To obtain definitive information regarding the transmission risks of SARS-CoV-2 through breast milk, we summarized the detection results of human breast milk and infants in Table 1 (Chambers et al., 2020; Fenizia et al., 2020; Gao et al., 2020; Sahin et al., 2020; Bertino et al., 2020; Liu et al., 2020; Sahin et al., 2021; Chen et al., 2020; Kunjumon et al., 2021; Kilic et al., 2021). Among the 285 breast milk samples from SARS-CoV-2 positive mothers, only 9 had SARS-CoV-2 RNA detected. Importantly, the virus culture in one of the RT-PCR positive samples was negative, indicating that it might not be replication-competent live virus that being discovered. Moreover, 279 nasopharyngeal swabs were performed in infants, with only 15 positive results for SARS-CoV-2 (Table 1). Therefore, we speculate that the virus was primarily transmitted through respiratory droplets and contact routes. Therefore, breastfeeding has a low risk of transmitting SARS-CoV-2 and it can be continued under prudent precautions.

Low et al. (2021a) detected a very low level of vaccine mRNA using phenol-chloroform extraction, the gold standard for RNA extraction and double quencher qPCR probes (Low et al., 2021a). However, the discrepancies in the sensitivity of the detection method would lead to different test results. In most cases, vaccine mRNA was not detected in milk samples after vaccination (Golan et al., 2021a; Golan et al., 2021b). Notably, even if a low level of vaccine mRNA was detected, it was expected to be easily destroyed by enzymes in the infant’s gut. At the same time, although allergic reactions have been reported in a few cases, no significant levels of PEG were found in breast milk after vaccination (Golan et al., 2021c). Nevertheless, lots of people are panicking about the lack of data on adverse effects of breastfeeding mothers and infants.

To explore the safety of vaccination during breastfeeding, we conducted literature review using keywords “SARS-CoV-2, lactation, breast milk, breastfed, breastfeeding, mRNA vaccine” in Pubmed, Science Direct and Google Scholar database, and made Table 2 to summarize the symptoms of breastfeeding women who received the COVID-19 mRNA vaccine (Pfizer or Moderna) and adverse events in their children (Perl et al., 2021; McLaurin-Jiang et al., 2021; Low et al., 2021a; Golan et al., 2021c; Gray et al., 2021; Jakuszko et al., 2021; Low et al., 2021b; Selma-Royo et al., 2021; Lechosa-Muñiz et al., 2021; Low et al., 2021c). In terms of the symptoms in mothers after vaccination, following Dose 1, the frequency of specific symptoms such as pain, redness, joint or muscle pain at the injection site was not differed by vaccine brands. Following Dose 2, women who received the Moderna brand vaccines were significantly more prone to experience chills, muscle/body pain, fever, and vomiting than received the Pfizer vaccine brand. Meanwhile, allergic reactions were less common in patients treated with the second dose of any COVID-19 vaccine, which is likely because an allergic reaction to the first dose led to a contraindication to receiving a subsequent dose. Furthermore, the incidences of mastitis after the first and second doses of vaccination were lower than or close to the 2.5% to 20% estimated by global mastitis epidemiology (Table 2). It was worth mentioning that the milk production of most mothers did not change after vaccination, with only a small number of mothers experiencing a mild increase or decrease in milk supply (Table 2), and all cases returned to normal within 72 h after receiving the vaccine without any intervention. Interestingly, one mother reported that her color of breast milk turned bluish-green within 24 h after receiving the first dose of the Pfizer vaccine, but the alteration might be attributed to maternal dietary changes rather than vaccination as it did not recur after the second dose vaccination (Low et al., 2021c). Additionally, the children whose mothers were vaccinated with either brand or either dose had almost no serious adverse events, and only a few cases had one or more symptoms (Table 2). Mothers who received a second vaccine dose were more likely to perceive some symptoms in their breastfed children, including irritability, lack of sleep, and restlessness. However, most of these symptoms disappeared up to 72 h after vaccination (Golan et al., 2021c). Four infants had fever at 7, 12, 15, and 20 days after maternal vaccination. Except for one infant who was admitted to the hospital for neonatal fever evaluation and received antibiotic treatment, all infants recovered on their own (Perl et al., 2021). Overall, no mothers or infants showed any serious adverse symptoms after vaccination. These results support the safety of vaccination during breastfeeding.

Infection or exposure to SARS-CoV-2 can cause the production of anti-SARS-CoV-2 Abs in human milk. On one hand, sIgA has been shown to be the main form of receptor-binding domain-specific IgA in milk samples obtained from COVID-19 patients and recovered donors (Fox et al., 2020). It can prevent adhesion to target epithelial cells through binding to the SARS-CoV-2 nucleocapsid protein or neutralization of the spike protein, and thereby provide a potential protective effect against gastrointestinal infection in the infant. Of note is that the specificity of sIgA is determined by the maternal immune response to prior infection and this may explain the low infection rate or milder symptoms of the infants who were breastfed by SARS-CoV-2-infected mothers. On another hand, IgM and IgG are less in human milk samples collected (Table 1), but these two Abs have known immune-surveillance properties. IgG not only plays an anti-inflammatory role, but also prevents infection at the intestinal level. High-avidity IgM Abs can act as an essential part of protecting the infant’s mucosal surfaces from bacteria and viruses. In addition, because the capillary bed connects gastrointestinal system with the circulatory and lymphatic systems, the lacteal lymphatic capillary located in intestinal villi of the small intestine may absorb and transport breast milk Abs to the respiratory system, thereby providing respiratory protection for newborns (Demers-Mathieu et al., 2021a). By the way, it has been reported that SARS-CoV-2-spiked donor milk samples have no cytopathic activity after pasteurization (Unger et al., 2020). Further, some have suggested that breast milk should be pasteurized. However, due to the heat load of milk exposure, Holder pasteurization can affect the immune protection provided by breast milk and reduce the immunological and biological value. Mothers should be supported and encouraged to offer fresh breast milk to their infants under the premise of applying appropriate hygiene measures.

After the 1st dose of COVID 19 mRNA vaccine, maternal plasma IgG and IgM Abs increased significantly, and the IgG level after the 2nd dose has been proven to increase by 6-fold (Golan et al., 2021c), which indicates the importance of the 2nd dose enhancing the antibody response. Besides, the antibody response was highly synchronized between serum and breast milk (Friedman et al., 2021). A large number of anti-SARS-CoV-2 IgA and IgG Abs were detected in breast milk beginning at Day 7 after the initial dose, and anti-SARS-CoV-2 IgG dominated (Baird et al., 2021). As we all know, IgG in breast milk has been shown to play a critical role in neonatal immunity against several other viral pathogens, including human immunodeficiency virus, influenza and respiratory syncytial virus (Fouda et al., 2011; Mazur et al., 2019; Demers-Mathieu et al., 2021b). By the way, the levels of Abs produced in breast milk after COVID-19 mRNA vaccination were significantly higher than those in the natural infection or convalescent period (Low et al., 2021a). Thus, even for lactating women who are naturally infected with COVID-19, vaccination may be helpful to induce and promote the transfer of anti-SARS-CoV-2 Abs in breast milk, as these protective Abs acquired after infection will weaken over time. Interestingly, unlike the significant anti-SARS-CoV-2 sIgA levels detected in breast milk after previous infections (Fox et al., 2020), only a few post-vaccination (mRNA-1273 and BNT162b2) milk samples contain spike-specific secretions and the titer is very low (Fox et al., 2021). It is mainly because the intramuscular (IM) vaccination may not elicit a robust sIgA response. Besides, although plasma levels of anti-SARS-CoV-2 IgG, IgM and IgA were not detectable in infants after maternal vaccination during lactation, breastmilk anti-SARS-CoV-2 IgA and IgG survived gastric digestion (Pieri et al., 2021), and notably, anti-SARS-CoV-2 IgG was detected in infant stool samples collected 4 and 8 weeks post maternal vaccine and were correlated with maternal milk anti-SARS-CoV-2 IgG levels (Golan et al., 2021c). Thus, milk-derived Abs might persist and provide mucosal immunity in the infant gastrointestinal tract.

By the way, spike-reactive T cells were also detected in the breast milk of vaccinated mothers (Gonçalves et al., 2021). The frequency seems low, but a suckling infant ingests a lot of milk daily, which implies the ingestion of quantities of spike-reactive T cells. As milk lymphocytes are capable of withstanding the gastric environment, infiltrating the gut mucosa, entering blood circulation and being distributed into infant tissues, further studies are needed to investigate whether milk transferred spike-reactive T cells could mediate protection against viral infection in the infant upper respiratory tract and gut.

Many bioactive molecules (such as LF, breast milk oligosaccharides, lactadherin, anti-protease and antioxidant factors, etc.) could provide passive protection to the baby. Among them, LF is widely distributed in milk, colostrum and most exocrine secretions that bathe mucosal surfaces. Recently, it has been considered to be one of the bioactive inhibitors for SARS-CoV-2 (Mattar et al., 2021) and causes extensive research. Naidu et al. (2020) suggested LF’s charge neutralization ability may also act as blocking viral adhesion to the proteoglycan-rich host cell surface (Naidu et al., 2020). Moreover, the interaction between the virus and the host can be interfered by it without internalization in the cell, which is especially effective in the throat, salivary glands, and upper respiratory tract in the early expansion phase of the virus. For example, heparan sulfate proteoglycans (HSPGs) have been proved to be a necessary co-factor for SARS-CoV-2 infection and promote specific attachment to ACE2 receptors and the internalization of the virion (Hu et al., 2021). LF can bind to them on the cell surface and prevent infection by blocking the interaction between SARS-CoV-2 and HSPGs. Besides, LF could also selectively inhibit cathepsin L, a lysosomal peptidase critical for endocytosis and a cell entry pathway used by SARS-CoV-2.

In addition to the interaction with host cells, LF can also modulate the immune response. On one hand, oral administration can improve the generation of CD+3, CD+4, and CD+8 lymphocytes population, and enhance T cell cytotoxic activities, natural killer cell cytotoxicity, and serum cytokine levels (Kawakami et al., 2015). On the other hand, excessive inflammation could be suppressed by LF. As well known, the virus could cause the propagation of the pro-inflammatory state, and LF in breast milk not only to promote the differentiation of CD4+ T cells into Th1 cells to block many inflammatory cytokines such as IL-1β, IL-6 and TNF-α, but also to stimulate pro-inflammatory macrophages to shift toward anti-inflammatory macrophages.

From the above results, these intrinsic functional properties make maternal-LF a potent innate defense factor to prevent the spread of COVID-19 from mother to newborn, and may also explain why infants have low COVID-19 morbidity and mortality. In addition, given its wide availability, limited cost, and lack of adverse effects, LF could be suggested as both a non-toxic health eement to prevent infection and an adjunct therapy for those who have developed COVID-19. However, more research to verify the dosage and efficacy is still needed.