Effect of Non-Rotavirus Enteric Infections on Vaccine Efficacy in a ROTASIIL Clinical Trial.

This study examined the relative proportion of enteric pathogens associated with severe gastroenteritis (GE) among children younger than 2 years in a phase III efficacy trial of the ROTASIIL® vaccine in India, evaluated the impact of co-infections on vaccine efficacy (VE), and characterized the association between specific pathogens and the clinical profile of severe GE. Stored stool samples collected from cases of severe GE in the phase III trial were tested by quantitative polymerase chain reaction using TaqMan™ Array Cards. Etiology was attributed by calculating the adjusted attributable fraction (AF) for each pathogen. A test-negative design was used to estimate VE. The pathogens with the highest AFs for severe diarrhea were rotavirus (23.5%), adenovirus 40/41 (17.0%), Shigella spp./enteroinvasive Escherichia coli, norovirus GII, enterotoxigenic E. coli, and Cryptosporidium spp. A considerable proportion of the disease in these children could not be explained by the pathogens tested. Severe GE cases associated with rotavirus and Shigella spp. were more likely to have a longer duration of vomiting and diarrhea, respectively. Cases attributed to Cryptosporidium spp. were more severe and required hospitalization. In the intention-to-treat population, VE was estimated to be 43.9% before and 46.5% after adjustment for co-infections; in the per-protocol population, VE was 46.7% before and 49.1% after adjustments. Rotavirus continued to be the leading cause of severe GE in this age group. The adjusted VE estimates obtained did not support co-infections as a major cause of lower vaccine performance in low- and middle-income countries.

Post-marketing surveillance of intussusception after Rotarix administration in Afghanistan, 2018-2022.

BACKGROUND: In January 2018, Afghanistan introduced the monovalent oral rotavirus vaccine (Rotarix) nationwide, administered as a 2-dose series at six and ten weeks of age. We describe characteristics of intussusception cases and assess potential intussusception risk associated with Rotarix vaccination in Afghan infants. METHODS: Multi-center prospective active hospital-based surveillance for intussusception was conducted from May 2018 to March 2022 in four sentinel sites in Afghanistan. We applied the Brighton Level 1 criteria for intussusception and verified vaccination status by reviewing vaccine cards. We used the self-controlled case series (SCCS) methodology to compare intussusception incidence in the 1 to 21 days after each dose of Rotarix vaccination against non-risk periods. RESULTS: A total of 468 intussusception cases were identified in infants under 12 months, with 264 cases aged between 28 and 245 days having confirmed vaccination status contributing to the SCCS analysis. Most case-patients (98 %) required surgery for treatment, and over half (59 %) of those who underwent surgery required intestinal resection. Nineteen (7 %) case-patients died. Eighty-six percent of case-patients received the first dose of Rotarix, and 69 % received the second dose before intussusception symptom onset. There was no increased risk of intussusception in the 1-7 days (relative incidence: 0.9, 95 % CI: 0.1, 7.5), 8-21 days (1.3, 95 % CI: 0.4, 4.2), or 1-21 days (1.1, 95 % CI: 0.4, 3.4) following receipt of the first dose or in the 1-7 days (0.2, 95 % CI: 0.3, 1.8), 8-21 days (0.7, 95 % CI: 0.3, 1.5), or 1-21 days (0.6, 95 % CI: 0.3, 1.2) following the second dose. CONCLUSION: Rotarix vaccination was not associated with an increased intussusception risk, supporting its continued use in Afghanistan's immunization program. However, there was a high level of death and resection due to intussusception among Afghan infants.

Rotavirus and adenovirus infections in children with acute gastroenteritis after introducing the Rotasiil® vaccine in Kisangani, Democratic Republic of the Congo.

BACKGROUND: Although rotavirus vaccination has reduced the global burden of the virus, morbidity and mortality from rotavirus infection remain high in Sub-Saharan Africa. This study aimed to determine the prevalence of rotavirus and adenovirus infections in children under five years with acute gastroenteritis and to identify factors associated with rotavirus infection after the introduction of the Rotasiil® vaccine in 2019 in Kisangani, Democratic Republic of the Congo (DRC). METHODS: This study consisted of a cross-sectional hospital-based survey conducted from May 2022 to April 2023 in four health facilities in Kisangani, using a fecal-based test (rapid antigenic immuno-chromatographic diagnostic test, BYOSYNEX adenovirus/rotavirus BSS, Biosynex SA, Illkirch-Graffenstaden, France) of rotavirus and adenovirus infections among children under five years of age with acute gastroenteritis. RESULTS: A total of 320 children under five years of age with acute gastroenteritis were included. The prevalence of rotavirus infection was 34.4%, that of adenovirus was 6.3%, and that of both rotavirus and adenovirus coinfection was 1.3%. The prevalence of rotavirus was significantly higher in unvaccinated children than in vaccinated children (55.4% versus 23.1%; P < 0.001). This difference was observed only in children who received all three vaccine doses. Multivariate logistic regression analysis shows that the rate of rotavirus infection was significantly reduced in vaccinated children (adjusted OR: 0.31 [95% confidence intervals (CI): 0.19-0.56]; P < 0.001) and those whose mothers had an average (adjusted OR: 0.51 [95% CI: 0.25-0.91]; P = 0.018) or high level (adjusted OR: 0.34 [95% CI: 0.20-0.64]; P < 0.001) of knowledge about the rotavirus vaccine. CONCLUSIONS: The prevalence of rotavirus infection remains high in Kisangani despite vaccination. However, the prevalence of adenovirus infections was low in our series. Complete vaccination with three doses and mothers' average and high level of knowledge about the rotavirus vaccine significantly reduces the rate of rotavirus infection. It is, therefore, essential to strengthen the mothers' health education, continue with the Rotasiil® vaccine, and ensure epidemiological surveillance of rotavirus infection.

Effect of COVID-19 protective measures on the epidemiology characteristics of rotavirus, adenovirus, and coinfections among pediatric patients with acute gastroenteritis in Hangzhou, China.

Human rotavirus (RV) and adenovirus (AdV) have been recognized as common enteric viruses associated with viral acute gastroenteritis (AGE) in children aged<5 years. However, with the transmission of coronavirus disease 2019 (COVID-19) has been suppressed due to various aggressive and effective anti-epidemic measures, the prevalence of other viruses has also been affected. Therefore, this study aimed to investigate the impact of COVID-19 on the epidemiological characterization of RV, AdV, and coinfections among children with AGE in a hospital in Hangzhou from 2019 to 2023. The overall changes, seasonal distribution, and age distribution of enteroviruses were analyzed based on 5 years of records. All data were analyzed using SPSS 27.0. A total of 102,049 samples were analyzed from January 2019 to August 2023, and among them 15,911 (15.59%) were positive specimens, 11,646 (11.41%) were RV-positive, 4,057 (3.98%) were AdV-positive, and 208 (0.20%) were coinfection. The positive rate among males was 15.54%, while among females was 15.66% with a male-to-female ratio of 1.42:1. There was no significant difference in the positive rates of enterovirus infection between males and females. Significant associations were found between the month group and RV/AdV infection, with RV detection peaking in winter (74.18%) and early spring (29.22%), while AdV has a high prevalence in summer (16.03%) and spring (12.71%). The age group was also found to be significantly associated with RV/AdV infection, with RV being most prevalent in the 1-3-year-old age group (16.99%), while AdV was highest in the 3-5-year-old age group (8.10%).IMPORTANCEThis study highlights the epidemiological changes of rotavirus (RV), adenovirus (AdV), and coinfections in children with acute gastroenteritis (AGE) before, during, and after coronavirus disease 2019 (COVID-19) periods. There was a highly statistically significant difference in the positive rates of RV-positive, AdV-positive, and coinfection (P < 0.001), indicating that RV remains the main pathogen causing AGE. It emphasizes the importance of continuous surveillance of RV and AdV at both local and global levels. Regular surveillance of prevalent rotavirus strains will facilitate the development of new inactivated rotavirus vaccines and aid in disease prevention and control.

Acute rotavirus infection is associated with the induction of circulating memory CD4+ T cell subsets.

Strong CD4+ T cell-mediated immune protection following rotavirus infection has been observed in animal models, but its relevance in humans remains unclear. Here, we characterized acute and convalescent CD4+ T cell responses in children who were hospitalized with rotavirus-positive and rotavirus-negative diarrhoea in Blantyre, Malawi. Children presenting with laboratory-confirmed rotavirus infection had higher proportions of effector and central memory T helper 2 cells during acute infection i.e., at disease presentation compared to convalescence, 28 days post-infection defined by a follow-up 28 days after acute infection. However, circulating cytokine-producing (IFN-γ and/or TNF-α) rotavirus-specific VP6-specific CD4+ T cells were rarely detectable in children with rotavirus infection at both acute and convalescent stages. Moreover, following whole blood mitogenic stimulation, the responding CD4+ T cells were predominantly non-cytokine producers of IFN-γ and/or TNF-α. Our findings demonstrate limited induction of anti-viral IFN-γ and/or TNF-α-producing CD4+ T cells in rotavirus-vaccinated Malawian children following the development of laboratory-confirmed rotavirus infection.

Histo-blood group antigen profile of Australian Aboriginal children and seropositivity following oral rotavirus vaccination.

BACKGROUND: Histo-blood group antigens (HBGAs) may influence immune responses to rotavirus vaccination. METHODS: HBGA phenotyping was determined by detection of antigens A, B, H and Lewis a and b in saliva using enzyme-linked immunosorbent assay. Secretor status was confirmed by lectin antigen assay if A, B and H antigens were negative or borderline (OD ± 0.1 of threshold of detection). PCR-RFLP analysis was used to identify the FUT2 'G428A' mutation in a subset. Rotavirus seropositivity was defined as serum anti-rotavirus IgA ≥ 20 AU/mL. RESULTS: Of 156 children, 119 (76 %) were secretors, 129 (83 %) were Lewis antigen positive, and 105 (67 %) were rotavirus IgA seropositive. Eighty-seven of 119 (73 %) secretors were rotavirus seropositive, versus 4/9 (44 %) weak secretors and 13/27 (48 %) non-secretors. CONCLUSIONS: Most Australian Aboriginal children were secretor and Lewis antigen positive. Non-secretor children were less likely to be seropositive to rotavirus antibodies following vaccination, but this phenotype was less common. HBGA status is unlikely to fully explain underperformance of rotavirus vaccines among Australian Aboriginal children.

Type III and Not Type I Interferons Efficiently Prevent the Spread of Rotavirus in Human Intestinal Epithelial Cells.

Rotavirus infects intestinal epithelial cells and is the leading cause of gastroenteritis in infants worldwide. Upon viral infection, intestinal cells produce type I and type III interferons (IFNs) to alert the tissue and promote an antiviral state. These two types of IFN bind to different receptors but induce similar pathways that stimulate the activation of interferon-stimulated genes (ISGs) to combat viral infection. In this work, we studied the spread of a fluorescent wild-type (WT) SA11 rotavirus in human colorectal cancer cells lacking specific interferon receptors and compared it to that of an NSP1 mutant rotavirus that cannot interfere with the host intrinsic innate immune response. We could show that the WT rotavirus efficiently blocks the production of type I IFNs but that type III IFNs are still produced, whereas the NSP1 mutant rotavirus allows the production of both. Interestingly, while both exogenously added type I and type III IFNs could efficiently protect cells against rotavirus infection, endogenous type III IFNs were found to be key to limit infection of human intestinal cells by rotavirus. By using a fluorescent reporter cell line to highlight the cells mounting an antiviral program, we could show that paracrine signaling driven by type III IFNs efficiently controls the spread of both WT and NSP1 mutant rotavirus. Our results strongly suggest that NSP1 efficiently blocks the type I IFN-mediated antiviral response; however, its restriction of the type III IFN-mediated one is not sufficient to prevent type III IFNs from partially inhibiting viral spread in intestinal epithelial cells. Additionally, our findings further highlight the importance of type III IFNs in controlling rotavirus infection, which could be exploited as antiviral therapeutic measures. IMPORTANCE Rotavirus is one of the most common causes of gastroenteritis worldwide. In developing countries, rotavirus infections lead to more than 200,000 deaths in infants and children. The intestinal epithelial cells lining the gastrointestinal tract combat rotavirus infection by two key antiviral compounds known as type I and III interferons. However, rotavirus has developed countermeasures to block the antiviral actions of the interferons. In this work, we evaluated the arms race between rotavirus and type I and III interferons. We determined that although rotavirus could block the induction of type I interferons, it was unable to block type III interferons. The ability of infected cells to produce and release type III interferons leads to the protection of the noninfected neighboring cells and the clearance of rotavirus infection from the epithelium. This suggests that type III interferons are key antiviral agents and could be used to help control rotavirus infections in children.

Effect of probiotic bacteria on porcine rotavirus OSU infection of porcine intestinal epithelial IPEC-J2 cells.

Rotavirus infections in nursing or post-weaning piglets are known to cause diarrhea, which can lead to commercial losses. Probiotic supplementation is used as a prophylactic or therapeutic approach to dealing with microbial infections in humans and animals. To evaluate the effect of probiotic bacteria on porcine rotavirus infections, non-transformed porcine intestinal epithelial IPEC-J2 cells were used as an in vitro model, and three different procedures were tested. When cells were exposed to seven probiotics at concentrations of 105, 106, or 107 CFU/mL for 16 h and removed before rotavirus challenge, infection reduction rates determined by flow cytometry were as follows: 15% (106) and 18% (105) for Bifidobacterium longum R0175, 15% (107) and 16% (106) for B. animalis lactis A026, and 15% (105) for Lactobacillus plantarum 299V. When cells were exposed to three selected probiotic strains for 1 h at higher concentrations, that is, 108 and 5 × 108 CFU/mL, before infection with rotavirus, no significant reduction was observed. When the probiotic bacteria were incubated with the virus before cell infection, a significant 14% decrease in the infection rate was observed for B. longum R0175. The results obtained using a cell-probiotics-virus platform combined with flow cytometry analysis suggest that probiotic bacteria can have a protective effect on IPEC-J2 cells before infection and can also prevent rotavirus infection of the cells.

Rotavirus vaccination is not associated with incident celiac disease or autoimmune thyroid disease in a national cohort of privately insured children.

Rotavirus infection is a potential trigger for autoimmune diseases, and previous reports note associations between rotavirus vaccination and type 1 diabetes. In this report, we examine the association between rotavirus vaccination and autoimmune diseases associated with type 1 diabetes: celiac disease and autoimmune thyroiditis. We conducted a retrospective cohort study using de-identified claims data (Optum Clinformatics® Data Mart). Eligible infants were born between 2001 and 2018 and continuously enrolled from birth for at least 365 days (n = 2,109,225). Twenty-nine percent (n = 613,295) of infants were born prior to the introduction of rotavirus vaccine in 2006; 32% (n = 684,214) were eligible for the vaccine but were not vaccinated; 9.6% (n = 202,016) received partial vaccination, and 28.9% received full vaccination (n = 609,700). There were 1379 cases of celiac disease and 1000 cases of autoimmune thyroiditis. Children who were born prior to the introduction of rotavirus vaccine in 2006 had lower risk of celiac disease compared to unvaccinated children born after 2006 (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.59, 0.85). However, children who were partially vaccinated (HR 0.90, 95% CI 0.73, 1.11) or fully vaccinated (HR 1.03, 95% CI 0.88, 1.21) had similar risk to eligible, unvaccinated children. Risk of autoimmune thyroiditis was similar by vaccination status. We conclude that rotavirus vaccination is not associated with increased or decreased risk for celiac disease or autoimmune thyroiditis.

Severity of Rotavirus-Vaccine-Associated Intussusception: Prospective Hospital-Based Surveillance, Australia, 2007-2018.

BACKGROUND: Multiple studies have shown an association between intussusception (IS) and receipt of monovalent or pentavalent rotavirus vaccine (RV) in the previous 21 days. Disease severity is an important consideration for risk-benefit evaluations of RV, but no studies have compared the severity of IS within 21 days of vaccination (vaccine-associated, VA) and later (not temporally-associated, VNA). METHODS: We used active hospital-based surveillance in the Australian Paediatric Active Enhanced Disease Surveillance (PAEDS) network (July 2007 to February 2018) to identify infants ≤9 months of age meeting Brighton level 1 criteria for IS. We used five severity levels: (1) no surgery and length of stay (LOS) ≤1 day, (2) no surgery and LOS ≥2 days, (3) surgery, no bowel resection, (4) bowel resection, and (5) ICU admission. RESULTS: Of 323 eligible cases, 87 (26.9%) were VA and 236 (73.1%) VNA. VA-IS cases (median 21 weeks; 24.1% ≤14 weeks) were significantly younger than VNA-IS cases (median 28 weeks, 7.2% ≤14 weeks). Cases 0-≤14 weeks of age were significantly more likely than cases ≥25 weeks to require bowel resection (relative risk ratio 4.6, 95% CI, 1.48-14.3). This effect was not associated with RV. After adjustment for age and sex, VA-IS was not significantly overrepresented in severity levels 2-5; adjusted RRR of 1.37 (95% CI: 0.61-3.11) for bowel resection in cases 0-≤14 weeks of age. CONCLUSIONS: IS was uncommon but significantly more severe under 14 weeks of age. After adjustment for age and sex, IS severity was not related to RV.

Caracterización clínico epidemiológica de la gastroenteritis por rotavirus. Estudio piloto. Hospital Pediátrico de Centro Habana. Noviembre 2017- abril 2018 / Clinical epidemiological characterization of rotavirus gastroenteritis. Pilot study. Paediatric Hospital of Centro Habana

La gastroenteritis causada por rotavirus constituye un importante problema de salud mundial, por lo que se recomienda incluir la vacunación contra el rotavirus en los programas de inmunización. Para evaluar el impacto de una futura introducción en Cuba de una vacuna contra este patógeno, resulta necesario crear una línea de base pre-vacunación de la carga de la gastroenteritis causada por este virus. Entre noviembre 2017 a abril 2018 se implementó en el Hospital Pediátrico de Centro Habana un sistema de vigilancia para la gastroenteritis causada por rotavirus. Se establecieron las definiciones para las categorías de caso sospechoso, probable y confirmado. Por cada niño captado se recogió una muestra de heces que se analizó con tiras rápidas y se confirmó la presencia de rotavirus por ELISA. Para determinar la severidad de la enfermedad se utilizó la escala de Vesikari. Los resultados fueron expresados en cifras absolutas y relativas, el análisis se realizó a través de la prueba de chi-cuadrado. Del total de ingresos por enfermedad diarreica aguda, el 26 por ciento cumplió los criterios de inclusión y el 46 por ciento resultó confirmado como rotavirus. El hacinamiento en el hogar y asistir al círculo infantil se comportaron como factores de riesgo. El servicio de gastroenterología absorbió la mayor carga de ingresos hospitalarios por esta causa. Los resultados mostrados validan la funcionalidad del sistema de vigilancia implementado y brindan nuevas evidencias sobre la carga de la enfermedad y la utilización de los servicios de un hospital pediátrico cubano, debido a la gastroenteritis provocada por rotavirus, lo que justifica la introducción de la vacuna(AU)

Gastroenteritis caused by rotavirus is a major global health problem, therefore it is recommended that vaccination against rotavirus be included in immunization programs. To evaluate the impact of a future introduction in Cuba of a vaccine against this pathogen, it is necessary to have a pre-vaccination baseline of the burden of gastroenteritis caused by rotavirus. Between November 2017 and April 2018, a surveillance system for gastroenteritis caused by rotavirus was implemented in the Paediatric Hospital of Centro Habana. Definitions were established for the categories of suspected, probable and confirmed cases. For each captured child, stool samples were collected, analyzed with rapid strips and confirmated by ELISA. To determine the severity of the disease, the Vesikari score was used. The results were expressed in absolute and relative figures; the analysis was performed through chi-square. Of the total admissions for acute diarrheal disease, 26 percent met the inclusion criteria and 46 percent were confirmed for rotavirus. Overcrowding at home and attending a day care center were risk factors. The gastroenterology service absorbed the greatest burden of hospital admissions for this cause. The results shown validate the role of the implemented surveillance system and provide new evidence on the burden of disease and use of services for rotavirus gastroenteritis in a cuban pediatric hospital(AU)

Bovine Lactoferricin Induces Intestinal Epithelial Cell Activation through Phosphorylation of FAK and Paxillin and Prevents Rotavirus Infection.

We investigated the effect of bovine lactoferricin (Lfcin-B), a peptide derived from bovine lactoferrin, on activation of intestinal epithelial cells in IEC-6 intestinal cell, and protection against in vivo rotavirus (RV) infection. Treatment with Lfcin-B significantly enhanced the growth of IEC-6 cells and increased their capacity for attachment and spreading in culture plates. Also, Lfcin-B synergistically augmented the binding of IEC-6 cells to laminin, a component of the extracellular matrix (ECM). In the analysis of the intracellular mechanism related to Lfcin-B-induced activation of IEC-6 cells, this peptide upregulated tyrosine-dependent phosphorylation of focal adhesion kinase (FAK) and paxillin, which are intracellular proteins associated with cell adhesion, spreading, and signal transduction during cell activation. An experiment using synthetic peptides with various sequences of amino acids revealed that a sequence of 9 amino acids (FKCRRWQWR) corresponding to 17-25 of the N-terminus of Lfcin-B is responsible for the epithelial cell activation. In an in vivo experiment, treatment with Lfcin-B one day before RV infection effectively prevented RV-induced diarrhea and significantly reduced RV titers in the bowels of infected mice. These results suggest that Lfcin-B plays meaningful roles in the maintenance and repair of intestinal mucosal tissues, as well as in protecting against intestinal infection by RV. Collectively, Lfcin-B is a promising candidate with potential applications in drugs or functional foods beneficial for intestinal health and mucosal immunity.

Development and characterization of a plant-derived rotavirus-like particle vaccine.

BACKGROUND: Virus-like particles (VLPs) are unable to replicate in the recipient but stimulate the immune system through recognition of repetitive subunits. Parenterally delivered rotavirus-VLP (Ro-VLP) vaccine could have the potential to overcome the weaknesses of licensed oral live-attenuated rotavirus vaccines, namely, low efficacy in low-income and high mortality settings and a potential risk of intussusception. METHODS: A monovalent Ro-VLP composed of viral protein (VP) 7, VP6 and VP2 of G1 genotype specificity was produced in Nicotiana benthamiana using Agrobacterium tumefaciens infiltration-based transient recombinant expression system. Plants expressing recombinant G1 Ro-VLP were harvested, then the resultant biomass was processed through a series of clarification and purification steps including standard extraction, filtration, ultrafiltration and chromatography. The purified G1 Ro-VLP was subsequently examined for its immunogenicity and toxicological profile using animal models. RESULTS: G1 Ro-VLP had a purity of ≥90% and was structurally similar to triple-layered rotavirus particles as determined by cryogenic transmission electron microscopy. Two doses of aluminum hydroxide-adjuvanted G1 Ro-VLP (1 µg, 5 µg or 30 µg), administered intramuscularly, elicited a robust homotypic neutralizing antibody response in rats. Also, rabbits administered G1 Ro-VLP (10 µg or 30 µg) four times intramuscularly with aluminum hydroxide adjuvant did not show any significant toxicity. CONCLUSIONS: Plant-derived Ro-VLP composed of VP7, VP6 and VP2 structural proteins would be a plausible alternative to live-attenuated oral rotavirus vaccines currently distributed worldwide.

Ligilactobacillus salivarius Strains Isolated From the Porcine Gut Modulate Innate Immune Responses in Epithelial Cells and Improve Protection Against Intestinal Viral-Bacterial Superinfection.

Previously, we constructed a library of Ligilactobacillus salivarius strains from the intestine of wakame-fed pigs and reported a strain-dependent capacity to modulate IFN-ß expression in porcine intestinal epithelial (PIE) cells. In this work, we further characterized the immunomodulatory activities of L. salivarius strains from wakame-fed pigs by evaluating their ability to modulate TLR3- and TLR4-mediated innate immune responses in PIE cells. Two strains with a remarkable immunomodulatory potential were selected: L. salivarius FFIG35 and FFIG58. Both strains improved IFN-ß, IFN-λ and antiviral factors expression in PIE cells after TLR3 activation, which correlated with an enhanced resistance to rotavirus infection. Moreover, a model of enterotoxigenic E. coli (ETEC)/rotavirus superinfection in PIE cells was developed. Cells were more susceptible to rotavirus infection when the challenge occurred in conjunction with ETEC compared to the virus alone. However, L. salivarius FFIG35 and FFIG58 maintained their ability to enhance IFN-ß, IFN-λ and antiviral factors expression in PIE cells, and to reduce rotavirus replication in the context of superinfection. We also demonstrated that FFIG35 and FFIG58 strains regulated the immune response of PIE cells to rotavirus challenge or ETEC/rotavirus superinfection through the modulation of negative regulators of the TLR signaling pathway. In vivo studies performed in mice models confirmed the ability of L. salivarius FFIG58 to beneficially modulate the innate immune response and protect against ETEC infection. The results of this work contribute to the understanding of beneficial lactobacilli interactions with epithelial cells and allow us to hypothesize that the FFIG35 or FFIG58 strains could be used for the development of highly efficient functional feed to improve immune health status and reduce the severity of intestinal infections and superinfections in weaned piglets.

Indirect impact of rotavirus vaccination on viral causes of acute gastroenteritis in the elderly.

BACKGROUND: Rotavirus is considered a childhood infection causing acute gastroenteritis however, it also causes disease in adults which may be underestimated due to less frequent testing in this age-group. OBJECTIVES: To determine if paediatric rotavirus vaccination, introduced into Ireland in December 2016, affected the viral aetiology in those aged ≥65 yrs presenting with gastroenteritis in the pre- and post-vaccination years. Additionally, rotavirus genotypes in this age-group will be described. METHODS: Faecal samples from 2015 to 2019 for the investigation of gastroenteritis were tested by real-time (RT-) PCR for norovirus, adenovirus, rotavirus, Rotarix, astrovirus and sapovirus. Rotaviruses were genotyped by multiplex real-time RT-PCR or hemi-nested RT-PCR and a proportion confirmed by sequencing. RESULTS: 22,593 samples from adults aged ≥65 yrs were tested and 2566 (11 %) had ≥1 virus detected. Of 2566 positive samples, norovirus was detected in 82 %, rotavirus 9 %, sapovirus 6 %, astrovirus 3 % and adenovirus 1 %. Rotavirus and norovirus infections decreased between pre and post-vaccine year groups p < 0.001, whereas sapovirus, astrovirus and adenovirus remained unchanged. Between 2015-16 and 2018-19, G2P[4] increased and G4P[8] decreased, p < 0.001. In 2015-2019 there were 37 rotavirus outbreaks. Five geriatric outbreaks were genotyped and caused by G4P[8] (n = 1), G1P[8] (n = 1), G2P[4] (n = 2) and G12P[8] (n = 1). CONCLUSION: Rotavirus causes acute gastroenteritis in older people. Paediatric vaccination may have contributed to a decline in infections in the elderly; nevertheless, rotavirus continued to circulate in older people following vaccine introduction. Genotype distribution changed between the pre- and post-vaccine era however genotypes in outbreak and endemic settings were comparable.

Epidemiology of Intussusception Hospitalizations in Children Under 2 Years of Age Post Rotavirus Vaccine Introduction in Tamil Nadu and Puducherry, India.

OBJECTIVE: High burden of rotavirus associated diarrhea has been documented among Indian children. The phased introduction of an indigenous rotavirus vaccine 'ROTAVAC' in India's national immunization programme began in 2017. Phase-III trial showed the vaccine to have a low-intussusception-risk profile. However, evaluation of post-licensure trends of intussusception is necessary to assess potential vaccine-associated intussusception risk. This study's objective was to describe the epidemiology of intussusception hospitalizations in children under two years of age in Tamil Nadu and Puducherry following ROTAVAC introduction. METHODS: A cross-sectional surveillance was established in six hospitals in Tamil Nadu and Puducherry. Children under two years of age with intussusception fulfilling Brighton Collaboration's criteria for level 1 diagnostic certainty were enrolled. Patient and disease characteristics were captured using a standardized questionnaire. Descriptive and inferential statistical analyses were performed using Stata Version 13. RESULTS: Overall, 287 cases were enrolled and had a median age of seven months. Frequently presenting symptoms were vomiting (78%), abdominal pain (76%), and blood in stool (71%). Abdominal ultrasonography or radiography confirmed diagnosis in 65% of cases and managed by nonoperative measures. Remaining 35% of cases were diagnosed and managed with surgery. Over 98% of the cases had positive treatment outcomes. Age less than five months (OR = 4.36), and hospitalization at a state government health facility (OR = 5.01) were significant predictors for children to receive surgical management. CONCLUSIONS: The present study documents the epidemiology of intussusceptions immediately after the rollout of rotavirus vaccine in Tamil Nadu and Puducherry. No appreciable increase in intussusception hospitalizations was seen in the study hospitals after vaccine introduction.

Reduced rotavirus vaccine efficacy in protein malnourished human-faecal-microbiota-transplanted gnotobiotic pig model is in part attributed to the gut microbiota.

The low efficacy of human rotavirus (HRV) vaccines in low- and middle-income countries (LMIC) remains a major challenge for global health. Protein-calorie malnutrition (kwashiorkor) affects the gut microbiota and compromises immune development, leading to environmental enteropathy, vaccine failures, and increased susceptibility to enteric diseases in young children. Relationship between diet and reduced vaccine efficacy in developing countries is not well established; therefore, we investigated the interconnections between the host-microbiota-nutrition-HRV vaccine using HRV-vaccinated, human infant faecal microbiota (HIFM)-transplanted neonatal gnotobiotic pigs fed with a protein deficient or sufficient diet. The microbiota from faecal, intestinal (duodenum, ileum, jejunum, and colon), and systemic tissue (liver, spleen, and mesenteric lymph node [MLN]) samples was analysed before and after HRV challenge using MiSeq 16S rRNA sequencing. Overall, microbiota from deficient fed HIFM pigs displayed, compared to the sufficient group, significantly higher Shannon index, especially in the faeces and lower intestines; higher level of Proteus and Enterococcus, and lower level of Bifidobacterium, Clostridium, and Streptococcus in the three types of samples collected (P<0.05); and higher unique operational taxonomic units (OTUs), especially in the systemic tissues. Further, the multivariate analysis between microbiota and immunologic data showed that 38 OTUs at the genus level correlated (r2≤0.5 or ≥-0.5; P<0.05) with at least one host immune response parameter (regulatory [Tregs and transforming growth factor-ß], effectors [interferon (IFN)-γ+ CD4+ and CD8+ T cells, IFN-γ and interleukin (IL)-12], and inflammatory [tumour necrosis factor-α, IL-17 and IL-22]) and with opposite trends between diet groups. Differences described above were increased after HRV challenge. We demonstrated that a protein deficient diet affects the composition of the gut microbiota and those changes may further correlate with immune responses induced by HRV and perturbed by the deficient diet. Thus, our findings suggest that the reduced efficacy of HRV vaccine observed in Gn pig model is in part attributed to the altered microbiota composition.

Diversity of rotavirus genotypes circulating in children < 5 years of age hospitalized for acute gastroenteritis in India from 2005 to 2016: analysis of temporal and regional genotype variation.

BACKGROUND: From 2016, the Government of India introduced the oral rotavirus vaccine into the national immunization schedule. Currently, two indigenously developed vaccines (ROTAVAC, Bharat Biotech; ROTASIIL, Serum Institute of India) are included in the Indian immunization program. We report the rotavirus disease burden and the diversity of rotavirus genotypes from 2005 to 2016 in a multi-centric surveillance study before the introduction of vaccines. METHODS: A total of 29,561 stool samples collected from 2005 to 2016 (7 sites during 2005-2009, 3 sites from 2009 to 2012, and 28 sites during 2012-2016) were included in the analysis. Stools were tested for rotavirus antigen using enzyme immunoassay (EIA). Genotyping was performed on 65.8% of the EIA positive samples using reverse transcription- polymerase chain reaction (RT-PCR) to identify the G (VP7) and P (VP4) types. Multinomial logistic regression was used to quantify the odds of detecting genotypes across the surveillance period and in particular age groups. RESULTS: Of the 29,561 samples tested, 10,959 (37.1%) were positive for rotavirus. There was a peak in rotavirus positivity during December to February across all sites. Of the 7215 genotyped samples, G1P[8] (38.7%) was the most common, followed by G2P[4] (12.3%), G9P[4] (5.8%), G12P[6] (4.2%), G9P[8] (4%), and G12P[8] (2.4%). Globally, G9P[4] and G12P[6] are less common genotypes, although these genotypes have been reported from India and few other countries. There was a variation in the geographic and temporal distribution of genotypes, and the emergence or re-emergence of new genotypes such as G3P[8] was seen. Over the surveillance period, there was a decline in the proportion of G2P[4], and an increase in the proportion of G9P[4]. A higher proportion of mixed and partially typed/untyped samples was also seen more in the age group 0-11 months. CONCLUSIONS: This 11 years surveillance highlights the high burden of severe rotavirus gastroenteritis in Indian children < 5 years of age before inclusion of rotavirus vaccines in the national programme. Regional variations in rotavirus epidemiology were seen, including the emergence of G3P[8] in the latter part of the surveillance. Having pre-introduction data is important to track changing epidemiology of rotaviruses, particularly following vaccine introduction.

Impact of rotavirus vaccination on intussusception hospital admissions in England.

BACKGROUND: An increased risk of intussusception has been reported following rotavirus vaccination. We sought to determine whether introduction of rotavirus vaccination in England in July 2013 was associated with a change in the burden of total and age group-specific childhood hospital admissions for intussusception. METHODS: We identified all children aged 0-36 months admitted to hospitals in England with intussusception using the Hospital Episode Statistics dataset. We performed a retrospective ecological analysis comparing hospital admission rates for intussusception during the periods before (2008/2009-2012/2013) and after (2014/2015-2017/2018) introduction of rotavirus vaccination using modified Poisson regression and interrupted time series analysis. Length of hospital stay and clinical outcomes were also examined. RESULTS: The mean annual admission rate for intussusception in infants over the ten-year study period was 31.5 per 100,000 person-years. An increase in the admission rate in the 8-16 weeks age group (RR 1.46, 95% CI 1.12-1.91), those receiving vaccination, was compensated for by decreases in the 17-24 weeks (RR 0.77, 0.63-0.94), 25-32 weeks (RR 0.71, 0.59-0.86) and 41-52 weeks (RR 0.80, 0.66-0.98) age groups. Using interrupted time series analysis, we observed a significant decrease in incidence in the 0-12 months age group (RR 0.80, 0.67-0.96), but not in the overall 0-36 months age group (RR 1.09, 0.98-1.20). There was no significant change in the proportion of children requiring surgical intervention or with major complications of intussusception. Length of hospital stay decreased among infants receiving surgery for intussusception. CONCLUSIONS: Our results suggest that introduction of rotavirus vaccination in England has resulted in a downward shift in the age at which intussusception occurs in infants, with no overall increase in hospital admission rate or disease severity. These findings support the view that the benefits of rotavirus vaccination outweigh the small increased risk of intussusception in the early post-vaccination period.