Severe diarrhea from rotavirus remains an important cause of illness in infants. In this trial, investigators in Indonesia assessed the potential benefit of a neonatal rotavirus vaccine.
Background & Aims Interleukin (IL)33 is a recently described alarmin that is highly expressed in the gastric mucosa and potently activates Th2 immunity. It may play a pivotal role during Helicobacter ...pylori infection. Here, we delineate the role of IL33 in the normal gastric mucosa and in response to gastropathy. Methods IL33 expression was evaluated in mice and human biopsy specimens infected with H pylori and in mice after dosing with aspirin. IL33 expression was localized in the gastric mucosa using immunofluorescence. Mice were given 1 or 7 daily doses of recombinant IL33 (1 μg/dose), and the stomach and the spleen responses were quantified morphologically, by flow cytometry and using quantitative reverse-transcription polymerase chain reaction and immunoblotting. Results In mice, the IL33 protein was localized to the nucleus of a subpopulation of surface mucus cells, and co-localized with the surface mucus cell markers Ulex Europaeus 1 (UEA1), and Mucin 5AC (Muc5AC). A small proportion of IL33-positive epithelial cells also were Ki-67 positive. IL33 and its receptor Interleukin 1 receptor-like 1 (ST2) were increased 4-fold after acute (1-day) H pylori infection, however, this increase was not apparent after 7 days and IL33 expression was reduced 2-fold after 2 months. Similarly, human biopsy specimens positive for H pylori had a reduced IL33 expression. Chronic IL33 treatment in mice caused systemic activation of innate lymphoid cell 2 and polarization of macrophages to the M2 phenotype. In the stomach, IL33-treated mice developed transmural inflammation and mucous metaplasia that was mediated by Th2/signal transducer and activator of transcription 3 signaling. Rag-1-/- mice, lacking mature lymphocytes, were protected from IL33-induced gastric pathology. Conclusions IL33 is highly expressed in the gastric mucosa and promotes the activation of T helper 2–cytokine–expressing cells. The loss of IL33 expression after prolonged H pylori infection may be permissive for the T helper 1–biased immune response observed during H pylori infection and subsequent precancerous progression.
The trefoil factor TFF2 is a member of a tripartite family of small proteins that is produced by the stomach and the colon. Recombinant TFF2, when applied intrarectally in a rodent model of hapten ...colitis, hastens mucosal healing and reduces inflammatory indexes. Additionally, TFF2 is expressed in immune organs, supporting a potential immunomodulatory and reparative role in the bowel. In this study we confirm that TFF2 is expressed in the colon and is specifically enriched in epithelial cells relative to colonic leukocytes. TFF2-deficient, but not TFF1-deficient, mice exhibit a more severe response to acute or chronic dextran sulfate (DSS)-induced colitis that correlates with a 50% loss of expression of TFF3, the principal colonic trefoil. In addition, the response to acute colitis is associated with altered expression of IL-6 and IL-33, but not other inflammatory cytokines. While TFF2 can reduce macrophage responsiveness and block inflammatory cell recruitment to the colon, the major role in limiting the susceptibility to acute colitis appears to be maintenance of barrier function. Bone marrow transfer experiments demonstrate that leukocyte expression of TFF2 is not sufficient for prevention of colitis induction but, rather, that the gastrointestinal epithelium is the primary source of TFF2. Together, these findings illustrate that epithelial TFF2 is an important endogenous regulator of gut mucosal homeostasis that can modulate immune and epithelial compartments. Because of its extreme stability, even in the corrosive gut lumen, TFF2 is an attractive candidate as an oral therapeutic scaffold for future drug development in the treatment of inflammatory bowel disease.
Background: 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.
Serum rotavirus IgA responses are an imperfect non-mechanistic correlate of protection, and the lack of an accurate serological marker is a challenge to the development of new rotavirus vaccines. ...Serological responses to rotavirus NSP2 occur following wild-type infection; however, it is unknown if serological responses to NSP2 occur following administration of rotavirus vaccines. The phase IIa immunogenicity trial of RV3-BB provided an opportunity to investigate the serological responses to NSP2 following vaccination. Healthy, full-term babies (n = 96) were previously recruited as part of a phase IIa safety and immunogenicity trial in Dunedin, New Zealand between January 2012 and April 2014. Participants received three doses of oral RV3-BB vaccine with the first dose given at 0-5 days after birth (neonatal schedule), or the first dose given at about 8 weeks after birth (infant schedule), or to receive placebo (placebo schedule). Serum IgA and IgG antibody responses to total RV3-BB and NSP2 protein (RV3-BB) were assessed using ELISA. Despite significant serum IgA response against total RV3-BB, we were unable to demonstrate a significant serological response to NSP2 in participants receiving RV3-BB when compared to placebo. Heterotypic antibodies against multiple NSP2 genotypes were detected following RV3-BB vaccination. Our data demonstrates that while serological responses to NSP2 were detectable in a subset of participants, it is a less useful marker when compared to total rotavirus serum IgA response.
Rotavirus vaccines reduce rotavirus-related deaths and hospitalisations but are less effective in high child mortality countries. The human RV3-BB neonatal G3P6 rotavirus vaccine administered in a ...neonatal schedule was efficacious in reducing severe rotavirus gastroenteritis in Indonesia but had not yet been evaluated in African infants.
We did a phase 2, randomised, double-blind, parallel group dose-ranging study of three doses of oral RV3-BB rotavirus vaccine in infants in three primary health centres in Blantyre, Malawi. Healthy infants less than 6 days of age with a birthweight 2·5 to 4·0 kg were randomly assigned (1:1:1:1) into one of four treatment groups: neonatal vaccine group, which included high-titre (1·0 × 107 focus-forming unit FFU per mL), mid-titre (3·0 × 106 FFU per mL), or low-titre (1·0 × 106 FFU per mL); and infant vaccine group, which included high-titre (1·0 × 107 FFU per mL) using a computer generated code (block size of four), stratified by birth (singleton vs multiple). Neonates received their three doses at 0–5 days to 10 weeks and infants at 6–14 weeks. Investigators, participant families, and laboratory staff were masked to group allocation. Anti-rotavirus IgA seroconversion and vaccine take (IgA seroconversion and stool shedding) were evaluated. Safety was assessed in all participants who received at least one dose of vaccine or placebo. The primary outcome was the cumulative IgA seroconversion 4 weeks after three doses of RV3-BB in the neonatal schedule in the high-titre, mid-titre, and low-titre groups in the per protocol population, with its 95% CI. With the high-titre group as the active control group, we did a non-inferiority analysis of the proportion of participants with IgA seroconversion in the mid-titre and low-titre groups, using a non-inferiority margin of less than 20%. This trial is registered at ClinicalTrials.gov (NCT03483116).
Between Sept 17, 2018, and Jan 27, 2020, 711 participants recruited were randomly assigned into four treatment groups (neonatal schedule high titre n=178, mid titre n=179, low titre n=175, or infant schedule high titre n=179). In the neonatal schedule, cumulative IgA seroconversion 4 weeks after three doses of RV3-BB was observed in 79 (57%) of 139 participants in the high-titre group, 80 (57%) of 141 participants in the mid-titre group, and 57 (41%) of 138 participants in the low-titre group and at 18 weeks in 100 (72%) of 139 participants in the high-titre group, 96 (67%) of 143 participants in the mid-titre group, and 86 (62%) of 138 of participants in the low-titre. No difference in cumulative IgA seroconversion 4 weeks after three doses of RV3-BB was observed between high-titre and mid-titre groups in the neonatal schedule (difference in response rate 0·001 95%CI −0·115 to 0·117), fulfilling the criteria for non-inferiority. In the infant schedule group 82 (59%) of 139 participants had a cumulative IgA seroconversion 4 weeks after three doses of RV3-BB at 18 weeks. Cumulative vaccine take was detected in 483 (85%) of 565 participants at 18 weeks. Three doses of RV3-BB were well tolerated with no difference in adverse events among treatment groups: 67 (39%) of 170 participants had at least one adverse event in the high titre group, 68 (40%) of 172 participants had at least one adverse event in the mid titre group, and 69 (41%) of 169 participants had at least one adverse event in the low titre group.
RV3-BB was well tolerated and immunogenic when co-administered with Expanded Programme on Immunisation vaccines in a neonatal or infant schedule. A lower titre (mid-titre) vaccine generated similar IgA seroconversion to the high-titre vaccine presenting an opportunity to enhance manufacturing capacity and reduce costs. Neonatal administration of the RV3-BB vaccine has the potential to improve protection against rotavirus disease in children in a high-child mortality country in Africa.
Bill & Melinda Gates Foundation, Australian Tropical Medicine Commercialisation Grant.
Abstract
Background
Histo-blood group antigen (HBGA) status may affect vaccine efficacy due to rotavirus strains binding to HBGAs in a P genotype–dependent manner. This study aimed to determine if ...HBGA status affected vaccine take of the G3P6 neonatal vaccine RV3-BB.
Methods
DNA was extracted from stool samples collected in a subset (n = 164) of the RV3-BB phase IIb trial in Indonesian infants. FUT2 and FUT3 genes were amplified and sequenced, with any single-nucleotide polymorphisms analyzed to infer Lewis and secretor status. Measures of positive cumulative vaccine take were defined as serum immune response (immunoglobulin A or serum-neutralizing antibody) and/or stool excretion of RV3-BB virus. Participants were stratified by HBGA status and measures of vaccine take.
Results
In 147 of 164 participants, Lewis and secretor phenotype were determined. Positive vaccine take was recorded for 144 (97.9%) of 147 participants with the combined phenotype determined. Cumulative vaccine take was not significantly associated with secretor status (relative risk, 1.00 95% CI, .94–1.06; P = .97) or Lewis phenotype (relative risk, 1.03 95% CI, .94–1.14; P = .33), nor was a difference observed when analyzed by each component of vaccine take.
Conclusions
The RV3-BB vaccine produced positive cumulative vaccine take, irrespective of HBGA status in Indonesian infants.
Population differences in histo-blood group antigen status may contribute to the varying performance of oral rotavirus vaccines. This study revealed that the RV3-BB vaccine produced positive cumulative vaccine take, irrespective of histo-blood group antigen status in Indonesian infants.
The paper illustrates a proposition for process model of the P&I maritime insurance sale. A specific feature of such a form of insurance relates to the collaboration between an insurance company and ...P&I clubs, which insure shipping company liability. The paper shows a decomposition diagram of the process of P&I insurance sales, from the aspect of the insurance company. The process of insurance sale is described. For process specification, the following methods are used: Work Flow. Activity Flow and Data Flow Diagram. The first two methods clearly show the position of processes in organizational parts of the insurance company and external business organizations. The Data Flow Diagram shows processes and data flows between them, not depending on where these are performed or who performs them. Such a model is the basis for information system development.
•IgA in breast milk was not associated with reduced RV3-BB vaccine take in Indonesia.•IgG titre in cord blood was associated with lower vaccine immunogenicity after one, not three doses of ...vaccine.•RV3-BB vaccine appears to be able to be given with breast-feeding in high rotavirus disease burden settings.
Placental or breast milk maternal antibodies can potentially reduce oral rotavirus vaccine efficacy in developing countries. We aimed to examine the relationship between the level of rotavirus specific immunoglobulin A (IgA) and neutralising antibodies (NA) in colostrum and breast milk and cord IgG, with cumulative vaccine take following one and three doses of oral RV3-BB rotavirus vaccine within a Phase IIb trial in Indonesia.
196 infants received three doses of RV3-BB in a randomized, double-blinded trial, using a neonatal schedule (first dose at 0–5 days of age, n = 61), an infant schedule (first dose at ~ 8 weeks of age, n = 67) or placebo (n = 68). Rotavirus specific IgA and NA in colostrum and breast milk, rotavirus specific cord IgG, Serum IgA and stool excretion were measured.
There was little evidence of an association between IgA in colostrum or breast milk and cumulative vaccine take after three doses in the neonatal or infant groups. In the neonatal group, there was a negative association between IgG titre in cord blood and cumulative vaccine take (odds ratio OR 0.96; 95% confidence interval CI 0.92–1.00; p = 0.03) and serum IgA response (OR 0.94; 95%CI 0.89–0.99; p = 0.02) after one dose of vaccine, which were not evident after three doses in the neonatal or infant groups.
Amongst Indonesian infants we did not find an association between IgA in colostrum or breast milk and vaccine take after 3 doses of RV3-BB vaccine. Maternal rotavirus antibodies in breast milk appear to have minimal impact on RV3-BB vaccine take when administered with a short delay in breast-feeding in settings with a high rotavirus disease burden.
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