Rotavirus-specific IgA and IgG Patterns During the First Two Years of Life in the PREVAIL Birth Cohort.

Maternal antibodies to rotavirus: Could they interfere with live rotavirus vaccines in developing countries?

Studies were carried out during an outbreak of rotavirus type 2 infection in a neonatal nursery to determine the protective role of antibodies in cord blood and breast milk. The range, distribution, and geometric mean titres of rotavirus-specific antibody in the cord blood were similar among rotavirus-positive and rotavirus-negative neonates, and the amount of virus excreted did not correlate with antibody levels. Despite the protective effect of breast feeding, the pattern of rotavirus-specific IgA and IgG antibodies in the expressed breast milk of mothers of babies who were rotavirus excreters and non-excreters was similar. Nevertheless, a higher proportion of expressed breast milk samples contained rotavirus-specific IgA group 2 (92%) and type 2 (97%) specific antibodies than type I (67%) antibodies, and the geometric mean titres of group 2 and type 2 specific antibodies were tenfold higher than type I antibodies. Among breast-fed babies who excreted rotavirus there was no correlation between type 2 rotavirus-specific IgA antibodies in expressed breast milk and the amount of neonatal virus excretion. These studies suggest that factors other than the rotavirus antibodies in expressed breast milk are of importance in preventing rotavirus infection in newborn infants.

The increase in incidence of atopic diseases (ADs) in the developed world over the past decades has been associated with reduced exposure of childhood infections. To investigate the relation between early intestinal viral infections in relation to the development of atopic symptoms (eczema, wheeze and atopic sensitization) in the first and second year(s) of life. In the KOALA Birth Cohort Study, we assessed IgG seropositivity for rota- and norovirus (GGI.1 and GGII.4) at 1 year of age. This was related to allergic sensitization [specific immunoglobulin E (IgE)] at 1 and 2 years, and parent reported eczema and wheeze in the first 2 years, using logistic regression analysis adjusted for confounders. Rotavirus seropositivity (39%) was associated with an unexpected higher risk of recurrent wheeze in the first and second year of life [adjusted odds ratio (OR) 3.1 and 95% confidence intervals (CI) 1.1-9.1] and persistent and new recurrent wheeze (adjusted OR 2.7 and 95% CI 1.1-6.2). No further associations were found between intestinal viral seropositivity and atopic manifestations. Our data did not show a clear protection by enteric viral infections in young children on development of IgE response to allergens, but rotavirus infection in the first year was a risk factor for wheeze. However, this needs to be followed up to older ages in order to establish the true importance of intestinal viral infections and especially cumulative effects in AD aetiology. Exposure to rotavirus may offer a new and interesting focus on infant wheeze and later asthma development.

ABSTRACTBackground: Maternal antibodies, acquired passively via placenta and/or breast milk, may contribute to the reduced efficacy of oral rotavirus vaccines observed in children in developing countries. This study aimed to investigate the effect of rotavirus specific maternal antibodies on the serum IgA response or stool excretion of vaccine virus after any dose of an oral rotavirus vaccine, RV3-BB, in parallel to a Phase IIa clinical trial conducted at Dunedin Hospital, New Zealand. At the time of the study rotavirus vaccines had not been introduced in New Zealand and the burden of rotavirus disease was evident.Methods: Rotavirus specific IgG and serum neutralizing antibody (SNA) levels in cord blood and IgA levels in colostrum and breast milk samples collected ∼4 weeks, ∼20 weeks and ∼28 weeks after birth were measured. Infants were randomized to receive the first dose of vaccine at 0–5 d (neonatal schedule) or 8 weeks (infant schedule). Breast feeding was with-held for 30 minutes before and after vaccine administration. The relationship between rotavirus specific IgG and SNA levels in cord blood and IgA in colostrum and breast milk at the time of first active dose of RV3-BB vaccine and level of IgA response and stool excretion after 3 doses of vaccine was assessed using linear and logistic regression.Results: Forty infants received 3 doses of RV3-BB rotavirus vaccine and were included in the analysis of the neonatal and infant groups. Rotavirus specific IgA in colostrum (neonatal schedule group) and breast milk at 4 weeks (infant schedule group) was identified in 14/21 (67%) and 14/17 (82%) of infants respectively. There was little evidence of an association between IgA in colostrum or breast milk IgA at 4 weeks, or between cord IgG or SNA level, and IgA response or stool excretion after 3 doses of RV3-BB, or after one dose (neonatal schedule) (all p>0.05).Conclusions: The level of IgA in colostrum or breast milk and level of placental IgG and SNA did not impact on the serum IgA response or stool excretion following 3 doses of RV3-BB Rotavirus Vaccine administered using either a neonatal or infant schedule in New Zealand infants.

The effect of heated tobacco products (HTPs) use and moderate alcohol drinking on immunogenicity to coronavirus disease (COVID-19) vaccines remain elusive. This study aimed to examine the association of tobacco product use and alcohol consumption with anti-SARS-CoV-2 spike IgG antibody titers after the BNT162b2 vaccine. Participants were 3433 healthcare workers receiving two vaccine doses in the 4 national centers for advanced medical and research in Japan. Smoking status and alcohol consumption were assessed via a questionnaire, and anti-SARS-CoV-2 spike IgG titers were measured with chemiluminescent enzyme immunoassay using serum collected on the median of 64 days after the second vaccination. Multilevel linear regression models were used to estimate the geometric mean titers (GMT) and the ratios of means (RoM) between groups with adjustment for covariates. Compared with never-smokers (GMT = 118), IgG antibody titers were significantly lower among HTPs users (including those who also smoked cigarettes) (GMT = 105; RoM = 0.89 [95%CI: 0.78–0.99]) and exclusive cigarettes smokers (GMT = 98; RoM = 0.81 [95%CI: 0.71–0.92]). Compared with non-drinkers of alcohol (GMT = 123), alcohol drinkers consuming <1 go/day (GMT = 113; RoM = 0.93 [95%CI: 0.88–0.98]), 1–1.9 go/day (GMT = 104; RoM = 0.85 [95%CI: 0.78–0.93]), and ≥ 2 go/day (GMT = 103; RoM = 0.84 [95%CI: 0.74–0.96]) had significantly lower antibody titers (P for trend<0.01). Spline analysis showed a large reduction of antibody until around 1 go/day of alcohol consumption, and then they gradually decreased. Results suggest that in addition to conventional cigarette smoking and heavy alcohol drinking, HTPs use and moderate alcohol drinking may be predictors of lower immunological response to COVID-19 vaccine.

Effect of reduced two-dose (1+1) schedule of 10 and 13-valent pneumococcal conjugate vaccines (SynflorixTM and Prevenar13TM)) on nasopharyngeal carriage and serotype-specific immune response in the first two years of life: Results from an open-labelled randomized controlled trial in Indian children.

Rotavirus-specific subclass antibody responses and cytokines, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-8 (IL-8), and IL-10, were measured in children 7-24 months of age with rotavirus diarrhoea (n = 29); the responses were compared with children with watery diarrhoea from whom no enteric pathogens were isolated (controls; n = 11). All children had diarrhoea for < 5 days and were enrolled from the Dhaka Hospital of the Centre for Health and Population Research. Samples of blood and stools were collected on the day of enrollment and 18-21 days after the onset of diarrhoea. Children showing a > or = 4-fold rise in antibody titre between the acute and convalescent stages were considered to have a response. The numbers of children with rotavirus-specific IgA and IgA1 responses in stool were similar in the two groups of children. In the plasma, more children with rotavirus diarrhoea had rotavirus-specific IgA, IgA1, IgG, IgG1, and IgG3 responses than did control children (P = 0.049, 0.007, 0.001, 0.002, and 0.012, respectively). IgA2 was not detectable. Among cytokines measured in supernatants from peripheral blood mononuclear cells (PBMCs) cultured for 6 and 24 hr, IFN-gamma was the only cytokine that was higher in children with rotavirus diarrhoea compared with controls (P = 0.013). Severity of illness did not correlate with nutritional status or antibody titres, but severity did correlate with TNF-alpha during the acute stage of illness. IFN-gamma correlated positively with IgG1 titres. These findings suggest a role for IFN-gamma in the pathogenesis of rotavirus infection, but this needs confirmation by other studies. The immune responses described are relevant to future vaccine trials, as immune responses in vaccinees should mimic those in natural infection.

Bifidobacterium species (B. bifidum and B. infantis), with or without prebiotic compounds (arabino-galactan, short-chain fructo-oligosaccharide, iso-malto-dextrins), were orally fed to Balb/c pups (n = 192) to evaluate their potential synergistic effects on modulating the course of rhesus rotavirus (RRV) infection, as well as their ability to mediate the associated mucosal and humoral immune responses. Rotavirus-specific IgA and IgG in serum, rotavirus antigen, and specific IgA in feces were measured by ELISA. Mucosal total IgA and IgG levels were determined in Peyer's patches by flow cytometry. Significantly delayed onset (p = 0.001) and early resolution (p < 0.001) of diarrhea were observed in bifidobacteria-treated, RRV-infected mice compared with RRV-infected control mice. Supplementation with prebiotic compounds did not shorten the clinical diarrhea course more than that observed with bifidobacteria treatment alone. Rotavirus-specific IgA in feces was 16-fold elevated on d 5 postinfection in bifidobacteria-treated, RRV-infected mice compared with the RRV-infected alone group. In addition, the level of rotavirus-specific IgA in serum was four-fold higher in bifidobacteria-treated, RRV-infected litters versus mice challenged with RRV alone on 28 and 42 d postinfection. No enhancement of the immune response was found in RRV-infected mice that were treated with both bifidobacteria and prebiotic compounds over those treated with bifidobacteria only. The findings suggest that bifidobacteria may act as an adjuvant by modulating early mucosal and strong humoral rotavirus-specific immune responses, and mitigate severity of rotavirus-induced diarrhea.

Children aged <2 years with chronic lung disease (CLD) have a 10-fold higher risk for respiratory syncytial virus-positive hospitalization (RSVH) compared to healthy term infants. Based on the updated position statements, we compared respiratory-related illness hospitalization (RIH) and RSVH risks in CLD children who received palivizumab during the first year (FY) versus second year (SY) of life in the Canadian Registry of Palivizumab (CARESS). Demographic data were collected at enrolment and RIH events recorded monthly from 2005 to 2015. Eight hundred forty-seven FY and 450 SY children with CLD were identified. SY children had a lower gestational age (27 versus 29 weeks) and required more days of respiratory support (64 versus 43), oxygen therapy (108 versus 55), and length of stay (118 versus 73) during the neonatal course compared to FY children; all p < 0.0005. RIH rates were 12.2 (FY) and 18.2 (SY), and RSVH rates were 2.3 (FY) and 3.9 (SY). Cox regression showed similar hazards for both RIH (hazard ratio 0.9, 95% CI 0.6–1.6, p = 0.812) and RSVH (hazard ratio 1.1, 95% CI 0.4–2.9, p = 0.920).Conclusions: SY and FY children had similar risks for RIH and RSVH. The findings imply that SY children with CLD are correctly selected for palivizumab based on neonatal illness severity and merit prophylaxis.What is Known:• Children with chronic lung disease have a 10-fold higher risk for RSV-positive hospitalization in comparison to healthy term infants and commonly receive palivizumab prophylaxis as a preventative measure against serious RSV-related lower respiratory tract infections.• The American Academy of Pediatrics [2] and the Canadian Paediatric Society [30] have recently modified their recommendations for RSV prophylaxis in children with chronic lung disease, limiting palivizumab to either those <32 weeks gestation or those in the first year of life who are oxygen dependent or require medical therapy for the treatment of their condition.What is New:• Children with chronic lung disease receiving an additional course of palivizumab in their second year of life were determined to be at similar risk for both respiratory illness-related hospitalization and RSV-positive hospitalization as palivizumab-naïve children enrolled in the first year of life in the Canadian Registry for palivizumab (CARESS).• CARESS physicians are correctly identifying high-risk children with chronic lung disease in their second year of life, whom they believe will benefit from an additional year of palivizumab prophylaxis, based on neonatal illness severity.

Enumeration of isotype-specific antibody-secreting cells derived from gnotobiotic piglets inoculated with porcine rotaviruses

Rotavirus infection and virus-like particle vaccines induce intestinal rotavirus-specific IgG in mice that appears to play a role in protection. The mechanism by which rotavirus-specific IgG reaches the intestinal lumen is unknown. The neonatal Fc receptor for IgG (FcRn) is the only known transporter of IgG in the intestines in neonatal and adult mice. Additionally, FcRn is implicated in antigen presentation in the intestines of adult mice. We tested whether FcRn is important in protecting the intestine against rotavirus infection and in transport of rotavirus-specific IgG into the intestinal lumen. Naïve FcRn deficient (FcRn−/−) and wild type BALB/c controls were orally inoculated with 103ID50 ECWT rotavirus. Fecal samples were collected 0–12 days post inoculation (dpi) and tested for rotavirus antigen and rotavirus-specific IgG by ELISA. Virus clearance from the intestine was significantly delayed by 3 days in FcRn−/− compared to BALB/c mice. Rotavirus-specific intestinal IgG titers were also significantly lower in FcRn−/− versus BALB/c mice. These data indicate that FcRn plays a role in clearance of a primary rotavirus infection from the intestine and intestinal transport of rotavirus-specific IgG. Studies are underway to elucidate the mechanism(s) by which FcRn contributes to clearance of intestinal rotavirus infection. VA Merit Review Grant, NIH RO1 AI24998

In 1969, Williams and McNicol [1] speculated that there was a spectrum of wheezing conditions in young children. At one end of the spectrum were children who had frequent regular episodes of wheeze from early life that continued into school age, and at the other end were children with ‘mild and evanescent’ wheeze, which was resolved by school age [1]. The hypothesis that preschool wheeze is not a single disease entity was confirmed in 1995 by the Tucson birth cohort study [2], which found that atopic sensitization is not a risk factor for preschool wheeze if wheeze resolves by school age, and that only a minority of children with preschool wheeze develop ‘atopic’ asthma during the school age years. To date, attempts to identify the minority of preschool ‘pre-asthmatics’ using the clinical pattern of wheeze (e.g. severe vs. mild, frequent vs. infrequent, episodic vs. continuous), or markers of atopy (e.g. low vs. high total IgE, specific IgE, and low vs. high blood eosinophils), have proved to be too inaccurate to be clinically useful [3,4]. Even the small proportion of young children with wheeze that is sufficiently severe to justify bronchial biopsy, do not have an airway wall eosinophilia that is characteristic of classical atopic asthma [5]. In reviewing this evidence, a 2008 European Respiratory Society (ERS) Task Force concluded that preschool children with wheeze should be divided into 2 groups: (i) ‘episodic (i.e. respiratory virus-triggered) wheeze’, and (ii) ‘multiple-trigger’ wheeze [6]. The term ‘persistent’ wheeze (i.e. wheeze both during and between colds) was dropped because it was also used by Martinez et al. [2] to describe a long-term outcome in the Tucson study. Although the ERS classification establishes a common framework for stratifying children in therapeutic trials, it begs the question whether the ‘multiple-trigger’ preschool wheeze phenotype is the same condition as school age asthma. Indeed, it remains entirely possible that, for the vast majority of wheezy preschool children, there is complete disassociation between atopic airway inflammation and wheeze – irrespective of ERS phenotype. How does this ongoing debate about preschool wheeze phenotypes affect research into the environmental influences on early atopic sensitization, and atopy-associated respiratory disease in young children? In this issue, Reimerink et al. [7] sought to assess the association between rotavirus and norovirus infection (determined by seropositivity) in the first year of life and both specific IgE to allergens and atopic symptoms. For respiratory outcomes, the authors divided children into: (i) recurrent wheeze in the first year of life, (ii) recurrent wheeze starting in the second year of life, and (iii) recurrent wheeze starting in the first year and continuing into the second year of life. Their finding that noravirus infection was associated with a lower risk of sensitization, but no reduction in the risk of recurrent wheeze, is entirely compatible with the hypothesis that most preschool wheeze is not atopic asthma. However, their finding of an association between rotavirus infection and recurrent preschool wheeze is more difficult to explain. Rotavirus is present in airway secretions from infants with diarrhoea [8], and it is possible that rotavirus infection enhances airway inflammation during subsequent colds – a putative interaction that merits assessment in animal and cell models. Because the environmental factors modulating the development of atopy remain elusive, well conducted studies with a clear testable hypothesis, such as that by Reimerink et al. [7], should be encouraged. It is very likely that further insights into preschool wheeze phenotypes will be provided by sophisticated mathematical techniques such as latent class analysis [9], and future studies of the development of atopic respiratory disease in young children will therefore require close collaboration between epidemiologists and academic respiratory paediatricians.

Maternal parenting skills, adverse clinical outcomes, and contextual factors in low-income families: Associations and predictors of the neurodevelopment of preterm children in the first two years of life

Zabaikalsky highlander is a spring-type, medium- to late-maturing forage crop that develops with a long daylight. It takes 1300°C to complete the "regrowth - full ripeness of seeds" period. From active (above +10°C) temperatures. The plant is long-lived, it takes root intensively in the first year of life, and the mass of roots increases significantly with the age of the plants. In the hill-plain steppe of the Akmola region, the mass of roots in the arable layer of 20-40 cm of the total weight of plants in the first year of life was 2.6%, in the second year of plant life it increased to 32.3% and in the third year - to 34.5%. For three years of life, the root system of the Zabaikalsky mountaineer evenly covers the soil profile up to 40-50 cm. Mass regrowth of shoots begins after a steady transition of air temperature through+10°C from the buds of renewal. The growth and development of shoots varies from 3-5 pieces in plants of the second year of life and depends on the age of the plants; on the initial set density of standing and the method of sowing; on the water and food regime of each particular year. In the green mass formed during the stalking period, foliage is 59% the highest. An intensive increase in green mass was noted during budding and flowering - 92.4 c/ha. The increase per day is 2.16%. In the conditions of the hill-plain steppe, the growing season from regrowth to full ripeness of seeds was 120-131 days. The seeds ripen within 65-80 days.

Efficacy of the oral pentavalent rotavirus vaccine in Mali