Rotavirus VP7 epitope chimeric proteins elicit cross-immunoreactivity in guinea pigs

Zhao, Beibei; Pan, Xiao-Xia; Teng, Yumei; Xia, W.-Y.; Wang, Jing; Wen, Yiping; Yuan-ding, Chen

doi:10.1007/s12250-015-3620-5

Cited by 5 publications

(3 citation statements)

References 30 publications

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“…14 Considerable efforts have been made toward development of subunit RV vaccine candidates (e.g., soluble antigens, virus-like particles) that are being evaluated in preclinical and early clinical studies. [15][16][17][18][19] One such candidate (referred to nonreplicating rotavirus [NRRV]) containing a trivalent mixture of recombinant truncated VP8* fusion proteins is in phase 1/2 clinical trials. Previously, one of the 3 antigens (P2-VP8-P [8]) was shown to be safe in healthy adults as well as to be well tolerated and immunogenic in infants and toddlers thus establishing the proof of concept.…”

Section: Introductionmentioning

confidence: 99%

Characterizing and Minimizing Aggregation and Particle Formation of Three Recombinant Fusion-Protein Bulk Antigens for Use in a Candidate Trivalent Rotavirus Vaccine

Sahni

Hickey

Robertson

et al. 2020

Journal of Pharmaceutical Sciences

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In a companion paper, the structural integrity, conformational stability, and degradation mechanisms of 3 recombinant fusion-protein antigens comprising a non-replicating rotavirus (NRRV) vaccine candidate (currently being evaluated in early-stage clinical trials) are described. In this work, we focus on the aggregation propensity of the 3 NRRV antigens coupled to formulation development studies to identify common frozen bulk candidate formulations. The P2-VP8-P[8] antigen was most susceptible to shaking and freeze-thaweinduced aggregation and particle formation. Each NRRV antigen formed aggregates with structurally altered protein (with exposed apolar regions and intermolecular b-sheet) and dimers containing a non-native disulfide bond. From excipient screening studies with P2-VP8-P[8], sugars or polyols (e.g., sucrose, trehalose, mannitol, sorbitol) and various detergents (e.g., Pluronic F-68, polysorbate 20 and 80, PEG-3350) were identified as stabilizers against aggregation. By combining promising additives, candidate bulk formulations were optimized to not only minimize agitation-induced aggregation, but also particle formation due to freeze-thaw stress of P2-VP8-P[8] antigen. Owing to limited material availability, stabilization of the P2-VP8-P[4] and P2-VP8-P[6] was confirmed with the lead candidate P2-VP8-P[8] formulations. The optimization of these bulk NRRV candidate formulations is discussed in the context of subsequent drug product formulations in the presence of aluminum adjuvants.

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Section: Introductionmentioning

confidence: 99%

Characterizing and Minimizing Aggregation and Particle Formation of Three Recombinant Fusion-Protein Bulk Antigens for Use in a Candidate Trivalent Rotavirus Vaccine

Sahni

Hickey

Robertson

et al. 2020

Journal of Pharmaceutical Sciences

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“…Emerging virus strains have been associated with mutations that render vaccines and other therapies, such as monoclonal antibodies, less effective as seen with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Starr et al 2021). Previous studies have shown that the VP5* and VP8* outer capsid proteins play a significant role in inducing neutralising antibodies against rotaviruses (Ludert et al 2002; Park et al 2021; Ruggeri and Greenberg 1991; Zhao et al 2015). The VP5* protein of the Malawian G3P[8] strains were 100% conserved when compared to that of Rotarix vaccine, consistent with previous studies that have reported that the VP5* is a highly conserved protein (Rasebotsa et al 2020; Mwangi et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Comparative whole genome analysis reveals re-emergence of typical human Wa-like and DS-1-like G3 rotaviruses after Rotarix vaccine introduction in Malawi

Mhango

Banda

Chinyama

et al. 2022

Preprint

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Genotype G3 rotaviruses rank among the most common rotavirus strains worldwide in humans and animals. However, despite a robust long-term rotavirus surveillance system from 1997 in Blantyre, Malawi, these strains were only detected from 1997 to 1999 and then disappeared and re-emerged in 2017, five years after the introduction of the Rotarix rotavirus vaccine. Here we analysed 27 whole genome sequences to understand how G3 strains re-emerged in Malawi. We randomly selected samples each month between November 2017 and August 2019 from stool samples of children hospitalised with acute diarrhoea at the Queen Elizabeth Hospital in Blantyre, Malawi. We found three genotypes namely G3P[4] (n=20), G3P[6] (n=1) and G3P[8] (n=6) associated with the re-emergence of G3 strains in Malawi post-Rotarix vaccine introduction. The identified genotypes co-circulated at different time points and were associated with three typical human G3 strains consisting of either a Wa-like or DS-1-like genetic constellation and reassortant strains possessing Wa-like and DS-1-like genetic backbones. Time-resolved phylogenetic trees demonstrated that the most recent common ancestor for each segment of the re-emerged G3 strains emerged between 1996 and 2012, possibly through introductions from outside the country due to the limited genetic similarity with G3 strains which circulated before their disappearance in the late 1990s. Further genomic analysis revealed that the reassortant DS-1-like G3P[4] strains acquired a Wa-like NSP2 genome segment (N1 genotype) through intergenogroup reassortment; an artiodactyl-like VP3 through intragenogroup interspecies reassortment; and VP6, NSP1 and NSP4 segments through intragenogroup reassortment likely before importation into Malawi. Additionally, the re-emerged G3 strains contain amino acid substitutions within the antigenic regions of the VP4 proteins which could potentially impact the binding of rotavirus vaccine-induced antibodies. Altogether, our findings shows that multiple rather than a single genotype have driven the re-emergence of G3 strains likely from other countries highlighting the role of human mobility and genome reassortment events in the dissemination and evolution of rotavirus strains in Malawi necessitating the need for long-term genomic surveillance of rotavirus in high disease burden settings to inform disease prevention and control.

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“…Consequently, they are utilized frequently as candidates for genetically engineered RV vaccines [ 36 ]. Glycoprotein VP7 is a structurally neutralizing antigen of RVs that can elicit the production of immunoglobulin (Ig)G antibodies, which are associated with protection afforded by the immune system [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

Safety, Immunogenicity, and Mechanism of a Rotavirus mRNA-LNP Vaccine in Mice

Lu,

Li,

Chen

et al. 2024

Viruses

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Rotaviruses (RVs) are a major cause of diarrhea in young children worldwide. The currently available and licensed vaccines contain live attenuated RVs. Optimization of live attenuated RV vaccines or developing non-replicating RV (e.g., mRNA) vaccines is crucial for reducing the morbidity and mortality from RV infections. Herein, a nucleoside-modified mRNA vaccine encapsulated in lipid nanoparticles (LNP) and encoding the VP7 protein from the G1 type of RV was developed. The 5′ untranslated region of an isolated human RV was utilized for the mRNA vaccine. After undergoing quality inspection, the VP7-mRNA vaccine was injected by subcutaneous or intramuscular routes into mice. Mice received three injections in 21 d intervals. IgG antibodies, neutralizing antibodies, cellular immunity, and gene expression from peripheral blood mononuclear cells were evaluated. Significant differences in levels of IgG antibodies were not observed in groups with adjuvant but were observed in groups without adjuvant. The vaccine without adjuvant induced the highest antibody titers after intramuscular injection. The vaccine elicited a potent antiviral immune response characterized by antiviral clusters of differentiation CD8+ T cells. VP7-mRNA induced interferon-γ secretion to mediate cellular immune responses. Chemokine-mediated signaling pathways and immune response were activated by VP7-mRNA vaccine injection. The mRNA LNP vaccine will require testing for protective efficacy, and it is an option for preventing rotavirus infection.

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Rotavirus VP7 epitope chimeric proteins elicit cross-immunoreactivity in guinea pigs

Cited by 5 publications

References 30 publications

Characterizing and Minimizing Aggregation and Particle Formation of Three Recombinant Fusion-Protein Bulk Antigens for Use in a Candidate Trivalent Rotavirus Vaccine

Characterizing and Minimizing Aggregation and Particle Formation of Three Recombinant Fusion-Protein Bulk Antigens for Use in a Candidate Trivalent Rotavirus Vaccine

Comparative whole genome analysis reveals re-emergence of typical human Wa-like and DS-1-like G3 rotaviruses after Rotarix vaccine introduction in Malawi

Safety, Immunogenicity, and Mechanism of a Rotavirus mRNA-LNP Vaccine in Mice

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