Infants are at high risk for infectious diseases, which account for over one third of deaths in children under 5 years of age1Levels & Trends in Child Mortality Report 2021. United Nations Inter-agency Group for Child Mortality Estimation. https://childmortality.org/wp-content/uploads/2021/12/UNICEF-2021-Child-Mortality-Report.pdf Last accessed on 2/7/2022.Google Scholar. Improving the effectiveness of vaccines, which have limited success in the first weeks of life, is important for better protection of this vulnerable population2Kollmann TR Kampmann B Mazmanian SK Marchant A Levy O Protecting the newborn and young infant from infectious diseases: lessons from immune ontogeny.Immunity. 2017; 46 (1:CAS:528:DC%2BC2sXkvVOitLk%3D, 28329702): 350-36310.1016/j.immuni.2017.03.009Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar. One overlooked avenue to help achieve long-term protection from infectious disease is newborn immunization through breast milk. Here we bring forward a new paradigm where imbibing microbial antigen-containing milk is akin to the process of vaccination, which captures the act of vaccine delivery. Bioactive agents in milk have potential to function as adjuvants, enhancing the infant's immune response against an antigen. The infant's immune response to the human milk containing microbial antigens with adjuvant molecules is the equivalent of immunization, resulting in less susceptibility to disease3Pollard AJ Bijker EM A guide to vaccinology: from basic principles to new developments.Nat. Rev. Immunol. 2021; 21 (1:CAS:528:DC%2BB3cXis1yhur%2FL, 33353987): 83-10010.1038/s41577-020-00479-7Crossref PubMed Scopus (349) Google Scholar. Human milk is known to be the most potent way to prevent respiratory and gastro-intestinal infections4Marchant A et al.Maternal immunisation: collaborating with mother nature.Lancet Infect. Dis. 2017; 17 (28433705): e197-e20810.1016/S1473-3099(17)30229-3Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar. This major impact is attributed to its high content in a wide array of anti-infective compounds such as maternal antibodies, lactoferrin and human milk oligosaccharides. These factors provide invaluable help for the developing immune system and can kill pathogens, inhibit their proliferation or prevent invasion of the mucosa of the breastfed child4Marchant A et al.Maternal immunisation: collaborating with mother nature.Lancet Infect. Dis. 2017; 17 (28433705): e197-e20810.1016/S1473-3099(17)30229-3Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar. In addition to providing short-lived protection, there is evidence that microbial antigens in human milk may represent the optimal characteristics for infant mucosal immunization4Marchant A et al.Maternal immunisation: collaborating with mother nature.Lancet Infect. Dis. 2017; 17 (28433705): e197-e20810.1016/S1473-3099(17)30229-3Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar. More in-depth understanding in this field is key for the prevention of infectious diseases and the development of age-tailored vaccination strategies. The most striking observations of breast milk actively stimulating antigen-specific immune defences are related to maternal HIV infection (reviewed in4Marchant A et al.Maternal immunisation: collaborating with mother nature.Lancet Infect. Dis. 2017; 17 (28433705): e197-e20810.1016/S1473-3099(17)30229-3Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). More than 80% of children that are breastfed by HIV-positive mothers do not acquire HIV, despite ingesting HIV daily for several months to years. Importantly, these uninfected infants secrete HIV-specific IgG and IgA in the intestinal mucosa, demonstrating mucosal immune activation in response to HIV exposure through breast milk. In addition, almost half of them show HIV-specific IFN-γ responses in the blood, which persist after breastfeeding has ceased. These data remarkably illustrate that viral antigens in breast milk can stimulate both mucosal and systemic immunity in children, with an impact beyond the duration of breastfeeding. Supporting evidence for infant immunization through pathogen antigen shedding in breast milk is also found in maternal vaccination studies with live attenuated rubella virus. Rubella antigen is detected in the mother's breast milk and infants born to rubella immunized mothers have rubella-specific IgG in serum and IgA in their nasopharyngeal secretions as well as virus-specific cellular immune reactivity in blood lymphocytes (reviewed in4Marchant A et al.Maternal immunisation: collaborating with mother nature.Lancet Infect. Dis. 2017; 17 (28433705): e197-e20810.1016/S1473-3099(17)30229-3Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). More recently, a study demonstrated development of mucosal immunity to SARS-CoV-2 in newborns breastfed by SARS-CoV-2 infected mothers, without any sign of infection in the offspring5Conti MG et al.Immune response of neonates born to mothers infected with SARS-CoV-2.JAMA Netw. Open. 2021; 4 (8567114, 34730817): e213256310.1001/jamanetworkopen.2021.32563Crossref PubMed Scopus (15) Google Scholar. Parasitic antigens such as from Schistosoma mansoni6Attallah AM Ghanem GE Ismail H El Waseef AM Placental and oral delivery of Schistosoma mansoni antigen from infected mothers to their newborns and children.Am. J. Trop. Med. Hyg. 2003; 68 (12887021): 647-65110.4269/ajtmh.2003.68.647Crossref PubMed Scopus (34) Google Scholar and Plasmodium falciparum7van den Elsen LW Verhasselt V Egwang T Malaria Antigen Shedding in the Breast Milk of Mothers From a Region With Endemic Malaria.JAMA Pediatr. 2020; 174 (6990713, 31904860): 297-29810.1001/jamapediatrics.2019.5209Crossref PubMed Scopus (7) Google Scholar are also present in breast milk of infected women. While currently there is no data from birth cohorts on the possible immunization of children exposed to parasite antigen through breast milk, one study demonstrated better defence against S. mansoni in young adult mice when they had been nursed by S. mansoni-infected mothers8Santos PD et al.Gestation and breastfeeding in schistosomotic mothers differently modulate the immune response of adult offspring to postnatal Schistosoma mansoni infection.Mem. Inst. Oswaldo Cruz. 2016; 111 (4750447, 1:CAS:528:DC%2BC1cXmsVCntL8%3D, 26872339): 83-9210.1590/0074-02760150293Crossref PubMed Scopus (12) Google Scholar. A few studies shed light on the possible ways breast milk vaccination may work and provide the optimal route to activate the newborn's immune system (Fig. 1). The very low amounts of antigens in human milk may fit the specific requirements for activation of the developing immune system. Neonates mount an efficient cytotoxic immune response to a viral dose 10,000 times lower than an adult, while higher doses are unable to activate an appropriate immune response9Macchiaverni P Rekima A van den Elsen L Renz H Verhasselt V Allergen shedding in human milk: Could it be key for immune system education and allergy prevention?.J. Allergy Clin. Immunol. 2021; 148 (1:CAS:528:DC%2BB38XitVSktrg%3D, 34310930): 679-68810.1016/j.jaci.2021.07.012Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar. The levels of P. falciparum antigen histidine-rich protein 2 and hepatitis B e antigen are 10-100-fold lower, and hepatitis B surface antigens are 30,000 times lower in human milk than in serum7van den Elsen LW Verhasselt V Egwang T Malaria Antigen Shedding in the Breast Milk of Mothers From a Region With Endemic Malaria.JAMA Pediatr. 2020; 174 (6990713, 31904860): 297-29810.1001/jamapediatrics.2019.5209Crossref PubMed Scopus (7) Google Scholar10Lin HH Hsu HY Chang MH Chen PJ Chen DS Hepatitis B virus in the colostra of HBeAg-positive carrier mothers.J. Pediatr. Gastroenterol. Nutr. 1993; 17 (1:STN:280:DyaK2c%2Fks1aqsw%3D%3D, 8229550): 207-21010.1097/00005176-199308000-00014Crossref PubMed Scopus (37) Google Scholar. These low levels may be an important cue for the developing immune system of the neonate. Exogenous proteins in human milk are pre-digested within the mammary gland. This process might be key for the generation of immunogenic peptides. As the newborn has only limited digestive abilities, predigesting pathogen-specific proteins in breast milk may be important for the newborn to generate a long-lasting and protective response9Macchiaverni P Rekima A van den Elsen L Renz H Verhasselt V Allergen shedding in human milk: Could it be key for immune system education and allergy prevention?.J. Allergy Clin. Immunol. 2021; 148 (1:CAS:528:DC%2BB38XitVSktrg%3D, 34310930): 679-68810.1016/j.jaci.2021.07.012Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar. The presence of both maternal pathogen-specific antibodies and pathogens in breast milk highly suggests the presence of pathogen antigen-immune complexes. Antigen-IgG antibody immune complexes improve the transport of pathogen across the gut barrier using the neonatal Fc receptor and enhance the stimulation of effector immune responses by antigen-presenting cells9Macchiaverni P Rekima A van den Elsen L Renz H Verhasselt V Allergen shedding in human milk: Could it be key for immune system education and allergy prevention?.J. Allergy Clin. Immunol. 2021; 148 (1:CAS:528:DC%2BB38XitVSktrg%3D, 34310930): 679-68810.1016/j.jaci.2021.07.012Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar. Antigen-presenting cells present in milk might play a role in the induction of a pathogen-specific immune response. Interestingly, the proportion of leucocytes in human milk increases upon maternal infection, which may increase pathogen-derived antigen presentation by milk antigen-presenting cells9Macchiaverni P Rekima A van den Elsen L Renz H Verhasselt V Allergen shedding in human milk: Could it be key for immune system education and allergy prevention?.J. Allergy Clin. Immunol. 2021; 148 (1:CAS:528:DC%2BB38XitVSktrg%3D, 34310930): 679-68810.1016/j.jaci.2021.07.012Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar. Human milk extracellular vesicles also express major histocompatibility complex molecules, which could contribute to the induction of antigen-specific immune responses in breastfed infants9Macchiaverni P Rekima A van den Elsen L Renz H Verhasselt V Allergen shedding in human milk: Could it be key for immune system education and allergy prevention?.J. Allergy Clin. Immunol. 2021; 148 (1:CAS:528:DC%2BB38XitVSktrg%3D, 34310930): 679-68810.1016/j.jaci.2021.07.012Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar. Finally, microbes and microbial antigens in breast milk are surrounded by thousands of immune modulatory factors. The breast milk milieu contains molecules including antibodies and enzymes that can alter, weaken or reduce the viability of microbes present in the milk. This could lead to the generation of live attenuated pathogens that are fit to immunize the infant without infecting them. Among the bioactive compounds in breast milk are also potential strong adjuvants such as cytokines, the milk microbiota, soluble CD14 and Toll-like receptors. The complex and dynamic composition of breast milk may have specifically been selected for and adapted to the newborn's situation, in order to effectively promote immune defence upon microbial antigen transfer in the milk. Rather than merely a potential vehicle for transmission of disease, breast milk likely acts as a route that activates the neonatal immune system to mount a protective, long-lasting response. Very few studies have considered that pathogens and their antigens in human milk may immunise offspring. Further research is required to conclusively establish whether and how human milk from infected or vaccinated mothers can immunise their offspring.