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Viruses Mar 2024Rotavirus infection is a leading cause of severe dehydrating gastroenteritis in children under 5 years of age. Although rotavirus-associated mortality has decreased...
Rotavirus infection is a leading cause of severe dehydrating gastroenteritis in children under 5 years of age. Although rotavirus-associated mortality has decreased considerably because of the introduction of the worldwide rotavirus vaccination, the global burden of rotavirus-associated gastroenteritis remains high. Current vaccines have a number of disadvantages; therefore, there is a need for innovative approaches in rotavirus vaccine development. In the current study, a universal recombinant rotavirus antigen (URRA) for a novel recombinant vaccine candidate against rotavirus A was obtained and characterised. This antigen included sequences of the VP8* subunit of rotavirus spike protein VP4. For the URRA, for the first time, two approaches were implemented simultaneously-the application of a highly conserved neutralising epitope and the use of the consensus of the extended protein's fragment. The recognition of URRA by antisera to patient-derived field rotavirus isolates was proven. Plant virus-based spherical particles (SPs), a novel, effective and safe adjuvant, considerably enhanced the immunogenicity of the URRA in a mouse model. Given these facts, a URRA + SPs vaccine candidate is regarded as a prospective basis for a universal vaccine against rotavirus.
Topics: Animals; Mice; Child; Humans; Child, Preschool; Rotavirus; Prospective Studies; Antibodies, Viral; Vaccines, Synthetic; Rotavirus Infections; Gastroenteritis; Rotavirus Vaccines
PubMed: 38543803
DOI: 10.3390/v16030438 -
Viruses Mar 2024Rotaviruses are a significant cause of severe, potentially life-threatening gastroenteritis in infants and the young of many economically important animals. Although...
Rotaviruses are a significant cause of severe, potentially life-threatening gastroenteritis in infants and the young of many economically important animals. Although vaccines against porcine rotavirus exist, both live oral and inactivated, their effectiveness in preventing gastroenteritis is less than ideal. Thus, there is a need for the development of new generations of porcine rotavirus vaccines. The Ohio State University (OSU) rotavirus strain represents a species with a G5P[7] genotype, the genotype most frequently associated with rotavirus disease in piglets. Using complete genome sequences that were determined via Nanopore sequencing, we developed a robust reverse genetics system enabling the recovery of recombinant (r)OSU rotavirus. Although rOSU grew to high titers (~10 plaque-forming units/mL), its growth kinetics were modestly decreased in comparison to the laboratory-adapted OSU virus. The reverse genetics system was used to generate the rOSU rotavirus, which served as an expression vector for a foreign protein. Specifically, by engineering a fused NSP3-2A-UnaG open reading frame into the segment 7 RNA, we produced a genetically stable rOSU virus that expressed the fluorescent UnaG protein as a functional separate product. Together, these findings raise the possibility of producing improved live oral porcine rotavirus vaccines through reverse-genetics-based modification or combination porcine rotavirus vaccines that can express neutralizing antigens for other porcine enteric diseases.
Topics: Humans; Animals; Swine; Reverse Genetics; Ohio; Rotavirus Vaccines; Universities; Rotavirus; Rotavirus Infections; Gastroenteritis
PubMed: 38543776
DOI: 10.3390/v16030411 -
Pathogens (Basel, Switzerland) Mar 2024The infant non-secretor histoblood group antigen phenotype is associated with reduced risk of symptomatic rotavirus diarrhea, one of the leading global causes of severe...
The infant non-secretor histoblood group antigen phenotype is associated with reduced risk of symptomatic rotavirus diarrhea, one of the leading global causes of severe pediatric diarrheal disease and mortality. However, little is known regarding the role of secretor status in asymptomatic rotavirus infections. Therefore, we performed a nested case-control study within a birth cohort study previously conducted in Dhaka, Bangladesh, to determine the association between infant secretor phenotype and the odds of asymptomatic rotavirus infection, in addition to the risk of rotavirus diarrhea, in unvaccinated infants. In the parent cohort, infants were enrolled in the first week of life and followed through the first two years of life with multiple clinic visits and active surveillance for diarrheal illness. Secretor phenotyping was performed on saliva. Eleven surveillance stools collected over the first year of life were tested for rotavirus by real-time RT-PCR, followed by conventional PCR and amplicon sequencing to identify the infecting P-type of positive specimens. Similar to findings for symptomatic diarrhea, infant non-secretors experienced significantly fewer primary episodes of asymptomatic rotavirus infection through the first year of life in a likely rotavirus P-genotype-dependent manner. These data suggest that non-secretors experienced reduced risk from rotavirus due to decreased susceptibility to infection rather than reduced infection severity.
PubMed: 38535566
DOI: 10.3390/pathogens13030223 -
Human Vaccines & Immunotherapeutics Dec 2024This open-label, randomized, phase 3 study in China (V260-074; NCT04481191) evaluated the immunogenicity and safety of concomitant and staggered administration of three... (Randomized Controlled Trial)
Randomized Controlled Trial
A phase 3 randomized, open-label study evaluating the immunogenicity and safety of concomitant and staggered administration of a live, pentavalent rotavirus vaccine and an inactivated poliomyelitis vaccine in healthy infants in China.
This open-label, randomized, phase 3 study in China (V260-074; NCT04481191) evaluated the immunogenicity and safety of concomitant and staggered administration of three doses of an oral, live, pentavalent rotavirus vaccine (RV5) and three doses of an intramuscular, inactivated poliomyelitis vaccine (IPV) in 400 healthy infants. The primary objective was the non-inferiority of neutralizing antibody (nAb) responses in the concomitant- versus the staggered-use groups. Antibody responses were measured at baseline and 1-month post-dose 3 (PD3). Parents/legal guardians recorded adverse events for 30 or 15 d after study vaccinations in the concomitant-use or staggered-use groups, respectively. At PD3, >98% of participants seroconverted to all three poliovirus types, and the primary objective was met as lower bounds of the two-sided 95% CI for between-group difference in nAb seroconversion percentages ranged from - 4.3% to - 1.6%, for all poliovirus types, < .001. At PD3, geometric mean titers (GMTs) of nAb responses to poliovirus types 1, 2, and 3 in the concomitant-use group and the staggered-use group were comparable; 100% of participants had nAb titers ≥1:8 and ≥1:64 for all poliovirus types. Anti-rotavirus serotype-specific IgA GMTs and participants with ≥3-fold rise in postvaccination titers from baseline were comparable between groups. Administration of RV5 and IPV was well tolerated with comparable safety profiles in both groups. The immunogenicity of IPV in the concomitant-use group was non-inferior to the staggered-use group and RV5 was immunogenic in both groups. No safety concerns were identified. These data support the concomitant use of RV5 and IPV in healthy Chinese infants.
Topics: Humans; Infant; Antibodies, Neutralizing; Antibodies, Viral; China; Immunogenicity, Vaccine; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Inactivated; Poliovirus Vaccine, Oral; Rotavirus Vaccines; Vaccines, Attenuated
PubMed: 38509699
DOI: 10.1080/21645515.2024.2324538 -
Microbial Pathogenesis May 2024Rotavirus infections in suckling and weaning piglets cause severe dehydration and death, resulting in significant economic losses in the pig breeding industry. With the...
Rotavirus infections in suckling and weaning piglets cause severe dehydration and death, resulting in significant economic losses in the pig breeding industry. With the continuous emergence of porcine rotavirus (PoRV) variants and poor vaccine cross-protection among various genotypes, there is an urgent need to develop alternative strategies such as seeking effective antiviral products from nature, microbial metabolites and virus-host protein interaction. Sialidases play a crucial role in various physiopathological processes and offer a promising target for developing antivirus drugs. However, the effect of bacterial-derived sialidases on the infection of PoRVs remains largely unknown. Herein, we investigated the impact of bacterial-derived sialidases (sialidase Cp and Vc) on PoRV strain OSU(Group A) infection, using differentiated epithelial monkey kidney cells (MA104) as a model. Our results indicated that the pretreatment of MA104 with exogenous sialidases effectively suppressed PoRV OSU in a concentration-dependent manner. Notably, even at a concentration of 0.01 μU/mL, sialidases significantly inhibited the virus (MOI = 0.01). Meanwhile, we found that sialidase Vc pretreatment sharply reduced the binding rate of PoRV OSU. Last, we demonstrated that PoRV OSU might recognize α-2,3-linked sialic acid as the primary attachment factor in MA104. Our findings provide new insights into the underlying mechanism of PoRV OSU infections, shedding lights on the development of alternative antivirus approaches based on bacteria-virus interaction.
Topics: Animals; Neuraminidase; Rotavirus; Swine; Virus Replication; Rotavirus Infections; Cell Line; Epithelial Cells; Virus Attachment; N-Acetylneuraminic Acid; Antiviral Agents; Haplorhini; Swine Diseases
PubMed: 38508422
DOI: 10.1016/j.micpath.2024.106628 -
The Pediatric Infectious Disease Journal Jun 2024
Topics: Rotavirus Vaccines; Humans; Rotavirus Infections; Rotavirus; Vaccine Efficacy; Infant
PubMed: 38506514
DOI: 10.1097/INF.0000000000004319 -
Clinical Gastroenterology and... Mar 2024Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of...
BACKGROUND & AIMS
Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of ustekinumab and vedolizumab levels and the time at which infant drug levels become undetectable.
METHODS
This multicenter prospective observational cohort study recruited pregnant or preconception women with inflammatory bowel disease receiving vedolizumab or ustekinumab. Trough drug levels, clinical data, and biochemical data were documented preconception, during each trimester of pregnancy, and postpartum. Maternal and cord blood drug levels were measured at delivery and in infants until undetectable. Infant outcomes were assessed until 2 years of age.
RESULTS
A total of 102 participants (vedolizumab, n = 58) were included. The majority of mothers were, and remained, in clinical and biochemical remission. Maternal vedolizumab levels decreased over the course of pregnancy in association with increasing weight, rather than increasing gestation. Maternal ustekinumab levels remained stable. The median time to drug becoming undetectable in the infant was shorter for vedolizumab (11 wk; range, 5-19 wk; n = 32) than ustekinumab (14 wk; range, 9-36 wk; n = 17) and correlated positively with infant delivery level. Thirty-two of 41 (88%) and 17 of 30 (67%) vedolizumab- and ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age, respectively. Pregnancy and infant outcomes were favorable. Twenty infants with undetectable drug levels received the rotavirus vaccine, with no adverse reactions reported.
CONCLUSIONS
Maternal vedolizumab levels decreased, whereas ustekinumab levels remained stable over the course of pregnancy. Most vedolizumab- and approximately half of ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age. No concerning maternal or infant safety signals were identified.
PubMed: 38492905
DOI: 10.1016/j.cgh.2024.02.025 -
Journal of Virology Apr 2024As one of the most important causative agents of severe gastroenteritis in children, piglets, and other young animals, species A rotaviruses have adversely impacted both...
As one of the most important causative agents of severe gastroenteritis in children, piglets, and other young animals, species A rotaviruses have adversely impacted both human health and the global swine industry. Vaccines against rotaviruses (RVs) are insufficiently effective, and no specific treatment is available. To understand the relationships between porcine RV (PoRV) infection and enterocytes in terms of the cellular lipid metabolism, we performed an untargeted liquid chromatography mass spectrometry (LC-MS) lipidomics analysis of PoRV-infected IPEC-J2 cells. Herein, a total of 451 lipids (263 upregulated lipids and 188 downregulated lipids), spanning sphingolipid, glycerolipid, and glycerophospholipids, were significantly altered compared with the mock-infected group. Interestingly, almost all the ceramides among these lipids were upregulated during PoRV infection. LC-MS analysis was used to validated the lipidomics data and demonstrated that PoRV replication increased the levels of long-chain ceramides (C16-ceramide, C18-ceramide, and C24-ceramide) in cells. Furthermore, we found that these long-chain ceramides markedly inhibited PoRV infection and that their antiviral actions were exerted in the replication stage of PoRV infection. Moreover, downregulation of endogenous ceramides with the ceramide metabolic inhibitors enhanced PoRV propagation. Increasing the levels of ceramides by the addition of C6-ceramide strikingly suppressed the replication of diverse RV strains. We further found that the treatment with an apoptotic inhibitor could reverse the antiviral activity of ceramide against PoRV replication, demonstrating that ceramide restricted RV infection by inducing apoptosis. Altogether, this study revealed that ceramides played an antiviral role against RV infection, providing potential approaches for the development of antiviral therapies.IMPORTANCERotaviruses (RVs) are among the most important zoonosis viruses, which mainly infected enterocytes of the intestinal epithelium causing diarrhea in children and the young of many mammalian and avian species. Lipids play an essential role in viral infection. A comprehensive understanding of the interaction between RV and lipid metabolism in the enterocytes will be helpful to control RV infection. Here, we mapped changes in enterocyte lipids following porcine RV (PoRV) infection using an untargeted lipidomics approach. We found that PoRV infection altered the metabolism of various lipid species, especially ceramides (derivatives of the sphingosine). We further demonstrated that PoRV infection increased the accumulation of ceramides and that ceramides exerted antiviral effects on RV replication by inducing apoptosis. Our findings fill a gap in understanding the alterations of lipid metabolism in RV-infected enterocytes and highlight the antiviral effects of ceramides on RV infection, suggesting potential approaches to control RV infection.
Topics: Animals; Ceramides; Lipid Metabolism; Lipidomics; Rotavirus; Swine; Enterocytes; Rotavirus Infections; Cell Line
PubMed: 38488360
DOI: 10.1128/jvi.00064-24 -
Human Vaccines & Immunotherapeutics Dec 2024Rotavirus (RV) vaccines were first introduced in 2011 and adopted for universal vaccination in 2020 in Japan. However, the effectiveness of RV vaccines after being...
Rotavirus (RV) vaccines were first introduced in 2011 and adopted for universal vaccination in 2020 in Japan. However, the effectiveness of RV vaccines after being adopted for universal vaccination in 2020 has not been reported. Because of the easy accessibility of clinics in Japan, many children are not usually hospitalized for RV gastroenteritis (RVGE). Therefore, in order to evaluate the impact of the RV vaccine since 2008, we investigated the incidence of hospitalization for RVGE as well as the frequency of children aged < 5 years who received medical treatment for severe RVGE at clinics in Shibata City, Japan. The RV vaccine coverage rate was 94.0% (1,046/1,113) in Shibata City after universal vaccination in 2020; this was a significant increase from previous rates. The incidence per 1000 person - years for RVGE hospitalization and severe RVGE at clinics were significantly higher among children aged < 3 years than in previous time periods. The incidence in children with all acute gastroenteritis (AGE) decreased significantly after universal vaccination during the COVID-19 pandemic. The proportion of severe RVGE among all AGE cases also decreased significantly after universal vaccination among children aged < 3 years (0.0%) and those aged 3-4 years (0.6%). There were significant differences in the distribution of RV genotypes isolated from the feces of children with RVGE between different eras divided by RV vaccination rates, especially G1P[8], which was the major genotype before it recently almost disappeared. Further studies are warranted to assess the impact of the COVID-19 pandemic.
Topics: Child; Humans; Infant; Rotavirus; Incidence; Japan; Pandemics; Gastroenteritis; Rotavirus Infections; Vaccination; Rotavirus Vaccines; Hospitalization; COVID-19
PubMed: 38478958
DOI: 10.1080/21645515.2024.2322202 -
Infectious Diseases of Poverty Mar 2024Immunization is a cornerstone of public health. Despite great success, China's National Immunization Program (NIP) faces challenges, such as the integration of several...
BACKGROUND
Immunization is a cornerstone of public health. Despite great success, China's National Immunization Program (NIP) faces challenges, such as the integration of several World Health Organization-recommended vaccines and other systemic issues. The Innovation Laboratory for Vaccine Delivery Research (VaxLab), supported by the Bill & Melinda Gates Foundation and established in 2021 at Duke Kunshan University, focuses on enhancing China's NIP through research and policy advocacy. This editorial aims to summarize the key findings of the manuscripts published in the collection contributed by VaxLab team and set the future research agenda.
KEY FINDINGS
The collection contains eleven manuscripts discussing China's immunization landscape and strategies to improve coverage, particularly for non-NIP vaccines like human papillomavirus vaccine (HPV), pneumococcal conjugate vaccine (PCV), Haemophilus influenzae type b vaccine (Hib), and rotavirus vaccines. Key findings include: (i) The COVID-19 vaccination campaign demonstrated China's capacity for rapid, large-scale immunization efforts, suggesting potential for broader vaccine coverage improvements; (ii) Efforts in combating cervical cancer through the HPV vaccine indicate progress but also highlight challenges like vaccine supply and equitable access; (iii) The lag in adopting higher-valent paediatric combination vaccines in China needs attention to address regulatory and health system hurdles; (iv) Disparities in access to non-NIP vaccines underscore the need for government initiatives to improve vaccine coverage, especially for remote areas and marginalized populations; (v) Original studies emphasize the influence of caregivers' knowledge, health workers' financial incentives, and concerns about vaccine efficacy on immunization rates; (vi) Case studies from the Weifang City of China and Indonesia to introduce PCV offer insights on successful vaccine introduction strategies and the impact of innovative financing and government support.
CONCLUSION
The articles emphasize the need for government leadership, strategic policymaking, and public awareness to enhance vaccine coverage and equity. The VaxLab will continue strengthening China's NIP by focusing on vaccine financing, emphasizing diversity, equity, and inclusion, and improving maternal vaccination coverage. Research will extend to Southeast Asian and Western Pacific regions, especially in middle-income countries facing challenges in vaccine financing and delivery. The collective efforts outlined in this collection show a commitment to evolving and adapting immunization strategies to meet global health goals and to provide equitable access to vaccines for all.
Topics: Child; Humans; COVID-19 Vaccines; Vaccines; Vaccination; Immunization Programs; China
PubMed: 38475849
DOI: 10.1186/s40249-024-01192-6