scholarly journals Human norovirus animal model essential for vaccine development

2021 ◽  
Keyword(s):  
Animal Model ◽  
Vaccine Development ◽  
Human Norovirus

scholarly journals Chimpanzees as an animal model for human norovirus infection and vaccine development

2010 ◽  
Vol 108 (1) ◽  
pp. 325-330 ◽  
Author(s):  
Karin Bok ◽  
Gabriel I. Parra ◽  
Tanaji Mitra ◽  
Eugenio Abente ◽  
Charlene K. Shaver ◽  
...  
Keyword(s):  
Animal Model ◽  
Vaccine Development ◽  
Control Strategies ◽  
Serum Antibody ◽  
Clinical Signs ◽  
Antigen Expression ◽  
Norwalk Virus ◽  
Human Norovirus ◽  
Virus Shedding ◽  
Model Studies

Noroviruses are global agents of acute gastroenteritis, but the development of control strategies has been hampered by the absence of a robust animal model. Studies in chimpanzees have played a key role in the characterization of several fastidious hepatitis viruses, and we investigated the feasibility of such studies for the noroviruses. Seronegative chimpanzees inoculated i.v. with the human norovirus strain Norwalk virus (NV) did not show clinical signs of gastroenteritis, but the onset and duration of virus shedding in stool and serum antibody responses were similar to that observed in humans. NV RNA was detected in intestinal and liver biopsies concurrent with the detection of viral shedding in stool, and NV antigen expression was observed in cells of the small intestinal lamina propria. Two infected chimpanzees rechallenged 4, 10, or 24 mo later with NV were resistant to reinfection, and the presence of NV-specific serum antibodies correlated with protection. We evaluated the immunogenicity and efficacy of virus-like particles (VLPs) derived from NV (genogroup I, GI) and MD145 (genogroup II, GII) noroviruses as vaccines. Chimpanzees vaccinated intramuscularly with GI VLPs were protected from NV infection when challenged 2 and 18 mo after vaccination, whereas chimpanzees that received GII VLPs vaccine or a placebo were not. This study establishes the chimpanzee as a viable animal model for the study of norovirus replication and immunity, and shows that NV VLP vaccines could induce protective homologous immunity even after extended periods of time.

scholarly journals Antibody response to the 45 kDa Candida albicans antigen in an animal model and potential role of the antigen in adherence

2008 ◽  
Vol 57 (12) ◽  
pp. 1466-1472 ◽  
Author(s):  
Helena Bujdáková ◽  
Ema Paulovičová ◽  
Silvia Borecká-Melkusová ◽  
Juraj Gašperík ◽  
Soňa Kucharíková ◽  
...  
Keyword(s):  
Animal Model ◽  
Candida Albicans ◽  
Biofilm Formation ◽  
Laser Scanning ◽  
Vaccine Development ◽  
Laser Scanning Microscopy ◽  
Model Systems ◽  
Confocal Laser

The Candida antigen CR3-RP (complement receptor 3-related protein) is supposed to be a ‘mimicry’ protein because of its ability to bind antibody directed against the α subunit of the mammalian CR3 (CD11b/CD18). This study aimed to (i) investigate the specific humoral isotypic response to immunization with CR3-RP in vivo in a rabbit animal model, and (ii) determine the role of CR3-RP in the adherence of Candida albicans in vitro using the model systems of buccal epithelial cells (BECs) and biofilm formation. The synthetic C. albicans peptide DINGGGATLPQ corresponding to 11 amino-acids of the CR3-RP sequence DINGGGATLPQALXQITGVIT, determined by N-terminal sequencing, was used for immunization of rabbits to obtain polyclonal anti-CR3-PR serum and for subsequent characterization of the humoral isotypic response of rabbits. A significant increase of IgG, IgA and IgM anti-CR3-RP specific antibodies was observed after the third (P<0.01) and the fourth (P<0.001) immunization doses. The elevation of IgA levels suggested peptide immunomodulation of the IgA1 subclass, presumably in coincidence with Candida epithelial adherence. Blocking CR3-RP with polyclonal anti-CR3-RP serum reduced the ability of Candida to adhere to BECs, in comparison with the control, by up to 35 % (P<0.001), and reduced biofilm formation by 28 % (P<0.001), including changes in biofilm thickness and integrity detected by confocal laser scanning microscopy. These properties of CR3-RP suggest that it has potential for future vaccine development.

scholarly journals A Mouse Model for Human Norovirus

mBio ◽  
2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Stefan Taube ◽  
Abimbola O. Kolawole ◽  
Marina Höhne ◽  
John E. Wilkinson ◽  
Scott A. Handley ◽  
...  
Keyword(s):  
Animal Model ◽  
Mouse Model ◽  
Small Animal ◽  
Morbidity And Mortality ◽  
Significant Morbidity ◽  
Wild Type ◽  
Small Animal Model ◽  
Human Norovirus ◽  
Human Noroviruses ◽  
Deficient Mice

ABSTRACT Human noroviruses (HuNoVs) cause significant morbidity and mortality worldwide. However, despite substantial efforts, a small-animal model for HuNoV has not been described to date. Since “humanized” mice have been successfully used to study human-tropic pathogens in the past, we challenged BALB/c mice deficient in recombination activation gene (Rag) 1 or 2 and common gamma chain (γc) (Rag-γc) engrafted with human CD34+ hematopoietic stem cells, nonengrafted siblings, and immunocompetent wild-type controls with pooled stool isolates from patients positive for HuNoV. Surprisingly, both humanized and nonhumanized BALB/c Rag-γc-deficient mice supported replication of a GII.4 strain of HuNoV, as indicated by increased viral loads over input. In contrast, immunocompetent wild-type BALB/c mice were not infected. An intraperitoneal route of infection and the BALB/c genetic background were important for facilitating a subclinical HuNoV infection of Rag-γc-deficient mice. Expression of structural and nonstructural proteins was detected in cells with macrophage-like morphology in the spleens and livers of BALB/c Rag-γc-deficient mice, confirming the ability of HuNoV to replicate in a mouse model. In summary, HuNoV replication in BALB/c Rag-γc-deficient mice is dependent on the immune-deficient status of the host but not on the presence of human immune cells and provides the first genetically manipulable small-animal model for studying HuNoV infection. IMPORTANCE Human noroviruses are a significant cause of viral gastroenteritis worldwide, resulting in significant morbidity and mortality. Antivirals and vaccines are currently not available, in part due to the inability to study these viruses in a genetically manipulable, small-animal model. Herein, we report the first mouse model for human noroviruses. This model will accelerate our understanding of human norovirus biology and provide a useful resource for evaluating antiviral therapies.

scholarly journals A Controlled Human Infection Model of Group AStreptococcusPharyngitis: Which Strain and Why?

mSphere ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Joshua Osowicki ◽  
Kristy I. Azzopardi ◽  
Liam McIntyre ◽  
Tania Rivera-Hernandez ◽  
Cheryl-lynn Y. Ong ◽  
...  
Keyword(s):  
Animal Model ◽  
Molecular Epidemiology ◽  
Virulence Factors ◽  
Healthy Adult ◽  
Vaccine Development ◽  
Human Infection ◽  
Infection Model ◽  
Vaccine Antigens ◽  
Adult Volunteers

ABSTRACTGroup AStreptococcus(GAS) is a major cause of global infection-related morbidity and mortality. A modern controlled human infection model (CHIM) of GAS pharyngitis can accelerate vaccine development and pathogenesis research. A robust rationale for strain selection is central to meeting ethical, scientific, and regulatory requirements. Multifaceted characterization studies were done to compare a preferred candidateemm75 (M75) GAS strain to three other strains: an alternative candidateemm12 (M12) strain, an M1 strain used in 1970s pharyngitis CHIM studies (SS-496), and a representative (5448) of the globally disseminated M1T1 clone. A range of approaches were used to explore strain growth, adherence, invasion, delivery characteristics, short- and long-term viability, phylogeny, virulence factors, vaccine antigens, resistance to killing by human neutrophils, and lethality in a murine invasive model. The strains grew reliably in a medium without animal-derived components, were consistently transferred using a swab method simulating the CHIM protocol, remained viable at −80°C, and carried genes for most candidate vaccine antigens. Considering GAS molecular epidemiology, virulence factors,in vitroassays, and results from the murine model, the contemporary strains show a spectrum of virulence, with M75 appearing the least virulent and 5448 the most. The virulence profile of SS-496, used safely in 1970s CHIM studies, was similar to that of 5448 in the animal model and virulence gene carriage. The results of this multifaceted characterization confirm the M75 strain as an appropriate choice for initial deployment in the CHIM, with the aim of safely and successfully causing pharyngitis in healthy adult volunteers.IMPORTANCEGAS (Streptococcus pyogenes) is a leading global cause of infection-related morbidity and mortality. A modern CHIM of GAS pharyngitis could help to accelerate vaccine development and drive pathogenesis research. Challenge strain selection is critical to the safety and success of any CHIM and especially so for an organism such as GAS, with its wide strain diversity and potential to cause severe life-threatening acute infections (e.g., toxic shock syndrome and necrotizing fasciitis) and postinfectious complications (e.g., acute rheumatic fever, rheumatic heart disease, and acute poststreptococcal glomerulonephritis). In this paper, we outline the rationale for selecting anemm75 strain for initial use in a GAS pharyngitis CHIM in healthy adult volunteers, drawing on the findings of a broad characterization effort spanning molecular epidemiology,in vitroassays, whole-genome sequencing, and animal model studies.

scholarly journals Advances and new insights in the neuropathogenesis of dengue infection

2015 ◽  
Vol 73 (8) ◽  
pp. 698-703 ◽  
Author(s):  
Marzia Puccioni-Sohler ◽  
Carolina Rosadas
Keyword(s):  
Animal Model ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Dengue Virus ◽  
Murine Model ◽  
Vaccine Development ◽  
Dengue Infection ◽  
Neurological Complications ◽  
Neurological Manifestations ◽  
Viral Antigens

Dengue virus (DENV) infects approximately 390 million persons every year in more than 100 countries. Reports of neurological complications are more frequently. The objective of this narrative review is to bring up the advances in the dengue neuropathogenesis. DENV can access the nervous system through blood-brain barrier disturbance mediated by cytokine. The blood-cerebrospinal fluid (CSF) barrier seems to be also involved, considering the presence of the virus in the CSF of patients with neurological manifestations. As for neurotropism, several studies showed the presence of RNA and viral antigens in brain tissue and CSF in humans. In murine model, different virus mutations were associated to neurovirulence. Despite the advances in the dengue neuropathogenesis, it is still necessary to determine a more appropriate animal model and increase the number of cases of autopsy. The detection of neurovirulence markers may contribute to establish a prognosis, the disease control and vaccine development.

scholarly journals Antigenic Diversity of Human Norovirus Capsid Proteins Based on the Cross-Reactivities of Their Antisera

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 986
Author(s):  
Junshan Gao ◽  
Yueting Zuo ◽  
Liang Xue ◽  
Linping Wang ◽  
Yanhui Liang ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Vaccine Development ◽  
Phylogenetic Analyses ◽  
Cross Reactivity ◽  
Clinical Value ◽  
Human Norovirus ◽  
Antigenic Diversity ◽  
P Proteins ◽  
The Relationship ◽  
Potential Use

Human norovirus (HuNoV), which is the major causative agent of acute gastroenteritis, has broad antigenic diversity; thus, the development of a broad-spectrum vaccine is challenging. To establish the relationship between viral genetic diversity and antigenic diversity, capsid P proteins and antisera of seven GI and 16 GII HuNoV genotypes were analyzed. Enzyme-linked immunosorbent assays showed that HuNoV antisera strongly reacted with the homologous capsid P proteins (with titers > 5 × 104). However, 17 (73.9%) antisera had weak or no cross-reactivity with heterologous genotypes. Interestingly, the GII.5 antiserum cross-reacted with seven (30.4%) capsid P proteins (including pandemic genotypes GII.4 and GII.17), indicating its potential use for HuNoV vaccine development. Moreover, GI.2 and GI.6 antigens reacted widely with heterologous antisera (n ≥ 5). Sequence alignment and phylogenetic analyses of the P proteins revealed conserved regions, which may be responsible for the immune crossover reactivity observed. These findings may be helpful in identifying broad-spectrum epitopes with clinical value for the development of a future vaccine.

scholarly journals Mammalian animal models for dengue virus infection: a recent overview

2021 ◽  
Author(s):  
Mohammad Enamul Hoque Kayesh ◽  
Kyoko Tsukiyama-Kohara
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Dengue Virus ◽  
Dengue Fever ◽  
Vaccine Development ◽  
Wide Spectrum ◽  
Tree Shrew ◽  
Clinical Signs ◽  
Denv Infection ◽  
Health Concern

AbstractDengue, a rapidly spreading mosquito-borne human viral disease caused by dengue virus (DENV), is a public health concern in tropical and subtropical areas due to its expanding geographical range. DENV can cause a wide spectrum of illnesses in humans, ranging from asymptomatic infection or mild dengue fever (DF) to life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Dengue is caused by four DENV serotypes; however, dengue pathogenesis is complex and poorly understood. Establishing a useful animal model that can exhibit dengue-fever-like signs similar to those in humans is essential to improve our understanding of the host response and pathogenesis of DENV. Although several animal models, including mouse models, non-human primate models, and a recently reported tree shrew model, have been investigated for DENV infection, animal models with clinical signs that are similar to those of DF in humans have not yet been established. Although animal models are essential for understanding the pathogenesis of DENV infection and for drug and vaccine development, each animal model has its own strengths and limitations. Therefore, in this review, we provide a recent overview of animal models for DENV infection and pathogenesis, focusing on studies of the antibody-dependent enhancement (ADE) effect in animal models.

scholarly journals Primary High-Dose Murine Norovirus 1 Infection Fails To Protect from Secondary Challenge with Homologous Virus

2009 ◽  
Vol 83 (13) ◽  
pp. 6963-6968 ◽  
Author(s):  
Guangliang Liu ◽  
Shannon M. Kahan ◽  
Yali Jia ◽  
Stephanie M. Karst
Keyword(s):  
Animal Model ◽  
Protective Immunity ◽  
Small Animal ◽  
High Dose ◽  
Murine Norovirus ◽  
Small Animal Model ◽  
Human Norovirus ◽  
Human Noroviruses ◽  
Inoculum Dose ◽  
Homologous Virus

ABSTRACT Human noroviruses in the Caliciviridae family are the major cause of nonbacterial epidemic gastroenteritis worldwide. Primary human norovirus infection does not elicit lasting protective immunity, a fact that could greatly affect the efficacy of vaccination strategies. Little is known regarding the pathogenesis of human noroviruses or the immune responses that control them because there has previously been no small-animal model or cell culture system of infection. Using the only available small-animal model of norovirus infection, we found that primary high-dose murine norovirus 1 (MNV-1) infection fails to afford protection against a rechallenge with a homologous virus. Thus, MNV-1 represents a valuable model with which to dissect the pathophysiological basis for the lack of lasting protection against human norovirus infection. Interestingly, the magnitude of protection afforded by a primary MNV-1 infection inversely correlates with the inoculum dose. Future studies will elucidate the mechanisms by which noroviruses avoid the induction of protective immunity and the role played by the inoculum dose in this process, ultimately translating this knowledge into successful vaccination approaches.

scholarly journals Advances in Human Norovirus Vaccine Research

Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 732
Author(s):  
Mudan Zhang ◽  
Ming Fu ◽  
Qinxue Hu
Keyword(s):  
Vaccine Development ◽  
World Health ◽  
In Vitro Cultivation ◽  
Vaccine Research ◽  
Human Norovirus ◽  
Major Barrier ◽  
Cultivation System ◽  
Virus Particles ◽  
Health Organization

Human norovirus (HuNoV) is the leading cause of acute gastroenteritis (AGE) worldwide, which is highly stable and contagious, with a few virus particles being sufficient to establish infection. Although the World Health Organization in 2016 stated that it should be an absolute priority to develop a HuNoV vaccine, unfortunately, there is currently no licensed HuNoV vaccine available. The major barrier to the development of an effective HuNoV vaccine is the lack of a robust and reproducible in vitro cultivation system. To develop a HuNoV vaccine, HuNoV immunogen alone or in combination with other viral immunogens have been designed to assess whether they can simultaneously induce protective immune responses against different viruses. Additionally, monovalent and multivalent vaccines from different HuNoV genotypes, including GI and GII HuNoV virus-like particles (VLPs), have been assessed in order to induce broad protection. Although there are several HuNoV vaccine candidates based on VLPs that are being tested in clinical trials, the challenges to develop effective HuNoV vaccines remain largely unresolved. In this review, we summarize the advances of the HuNoV cultivation system and HuNoV vaccine research and discuss current challenges and future perspectives in HuNoV vaccine development.

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