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We evaluated safety and immunogenicity of two orally administered human rotavirus vaccine candidates 116E and I321. Ninety healthy infants aged 8 weeks received a single dose of 116E (10 5 FFu (florescence focus units)), I321 (10 5 FFu) or placebo. There were no significant differences in the number of adverse events. Fever was reported by 6/30, 1/30 and 5/30 in the 116E, I321 and placebo groups; the corresponding figures for diarrhoea were 5/30, 8/29 and 3/30. Serum IgA seroconversion rates were 73%, 39% and 20% in the 116E, I321 and placebo groups, respectively. Vaccine virus was shed on days 3, 7 or 28 in 11/30 infants of the 116E and none in the other two groups. The 116E strain is attenuated, clinically safe and highly immunogenic with a single dose.

Background. The live oral rotavirus (RV) vaccines have shown a reduced efficacy in Africa. Recent in vitro studies have shown binding of the RV surface protein (VP4) to histo–blood group antigens (HBGAs) in an RV genotype–dependent manner, suggesting them to be putative receptors for RV. The diversity of HBGA phenotypes in different ethnic populations, combined with prevalence/absence of specific RV genotypes, led us to hypothesize whether the genetic variations in HBGAs in a population limit susceptibility to certain RV genotypes, plausibly leading to reduced vaccine efficacy. Methods. Association between HBGAs status and susceptibility to RV P genotypes was investigated in children in Burkina Faso and Nicaragua. In total, 242 children with diarrhea in Burkina Faso and Nicaragua were investigated, 93 of whom were RV positive. Results. In Burkina Faso, the P[8] RV strains (n = 27) infected only Lewis- and secretor-positive children (27/27; P < .0001), but no Lewis-negative children. In contrast, the P[6] strains (n = 27) infected predominantly Lewis-negative children (n = 18; P < .0001) but also Lewis-positive children, irrespective of their secretor status. The results from Nicaragua confirmed that all P[8]-infected children (n = 22) were secretor Lewis positive. Conclusions. As VP4 of genotype P[8] is a component of current RV vaccines, our finding that Lewis-negative children are resistant to P[8] strains provides a plausible explanation for the reduced vaccine efficacy in populations with a high percentage of Lewis-negative individuals, such as in Africa. Furthermore, our findings provide a plausible explanation as to why P[6] RV strains are more common in Africa.

Epithelial surfaces are the main entry point for viruses and thus are important immunological sites. Diefenbach and colleagues show that the related cytokines IL-22 and IFN-λ act together in the control of enterovirus infection. The epithelium is the main entry point for many viruses, but the processes that protect barrier surfaces against viral infections are incompletely understood. Here we identified interleukin 22 (IL-22) produced by innate lymphoid cell group 3 (ILC3) as an amplifier of signaling via interferon-λ (IFN-λ), a synergism needed to curtail the replication of rotavirus, the leading cause of childhood gastroenteritis. Cooperation between the receptor for IL-22 and the receptor for IFN-λ, both of which were 'preferentially' expressed by intestinal epithelial cells (IECs), was required for optimal activation of the transcription factor STAT1 and expression of interferon-stimulated genes (ISGs). These data suggested that epithelial cells are protected against viral replication by co-option of two evolutionarily related cytokine networks. These data may inform the design of novel immunotherapy for viral infections that are sensitive to interferons.

Type I IFNs are key cytokines mediating innate antiviral immunity. cGMP-AMP synthase, ritinoic acid-inducible protein 1 (RIG-I)–like receptors, and Toll-like receptors recognize microbial double-stranded (ds)DNA, dsRNA, and LPS to induce the expression of type I IFNs. These signaling pathways converge at the recruitment and activation of the transcription factor IRF-3 (IFN regulatory factor 3). The adaptor proteins STING (stimulator of IFN genes), MAVS (mitochondrial antiviral signaling), and TRIF (TIR domain-containing adaptor inducing IFN-β) mediate the recruitment of IRF-3 through a conserved pLxIS motif. Here we show that the pLxIS motif of phosphorylated STING, MAVS, and TRIF binds to IRF-3 in a similar manner, whereas residues upstream of the motif confer specificity. The structure of the IRF-3 phosphomimetic mutant S386/396E bound to the cAMP response element binding protein (CREB)-binding protein reveals that the pLxIS motif also mediates IRF-3 dimerization and activation. Moreover, rotavirus NSP1 (nonstructural protein 1) employs a pLxIS motif to target IRF-3 for degradation, but phosphorylation of NSP1 is not required for its activity. These results suggest a concerted mechanism for the recruitment and activation of IRF-3 that can be subverted by viral proteins to evade innate immune responses.

The intestinal epithelium can limit enteric pathogens by producing antiviral cytokines, such as IFNs. Type I IFN (IFN-α/β) and type III IFN (IFN-λ) function at the epithelial level, and their respective efficacies depend on the specific pathogen and site of infection. However, the roles of type I and type III IFN in restricting human enteric viruses are poorly characterized as a result of the difficulties in cultivating these viruses in vitro and directly obtaining control and infected small intestinal human tissue. We infected nontransformed human intestinal enteroid cultures frommultiple individuals with human rotavirus (HRV) and assessed the host epithelial response by using RNA-sequencing and functional assays. The dominant transcriptional pathway induced by HRV infection is a type III IFN-regulated response. Early after HRV infection, low levels of type III IFN protein activate IFN-stimulated genes. However, this endogenous response does not restrict HRV replication because replication-competent HRV antagonizes the type III IFN response at pre- and posttranscriptional levels. In contrast, exogenous IFN treatment restricts HRV replication, with type I IFN being more potent than type III IFN, suggesting that extraepithelial sources of type I IFN may be the critical IFN for limiting enteric virus replication in the human intestine.

Timely induction of interferons and interferon-stimulated genes (ISGs) is critical for successful host defense against viral infections. VP3 encoded by rotavirus is implicated in interferon antagonism. However, the precise mechanisms remain incompletely understood. By conducting tandem-affinity purification coupled with high-resolution mass spectrometry, we identify the prefoldin complex as the top cellular binding partner of VP3. Rotavirus infection is significantly enhanced in prefoldin subunit knockout cells. Using proteome-wide label-free quantification, we find that prefoldin assists in folding ubiquitin-like-modifier-activating-enzyme-3 (UBA3), both of which positively regulate ISG expression. Through direct and competitive binding, VP3 interferes with the chaperone activity of prefoldin, leading to unstable UBA3, reduces IRF9, and suppresses ISG transcription. Our findings report a novel function of a prefoldin-UBA3-IRF9-ISG axis in antiviral immunity and uncover new aspects of virus-host interactions that could be exploited for broad-spectrum antiviral therapeutic development. Interferons are a key part of antiviral immunity. Here, the authors identify prefoldin and UBA3 as previously unrecognized regulators of interferon responses. Rotavirus VP3 effectively subverts this pathway to promote viral replication and represents a target for antiviral development.

Porcine rotavirus A (PoRVA) is an enteric pathogen capable of causing severe diarrhea in suckling piglets. Investigating the prevalence and molecular characteristics of PoRVA in the world, including China, is of significance for disease prevention. In 2022, a total of 25,768 samples were collected from 230 farms across China, undergoing porcine RVA positivity testing. The results showed that 86.52% of the pig farms tested positive for porcine RVA, with an overall positive rate of 51.15%. Through the genetic evolution analysis of VP7, VP4 and VP6 genes, it was revealed that G9 is the predominant genotype within the VP7 segment, constituting 56.55%. VP4 genotypes were identified as P[13] (42.22%), P[23] (25.56%) and P[7] (22.22%). VP6 exhibited only two genotypes, namely I5 (88.81%) and I1 (11.19%). The prevailing genotype combination for RVA was determined as G9P[23]I5. Additionally, some RVA strains demonstrated significant homology between VP7, VP4 and VP6 genes and human RV strains, indicating the potential for human RV infection in pigs. Based on complete genome sequencing analysis, a special PoRVA strain, CHN/SD/LYXH2/2022/G4P[6]I1, had high homology with human RV strains, revealing genetic reassortment between human and porcine RV strains in vivo. Our data indicate the high prevalence, major genotypes, and cross-species transmission of porcine RVA in China. Therefore, the continuous monitoring of porcine RVA prevalence is essential, providing valuable insights for virus prevention and control, and supporting the development of candidate vaccines against porcine RVA.

Background. Norovirus and rotavirus are prominent enteric viruses responsible for severe acute gastroenteritis disease burden around the world. Both viruses recognize and bind to histo-blood group antigens, which are expressed by the fucosyltransferase 2 (FUT2) gene. Individuals with a functional FUT2 gene are termed \"secretors.\" FUT2 polymorphisms may influence viral binding patterns and, therefore, may influence host susceptibility to infection by these viruses. Methods. We performed a systematic review of the published literature on this topic. Data were abstracted and compiled for descriptive analyses and metaanalyses. We estimated pooled odds ratios (ORs) for infection using random-effects models. Results. We found that secretors were 9.9 times (95% confidence interval [CI], 3.9–24.8) as likely to be infected with genogroup II.4 noroviruses and 2.2 times as likely to be infected with genogroup II non-4 noroviruses (95% CI, 1.2–4.2) compared with nonsecretors. Secretors were also 26.6 times more susceptible to infections from P[8]-type rotaviruses compared with nonsecretors (95% CI, 8.3–85.0). Conclusions. Our analyses indicate that host genetic susceptibility to norovirus and rotavirus infection may be strain specific. As strain distribution and the proportion of genetic phenotypes vary in different countries, future studies should focus on differences in susceptibility among various ethnicities. Knowledge of innate susceptibility to rotavirus and norovirus can lead to improved under-standing of both vaccine performance and individual risk of disease.

Attachment to carbohydrates of the histo-blood group type of several human Rotavirus strains (RVA) has recently been described. Synthesis of these ligands requires a functional FUT2 enzyme, suggesting that FUT2 null homozygote (ie, nonsecretor) individuals may not be recognized by most human RVA strains. Whereas such individuals represent 20% of the control population, this retrospective study determined that none of 51 patients infected by P[8] rotavirus strains were nonsecretors. The lack of α1,2fucosylated carbohydrate motifs in the gut surface mucosa is thus associated with resistance to symptomatic infection and virus attachment to such motifs is essential to the infection process.

Group A rotaviruses (RVAs) are major etiologic agents of gastroenteritis in infants and young children worldwide. To study the prevalence and genetic characteristics of RVAs, a hospital-based surveillance study was conducted in Wuhan, China from June 2019 through May 2022. The detection rates of RVAs were 19.40% (142/732) and 3.51% (8/228) in children and adults, respectively. G9P[8] was the predominant genotype, followed by G8P[8] and G3P[8]. G8P[8] emerged and was dominant in the 2021–2022 epidemic season. The genome constellation of six G8P[8] strains was assigned to G8-P[8]-I2-R2-C2-M2-A2-N2-T2-E2-H2. Phylogenetic analysis revealed that the VP7, VP4, VP2, VP3, NSP1, NSP2, NSP3, and NSP5 genes of these G8P[8] strains clustered closely with those of the G8P[8] strains in Asia and were distant from those of the P[8] and G2P[4] strains simultaneously detected in Wuhan. In contrast, the VP1, VP6, and NSP4 genes were closely related to the typical G2P[4] rotavirus, including those of G2P[4] strains simultaneously detected in Wuhan. The detection rate of RVAs decreased in the COVID-19 pandemic era. It was deduced that the G8P[8] rotaviruses that emerged in China may be reassortants, carrying the VP6, VP1, and NSP4 genes derived from the G2P[4] rotavirus in the backbone of the neighboring DS-1-like G8P[8] strains represented by CAU17L-103.