al. (2022) (USA)¹⁵¹151 Narayanaswamy V, Pentecost BT, Schoen CN, Alfandari D, Schneider SS, Baker R, et al. Neutralizing antibodies and cytokines in breast milk after coronavirus disease 2019 (COVID-19) mRNA vaccination. Obstet Gynecol 2022;139(2):181–91.	BNT162b2 (BioNTech/Pfizer) mRNA-1273 (Moderna/NIH)	(n = 30) Milk samples collected at 2 timepoints before 1^st vaccine dose and at 11‒15 timepoints over 42‒48 days	↑ (Anti-RBD IgA) Anti-S and anti-RBD IgA neutralizing antibodies	↑ (Anti-RBD IgG) Anti-RBD IgG neutralizing antibodies
Yeo et al. (2022) (Singapore)¹⁵²152 Yeo KT, Chia WN, Tan CW, Ong C, Yeo JG, Zhang J, et al. Neutralizing activity and SARS-CoV-2 vaccine mRNA persistence in serum and breastmilk after BNT162b2 vaccination in lactating women. Front Immunol 2021;12:783975.	BNT162b2 vaccine (Pfizer/BioNTech)	(n = 35) Milk samples across 21 days after the second dose	↑ (Anti-RBD IgA and IgM) Neutralizing antibodies	↑ (Anti-RBD IgG1) Neutralizing antibodies
Perez et al. (2022) (USA)¹⁵³153 Perez SE, Luna Centeno LD, Cheng WA, Marentes Ruiz CJ, Lee Y, Congrave-Wilson Z, et al. Human milk SARS-CoV-2 antibodies up to 6 months after vaccination. Pediatrics 2022;149(2):e2021054260.	1. BNT162b2 (Pfizer/BioNTech) 2. mRNA-1273 (Moderna/NIH)	(n = 30) Milk samples across 1.3 and 6 months after the second dose	↑ (Anti-RBD IgA) Neutralizing antibodies	↑ (Anti-RBD IgG1) Neutralizing antibodies with greater activity than IgA

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[1] *Corresponding author: Magda Carneiro-Sampaio Department of Pediatrics, Faculdade de Medicina, Universidade de São Paulo. Av. Dr. Enéas Carvalho de Aguiar, 647 - Instituto da Crianca - CEP: 05403-900, São Paulo, SP, Brazil - Tel/Fax: 55-11- 2661-8790 (magdascs@usp.br) E-mail addresses: yingying.zheng@usp.br (Y. Zheng), simonecs@alumni.usp.br (S. Correa-Silva), patricia.palmeira@hc.fm.usp.br (P. Palmeira), magdascs@usp.br (M. Carneiro-Sampaio).