Impact of maternal antibodies and microbiota development on the immunogenicity of oral rotavirus vaccine in African, Indian, and European infants.

Identifying risk factors for impaired oral rotavirus vaccine (ORV) efficacy in low-income countries may lead to improvements in vaccine design and delivery. In this prospective cohort study, we measure maternal rotavirus antibodies, environmental enteric dysfunction (EED), and bacterial gut microbiota development among infants receiving two doses of Rotarix in India (n = 307), Malawi (n = 119), and the UK (n = 60), using standardised methods across cohorts. We observe ORV shedding and seroconversion rates to be significantly lower in Malawi and India than the UK. Maternal rotavirus-specific antibodies in serum and breastmilk are negatively correlated with ORV response in India and Malawi, mediated partly by a reduction in ORV shedding. In the UK, ORV shedding is not inhibited despite comparable maternal antibody levels to the other cohorts. In both India and Malawi, increased microbiota diversity is negatively correlated with ORV immunogenicity, suggesting that high early-life microbial exposure may contribute to impaired vaccine efficacy.

Measurement of Cellular Immune Response to Viral Infection and Vaccination.

Combined cellular and humoral host immune response determine the clinical course of a viral infection and effectiveness of vaccination, but currently the cellular immune response cannot be measured on simple blood samples. As functional activity of immune cells is determined by coordinated activity of signaling pathways, we developed mRNA-based JAK-STAT signaling pathway activity assays to quantitatively measure the cellular immune response on Affymetrix expression microarray data of various types of blood samples from virally infected patients (influenza, RSV, dengue, yellow fever, rotavirus) or vaccinated individuals, and to determine vaccine immunogenicity. JAK-STAT1/2 pathway activity was increased in blood samples of patients with viral, but not bacterial, infection and was higher in influenza compared to RSV-infected patients, reflecting known differences in immunogenicity. High JAK-STAT3 pathway activity was associated with more severe RSV infection. In contrast to inactivated influenza virus vaccine, live yellow fever vaccine did induce JAK-STAT1/2 pathway activity in blood samples, indicating superior immunogenicity. Normal (healthy) JAK-STAT1/2 pathway activity was established, enabling assay interpretation without the need for a reference sample. The JAK-STAT pathway assays enable measurement of cellular immune response for prognosis, therapy stratification, vaccine development, and clinical testing.

Ziyuglycoside II Inhibits Rotavirus Induced Diarrhea Possibly via TLR4/NF-κB Pathways.

Rotavirus (RV) induced diarrhea has been a major reason affecting children healthy under 5 years old especially in developing countries. Although specific vaccines have preventive effects, antiviral therapy is essential for the diarrhea patients. Ziyuglycoside II is a traditional Chinese herb which has been proven to possess anti-virus effects. This study aimed to investigate the roles of Ziyuglycoside II in rotavirus-induced diarrhea and the underlying molecular mechanism. We found that normal MA104 cells treated with RV became swollen and gather together. However, Ziyuglycoside II treatment inhibited cell growth in a dose- and time dependent manner and suppressed RV replication. Moreover, Ziyuglycoside II reversed RV-induced downregulation of anti-inflammatory cytokine interleukin (IL)-10 and upregulation of pro-inflammatory factors, such as interferon-γ (IFN-γ), IL-1ß, IL-6, and tumor necrosis factor (TNF-α). Moreover, Ziyuglycoside II administration and ribavirin blocked toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway both in mRNA and protein level, which was paralleled with immunohistochemical assay. Additionally, Ziyuglycoside II administration improved diarrhea symptoms and decreased diarrhea scores. Ziyuglycoside II and ribavirin inhibited the apoptosis of small intestine epithelial cells induced by RV. Taken together, RV treatment induced diarrhea. Ziyuglycoside II administration inhibited TLR4/NF-κB pathway and inflammatory response and improved RV-induced diarrhea. The inhibitory effects of Ziyuglycoside II on RV-induced diarrhea predicted Ziyuglycoside II may be a promising drug for diarrhea.

Molecular and serologic characterization of rotavirus from children with acute gastroenteritis in northern Iran, Gorgan.

BACKGROUND: The pattern and distribution of human rotavirus genotypes in young children in developing countries play an important role in epidemiological studies, as well as providing a strategy for the development of future rotavirus vaccine. METHODS: We evaluated stool samples from 349 children with acute gastroenteritis from Northern Iran (Gorgan city, Golestan province). Polyacrylamide Gel Electrophoresis (PAGE) and Latex Agglutination Test (LAT) were utilized to determine the prevalence of human rotavirus in fecal samples. Moreover semi-multiplex RT-PCR technique was carried out in order to determine the P and G genotypes of human rotavirus in rotavirus-positive samples. RESULTS: A total of 46 rotavirus-positive samples were G and P genotyped. Whereas 28 (60.8%) fecal specimens contained only one rotavirus strain, 14 (30.4%) were mixed rotavirus infections and 4 (8.8%) was non-typeable. Overall, during the study, 57.82% of strains identified as genotype G1, G2 (18.70%), G3 (4.69%), G4 (3.13%), G8 (3.13%), G9 (6.26%) and non-typeable G (6.26%). From all these mentioned rotavirus strains, 46 were characterized as P [8] (97.80%) and P [4] (2.20%).Our analysis of the G and P genotyping of strains from all 46 rotavirus-infected children has revealed that 4/46(6.26%) of G type strains were non-typeable. The predominant single G/P combination was G1P [8] (57.82%), followed by, G2P [8] (16.98%), G2P [4] (1.72%), G3P [8] (4.69%), G4P [8] (3.13%) G8P [8] (3.13%), G9P [8] (6.26%) and four cases of non-typeable G (6.26%). Rotavirus was detected in 39 specimens (11.17%) by PAGE and in 38 specimens (10.88%) by LAT. Both tests were 100% specific; however, the LAT was 82.61% sensitive compared to the PAGE, which was 84.78% sensitive. CONCLUSIONS: The results suggest that to characterize rotavirus strains as well as design new effective vaccines for children with acute gastroenteritis, a large-scale study is needed in future.

How the gut microbiome regulates host immune responses to viral vaccines.

The co-evolution of the microbiota and immune system has forged a mutually beneficial relationship. This relationship allows the host to maintain the balance between active immunity to pathogens and vaccines and tolerance to self-antigens and food antigens. In children living in low-income and middle-income countries, undernourishment and repetitive gastrointestinal infections are associated with the failure of oral vaccines. Intestinal dysbiosis associated with these environmental influences, as well as some host-related factors, compromises immune responses and negatively impacts vaccine efficacy. To understand how immune responses to viral vaccines can be optimally modulated, mechanistic studies of the relationship between the microbiome, host genetics, viral infections and the development and function of the immune system are needed. We discuss the potential role of the microbiome in modulating vaccine responses in the context of a growing understanding of the relationship between the gastrointestinal microbiota, host related factors (including histo-blood group antigens) and resident immune cell populations.

Development of T cell immunity to norovirus and rotavirus in children under five years of age.

Most of the research effort to understand protective immunity against norovirus (NoV) has focused on humoral immunity, whereas immunity against another major pediatric enteric virus, rotavirus (RV), has been studied more thoroughly. The aim of this study was to investigate development of cell-mediated immunity to NoV in early childhood. Immune responses to NoV GI.3 and GII.4 virus-like particles and RV VP6 were determined in longitudinal blood samples of 10 healthy children from three months to four years of age. Serum IgG antibodies were measured using enzyme-linked immunosorbent assay and production of interferon-gamma by peripheral blood T cells was analyzed by enzyme-linked immunospot assay. NoV-specific T cells were detected in eight of 10 children by the age of four, with some individual variation. T cell responses to NoV GII.4 were higher than those to GI.3, but these responses were generally lower than responses to RV VP6. In contrast to NoV-specific antibodies, T cell responses were transient in nature. No correlation between cell-mediated and antibody responses was observed. NoV exposure induces vigorous T cell responses in children under five years of age, similar to RV. A role of T cells in protection from NoV infection in early childhood warrants further investigation.

Persistent systemic rotavirus vaccine infection in a child with X-linked severe combined immunodeficiency.

OBJECTIVE: The main aims of the present study were to elucidate the systemic group A rotavirus (RVA) infection and to clarify the genetic changes of persistent virus in the X-linked severe combined immunodeficiency (SCID) patient. METHODS: RotaTeq vaccine (RV5) genotype-specific real-time reverse transcription polymerase chain reaction was used to monitor viral RNA load in serially collected serum and stool samples. Next-generation sequence analysis was used to determine the genotype of the virus by sequencing 11 gene segments. Polyacrylamide gel electrophoresis (PAGE) analysis was used to identify rearrangement of viral genes. The gene rearrangement was examined in NSP5 gene by using Sanger sequence. RESULTS: A 7-month-old boy demonstrated chronic diarrhea following the third administration of RV5 and failure to thrive. He was diagnosed with X-linked SCID and successfully underwent cord blood transplantation. High copy numbers of RV5 genotype G1 RNA were detected in serially collected stool and serum samples and the kinetics of viral RNA loads were correlated with the degree of clinical disease. Next-generation sequence analysis revealed genetic reassortment at least between the strains WI79-9/G1P7[5] and WI79-4/G6P1A[8] in the VP7 gene and the VP4 gene among the vaccine-derived rotavirus strains. In addition, PAGE analysis suggested genetic rearrangements in several genes, and it was confirmed in the NSP5 gene by sequence analysis. CONCLUSIONS: The kinetics of RVA RNA load in serum and stool samples was consistent with the clinical course of the patient. Among five genotypes of RV5 vaccine, G1 genotype replicated well in this patient. Reassortment and rearrangements were demonstrated in persistently infected G1 genotype of RV5.

Rotavirus-mediated alteration of gut microbiota and its correlation with physiological characteristics in neonatal calves.

Diarrhea is a fatal disease to neonatal calves, and rotavirus is the main pathogen associated with neonatal calf diarrhea. Although previous studies have reported that the gut microbiota is changed in calves during diarrhea, less is known about whether rotavirus infection alters the structure of the gut microbiota. Here, we characterized fecal microbial communities and identified possible relationships between the gut microbiota profiles and physiological parameters. Five fecal specimens of rotavirus-infected calves from 1 to 30 days after birth and five fecal specimens of age-matched healthy calves were used for the microbial community analysis using the Illumina MiSeq sequencer. Rotavirus infection was associated with reduced rotavirus infection significantly reduced the richness and diversity of the bacterial community. Weighted unique fraction metric analysis exhibited significant differences in community membership and structure between healthy and rotavirus-infected calves. Based on relative abundance analysis and linear discriminant analysis effect size, we found that the representative genera from Lactobacillus, Subdoligranulum, Blautia, and Bacteroides were closely related to healthy calves, while the genera Escherichia and Clostridium were closely affiliated to rotavirus-infected calves. Furthermore, canonical correlation analysis and Pearson correlation coefficient results revealed that the increased relative abundances of Lactobacillus, Subdoligranulum, and Bacteroides were correlated with normal levels of physiological characteristics such as white blood cells, blood urea nitrogen, serum amyloid protein A, and glucose concentration in serum. These results suggest that rotavirus infection alters the structure of the gut microbiota, correlating changes in physiological parameters. This study provides new information on the relationship between gut microbiota and the physiological parameters of rotavirus-mediated diarrheic calves.

Nonsecretor Histo-blood Group Antigen Phenotype Is Associated With Reduced Risk of Clinical Rotavirus Vaccine Failure in Malawian Infants.

BACKGROUND: Histo-blood group antigen (HBGA) Lewis/secretor phenotypes predict genotype-specific susceptibility to rotavirus gastroenteritis (RVGE). We tested the hypothesis that nonsecretor/Lewis-negative phenotype leads to reduced vaccine take and lower clinical protection following vaccination with G1P[8] rotavirus vaccine (RV1) in Malawian infants. METHODS: A cohort study recruited infants receiving RV1 at age 6 and 10 weeks. HBGA phenotype was determined by salivary enzyme-linked immunosorbent assay (ELISA). RV1 vaccine virus shedding was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in stool collected on alternate days for 10 days post-immunization. Plasma rotavirus-specific immunoglobulin A was determined by ELISA pre- and post-immunization. In a case-control study, HBGA phenotype distribution was compared between RV1-vaccinated infants with RVGE and 1:1 age-matched community controls. Rotavirus genotype was determined by RT-PCR. RESULTS: In 202 cohort participants, neither overall vaccine virus fecal shedding nor seroconversion differed by HBGA phenotype. In 238 case-control infants, nonsecretor phenotype was less common in infants with clinical vaccine failure (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.20-0.75). Nonsecretor phenotype was less common in infants with P[8] RVGE (OR, 0.12; 95% CI, 0.03-0.50) and P[4] RVGE (OR, 0.17; 95% CI, 0.04-0.75). Lewis-negative phenotype was more common in infants with P[6] RVGE (OR, 3.2; 95% CI, 1.4-7.2). CONCLUSIONS: Nonsecretor phenotype was associated with reduced risk of rotavirus vaccine failure. There was no significant association between HBGA phenotype and vaccine take. These data refute the hypothesis that high prevalence of nonsecretor/Lewis-negative phenotypes contributes to lower rotavirus vaccine effectiveness in Malawi.

Cynomolgus Monkeys (Macaca fascicularis) as an Experimental Infection Model for Human Group A Rotavirus.

Group A rotaviruses (RVA) are one of the most common causes of severe acute gastroenteritis in infants worldwide. Rotaviruses spread from person to person, mainly by faecal⁻oral transmission. Almost all unvaccinated children may become infected with RVA in the first two years of life. The establishment of an experimental monkey model with RVA is important to evaluate new therapeutic approaches. In this study, we demonstrated viral shedding and viraemia in juvenile⁻adult Macaca fascicularis orally inoculated with Wa RVA prototype. Nine monkeys were inoculated orally: seven animals with human RVA and two control animals with saline solution. During the study, the monkeys were clinically monitored, and faeces and blood samples were tested for RVA infection. In general, the inoculated animals developed an oligosymptomatic infection pattern. The main clinical symptoms observed were diarrhoea in two monkeys for three days, associated with a reduction in plasmatic potassium content. Viral RNA was detected in seven faecal and five sera samples from inoculated animals, suggesting virus replication. Cynomolgus monkeys are susceptible hosts for human Wa RVA infection. When inoculated orally, they presented self-limited diarrhoea associated with presence of RVA infectious particles in faeces. Thus, cynomolgus monkeys may be useful as animal models to evaluate the efficacy of new antiviral approaches.

Detection, molecular characterization and phylogenetic analysis of G3P[12] and G14P[12] equine rotavirus strains co-circulating in central Kentucky.

Equine rotavirus A (ERVA) is the leading cause of diarrhea in neonatal foals and a major health problem to the equine breeding industry worldwide. The G3P[12] and G14P[12] ERVA genotypes are the most prevalent in foals with diarrhea. Control and prevention strategies include vaccination of pregnant mares with an inactivated vaccine containing a prototype ERVA G3P[12] strain with limited and controversial field efficacy. Here, we performed the molecular characterization of ERVA strains circulating in central Kentucky using fecal samples collected during the 2017 foaling season. The data indicated for the first time that the G14P[12] genotype is predominant in this region in contrast to a previous serotyping study where only G3 genotype strains were reported. Overall, analysis of antigenic sites in the VP7 protein demonstrated the presence of several amino acid substitutions in the epitopes exposed on the surface including a non-conserved N-linked glycosylation site (D123N) in G14P[12] strains, while changes in antigenic sites of VP8* were minor. Also, we report the successful isolation of three ERVA G14P[12] strains which presented a high identity with other G14 strains from around the world. These may constitute ideal reference strains to comparatively study the molecular biology of G3 and G14 strains and perform vaccine efficacy studies following heterologous challenge in the future.

Interrelationship of rotavirus infection and Creatine Kinase-MB isoenzyme levels in children hospitalized with acute gastroenteritis in Guangzhou, China, 2012-2015.

Elevated levels of Creatine Kinase-MB (CK-MB) Isoenzyme are a common phenomenon among rotavirus (RV) diarrhea. However, few studies have addressed this issue using large sample size. In current study, 1,118 children (age <5 years) hospitalized with diarrhea in Guangzhou Women and Children's Medical Center from 2012 to 2015 were finally included. Changing pattern of CK-MB and its relationship with RV-infection were analyzed and characterized. Multivariate linear regression models showed that RV-positive cases had a 28% rise in CK-MB compared to RV-negative cases (OR = 1.28, 95% CI: 1.15 to 1.41, P < 0.01) after controlling for age, gender, season of admission, and weight. The pattern of change showed that CK-MB level of RV-positive group started to rise immediately at the 1st day of diarrhea, reached the peak on days 2 to 4, declined during 4-9 days, and then reached a relatively stable level when compared to the RV-negative group. Mediation analyses showed that indirect effect of RV infection on the increase of CK-MB via Vesikari score was significant (ß = 8.01, P < 0.01), but direct effect was not (ß = 9.96, P = 0.12). Thus, elevated CK-MB value is a common finding in RV-infection and completely mediated by the severity of diarrhea. CK-MB monitoring may help to identify children with more severe viral infection.

Zonulin: A Potential Marker of Intestine Injury in Newborns.

INTRODUCTION: Zonulin (ZO), a new diagnostic biomarker of intestinal permeability, was tested in newborns presenting symptoms of infection and/or inflammation of the gut or being at risk of intestinal pathology. MATERIAL AND METHODS: Serum ZO was assessed in 81 newborns diagnosed with sepsis, necrotizing enterocolitis (NEC), rotavirus infection, and gastroschisis, also in extremely low gestational age babies, and in controls (healthy newborns). ZO concentration was compared to C-reactive protein (CRP) and procalcitonin (PCT) values, leucocyte and platelet count, basic demographic data, and the value of the Neonatal Therapeutic Intervention Scoring System (NTISS). RESULTS: Median values of ZO were markedly higher in groups with rotavirus infection and gastroschisis (36.0 (1-3Q: 26.0-43.2) and 20.3 (1-3Q: 17.7-28.2) ng/ml, resp.) versus controls (3.5 (1-3Q: 2.7-4.8) ng/ml). Its concentration in the NEC group was twice as high as in controls but did not reach statistical significance. ZO levels were not related to NTISS, CRP, and PCT. CONCLUSIONS: Zonulin is a promising biomarker of intestinal condition, markedly elevated in rotavirus infections. Its role in defining the severity of necrotizing enterocolitis and the risk for perforation is not well described and needs further evaluation. An increase in zonulin may not be parallel to the release of inflammatory markers, and low CRP should not exclude an injury to neonatal intestine.

Changes of haemogram and serum biochemistry in neonatal piglet diarrhoea associated with porcine rotavirus type A.

Porcine rotavirus type A (RVA) is a major cause of neonatal piglet mortality in India. The effect of the disease on haemogram and serum biochemical profile is not well established in piglets. Accordingly, we assessed the haemogram and serum biochemical profile in the neonatal piglet diarrhoea with RVA infection (n = 17). The diagnosis of RVA was confirmed using RNA-polyacrylamide gel electrophoresis (RNA-PAGE), commercially available enzyme-linked immunosorbent assay (ELISA) kit and reverse transcription-polymerase chain reaction (RT-PCR). Non-infected healthy piglets (n = 6) served as control. The concentrations of total protein, albumin, alanine amino transaminase (ALT), aspartate amino transaminase (AST), blood urea nitrogen (BUN) and creatinine in serum were measured by spectrophotometric method. Haemogram was done in the blood using sodium ethylenediaminetetraacetic acid (Na2 EDTA) as anticoagulant. The mean values of total protein, albumin and globulin concentrations were significantly (P < 0.001) decreased and concentrations of ALT, AST, BUN and creatinine were significantly increased (P < 0.001) in the RVA-infected piglets. Haemogram showed marked haemoconcentration (P < 0.001), leukopenia (P < 0.01) and neutropenia (P < 0.01) in the presence of RVA infection than healthy piglets. The results indicated a possible extra-intestinal spread of RVA in piglets during neonatal diarrhoea. The finding might be helpful to clinicians and while treating such type of clinical cases, incorporation of organ protective drugs will be helpful for better response in the treatment schedule.

Rotavirus antigen, cytokine, and neutralising antibody profiles in sera of children with and without HIV infection in Blantyre, Malawi.

BACKGROUND: Rotavirus and HIV infection are major causes of death among children in sub-Saharan Africa. A previous study reported no association between concomitant HIV infection and rotavirus disease severity among hospitalised children in Malawi. This study examined rotavirus antigenaemia and broader immune responses among HIV-infected and uninfected children. METHODS: Stored (-80°C), paired sera from acute and convalescent phases of Malawian children less than 5 years old, hospitalised for acute gastroenteritis in the primary study, collected from July 1997 to June 1999, were utilised. Among children older than 15 months, HIV infection was defined as the presence of HIV antibody in the blood, when confirmed by at least 2 established methods. For those younger than 15 months, nested polymerase chain reaction (PCR) amplification of proviral DNA was used for verification. All were followed for up to 4 weeks after hospital discharge. Rotavirus antigen levels in sera were measured with Premier™ Rotaclone® rotavirus enzyme immunoassay (EIA) kit. Acute-phase sera were examined for 17 cytokines, using Luminex fluorescent bead human cytokine immunoassay kit. Rotavirus-specific IgA and neutralising activity were determined by EIA and microneutralisation (MN) assay, respectively. Human strains and bovine-human reassortants were propagated in MA104 cells with serum-free Iscove's Modified Dulbecco's Medium (IMDM). Differences in results, from specimens with and without HIV infection, were analysed for statistical significance using the chi-square test. RESULTS: We detected rotavirus antigen in 30% of the HIV-infected and 21% HIV-uninfected, in the acute-phase sera. HIV-infected children developed slightly prolonged rotavirus antigenaemia compared to HIV-uninfected children. CONCLUSIONS: Rotavirus-specific IgA seroconversion rates and neutralising titres were similar in HIV-infected and HIV-uninfected children, thus, HIV infection had no major effect on immune responses to rotavirus infection.

Evaluation of benign afebrile convulsions in 16 children with rotavirus gastroenteritis.

In this study, we aimed to investigate the demographic, clinical, and laboratory findings of the patients hospitalized with rotavirus gastroenteritis-related afebrile seizure, retrospectively. The study population consisted of 16 patients (9 girls and 7 boys) with a mean age of 13.81 ± 5.98 months (age range 6-26). The male/female ratio was 0.77. None of the patients had any psychomotor developmental retardation. Neurological examinations of all the patients were normal. There were 7 patients with generalized tonic (43.75%), 8 generalized tonic-clonic (50%), and 1 focal seizure (6.25%). The duration of the seizures varied at a range of 2-7 min (mean 3.68 ± 1.35 min). The period between the onset of the clinical findings of the rotavirus infection and the occurrence of the seizures was ranged from 12 to 48 h (mean 31.5 ± 12.2 h). The prognosis of the rotavirus gastroenteritis-related afebrile convulsions was generally benign. Rotavirus infection should be taken into consideration in infants with gastroenteritis and afebrile convulsions.

NSP4 antibody levels in rotavirus gastroenteritis patients with seizures.

BACKGROUND: Rotavirus nonstructural protein 4 (NSP4) has been suggested as a pathogen of rotavirus-associated seizures. We investigated pre-existing serum antibodies against NSP4 and VP6 (the most highly immunogenic rotavirus protein) in patients with rotavirus gastroenteritis and its correlation with the occurrence of seizures. METHODS: With an enzyme-linked immunosorbent assay, IgG and IgA titers against NSP4 (genotype [A] and [B]) and VP6 were measured in acute-phase sera of 202 children aged 0.5-6.0 years with rotavirus gastroenteritis. The clinical characteristics and antibody levels were compared between patients with (seizure group) and without seizures (non-seizure group). RESULTS: The non-seizure and seizure groups comprised 173 and 29 patients, respectively. Age, sex, hospital stay, presence of fever, white blood cell counts, C-reactive protein, vaccine status, IgG/IgA titers for VP6, and IgA titers for both NSP4s did not differ between the groups. The seizure group showed a lower level of IgG against NSP4 [A] (184.5 vs. 163.0 U/mL; P = 0.03) and NSP4 [B] (269.0 vs. 196.0 U/mL; P = 0.02). Delayed sampling time from the onset of gastroenteritis symptoms (3 vs. 2 days; P = 0.02) and lower serum sodium level (133.4 vs. 136.3 mEq/L; P < 0.01) were observed in the seizure group. Even after adjusting these factors, anti-NSP4 [A] IgG (OR 2.56 per 100 U/mL increment; 95% CI, 1.20-5.26, P = 0.01) and anti-NSP4 [B] IgG (OR 1.51 per 100 U/mL-increment; 95% CI, 1.04-2.22, P = 0.03) were independently associated with protection against seizures. CONCLUSIONS: Serum anti-NSP4 IgG might protect rotavirus-associated seizures.

Rotavirus infection and histo-blood group antigens in the children hospitalized with diarrhoea in China.

To explore the association between rotavirus (RV) infection and histo-blood group antigens (HBGAs), a cross-sectional study was conducted in children hospitalized with diarrhoea in China from November 2014 to February 2015. In total, 424 sets of stool, saliva and buccal cell samples were collected. For the 125 RV-negative samples, 92% (104/125) were secretors/partial secretors, 8% (10/125) were non-secretors. Among the 299 RV-positive samples, 277 were P[8] and 22 were P[4]. All P[4] and P[8] positive individuals were secretors/partial secretors except for one P[8] (0.3%, 1/299), which was a non-secretor. These findings indicate that P[8] and P[4] RVs preferably infect secretors/partial secretors (p <0.001).

Association of Maternal Immunity with Rotavirus Vaccine Immunogenicity in Zambian Infants.

INTRODUCTION: Live attenuated oral vaccines against rotavirus (RV) have been shown to be less efficacious in children from developing countries. Reasons for this disparity are not fully understood. We assessed the role of maternal factors including breast milk RV-specific IgA, transplacentally acquired infant serum RV-specific IgG and maternal HIV status in seroconversion among Zambian infants routinely immunized with Rotarix™ (RV1). METHODS: 420 mother-child pairs were recruited at infant age 6-12 weeks in Lusaka. Clinical information and samples were collected at baseline and at one month following the second dose of RV1. Determination of breast milk RV-specific IgA and serum RV-specific IgA and IgG was done using standardized ELISA. Seroconversion was defined as a ≥ 4 fold rise in serum IgA titre from baseline to one-month post RV1 dose 2, while seropositivity of IgA was defined as serum titre ≥ 40 and antibody variables were modelled on log-base 2. Logistic regression was used to identify predictors of the odds of seroconversion. RESULTS: Baseline infant seropositivity was 25.5% (91/357). The seroconversion frequency was 60.2% (130/216). Infants who were IgA seropositive at baseline were less likely to seroconvert compared to their seronegative counterparts (P = 0.04). There was no evidence of an association between maternal HIV status and seroconversion (P = 0.25). Higher titres of breast milk rotavirus-specific IgA were associated with a lower frequency of seroconverson (Nonparametric test for trend Z = -2.84; P<0.01): a two-fold increase in breast milk RV-specific IgA titres was associated with a 22% lower odds of seroconversion (OR = 0.80; 95% CI = 0.68-0.94; P = 0.01). There was seasonal variation in baseline breast milk rotavirus-specific IgA titres, with significantly higher GMTs during the cold dry months (P = 0.01). CONCLUSION: Low immunogenicity of RV1 vaccine could be explained in part by exposure to high antibody titres in breast milk and early exposure to wild-type rotavirus infections. Potential interference of anti-RV specific IgA in breast milk and pre-vaccination serum RV specific-IgA and IgG titres with RV1 seroconversion and effectiveness requires further research.

Association of elevated rotavirus-specific antibody titers with HBGA secretor status in Swedish individuals: The FUT2 gene as a putative susceptibility determinant for infection.

The histo-blood group antigens (HBGAs) have recently been suggested to serve as attachment factors for rotavirus VP8* (P-genotype) in vitro and associated with susceptibility in vivo. We thus investigated whether rotavirus antibody titers and genotype specific neutralization titers correlate with HBGA status in Swedish individuals. We investigated the effect of inactivating mutations in the secretor FUT2 (rs601338) and Lewis FUT3 genes (rs28362459, rs3894326, rs812936 and rs778986) on serum IgG antibody titers and neutralizing antibody titers to rotavirus strains of the P[8] and P[6] genotypes in Swedish healthy blood donors and patients with IgA deficiency using genotyping, enzyme linked immunosorbent assay and a neutralization assay. Rotavirus-specific serum IgG and neutralizing antibody titers to the Wa strain (G1P[8]), but not to the ST3 (G4P[6]) strain, were significantly higher in secretors (with at least one functional FUT2 gene) than in non-secretors (P<0.001) (with homozygous nonsense mutation in the FUT2 gene). Thus, our results represent that secretors show elevated rotavirus specific serum antibodies, suggesting a higher susceptibility to rotavirus infections, as compared to non-secretors in Sweden.