RESUMO
Rotavirus, a dsRNA virus in the Reoviridae family, shows a segmented genome. The VP1 gene encodes the RNA-dependent RNA polymerase (RdRp). This study aims to develop a multiepitope-based vaccine targeting RdRp using immunoinformatic approaches. In this study, 100 available nucleotide sequences of VP1-Rotavirus belonging to different strains across the world were retrieved from NCBI database. The selected sequences were aligned, and a global consensus sequence was developed by using CLC work bench. The study involved immunoinformatic approaches and molecular docking studies to reveal the promiscuous epitopes that can be eventually used as active vaccine candidates for Rotavirus. In total, 27 highly immunogenic, antigenic, and non-allergenic T-cell and B-cell epitopes were predicted for the Multiepitope vaccine (MEV) against rotavirus. It was also observed that MEV can prove to be effective worldwide due to its high population coverage, demonstrating the consistency of this vaccine. Moreover, there is a high docking interaction and immunological response with a binding score of -50.2 kcal/mol, suggesting the vaccine's efficacy. Toll-like receptors (TLRs) also suggest that the vaccine is physiologically and immunologically effective. Collectively, our data point to an effective MEV against rotavirus that can effectively reduce viral infections and improve the health status worldwide.
Assuntos
Simulação de Acoplamento Molecular , Vacinas contra Rotavirus , Rotavirus , Vacinas de Subunidades Antigênicas , Rotavirus/imunologia , Rotavirus/genética , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/genética , Vacinas contra Rotavirus/imunologia , RNA Polimerase Dependente de RNA/imunologia , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/química , Biologia Computacional , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/genética , Humanos , Epitopos/imunologia , Epitopos/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/genética , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/imunologia , Imunoinformática , Vacinas de Subunidades ProteicasRESUMO
High titres of rotavirus-specific maternal antibodies may contribute to lower rotavirus vaccine efficacy in low- and middle-income countries (LMICs). RV3-BB vaccine (G3P[6]) is based on a neonatal rotavirus strain that replicates well in the newborn gut in the presence of breast milk. This study investigated the association between maternal serum antibodies and vaccine response in infants administered the RV3-BB vaccine. Serum was collected antenatally from mothers of 561 infants enrolled in the RV3-BB Phase II study conducted in Blantyre, Malawi, and analysed for rotavirus-specific serum IgA and IgG antibodies using enzyme-linked immunosorbent assay. Infant vaccine take was defined as cumulative IgA seroconversion (≥3 fold increase) and/or stool vaccine shedding. Maternal IgA or IgG antibody titres did not have a negative impact on vaccine-like stool shedding at any timepoint. Maternal IgG (but not IgA) titres were associated with reduced take post dose 1 (p < 0.005) and 3 (p < 0.05) in the neonatal vaccine schedule group but not at study completion (week 18). In LMICs where high maternal antibodies are associated with low rotavirus vaccine efficacy, RV3-BB in a neonatal or infant vaccine schedule has the potential to provide protection against severe rotavirus disease.
Assuntos
Anticorpos Antivirais , Imunoglobulina A , Imunoglobulina G , Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Humanos , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Malaui , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/imunologia , Feminino , Rotavirus/imunologia , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lactente , Recém-Nascido , Esquemas de Imunização , Adulto , Imunidade Materno-Adquirida , Eficácia de Vacinas , Fezes/virologia , Masculino , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/administração & dosagem , Vacinação , Adulto JovemRESUMO
The functions of the natural dsRNA sensors TLR3 (TRIF) and RIG-I (MAVS) are crucial during viral challenge and have not been accurately clarified in adaptive immune responses to rotavirus (RV) infection. In this study, we found that RV infection caused severe pathological damage to the small intestine of TLR3-/- and TRIF-/- mice. Our data found that dendritic cells from TLR3-/- and TRIF-/- mice had impaired Ag presentation to the RV and attenuated initiation of T cells upon viral infection. These attenuated functions resulted in impaired CD4+ T and CD8+ T function in mice lacking TLR3-TRIF signaling postinfection. Additionally, attenuated proliferative capacity of T cells from TLR3-/- and TRIF-/- mice was observed. Subsequently, we observed a significant reduction in the absolute number of memory T cells in the spleen and mesenteric lymph node (MLN) of TRIF-/- recipient mice following RV infection in a bone marrow chimeric model. Furthermore, there was reduced migration of type 2 classical dendritic cells from the intestine to MLNs after RV infection in TLR3-/- and TRIF-/- mice. Notably, RV infection resulted in attenuated killing of spleen and MLN tissues in TRIF-/- and MAVS-/- mice. Finally, we demonstrated that RV infection promoted apoptosis of CD8+ T cells in TRIF-/- and TLR3-/-MAVS-/- mice. Taken together, our findings highlight an important mechanism of TLR3 signaling through TRIF in mucosal T cell responses to RV and lay the foundation for the development of a novel vaccine.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular , Células Dendríticas , Camundongos Knockout , Infecções por Rotavirus , Rotavirus , Transdução de Sinais , Receptor 3 Toll-Like , Animais , Receptor 3 Toll-Like/imunologia , Camundongos , Infecções por Rotavirus/imunologia , Transdução de Sinais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Rotavirus/imunologia , Células Dendríticas/imunologia , Camundongos Endogâmicos C57BL , Mucosa Intestinal/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade nas Mucosas , Apresentação de Antígeno/imunologiaRESUMO
Equine rotavirus species A (ERVA) G3P[12] and G14P[12] are two dominant genotypes that cause foal diarrhoea with a significant economic impact on the global equine industry. ERVA can also serve as a source of novel (equine-like) rotavirus species A (RVA) reassortants with zoonotic potential as those identified previously in 2013-2019 when equine G3-like RVA was responsible for worldwide outbreaks of severe gastroenteritis and hospitalizations in children. One hurdle to ERVA research is that the standard cell culture system optimized for human rotavirus replication is not efficient for isolating ERVA. Here, using an engineered cell line defective in antiviral innate immunity, we showed that both equine G3P[12] and G14P[12] strains can be rapidly isolated from diarrhoeic foals. The genome sequence analysis revealed that both G3P[12] and G14P[12] strains share the identical genotypic constellation except for VP7 and VP6 segments in which G3P[12] possessed VP7 of genotype G3 and VP6 of genotype I6 and G14P[12] had the combination of VP7 of genotype G14 and VP6 of genotype I2. Further characterization demonstrated that two ERVA genotypes have a limited cross-neutralization. The lack of an in vitro broad cross-protection between both genotypes supported the increased recent diarrhoea outbreaks due to equine G14P[12] in foals born to dams immunized with the inactivated monovalent equine G3P[12] vaccine. Finally, using the structural modelling approach, we provided the genetic basis of the antigenic divergence between ERVA G3P[12] and G14P[12] strains. The results of this study will provide a framework for further investigation of infection biology, pathogenesis and cross-protection of equine rotaviruses.
Assuntos
Antígenos Virais , Diarreia , Genótipo , Doenças dos Cavalos , Infecções por Rotavirus , Rotavirus , Animais , Cavalos , Rotavirus/genética , Rotavirus/imunologia , Rotavirus/isolamento & purificação , Rotavirus/classificação , Infecções por Rotavirus/veterinária , Infecções por Rotavirus/virologia , Infecções por Rotavirus/imunologia , Doenças dos Cavalos/virologia , Doenças dos Cavalos/imunologia , Diarreia/virologia , Diarreia/veterinária , Antígenos Virais/genética , Antígenos Virais/imunologia , Genoma Viral/genética , Filogenia , Linhagem CelularRESUMO
INTRODUCTION: Rotavirus vaccines may provide indirect protection by reducing transmission in the population and thus reducing disease burden. METHODS: This systematic review summarizes estimates of indirect protection from rotavirus vaccines and the methods used to obtain these estimates. RESULTS: We identified 71 studies published between 2009 and 2022 that provided 399 estimates of indirect protection from rotavirus vaccine. Most estimates (73%) evaluated hospitalizations due to rotavirus gastroenteritis as the outcome and unvaccinated children <5 years old as the agegroup (64%), but there was considerable variability in methods to evaluate indirect protection. For hospitalizations due to rotavirus gastroenteritis among unvaccinated children <5 years old, the median incidence rate ratio was 0.60 (IQR: 0.40-0.87, n = 110 estimates), the median relative percent change in percent positivity was 25% (IQR: 13-44%, n = 49 estimates), and the median relative percent change in absolute number of rotavirus positive tests or rotavirus-specific International Classification of Diseases codes was 42% (IQR: 16-66%, n = 40 estimates). CONCLUSIONS: These findings broadly suggest rotavirus vaccines provide some indirect protection. There is a need to standardize measurement of indirect rotavirus vaccine protection, particularly using consistent outcomes and metrics, and stratifying results by standardized age groups and years since vaccine introduction.
Assuntos
Gastroenterite , Infecções por Rotavirus , Vacinas contra Rotavirus , Pré-Escolar , Humanos , Lactente , Gastroenterite/prevenção & controle , Gastroenterite/virologia , Gastroenterite/epidemiologia , Gastroenterite/imunologia , Hospitalização/estatística & dados numéricos , Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/imunologiaRESUMO
Rotavirus remains a significant public health threat, especially in low-income countries, where it is the leading cause of severe acute childhood gastroenteritis, contributing to over 128,500 deaths annually. Although the introduction of the Rotarix and RotaTeq vaccines in 2006 marked a milestone in reducing mortality rates, approximately 83,158 preventable deaths persisted, showing ongoing challenges in vaccine accessibility and effectiveness. To address these issues, a novel subcutaneous vaccine formulation targeting multiple rotavirus genotypes has been developed. This vaccine consists of nine VP8* proteins from nine distinct rotavirus genotypes and sub-genotypes (P[4], P[6], P[8]LI, P[8]LIII, P[8]LIV, P[9], P[11], P[14], and P[25]) expressed in E. coli. Two groups of mice were immunized either with a single immunogen, the VP8* from the rotavirus Wa strain (P[8]LI), or with the nonavalent formulation. Preliminary results from mouse immunization studies showed promising outcomes, eliciting antibody responses against six of the nine immunogens. Notably, significantly higher antibody titers against VP8* P[8]LI were observed in the group immunized with the nonavalent vaccine compared to mice specifically immunized against this genotype alone. Overall, the development of parenteral vaccines targeting multiple rotavirus genotypes represents a promising strategy in mitigating the global burden of rotavirus-related morbidity and mortality, offering new avenues for disease prevention and control.
Assuntos
Anticorpos Antivirais , Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Vacinas de Subunidades Antigênicas , Animais , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Camundongos , Rotavirus/imunologia , Rotavirus/genética , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/genética , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/virologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Feminino , Camundongos Endogâmicos BALB C , Proteínas não Estruturais Virais/imunologia , Proteínas não Estruturais Virais/genética , Imunogenicidade da Vacina , Genótipo , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Proteínas de Ligação a RNA/imunologia , Proteínas de Ligação a RNA/genéticaRESUMO
The leading cause of gastroenteritis in children under the age of five is rotavirus infection, accounting for 37% of diarrhoeal deaths in infants and young children globally. Oral rotavirus vaccines have been widely incorporated into national immunisation programs, but whilst these vaccines have excellent efficacy in high-income countries, they protect less than 50% of vaccinated individuals in low- and middle-income countries. In order to facilitate the development of improved vaccine strategies, a greater understanding of the immune response to existing vaccines is urgently needed. However, the use of mouse models to study immune responses to human rotavirus strains is currently limited as rotaviruses are highly species-specific and replication of human rotaviruses is minimal in mice. To enable characterisation of immune responses to human rotavirus in mice, we have generated chimeric viruses that combat the issue of rotavirus host range restriction. Using reverse genetics, the rotavirus outer capsid proteins (VP4 and VP7) from either human or murine rotavirus strains were encoded in a murine rotavirus backbone. Neonatal mice were infected with chimeric viruses and monitored daily for development of diarrhoea. Stool samples were collected to quantify viral shedding, and antibody responses were comprehensively evaluated. We demonstrated that chimeric rotaviruses were able to efficiently replicate in mice. Moreover, the chimeric rotavirus containing human rotavirus outer capsid proteins elicited a robust antibody response to human rotavirus antigens, whilst the control chimeric murine rotavirus did not. This chimeric human rotavirus therefore provides a new strategy for studying human-rotavirus-specific immunity to the outer capsid, and could be used to investigate factors causing variability in rotavirus vaccine efficacy. This small animal platform therefore has the potential to test the efficacy of new vaccines and antibody-based therapeutics.
Assuntos
Anticorpos Antivirais , Proteínas do Capsídeo , Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Animais , Rotavirus/imunologia , Rotavirus/genética , Camundongos , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/virologia , Humanos , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Modelos Animais de Doenças , Antígenos Virais/imunologia , Antígenos Virais/genética , Formação de Anticorpos , Eliminação de Partículas Virais , Replicação Viral , Fezes/virologia , Diarreia/virologia , Diarreia/imunologiaRESUMO
Rotavirus, a primary contributor to severe cases of infantile gastroenteritis on a global scale, results in significant morbidity and mortality in the under-five population, particularly in middle to low-income countries, including India. WHO-approved live-attenuated vaccines are linked to a heightened susceptibility to intussusception and exhibit low efficacy, primarily attributed to the high genetic diversity of rotavirus, varying over time and across different geographic regions. Herein, molecular data on Indian rotavirus A (RVA) has been reviewed through phylogenetic analysis, revealing G1P[8] to be the prevalent strain of RVA in India. The conserved capsid protein sequences of VP7, VP4 and VP6 were used to examine helper T lymphocyte, cytotoxic T lymphocyte and linear B-cell epitopes. Twenty epitopes were identified after evaluation of factors such as antigenicity, non-allergenicity, non-toxicity, and stability. These epitopes were then interconnected using suitable linkers and an N-terminal beta defensin adjuvant. The in silico designed vaccine exhibited structural stability and interactions with integrins (αvß3 and αIIbß3) and toll-like receptors (TLR2 and TLR4) indicated by docking and normal mode analyses. The immune simulation profile of the designed RVA multiepitope vaccine exhibited its potential to trigger humoral as well as cell-mediated immunity, indicating that it is a promising immunogen. These computational findings indicate potential efficacy of the designed vaccine against rotavirus infection.
Assuntos
Antígenos Virais , Proteínas do Capsídeo , Epitopos de Linfócito T , Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Rotavirus/imunologia , Rotavirus/genética , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/genética , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/imunologia , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/química , Antígenos Virais/imunologia , Antígenos Virais/genética , Humanos , Índia , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/genética , Vacinologia/métodos , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/genética , Filogenia , Simulação de Acoplamento Molecular , Epitopos/imunologia , Epitopos/genética , Desenvolvimento de VacinasRESUMO
Porcine Rotavirus (PoRV) is a significant pathogen affecting swine-rearing regions globally, presenting a substantial threat to the economic development of the livestock sector. At present, no specific pharmaceuticals are available for this disease, and treatment options remain exceedingly limited. This study seeks to design a multi-epitope peptide vaccine for PoRV employing bioinformatics approaches to robustly activate T-cell and B-cell immune responses. Two antigenic proteins, VP7 and VP8*, were selected from PoRV, and potential immunogenic T-cell and B-cell epitopes were predicted using immunoinformatic tools. These epitopes were further screened according to non-toxicity, antigenicity, non-allergenicity, and immunogenicity criteria. The selected epitopes were linked with linkers to form a novel multi-epitope vaccine construct, with the PADRE sequence (AKFVAAWTLKAAA) and RS09 peptide attached at the N-terminus of the designed peptide chain to enhance the vaccine's antigenicity. Protein-protein docking of the vaccine constructs with toll-like receptors (TLR3 and TLR4) was conducted using computational methods, with the lowest energy docking results selected as the optimal predictive model. Subsequently, molecular dynamics (MD) simulation methods were employed to assess the stability of the protein vaccine constructs and TLR3 and TLR4 receptors. The results indicated that the vaccine-TLR3 and vaccine-TLR4 docking models remained stable throughout the simulation period. Additionally, the C-IMMSIM tool was utilized to determine the immunogenic triggering capability of the vaccine protein, demonstrating that the constructed vaccine protein could induce both cell-mediated and humoral immune responses, thereby playing a role in eliciting host immune responses. In conclusion, this study successfully constructed a multi-epitope vaccine against PoRV and validated the stability and efficacy of the vaccine through computational analysis. However, as the study is purely computational, experimental evaluation is required to validate the safety and immunogenicity of the newly constructed vaccine protein.
Assuntos
Antígenos Virais , Biologia Computacional , Epitopos de Linfócito B , Epitopos de Linfócito T , Simulação de Dinâmica Molecular , Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Vacinas de Subunidades Antigênicas , Animais , Suínos , Rotavirus/imunologia , Rotavirus/genética , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/química , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/genética , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/química , Vacinas contra Rotavirus/genética , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/virologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/química , Antígenos Virais/imunologia , Antígenos Virais/genética , Antígenos Virais/química , Simulação de Acoplamento Molecular , Doenças dos Suínos/prevenção & controle , Doenças dos Suínos/imunologia , Doenças dos Suínos/virologia , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/química , Desenvolvimento de Vacinas , Imunogenicidade da VacinaRESUMO
Adjuvant is a major supplementary component of vaccines to boost adaptive immune responses. To select an efficient adjuvant from the heat-labile toxin B subunit (LTB) of E. coli, four LTB mutants (numbered LTB26, LTB34, LTB57, and LTB85) were generated by multi-amino acid random replacement. Mice have been intranasally vaccinated with human rotavirus VP8 admixed. Among the four mutants, enzyme-linked immunosorbent assay (ELISA) revealed that LTB26 had enhanced mucosal immune adjuvanticity compared to LTB, showing significantly enhanced immune responses in both serum IgG and mucosal sIgA levels. The 3D modeling analysis suggested that the enhanced immune adjuvanticity of LTB26 might be due to the change of the first LTB α-helix to a ß-sheet. The molecular mechanism was studied using transcriptomic and flow cytometric (FCM) analysis. The transcriptomic data demonstrated that LTB26 enhanced immune response by enhancing B cell receptor (BCR) and major histocompatibility complex (MHC) II+-related pathways. Furthermore, LTB26 promoted Th1 and Th2-type immune responses which were confirmed by detecting IFN-γ and IL-4 expression levels. Immunohistochemical analysis demonstrated that LTB26 enhanced both Th1 and Th2 type immunity. Therefore, LTB26 was a potent mucosal immune adjuvant meeting the requirement for use in human clinics in the future.
Assuntos
Adjuvantes Imunológicos , Enterotoxinas , Proteínas de Escherichia coli , Animais , Feminino , Humanos , Camundongos , Antígenos Virais/imunologia , Antígenos Virais/genética , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/genética , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Enterotoxinas/imunologia , Enterotoxinas/genética , Escherichia coli/imunologia , Proteínas de Escherichia coli/imunologia , Proteínas de Escherichia coli/genética , Imunidade nas Mucosas/imunologia , Imunoglobulina G/imunologia , Camundongos Endogâmicos BALB C , Mutação , Rotavirus/imunologia , Infecções por Rotavirus/imunologia , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagemRESUMO
Porcine rotavirus (PoRV) is one of the main pathogens causing diarrhea in piglets, and multiple genotypes coexist. However, an effective vaccine is currently lacking. Here, the potential adjuvant of nonstructural protein 4 (NSP4) and highly immunogenic structural protein VP4 prompted us to construct recombinant NSP486-175aa (NSP4*) and VP426-476aa (VP4*) proteins, combine them as immunogens to evaluate their efficacy. Results indicated that NSP4* enhanced systemic and local mucosal responses induced by VP4*. The VP4*-IgG, VP4*-IgA in feces and IgA-secreting cells in intestines induced by the co-immunization were significantly higher than those induced by VP4* alone. Co-immunization of NSP4* and VP4* also induced strong cellular immunity with significantly increased IFN-λ than the single VP4*. Summarily, the NSP4* as a synergistical antigen exerted limited effects on the PoRV NAbs elevation, but conferred strong VP4*-specific mucosal and cellular efficacy, which lays the foundation for the development of a more effective porcine rotavirus subunit vaccine.
Assuntos
Anticorpos Antivirais , Proteínas do Capsídeo , Imunidade nas Mucosas , Infecções por Rotavirus , Rotavirus , Proteínas não Estruturais Virais , Animais , Suínos , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia , Rotavirus/imunologia , Rotavirus/genética , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Infecções por Rotavirus/virologia , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/veterinária , Infecções por Rotavirus/prevenção & controle , Anticorpos Antivirais/imunologia , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/genética , Toxinas Biológicas/genética , Toxinas Biológicas/imunologia , Glicoproteínas/genética , Glicoproteínas/imunologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/genética , Imunoglobulina A/imunologia , Doenças dos Suínos/virologia , Doenças dos Suínos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Fezes/virologia , Imunoglobulina G/imunologia , Antígenos Virais/imunologia , Antígenos Virais/genéticaRESUMO
Rotavirus infection continues to be a significant public health problem in developing countries, despite the availability of several vaccines. The efficacy of oral rotavirus vaccines in young children may be affected by significant immunological differences between individuals in early life and adults. Therefore, understanding the dynamics of early-life systemic and mucosal immune responses and the factors that affect them is essential to improve the current rotavirus vaccines and develop the next generation of mucosal vaccines. This review focuses on the advances in T-cell development during early life in mice and humans, discussing how immune homeostasis and response to pathogens is established in this period compared to adults. Finally, the review explores how this knowledge of early-life T-cell immunity could be utilized to enhance current and novel rotavirus vaccines.
Assuntos
Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Linfócitos T , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Humanos , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/imunologia , Animais , Rotavirus/imunologia , Linfócitos T/imunologia , Administração Oral , Imunidade nas Mucosas , CamundongosRESUMO
The suboptimal performance of rotavirus (RV) vaccines in developing countries and in animals necessitates further research on the development of novel therapeutics and control strategies. To initiate infection, RV interacts with cell-surface O-glycans, including histo-blood group antigens (HBGAs). We have previously demonstrated that certain non-pathogenic bacteria express HBGA- like substances (HBGA+) capable of binding RV particles in vitro. We hypothesized that HBGA+ bacteria can bind RV particles in the gut lumen protecting against RV species A (RVA), B (RVB), and C (RVC) infection in vivo. In this study, germ-free piglets were colonized with HBGA+ or HBGA- bacterial cocktail and infected with RVA/RVB/RVC of different genotypes. Diarrhea severity, virus shedding, immunoglobulin A (IgA) Ab titers, and cytokine levels were evaluated. Overall, colonization with HBGA+ bacteria resulted in reduced diarrhea severity and virus shedding compared to the HBGA- bacteria. Consistent with our hypothesis, the reduced severity of RV disease and infection was not associated with significant alterations in immune responses. Additionally, colonization with HBGA+ bacteria conferred beneficial effects irrespective of the piglet HBGA phenotype. These findings are the first experimental evidence that probiotic performance in vivo can be improved by including HBGA+ bacteria, providing decoy epitopes for broader/more consistent protection against diverse RVs.
Assuntos
Bactérias , Antígenos de Grupos Sanguíneos , Infecções por Rotavirus , Animais , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Bactérias/imunologia , Antígenos de Grupos Sanguíneos/imunologia , Citocinas/metabolismo , Diarreia/prevenção & controle , Diarreia/virologia , Vida Livre de Germes , Imunoglobulina A/imunologia , Rotavirus/imunologia , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/virologia , Suínos , Doenças dos Suínos/imunologia , Doenças dos Suínos/virologia , Eliminação de Partículas ViraisRESUMO
Rotavirus is the main cause of acute diarrhea in children up to five years of age. In this regard, probiotics are commonly used to treat or prevent gastroenteritis including viral infections. The anti-rotavirus effect of Bifidobacterium longum and Chlorella sorokiniana, by reducing viral infectivity and improving IFN-type I response, has been previously reported. The present study aimed to study the effect of B. longum and/or C. sorokiniana on modulating the antiviral cellular immune response mediated by IFN-γ, IL-10, SOCS3, STAT1, and STAT2 genes in rotavirus-infected cells. To determine the mRNA relative expression of these genes, HT-29 cells were treated with B. longum and C. sorokiniana alone or in combination, followed by rotavirus infection. In addition, infected cells were treated with B. longum and/or C. sorokiniana. Cellular RNA was purified, used for cDNA synthesis, and amplified by qPCR. Our results demonstrated that the combination of B. longum and C. sorokiniana stimulates the antiviral cellular immune response by upregulating IFN-γ and may block pro-inflammatory cytokines by upregulating IL-10 and SOCS3. The results of our study indicated that B. longum, C. sorokiniana, or their combination improve antiviral cellular immune response and might modulate pro-inflammatory responses.
Assuntos
Bifidobacterium longum , Chlorella , Interferon gama , Interleucina-10 , Probióticos , Infecções por Rotavirus , Proteína 3 Supressora da Sinalização de Citocinas , Humanos , Células HT29 , Interferon gama/metabolismo , Interleucina-10/metabolismo , Probióticos/farmacologia , Rotavirus/fisiologia , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/virologia , Fator de Transcrição STAT1/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismoRESUMO
We conducted a phase I, randomized, double-blind, placebo-controlled trial including healthy adults in Sui County, Henan Province, China. Ninety-six adults were randomly assigned to one of three groups (high-dose, medium-dose, and low-dose) at a 3:1 ratio to receive one vaccine dose or placebo. Adverse events up to 28 days after each dose and serious adverse events up to 6 months after all doses were reported. Geometric mean titers and seroconversion rates were measured for anti-rotavirus neutralizing antibodies using microneutralization tests. The rates of total adverse events in the placebo group, low-dose group, medium-dose group, and high-dose group were 29.17 % (12.62 %-51.09 %), 12.50 % (2.66 %-32.36 %), 50.00 % (29.12 %-70.88 %), and 41.67 % (22.11 %-63.36 %), respectively, with no significant difference in the experimental groups compared with the placebo group. The results of the neutralizing antibody assay showed that in the adult group, the neutralizing antibody geometric mean titer at 28 days after full immunization in the low-dose group was 583.01 (95 % confidence interval [CI]: 447.12-760.20), that in the medium-dose group was 899.34 (95 % CI: 601.73-1344.14), and that in the high-dose group was 1055.24 (95 % CI: 876.28-1270.75). The GMT of serum-specific IgG at 28 days after full immunization in the low-dose group was 3444.26 (95 % CI: 2292.35-5175.02), that in the medium-dose group was 6888.55 (95 % CI: 4426.67-10719.6), and that in the high-dose group was 7511.99 (95 % CI: 3988.27-14149.0). The GMT of serum-specific IgA at 28 days after full immunization in the low-dose group was 2332.14 (95 % CI: 1538.82-3534.45), that in the medium-dose group was 4800.98 (95 % CI: 2986.64-7717.50), and that in the high-dose group was 3204.30 (95 % CI: 2175.66-4719.27). In terms of safety, adverse events were mainly Grades 1 and 2, indicating that the safety of the vaccine is within the acceptable range in the healthy adult population. Considering the GMT and positive transfer rate of neutralizing antibodies for the main immunogenicity endpoints in the experimental groups, it was initially observed that the high-dose group had higher levels of neutralizing antibodies than the medium- and low-dose groups in adults aged 18-49 years. This novel inactivated rotavirus vaccine was generally well-tolerated in adults, and the vaccine was immunogenic in adults (ClinicalTrials.gov number, NCT04626856).
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra Rotavirus , Vacinas de Produtos Inativados , Humanos , Adulto , Método Duplo-Cego , Masculino , Feminino , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Pessoa de Meia-Idade , Adulto Jovem , Adolescente , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/efeitos adversos , China , Imunogenicidade da Vacina , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/imunologia , Rotavirus/imunologia , Voluntários Saudáveis , Testes de NeutralizaçãoRESUMO
Group A rotavirus (RVA) is the primary etiological agent of acute gastroenteritis (AGE) in children under 5 years of age. Despite the global implementation of vaccines, rotavirus infections continue to cause over 120,000 deaths annually, with a majority occurring in developing nations. Among infants, the P[8] rotavirus strain is the most prevalent and can be categorized into four distinct lineages. In this investigation, we expressed five VP4(aa26-476) proteins from different P[8] lineages of human rotavirus in E. coli and assessed their immunogenicity in rabbits. Among the different P[8] strains, the Wa-VP4 protein, derived from the MT025868.1 strain of the P[8]-1 lineage, exhibited successful purification in a highly homogeneous form and significantly elicited higher levels of neutralizing antibodies (nAbs) against both homologous and heterologous rotaviruses compared to other VP4 proteins derived from different P[8] lineages in rabbits. Furthermore, we assessed the immunogenicity of the Wa-VP4 protein in mice, pigs, and cynomolgus monkeys, observing that it induced robust production of nAbs in all animals. Interestingly, there was no significant difference between in nAb titers against homologous and heterologous rotaviruses in pigs and mankeys. Collectively, these findings suggest that the Wa-VP4* protein may serve as a potential candidate for a rotavirus vaccine.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Proteínas do Capsídeo , Macaca fascicularis , Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Suínos , Coelhos , Camundongos , Rotavirus/imunologia , Rotavirus/genética , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/imunologia , Feminino , Camundongos Endogâmicos BALB C , Humanos , Imunogenicidade da Vacina , Proteínas não Estruturais Virais/imunologia , Proteínas não Estruturais Virais/genéticaRESUMO
Porcine rotaviruses (PoRVs) cause severe economic losses in the swine industry. P[7] and P[23] are the predominant genotypes circulating on farms, but no vaccine is yet available. Here, we developed a bivalent subunit PoRV vaccine using truncated versions (VP4*) of the VP4 proteins from P[7] and P[23]. The vaccination of mice with the bivalent subunit vaccine elicited more robust neutralizing antibodies (NAbs) and cellular immune responses than its components, even at high doses. The bivalent subunit vaccine and inactivated bivalent vaccine prepared from strains PoRVs G9P[7] and G9P[23] were used to examine their protective efficacy in sows and suckling piglets after passive immunization. The immunized sows showed significantly elevated NAbs in the serum and colostrum, and the suckling piglets acquired high levels of sIgA antibodies from the colostrum. Challenging subunit-vaccinated or inactivated-vaccinated piglets with homologous virulent strains did not induce diarrhea, except in one or two piglets, which had mild diarrhea. Immunization with the bivalent subunit vaccine and inactivated vaccine also alleviated the microscopic lesions in the intestinal tissues caused by the challenge with the corresponding homologous virulent strain. However, all the piglets in the challenged group displayed mild to watery diarrhea and high levels of viral shedding, whereas the feces and intestines of the piglets in the bivalent subunit vaccine and inactivated vaccine groups had lower viral loads. In summary, our data show for the first time that a bivalent subunit vaccine combining VP4*P[7] and VP4*P[23] effectively protects piglets against the diarrhea caused by homologous virulent strains.IMPORTANCEPoRVs are the main causes of diarrhea in piglets worldwide. The multisegmented genome of PoRVs allows the reassortment of VP4 and VP7 genes from different RV species and strains. The P[7] and P[23] are the predominant genotypes circulating in pig farms, but no vaccine is available at present in China. Subunit vaccines, as nonreplicating vaccines, are an option to cope with variable genotypes. Here, we have developed a bivalent subunit candidate vaccine based on a truncated VP4 protein, which induced robust humoral and cellular immune responses and protected piglets against challenge with homologous PoRV. It also appears to be safe. These data show that the truncated VP4-protein-based subunit vaccine is a promising candidate for the prevention of PoRV diarrhea.
Assuntos
Vacinas contra Rotavirus , Vacinas de Subunidades Antigênicas , Animais , Feminino , Camundongos , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Diarreia/prevenção & controle , Diarreia/virologia , Diarreia/veterinária , Diarreia/imunologia , Genótipo , Imunidade Celular , Camundongos Endogâmicos BALB C , Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/veterinária , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/virologia , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Suínos , Doenças dos Suínos/prevenção & controle , Doenças dos Suínos/virologia , Doenças dos Suínos/imunologia , Vacinação , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/administração & dosagemRESUMO
Porcine rotavirus (PoRV) poses a threat to the development of animal husbandry and human health, leading to substantial economic losses. VP6 protein is the most abundant component in virus particles and also the core structural protein of the virus. Firstly, this study developed an antibiotic-resistance-free, environmentally friendly expression vector, named asd-araC-PBAD-alr (AAPA). Then Recombinant Lactiplantibacillus plantarum (L. plantarum) strains induced by arabinose to express VP6 and VP6-pFc fusion proteins was constructed. Subsequently, This paper discovered that NC8/Δalr-pCXa-VP6-S and NC8/Δalr-pCXa-VP6-pFc-S could enhance host immunity and prevent rotavirus infection in neonatal mice and piglets. The novel recombinant L. plantarum strains constructed in this study can serve as oral vaccines to boost host immunity, offering a new strategy to prevent PoRV infection.
Assuntos
Proteínas do Capsídeo , Lactobacillus plantarum , Infecções por Rotavirus , Doenças dos Suínos , Animais , Camundongos , Animais Recém-Nascidos , Antígenos Virais/imunologia , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Lactobacillus plantarum/imunologia , Camundongos Endogâmicos BALB C , Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/virologia , Suínos , Doenças dos Suínos/prevenção & controle , Doenças dos Suínos/virologia , Doenças dos Suínos/microbiologia , Doenças dos Suínos/imunologiaRESUMO
Oral rotavirus vaccines demonstrate diminished immunogenicity in low-income settings where human cytomegalovirus infection is acquired early in childhood and modulates immunity. We hypothesized that human cytomegalovirus infection around the time of vaccination may influence immunogenicity. We measured plasma human cytomegalovirus-specific immunoglobulin M antibodies in rotavirus vaccinated infants from 6 weeks to 12 months old and compared rotavirus immunoglobulin A antibody titers between human cytomegalovirus seropositive and seronegative infants. There was no evidence of an association between human cytomegalovirus serostatus at 9 months and rotavirus-specific antibody titers at 12 months (geometric mean ratio 1.01, 95% CI: 0.70, 1.45; Pâ =â 0.976) or fold-increase in RV-IgA titer between 9 and 12 months (risk ratio 0.999, 95%CI: 0.66, 1.52; Pâ =â 0.995) overall. However, HIV-exposed-uninfected infants who were seropositive for human cytomegalovirus at 9 months old had a 63% reduction in rotavirus antibody geometric mean titers at 12 months compared to HIV-exposed-uninfected infants who were seronegative for human cytomegalovirus (geometric mean ratio 0.37, 95% CI: 0.17, 0.77; Pâ =â 0.008). While the broader implications of human cytomegalovirus infections on oral rotavirus vaccine response might be limited in the general infant population, the potential impact in the HIV-exposed-uninfected infants cannot be overlooked. This study highlights the complexity of immunological responses and the need for targeted interventions to ensure oral rotavirus vaccine efficacy, especially in vulnerable subpopulations.
Assuntos
Anticorpos Antivirais , Infecções por Citomegalovirus , Citomegalovirus , Infecções por HIV , Infecções por Rotavirus , Vacinas contra Rotavirus , Humanos , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Citomegalovirus/imunologia , Lactente , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Infecções por HIV/imunologia , Masculino , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Feminino , Imunogenicidade da Vacina/imunologia , Rotavirus/imunologia , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Administração Oral , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , VacinaçãoRESUMO
BACKGROUND: Rotavirus is a leading cause of severe pediatric gastroenteritis; 2 highly effective vaccines are used in the United States (US). We aimed to identify correlates of immune response to rotavirus vaccination in a US cohort. METHODS: Pediatric Respiratory and Enteric Virus Acquisition and Immunogenesis Longitudinal (PREVAIL) is a birth cohort of 245 mother-child pairs enrolled in 2017-2018 and followed for 2 years. Infant stool samples and symptom information were collected weekly. Shedding was defined as reverse-transcription polymerase chain reaction detection of rotavirus vaccine virus in stools collected 4-28 days after dose 1. Seroconversion was defined as a 3-fold rise in immunoglobulin A between the 6-week and 6-month blood draws. Correlates were analyzed using generalized estimating equations and logistic regression. RESULTS: Prevaccination immunoglobulin G (IgG) (odds ratio [OR], 0.84 [95% confidence interval {CI}, .75-.94] per 100-unit increase) was negatively associated with shedding. Shedding was also less likely among infants with a single-nucleotide polymorphism inactivating FUT2 antigen secretion ("nonsecretors") with nonsecretor mothers, versus all other combinations (OR, 0.37 [95% CI, .16-.83]). Of 141 infants with data, 105 (74%) seroconverted; 78 (77%) had shed vaccine virus following dose 1. Prevaccination IgG and secretor status were significantly associated with seroconversion. Neither shedding nor seroconversion significantly differed by vaccine product. CONCLUSIONS: In this US cohort, prevaccination IgG and maternal and infant secretor status were associated with rotavirus vaccine response.