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

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.

Passive acquisition of anti-Staphylococcus aureus antibodies by newborns via transplacental transfer and breastfeeding, regardless of maternal colonization

OBJECTIVE: To investigate the transmission of anti-Staphylococcus aureus (Sa) IgG, IgG1 and IgG2 via placental transfer and the transfer of IgA via the colostrum according to maternal Sa carrier status at delivery. METHODS: We evaluated anti-Sa IgG, IgG1 and IgG2 in maternal and cord sera and IgA in colostrum from a case (n=49, Sa+) and a control group (n=98, Sa-). RESULTS: Of the 250 parturients analyzed for this study, 49 were nasally colonized with S. aureus (prevalence of 19.6%). Ninety-eight non-colonized subjects were selected for the control group. The anti-Sa IgG, IgG1 and IgG2 levels and the IgG avidity indexes in the maternal and cord sera did not differ between the groups, with a low transfer ratio of anti-Sa IgG to the newborns in both groups. The anti-Sa IgG2 titers were significantly higher than the IgG1 titers in the maternal and cord sera. Inversely, the transfer ratios were higher for anti-Sa IgG1 compared with IgG2; however, no differences between the groups were detected. The Sa-specific IgA levels and avidity indexes in the colostrum were equivalent between groups. CONCLUSIONS: Maternal Sa nasal colonization at delivery is not associated with higher antibody levels in the mother or newborns. The high titers of anti-Sa IgG2 found in the cord serum indicate a greater reactivity with non-protein antigens, which may further contribute to the susceptibility to staphylococcal infections at birth. The presence of IgA in the colostrum with avidity to S. aureus reinforces the importance of breastfeeding shortly after birth.

Immunology of breast milk / Imunologia do leite materno

Summary In the critical phase of immunological immaturity of the newborn, particularly for the immune system of mucous membranes, infants receive large amounts of bioactive components through colostrum and breast milk. Colostrum is the most potent natural immune booster known to science. Breastfeeding protects infants against infections mainly via secretory IgA (SIgA) antibodies, but also via other various bioactive factors. It is striking that the defense factors of human milk function without causing inflammation; some components are even anti-inflammatory. Protection against infections has been well evidenced during lactation against, e.g., acute and prolonged diarrhea, respiratory tract infections, including otitis media, urinary tract infection, neonatal septicemia, and necrotizing enterocolitis. The milk’s immunity content changes over time. In the early stages of lactation, IgA, anti-inflammatory factors and, more likely, immunologically active cells provide additional support for the immature immune system of the neonate. After this period, breast milk continues to adapt extraordinarily to the infant’s ontogeny and needs regarding immune protection and nutrition. The need to encourage breastfeeding is therefore justifiable, at least during the first 6 months of life, when the infant’s secretory IgA production is insignificant.

Resumo Na fase crítica de imaturidade imunológica do recém-nascido, em especial do sistema imune de mucosas, o lactente recebe grandes quantidades de componentes bioativos através do colostro e do leite materno. O colostro é o reforço imunológico natural mais potente conhecido pela ciência. O aleitamento materno protege o lactente de infecções principalmente por meio dos anticorpos IgA secretores (IgAS), mas também por meio de vários outros fatores bioativos. É surpreendente que os fatores de defesa do leite humano ajam sem causar inflamação e alguns componentes são, de fato, anti-inflamatórios. A proteção contra infecções tem sido bem evidenciada durante a lactação, combatendo, por exemplo, diarreia aguda e prolongada, infecções do trato respiratório, incluindo otite média, infecção do trato urinário, sepse neonatal e enterocolite necrosante. O conteúdo imunológico do leite evolui ao longo do tempo: nas fases iniciais de lactação, IgAS, fatores anti-inflamatórios e, mais provavelmente, as células imunologicamente ativas provêm ajuda adicional para o sistema imune imaturo do neonato. Depois desse período, o leite materno continua a adaptar-se extraordinariamente à ontogenia infantil, às suas necessidades de proteção imune e nutricionais. Entende-se, portanto, a necessidade de se estimular o aleitamento materno pelo menos durante o primeiro semestre de vida, período em que a produção própria de IgA secretória é ainda pouco significativa.

Regulation of Intestinal Immune System by Dendritic Cells

Innate immune cells survey antigenic materials beneath our body surfaces and provide a front-line response to internal and external danger signals. Dendritic cells (DCs), a subset of innate immune cells, are critical sentinels that perform multiple roles in immune responses, from acting as principal modulators to priming an adaptive immune response through antigen-specific signaling. In the gut, DCs meet exogenous, non-harmful food antigens as well as vast commensal microbes under steady-state conditions. In other instances, they must combat pathogenic microbes to prevent infections. In this review, we focus on the function of intestinal DCs in maintaining intestinal immune homeostasis. Specifically, we describe how intestinal DCs affect IgA production from B cells and influence the generation of unique subsets of T cell.

Mucosal dendritic cells shape mucosal immunity

Dendritic cells (DCs) are key modulators that shape the immune system. In mucosal tissues, DCs act as surveillance systems to sense infection and also function as professional antigen-presenting cells that stimulate the differentiation of naive T and B cells. On the basis of their molecular expression, DCs can be divided into several subsets with unique functions. In this review, we focus on intestinal DC subsets and their function in bridging the innate signaling and adaptive immune systems to maintain the homeostasis of the intestinal immune environment. We also review the current strategies for manipulating mucosal DCs for the development of efficient mucosal vaccines to protect against infectious diseases.

Leite de mulheres brasileiras apresenta anticorpos IgA secretores (SIgA) que neutralizam o rotavírus G9P[5] / Milk from Brazilian women presents secretory IgA antibodies and neutralizes rotavirus G9P[5]

OBJETIVO: Verificar a presença de SIgA anti-rotavírus sorotipo G9P[5] e a capacidade de neutralização do vírus de amostras de leite de mulheres brasileiras. MÉTODOS: Foram determinados os níveis de anticorpos SIgA reativos contra rotavírus G9 em 30 amostras de leite materno por ELISA usando suspensões purificadas do vírus. A capacidade das amostras de neutralizarem o rotavírus G9P[5] foi analisada em ensaio de de Neutralização utilizando células MA-104. RESULTADOS: Foram observadas grandes variações individuais referentes aos níveis de SIgA e títulos de neutralização, mas todas as amostras mostraram certa capacidade de neutralizar o G9P[5]. Verificamos uma correlação positiva altamente significativa entre os níveis de anticorpos e os títulos de neutralização. CONCLUSÕES: A alta correlação entre níveis de anticorpos anti-rotavírus e a capacidade neutralizante das amostras de leite sugere um possível papel protetor desses anticorpos contra a infecção. Esses resultados também apoiam o incentivo à prática do aleitamento materno.

OBJECTIVE: To verify the presence of anti-rotavirus serotype G9P[5] SIgA and the virus neutralization capacity of milk samples from Brazilian women. METHODS: SIgA antibody levels reactive to rotavirus G9 were determined in 30 maternal milk samples by enzyme-linked immunosorbent assay (ELISA) using purified virus suspensions. The samples' capacity to neutralize rotavirus G9P[5] was analyzed using the MA-104 cells neutralization assay. RESULTS: Great individual variations were observed regarding the SIgA levels and neutralization titers, but all samples showed some G9P[5] neutralizing ability. A highly significant positive correlation was observed between antibody levels and neutralization titers. CONCLUSIONS: The high correlation between anti-rotavirus antibody levels and neutralizing capacity of the milk samples suggests a possible protective role of these antibodies against infection. These results also support the encouragement of the breast-feeding practice.

Ocular toxoplasmosis: evaluation of lacrimal - specific secretory IgA levels in both patients with active and inactive phases of the disease

Ocular toxoplasmosis can result in recurrent uveitis. Studies have shown that a correlation between active ocular toxoplasmosis and the presence of anti-Toxoplasma gondii secretory IgA (SIgA) in tears. This study compares anti-T. gondii SIgA levels in patients' tears during the acute and inactive phases of toxoplasmic uveitis. Twenty-nine positive tear specific SIgA for T. gondii patients with acute toxoplasmic uveitis were selected and were followed-up for at least two years, when the anti-T. gondii SIgA tears levels were determined. Specific SIgA for T. gondii was negative in 22 patients (75.86 percent) and positive in seven patients (24.13 percent) of whom six (85.7 percent) were followed over three years. Average SIgA levels during the acute phase are 1.54 and decrease significantly to 0.72 (p = 0.0001) during the inactive phase of disease. Because anti-T. gondii SIgA in the tear is negative in 75.86 percent of patients after the acute phase of infection, T. gondii SIgA levels may be used as a complementary diagnostic marker for active ocular toxoplasmosis.

Reduction of the amount of intestinal secretory IgA in fulminant hepatic failure

Intestinal barrier dysfunction plays an important role in spontaneous bacterial peritonitis. In the present study, changes in the intestinal barrier with regard to levels of secretory immunoglobulin A (SIgA) and its components were studied in fulminant hepatic failure (FHF). Immunohistochemistry and double immunofluorescent staining were used to detect intestinal IgA, the secretory component (SC) and SIgA in patients with FHF (20 patients) and in an animal model with FHF (120 mice). Real-time PCR was used to detect intestinal SC mRNA in the animal model with FHF. Intestinal SIgA, IgA, and SC staining in patients with FHF was significantly weaker than in the normal control group (30 patients). Intestinal IgA and SC staining was significantly weaker in the animal model with FHF than in the control groups (normal saline: 30 mice; lipopolysaccharide: 50 mice; D-galactosamine: 50 mice; FHF: 120 mice). SC mRNA of the animal model with FHF at 2, 6, and 9 h after injection was 0.4 ± 0.02, 0.3 ± 0.01, 0.09 ± 0.01, respectively. SC mRNA of the animal model with FHF was significantly decreased compared to the normal saline group (1.0 ± 0.02) and lipopolysaccharide group (0.89 ± 0.01). The decrease in intestinal SIgA and SC induced failure of the intestinal immunologic barrier and the attenuation of gut immunity in the presence of FHF.

Effect of hyperoxia on the intestinal IgA secretory component in neonatal rats and on intestinal epithelial cells in vitro

Oxygen therapy is essential for the treatment of some neonatal critical care conditions but its extrapulmonary effects have not been adequately investigated. We therefore studied the effects of various oxygen concentrations on intestinal epithelial cell function. In order to assess the effects of hyperoxia on the intestinal immunological barrier, we studied two physiological changes in neonatal rats exposed to hyperoxia: the change in intestinal IgA secretory component (SC, an important component of SIgA) and changes in intestinal epithelial cells. Immunohistochemistry and Western blot were used to detect changes in the intestinal tissue SC of neonatal rats. To detect intestinal epithelial cell growth, cells were counted, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Giemsa staining were used to assess cell survival. Immunohistochemistry was used to determine SC expression. The expression of intestinal SC in neonatal rats under hyperoxic conditions was notably increased compared with rats inhaling room air (P < 0.01). In vitro, 40 percent O2 was beneficial for cell growth. However, 60 percent O2 and 90 percent O2 induced rapid cell death. Also, 40 percent O2 induced expression of SC by intestinal epithelial cells, whereas 60 percent O2did not; however, 90 percent O2 limited the ability of intestinal epithelial cells to express SC. In vivo and in vitro, moderate hyperoxia brought about increases in intestinal SC. This would be expected to bring about an increase in intestinal SIgA. High levels of SC and SIgA would serve to benefit hyperoxia-exposed individuals by helping to maintain optimal conditions in the intestinal tract.

Diagnosis and follow-up of genital chlamydial infection by direct methods and by detection of serum IgG, IgA and secretory IgA.

Purpose: To determine the prevalence of Chlamydia trachomatis infection in a high-risk population by direct and indirect methods and to evaluate the diagnosis of secretory immunoglobulin A (sIgA). Patients and Methods: Urethral or endocervical specimens from 78 patients (48 females and 30 males) were examined by cell culture, direct fluorescence assay, PCR Cobas Amplicor (Roche Molecular Diagnostics), and sIgA was detected by the recombinant lipopolysaccharide (LPS)-enzyme-linked immunoassay (rELISA). Serum from each patient was also obtained and analysed for the presence of IgG and IgA antibody by in-house microimmunofluorescence (MIF) and by the rELISA method (Medac, Hamburg, Germany). Results: The overall C. trachomatis prevalence determined by direct methods was 28%. The detection of sIgA antibodies was significantly higher in the group of patients with a positive direct detection (50%) than in the group of negative direct detection (10.7%). The Chlamydia-specific IgA antibodies were detected by the rELISA in 40.9 and 53.6% of group I (positive direct detection) and group II patients (negative direct detection), respectively. The species-specific IgA antibodies were detected by the MIF method in 18.2 and 16.1% of group I and II patients, respectively. Chlamydia genus-specific IgG antibodies were detected by the rELISA in 86.4 and 83.9% of group I and group II patients and, C. trachomatis specific IgG were present in 81.8 and 73.2% of group I and group II patients, respectively, as assessed by the MIF test. Conclusion: Combining the positive direct methods and/or positive sIgA antibody results from cervical or urethral specimens had an indication of current C. trachomatis infection.

Evaluación de la respuesta de inmunoglobulina a secretora anti-helicobacter pylori en saliva de pacientes con gastritis crónica / Evaluation of the response to secretory immunoglobulin anti-helicobacter pylori in saliva from patients with chronic gastritis

Helicobacter pylori ha sido implicado como el principal agente asociado a la patogénesis de gastritis crónica, úlcera péptica y neoplasias gástricas en humanos. El microorganismo ha sido detectado en placa dental, saliva y heces. En el presente estudio se determinó la respuesta immune de Ig A secretora anti- H.pylori en la saliva de 39 pacientes con dispepsia y en 20 sujetos sanos. Se tomaron biopsias gástricas de cada paciente para estudio histopatológico, prueba de ureasa, cultivo microbiológico y Reacción en Cadena de la Polimerasa (RCP), así como 5 ml de saliva no estimulada. Las muestras fueron obtenidas previo a la endoscopia. Los niveles de anticuerpos específicos de IgA secretora-Anti H.pylori fueron determinados por ensayo inmunoabsorbente ELISA. El antígeno utilizado fué preparado por sonicación de 5 cepas de H. pylori aislados de pacientes con úlceras duodenales. H. pylori fue detectado en 24/39 (62 por ciento) de los pacientes, todos con gastritis crónica. Los pacientes sintomáticos infectados con H.pylori presentaron niveles significativamente mayores de IgA secretora en saliva (0,2862 ± 0,144), que los pacientes del grupo control (0,1511 ± 0,069) (p>0005). Nuestros resultados indican que existe una correlación entre la presencia de H. pylori en la mucosa gástrica de pacientes con enfermedad de las vías digestivas superiors y la presencia de IgA secretora anti-H.pylori en saliva. Este ensayo a nivel de saliva representa una prueba rápida, no invasiva que puede ser utilizado en estudios epidemiológicos sobre todo en pacientes pediátricos

Helicobacter pylori has been implicated as the major acquired factor in the pathogenesis of chronic gastritis, peptic ulcer disease, and gastric neoplasia in humans. The microorganism has been detected in dental plaque, saliva and feces. In this study, we investigated the salivary anti H. pylori immunoglubulin A (IgA) immune response in 39 dyspeptic patients and 20 healthy volunteers. Gastric antrum biopsies were taken for histological examination, urease test, culture and polymerase chain reaction (PCR). Five mililiters of unstimulated saliva were obtained from all subjects before the endoscopy. The levels of specific antibodies in saliva were determined by ELISA test. The soluble antigen material for immunoenzymatic assay was prepared by sonication of five H. pylori strains isolated from duodenal ulcer patients. H. pylori was detected in antral samples from 24/39 (62 percent) patients, all of whom had chronic gastritis. Symptomatic patients infected with H. pylori showed levels significantly higher of secretory Ig A in saliva ( 0.2862 ± 0.144) than asymptomatic patients. (0.1511 ± 0.069) (p>0.005). Our results indicate that there is a correlation between the presence of H. pylori in gastric mucosa of symptomatic patients and the occurrence of secretory Ig A antibodies against H. pylori in saliva. Saliva testing is a rapid, noninvasive test that may have a role in epidemiological studies and in screening dyspeptic patients, specially in pediatric populations

Clinical Significance of Nasal Secretory Proteins in Chronic Sinonasal Diseases / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Many studies report changes in the expressions of nasal secretory proteins which play important roles in the evaluation of sinonasal mucosal status. The biomarkers in nasal secretions provide valuable information on pathophysiological status of the rhinosinusitis. We have monitored the level and ratio of nasal secretion markers, especially secretory IgA (sIgA) and lactoferrin as markers of sinonasal submucosal glands to evaluate mucosal status for chronic sinonasal diseases and allergic rhinitis. SUBJECTS AND METHOD: Samples were obtained with the filter paper absorption method from 20 normal healthy controls (Group I), 20 patients with chronic rhinosinusitis (Group II), 20 patients with allergic rhinitis (Group III), 20 normalized persons of chronic rhinosinusitis patients treated with antibiotics, previously (Group IV). We estimated concentrations of sIgA and lactoferrin determined by enzyme-linked immunosorbent assay method. RESULTS: The concentration of sIgA and lactoferrin in nasal secretion showed a significant difference between the control group and other groups (p<0.05). The sIgA/lactoferrin ratio was more highly significant in the normal group and normalized in chronic rhinosinusitis patients treated with antibiotics (Group IV) than other groups (p<0.05). CONCLUSION: In this study, sIgA and lactoferrin are useful secretion markers and the levels of sIgA, lactoferrin and sIgA/lactoferrin ratios in nasal secretions seem to be very useful parameters for monitoring and assessing the conditions of the sinonasal mucosal diseases.

Effects of Hot Spring Bathing on Salivary Secretion and Secretory IgA secretion in Healthy Volunteers / 日本温泉気候物理医学会雑誌

This study examined the effect of hot-spring bathing (40 to 41°C) on salivary secretion and salivary secretory IgA (sIgA) in healthy volunteers. Ten volunteers (10 men, average 33.6±9.3 years old) bathed in a hot-spring for 10 minutes.<br>Saliva samples were collected before bathing, during bathing (from 5 to 7 min), and after bathing using the Saxon test. The saliva flow rates and sIgA concentration were determined and then the sIgA secretion rates were calculated.<br>The saliva flow rates increased significantly during the bathing (p<0.02) and decreased after bathing. The sIgA secretion rates during bathing were significantly higher than those before and after bathing (p<0.02).<br>The increases in saliva flow rates and sIgA secretion rates during bathing were considered to indicate the improvement of local immunity in the oral cavity and thus considered to be useful for preventing upper respiratory tract infections.

The mucosal adjuvanticity of two nontoxic mutants of Escherichia coli heat-labile enterotoxin varies with immunization routes

Escherichia coli heat-labile enterotoxin (LT), which causes a characteristic diarrhea in humans and animals, is a strong mucosal immunogen and has powerful mucosal adjuvant activity towards coadministered unrelated antigens. Here we report the different mucosal adjuvanticity of nontoxic LT derivatives, LTS63Y and LTdelta110/112, generated by immunizing through two different mucosal routes. Intragastric (IG) immunization with Helicobacter pylori urease alone resulted in poor systemic IgG and IgA responses and no detectable local secretory IgA, but IG co-immunization with urease and LTdelta110/112 induced high titers of urease-specific local secretory IgA and systemic IgG and IgA, comparable to those induced by wild-type LT. LTS63Y showed far lower adjuvant activity towards urease than LTdelta110/112 in IG immunization, but was more active than LTdelta110/112 in inducing immune responses to urease by intranasal (IN) immunization. LTdelta110/112 predominantly enhanced the induction of urease-specific IgG1 levels following IG immunization, whereas LTS63Y induced high levels of IgG1, IgG2a and IgG2b following IN immunization. In addition, quantitative H. pylori culture of stomach tissue following challenge with H. pylori demonstrated a 90-95% reduction (p < 0.0002) in bacterial burden in mice immunized intranasally with urease using either mutant LT as an adjuvant. These results indicate that the mechanism(s) underlying the adjuvant activities of mutant LTs towards coadmnistered H. pylori urease may differ between the IN and IG mucosal immunization routes.

Development of two novel nontoxic mutants of Escherichia coli heat-labile enterotoxin

Escherichia coli heat-labile enterotoxin (LT) is composed of catalytic A and non-catalytic homo-pentameric B subunits and causes diarrheal disease in human and animals. In order to produce a nontoxic LT for vaccine and adjuvant development, two novel derivatives of LT were constructed by a site-directed mutagenesis of A subunit; Ser63 to Tyr63 in LTS63Y and Glu110, Glu112 were deleted in LT delta 110/112. The purified mutant LTs (mLTs) showed a similar molecular structural complex as AB5 to that of wild LT. In contrast to wild-type LT, mLTs failed to induce either elongation activity, ADP-ribosyltransferase activity, cAMP synthesis in CHO cells or fluid accumulation in mouse small intestine in vivo. Mice immunized with mLTs either intragastrically or intranasally elicited high titers of LT-specific serum and mucosal antibodies comparable to those induced by wild-type LT. These results indicate that substitution of Ser63 to Tyr63 or deletion of Glu110 and Glu112 eliminate the toxicity of LT without a change of AB5 conformation, and both mutants are immunogenic to LT itself. Therefore, both mLTs may be used to develop novel anti-diarrheal vaccines against enterotoxigenic E. coli.

Expression of the Secretory IgA in the Olfactory Mucosa of Developing Mice

Although secretory immunoglobulin A (sIgA) is a very important substance in the defence mechanism of respiratory and nasal mucosa, research on its expression in the olfactory mucosa and differences according to development is limited. Therefore, we planned to uncover the sites of sIgA expression in the olfactory mucosa as well as changes in its expression depending on the developmental progress of mice. Our results showed the expression of sIgA in the mucus layer, the Bowman's gland, some of the blood cells and secretory ducts of the olfactory mucosa, and these findings were relatively consistent from gestational day 15 through to the adult stage. The different findings between the gestational day 15 specimens and others include a positive reaction in the Bowman's gland for gestational day 15 specimens. Therefore, we would like to predict with caution that the Immunologic regulation of mice should be completed at least after the 15th gestational day.